Note Cite This: J. Org. Chem. 2018, 83, 12869−12879
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Tandem Achmatowicz Rearrangement and Acetalization of 1‑[5(Hydroxyalkyl)-furan-2-yl]-cyclobutanols Leading to Dispiroacetals and Subsequent Ring-Expansion to Form 6,7-Dihydrobenzofuran4(5H)‑ones Hui Peng, Wenkun Luo, Huanfeng Jiang, and Biaolin Yin*
J. Org. Chem. 2018.83:12869-12879. Downloaded from pubs.acs.org by UNIV OF NEW ENGLAND on 10/19/18. For personal use only.
Key Laboratory of Functional Molecular Engineering of Guangdong Province, School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, P.R. China S Supporting Information *
ABSTRACT: Herein, we report a one-pot protocol for the synthesis of dispiroacetals 4 bearing a cyclobutane motif via tandem Achmatowicz rearrangement and acetalization of 1-[5-(hydroxyalkyl)-furan-2-yl]-cyclobutanols 3 with m-CPBA as the oxidant and AgSbF6 as an additive to promote the cyclization step in an aqueous medium. Dispiroacetals 4 could subsequently undergo Lewis acid-catalyzed ring expansion and skeletal rearrangement to afford 6,7-dihydro-5H-benzofuran-4-ones 5.
D
Scheme 1. Synthetic Applications of the Achmatowicz Rearrangement
ispiroheterocycles are present in a variety of natural products, pharmaceuticals, and other biologically active molecules,1−5 and the development of efficient methods for their construction is therefore of interest to researchers in the fields of organic synthesis and medicinal chemistry.6−11 Spiroacetals are of particular interest because they are found in numerous biologically active natural products isolated from plants, fungi, and marine organisms.12−17 In addition, the spiroacetal moiety contributes to the bioactivities of insect sex pheromones, polyketide antibiotics, and microtubule stabilizing agents, and it represents a privileged scaffold in drug discovery research.18−23 Accordingly, the synthesis of structurally novel dispiroacetals and developing efficient methods for them are highly desirable. The Achmatowicz rearrangement is an oxidative ringexpansion rearrangement of functionalized furfuryl alcohols 1 into densely functionalized hemiacetals 2.24−27 Because these hemiacetals can undergo further transformations, the Achmatowicz rearrangement is a versatile tool for the preparation of tetrahydropyrans,28−34 dihydropyanones,35−38 δ-lactones,39−41 spiroacetals,42,43 and other compounds (Scheme 1). Given that numerous bioactive compounds contain a cyclobutane moiety,44−49 which tends to undergo a ring-opening reaction when exposed to an acid due to the considerable strain in the cyclobutane ring,50−57 we herein choose 1-[5-(hydroxyalkyl)furan-2-yl]-cyclobutanols 3 as test substrates to synthesize an arrangement of cyclobutylated dispiroacetals 4, which might be of biological interest, via a one-pot protocol for a tandem Achmatowicz rearrangement and acetalization of furfuryl alcohols 3. In addition, we also report an acid-catalyzed expansion of the cyclobutane ring accompanied by a skeletal © 2018 American Chemical Society
rearrangement of 4 with multiple reactive sites to give 6,7dihydro-5H-benzofuran-4-ones 5 (Scheme 2). To our knowledge, dispiroacetals have never previously been synthesized from cyclic tertiary furfuryl alcohols via Achmatowicz rearrangement. Initially, we chose 1-(5-(3-hydroxypropyl)furan-2-yl)cyclobutan-1-ol (3a) as a model substrate (Table 1). Given that m-CPBA is usually used as the oxidant in Achmatowicz rearrangements, we began by treating 3a with 1.5 equiv of mReceived: July 11, 2018 Published: September 21, 2018 12869
DOI: 10.1021/acs.joc.8b01765 J. Org. Chem. 2018, 83, 12869−12879
Note
The Journal of Organic Chemistry
byproduct. We reasoned that the addition of H2O might suppress these dehydrative etherification reactions and thus improve the yield of 4a. Indeed, we found that when a 1:1 (v/ v) mixture of DCM and H2O was used as the solvent, the yield of 4a increased to 65% yield (entry 13). Various other solvent mixtures were evaluated (entries 14−16), and 1:1 (v/v) MeCN/H2O was found to increase the yield to 81% (entry 16). Screening of other silver salts did not improve the yield (entries 17−20). On the basis of the above-described results, we concluded that the optimal conditions involved the use of 1:1 MeCN/H2O as the solvent, m-CPBA as the oxidant, and AgSbF6 as the additive (entry 16). With the optimized conditions in hand, we explored the substrate scope of the acetalization reaction (Scheme 3). We began by investigating the influence of the side-chain structure. For R1 = R2 = H and X = CH2, substrates with Y = CH2, CH2CH2, or OCH2 gave the corresponding products (4a−4c) in 63−81% yields. When Y = CH(CH2CH3)O, 4d was obtained in 62% yield, and the diastereoselectivity was low (3/ 2 dr). However, when Y = CH2CH2CH2, the yield of expected product 4e was low (45%). Substrate 3f (R1 = R2 = Me) gave 4f in 70% yield. When R1 and R2 were Me and H, Me and Ph, or Ph and H, respectively, the corresponding products (4g−4i) were obtained in moderate to good yields with no or low diastereoselectivity. Next, we screened substrates with a variety of substituted cyclobutyl groups. For R1 = R2 = H and Y = CH2, substrates with X = PhCH and (4-MeO)PhCH gave products 4j and 4l diastereospecifically in moderate yields. However, when X = (4-Me)PhCH, (4-Cl)PhCH, or BnCH, 4k, 4m, and 4n, respectively, were obtained in acceptable yields with dr values of 6/1, 6/1, and 2.5/1. The stereochemistry of the major isomer was determined by means of single-crystal X-ray analysis of the 2,4-dinitrophenylhydrazine derivative of 4k, which indicated that the Tol group was located on the opposite face of the cyclobutane ring from the carbonyl group. Reaction of spirocyclobutanol 3o afforded trispiroacetal 4o in 65% yield. When X = O, dispiroacetal 4p was obtained, albeit in a yield of only 46%. We also investigated the reactions of substrates 3q−3s (X = CH2CH2), each of which bears a cyclopentanol moiety rather than a cyclobutanol moiety. Reaction of 3q (R1 = Me, R2 = Ph) afforded [4.1.4.3] dispiroacetal 4q in 57% yield, which is comparable to the yield of 4h. In contrast, the yields of 4r and 4s were quite low. This difference in yield may have been due to the Thorpe−Ingold effect. The relative stereochemistries of 4d, 4g−4i, and 4q were assigned by means of NOESY experiments (see the SI). Because dispiroacetals 4 bear multiple reactive sites and the cyclobutyl rings tend to undergo ring expansion when exposed to acid, owing to ring strain, we were interested in investigating the acid-catalyzed ring-expansion reactions of 4 to afford 6,7dihydro-5H-benzofuran-4-ones 5,58−66 which possibly serve as synthetic intermediates for access to structurally complex fused furans67−71 (Table 2). We found that all the acetals except 4c, 4d, and 4p gave moderate to good yields of the corresponding 6,7-dihydro-5H-benzofuran-4-ones when treated with BF3· Et2O in DCM at rt for 1.5 h. The structures of products 5 were assigned on the basis of single-crystal X-ray analysis of 5l (see the SI, CCDC 1838738). The fact that 5c, 5d, and 5p did not form may have been due to their instability under the reaction conditions; indeed, complicated reaction mixtures were obtained. Interestingly, when compound 4t, which lacks a spiroacetal moiety, was subjected to the standard conditions, a
Scheme 2. Synthesis of 4 and 5
Table 1. Optimization of Conditions for the Acetalization Reactiona
entry
additive (x equiv)
solvent
yield (%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
CSA (1.0) PTSA (1.0) HOAc (1.0) ZnCl2 (1.0) FeCl3 (1.0) AlCl3 (1.0) SnCl4 (1.0) AgSbF6 (1.0) AgSbF6 (0.5) AgSbF6 (0.2) AgSbF6 (0.1) AgSbF6 (0.2) AgSbF6 (0.2) AgSbF6 (0.2) AgSbF6 (0.2) Ag2O (0.2) Ag(OTf) (0.2) Ag2CO3 (0.2) AgBF4 (0.2)
DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM DCM/H2O CH3OH/H2O THF/H2O MeCN/H2O MeCN/H2O MeCN/H2O MeCN/H2O MeCN/H2O
15 trace ND 13 trace ND ND ND 18 19 53 39 65 66 51 81
