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Palladium-Catalyzed #-Allylation of Secondary Nitroalkanes with Allylic Alcohols and Strategic Exploitation of Seebach’s Reagent for the Total Synthesis of (±)-Adalinine Chieh-Yu Chang, and Yen-Ku Wu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00710 • Publication Date (Web): 16 May 2018 Downloaded from http://pubs.acs.org on May 16, 2018
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The Journal of Organic Chemistry
Palladium-Catalyzed α-Allylation of Secondary Nitroalkanes with Allylic Alcohols and Strategic Exploitation of Seebach’s Reagent for the Total Synthesis of (±)-Adalinine Chieh-Yu Chang and Yen-Ku Wu* Department of Applied Chemistry, National Chiao Tung University, 1001 University Road, Hsinchu 30010, Taiwan Supporting Information Placeholder NO2 R1
R2
allyl alcohol Pd catalyst Ti(OR)4
R1
O
steps
NO2
Me
R3 O
R2
N H (±)-adalinine
Me
ABSTRACT: A method is reported for the catalytic direct coupling of allylic alcohols and nitroalkanes. In the allylation process, the synergistic action of palladium complexes and titanium(IV) alkoxide facilitates the formation of nitronate and π-allylpalladium intermediate. In the cases of reluctant allylations, typically with sterically demanding nitroalkanes, we found the addition of substoichiometric amount of DBU greatly facilitates the desired transformation. We also accomplished a total synthesis of (±)adalinine through a homoallyl nitroalkane derived from Seebach’s reagent.
Palladium-catalyzed Tsuji-Trost reaction of carbonyl derivatives has emerged as an indispensible method for constructing carbon−carbon bonds.1 A range of pronucleophiles including 1,3-dicarbonyls, ketones, and aldehydes has been employed in this type of transformation.2 Due to the versatility of the nitro functionality, 3 chemists have also explored the Tsuji-Trost reaction of nitro-based nucleophiles that primarily involves the use of nitromethane and primary nitroalkanes. 4 In contrast, there were merely sporadic efforts at engaging secondary nitroalkanes in the catalytic allylic alkylation. Difficulties associated with the α-allylation of secondary nitroalkanes were attributed to few factors including the competition between Cand O-alkylation and the modest reactivity of bulky nitro substrates; indeed, Aleksandrowicz et al. observed that 2nitropentane and 2-nitrobutane are surprisingly much less reactive than 2-nitropropane.5 In spite of these challenges, Shibasaki and co-workers have developed a catalytic system for the coupling of allyl carbonates and sterically demanding secondary nitroalkanes.6
On the other hand, the electrophilic allyl donor in the context of the Tsuji-Trost-type transformations is generally an activated form of allylic alcohols such as an acetate, carbonate, or phosphate. In pursuit of sustainable and atom-economical chemical processes, the direct use of allylic alcohols in the allylation reactions has attracted considerable research attention.7 Recently, the Tunge group presented an elegant strategy for the α-allylation of secondary nitroalkanes with allylic alcohols (Scheme 1a).8 The mechanism features an activation of the hydroxyl group with carbon dioxide.8 However, a general reaction system which is applicable for the synthesis of structurally diverse α-allylated nitroalkanes is still in demand. Here we present a practical method for the direct allylation of a range of secondary nitroalkanes with allylic alcohols (Scheme 1b) and its application to the total synthesis of racemic adalinine. Scheme 2. Proposed Ti(IV)-Activation of C−O Bond in the αAllylation of Nitroalkanes
Scheme 1. Pd-Catalyzed Allylation with Alcohol Precursors a) Tunge and co-workers (2014): NO2 R1
R2
+
OH
b) This work: NO2 R1
R2
+
R3
OH
CO2 (1 atm), DMSO, 80 °C
R1
Pd2(dba)3 (4 mol%) dppf (12 mol%) Ti(Oi-Pr)4, DMSO, 80 °C
D
NO2 R3
Pd(PPh3)4 (10 mol%)
R3
R1
OTi(OR)3
R2
OTi(OR)3 B NO2 R1
[Pd] R3
C
R2
Ti(OR)4
OH
A
LnPd(0)
R2
NO2 R1
NO2
[Pd]
O R1
N
O
NO2 R1
R2
HOTi(OR)3
R2
R2
Titanium(IV) isopropoxide is a commercially available, inexpensive, and easy-to-handle reagent. Although it is known that
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The Journal of Organic Chemistry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Ti(Oi-Pr)4 can activate allylic alcohols toward palladiumcatalyzed nucleophilic substitution with phenols, 9 anilines 10 and tosylamides,11 there had been only one report delineating the employment of a carbon-based nucleophile, namely zinc enolates. 12 With inspiration from these seminal studies, we envisaged that an oxidative addition of palladium(0) catalysts with in situ generated allyl titanate A would collapse into a πallyl species and a putative base B to deprotonate nitroalkane 1 (Scheme 2). Subsequent nucleophilic attack of the resulting nitronate to the allylpalladium intermediate is expected to lead to the formation of allylated product D. Table 1. Evaluation of Conditions for the Direct Coupling of nitrocyclohexane 1a and β-methallyl alcohola Pd catalyst (4 mol%) ligand (12 mol%)
NO2 +
Me
OH
1a
NO2 R1
entry
R2
+
R3
2a
ligand
additive
yield%b
1
−
Ti(Oi-Pr)4
28
2
Pd2(dba)3
BINAP
Ti(Oi-Pr)4
