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The Formal [3+2] Reaction of alpha,alpha-Diaryl Allylic Alcohols with Sec-Alcohols: Proceeding with Sequential Radical Addition/ Migration toward 2,3-Dihydrofurans Bearing Quaternary Carbon Centers Weiming Hu, Song Sun, and Jiang Cheng J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b00643 • Publication Date (Web): 02 May 2016 Downloaded from http://pubs.acs.org on May 7, 2016
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The Journal of Organic Chemistry
The Formal [3+2] Reaction of α,α-Diaryl Allylic Alcohols with SecAlcohols: Proceeding with Sequential Radical Addition/Migration toward 2,3-Dihydrofurans Bearing Quaternary Carbon Centers
Weiming Hu, Song Sun and Jiang Cheng * School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Jiangsu Province Key Laboratory of Fine Petrochemical Engineering, Changzhou University, Changzhou 213164, P. R. China.
[email protected] RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required according to the journal that you are submitting your paper to)
ABSTRACT
An unprecedented TBHP-promoted formal [3 + 2] annulation of sec-alcohols with α,α-diaryl allylic alcohols has been developed, leading to 2,3-dihydrofurans in moderate to excellent yields with good functional groups tolerance. This procedure involves sequential radical addition, 1,2-aryl migration and dehydration process, where the migration of aryl with lower electron density is favored. Notably, cyclic sec-alcohols also ran smoothly, providing a novel method to access oxaspiro compounds. Dihydrofurans and their derivatives are important backbones of many bioactive natural products as well as medicinal molecules.1,2 Besides, they served as organic intermediates toward an array of highly functionalized tetrahydrofurans.3 As such, a variety of synthetic approaches have been discovered (Scheme 1), including the [4 + 1] transition metal catalyzed cycloaddition of enones with diazo compounds (Scheme 1, eq 1),4 ionic5 or radical6 reactions of olefins with 1,3-dicarbonyl compounds (Scheme 1, eq 2), as well as the formal [3 + 2] annulations of β-ketosulfides/β-ketosulfones with aldehydes (Scheme 1, eq 3).7 Quite recently, Qu reported Cu-catalyzed intra-molecular aryl-etherification reactions of alkoxyl alkynes with diaryliodonium salts to construct oxo-heterocycles via cleavage of a stable C–O bond ACS Paragon Plus Environment
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(Scheme 1, eq 4).8 Zhang and coworkers developed a gold(I)-catalyzed formal [4 + 1] cycloaddition of α-diazoesters and propargyl alcohols toward 2,5-dihydrofurans (Scheme 1, eq 5).9 In the past years, alcohol proved to be efficient reaction partner for the construction of C–C bond thanks to the activation of sp3 α-C–H bond by the vicinal hydroxy group.10 Meanwhile, being nucleophile, the hydroxyl group may take part in potentially further functionalization. Thus, in combination of the two types of reactivities, alcohol may serve as a component in the formal [n + 2] cyclization leading to oxygen containing heterocycle. In light of the application of α,α-diaryl allylic alcohols in the construction of a variety of α-aryl-β-functionalized carbonyl ketones through radical 1,2-aryl migration,11 we envisioned to develop a novel avenue to construct 4,5-diaryl-2,3-dihydrofuran via such a strategy (Scheme 1, eq 6). In comparison with the reported intra-molecular cyclization via C-O bond formation leading to oxygen containing heterocycles,12 this strategy is beneficial to the diversity and complexity of the final product, allowing to introduce four groups in 2,3-dihydrofurans.
Scheme 1. The Examples on the Synthesis of Dihydrofurans.
previous works: COOAr
O
O + R
OAr
R1 O
O
CuOTf, (-)-bpy* R
O
Ph
Ph
Ph
R
Ph
R HO R'
+
R
piperidine ArCHO
O
R
+
Ar
R eq 3 SO2Rf
Ar Ar n +
Ar2IPF6
Cu(OTf)2
O
o
DCE, 60 C
R1 eq 4
R
N2 OH
O
R
Toluene, reflux
R1
n
eq 2
O
O O
R
O
oxone (10-15 equiv), acetone, water, base
R'
RfO2S
eq 1
R1
CH2Cl2, rt
N2
JohnPhosAuCl/AgSbF6 (3 mol %) COOR' DCE, rt
R'OOC Ar
eq 5 O
this work : HO +
OH
O TBHP, PivOH
eq 6
We commenced our study with the reaction of α,α-diphenyl allylic alcohol 1a and isopropanol 2a in the presence of di-tert-butyl peroxide (DTBP) under nitrogen atmosphere. To our delight, the reaction afforded 4,5-diaryl-2,3dihydrofuran 3aa in 40% yield (Table 1, entry 1). Inspired by this exciting result, we tested dicumyl peroxide (DCP), benzoyl peroxide (BPO), tert-butyl peroxybenzoate (TBPB), K2S2O8 and benzoquinone (BQ), respectively. UnfortuACS Paragon Plus Environment
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nately, they all had no positive effect on the reaction efficiency (Table 1, entries 2-6). Gratifyingly, the yield increased to 56% when tert-butyl hydroperoxide (TBHP) was used (Table 1, entry 7). Considering that proton might take part in the dehydration process, pivalic acid, acetic acid and n-hexylic acid were tested, respectively. They all had some effect on the reaction efficiency (Table 1, entries 8-10), among which the pivalic acid was the best (3aa, 60%). Blank experiment revealed no reaction took place without DTBP (Table 1, entry 11). Further screening of the parameters such as the loading of pivalic acid, the amount of solvent, reaction atmosphere and temperature established the optimized condition as follows: α,α-diphenyl allylic alcohol 1a (0.2 mmol, 1 equiv), TBHP (4 equiv), pivalic acid (0.1 equiv) in isopropanol 2a (2 mL) at 130 oC for 24 h under N2 ( Table 1, entries 12-16), where the yield of 3aa reached 84% (Table 1, entry 13). Table 1. The optimization of reaction conditionsa
a
Reaction conditions: 1a (0.2 mmol), 2a (2 mL), oxidant (4.0 equiv) at 130 oC under N2 for 24 h in a sealed tube. b DTBP = di-tert-butyl peroxide, DCP = dicumyl peroxide, BPO = benzoyl peroxide, TBPB = tert-butyl peroxybenzoate, BQ = 1,4-benzoquinone, TBHP = tertbutyl hydroperoxide (70% in water). c isolated yields. d under O2, e under air. f at 110 oC. g at 120 oC. h at 140 oC, i 2a (1.0 mL), j 2a (1.5 mL), k 2a (2.5 mL).
With the optimal conditions in hand (Table 1, entry 13), we next evaluated the substrate scope of this procedure. Initially, various α,α-diaryl allylic alcohols were investigated (Figure 1). A series of symmetric allylic alcohols containing electron-rich or -deficient aryl groups all ran smoothly, providing the corresponding products in moderate to good yields (3aa-3fa, 63-84%). Meanwhile, unsymmetric allylic alcohols also worked well under standard conditions (3ga-3na, 45-81% yield). In these cases, two isomers were produced with good selectivities (3ia, 3ia’-3na and 3na’), which were consistent with Wu and others’ works.11,13 Particularly, allylic alcohol with nitrogen-containing heteroaryl ACS Paragon Plus Environment
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ran smoothly in this procedure, providing the desired product in 41% yield (3qa). However, no desired product 3ra was isolated when using α-aryl-α-cyclic alkyl allylic alcohol.
Next, a series of sec-alcohols were tested (Figure 2). 2-Butanol, 2- and 3-pentanol all served as good reaction partners to deliver the corresponding 4,5-diaryl-2,3-dihydrofurans in moderate yields (3ab-3ad, 45%-51%). Notably, cyclic secondary alcohols also reacted smoothly with allylic alcohols(3ae-3ag, 56-65%), which offered a novel method to access oxaspiro compounds. By-product mainly accounted for the low yields in the cases of 3ma-3qa, and 3ab-3ad, like (E)-1-bromo-4-(3-isopropoxy-1-phenylallyl)benzene (3ma-byproduct).
Figure 1. The Substrates Scope of α,α-Diaryl Allylic Alcohols.a,b HO Ar1
+
OH
TBHP, PivOH N2, 130 oC, 24 h
Ar2
O Ar
1
1
2a
Ar2 3
O
O
O
3aa, 84%
3ba, 79%
F
O
F 3ca, 78%
O
O F3C
Cl
Cl
Br
Br
3da, 70%
3ea, 63%
F3C 3fa, 68%
O
O
O
Ph
CF3 3ga, 56%
O
O
O
Cl 3la, 72%c (3.1:1)d
F 3ka, 81%c (2.4:1)d
3ja, 81%c (1.4:1)d O
O F
Br 3ma, 55%c (3.3:1)d
O
3ia, 69%c (1.9:1)d
3ha, 68%
O OMe
F
3na, 55%c (1.9:1)d O
3oa, 45% O
Cl N 3pa, 56% a
b
3qa, 41%
3ra,
