Letter Cite This: Org. Lett. 2018, 20, 692−695
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Synthesis and Reaction of ortho-Benzoquinone Monohemiaminals Emi Saito, Yuri Matsumoto, Akihiko Nakamura, Yuki Namera, and Masahisa Nakada* Department of Chemistry and Biochemistry, School of Advanced Science and Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku, Tokyo 169-8555, Japan S Supporting Information *
ABSTRACT: The preparation and reactions of ortho-benzoquinone monohemiaminals are described. The oxidative dearomatization of phenols bearing amino alcohol groups induced N-cyclization to afford ortho-benzoquinone monohemiaminals. The N-cyclization stereoselectively affords the product when a chiral amino alcohol is used as the substituent. The chiral ortho-benzoquinone monohemiaminal undergoes stereoselective Diels−Alder reactions with electrondeficient alkenes, as expected, confirming the promising utility of ortho-benzoquinone monohemiaminals. Scheme 2. Stereoselective Diels−Alder Reaction of orthoBenzoquinone Monohemiaminals
T
he oxidative dearomatization of phenols bearing an ether group at the ortho-position affords 2,4-cyclohexadienones with a ketal group at the C6 position, known as masked orthobenzoquinones (MOBs).1 As shown in Scheme 1, MOBs Scheme 1. Synthetically Useful Transformations of Masked ortho-Benzoquinones
ans,6 spiro-lactones,7 spiro-lactams,8 spiro-amides,9 spiro-cyclopentanes,10 and spiro-oxyindoles11 at the ortho-position of phenols by oxidative dearomatization have been previously reported. However, to the best of our knowledge, formation of cyclic hemiaminals at the ortho-position of phenols has never been reported.12 In principle, the formation of ortho-benzoquinone monohemiaminal 4 (Scheme 3) would be possible by the oxidative Scheme 3. Two Possible Methods for Preparing orthoBenzoquinone Monohemiaminals
undergo a variety of reactions such as Diels−Alder reactions, epoxidations, and nucleophilic additions.1 Hence, they have been used as valuable synthetic intermediates in natural product syntheses.1,2 However, the synthesis and reactions of chiral MOBs have been limited despite their potential utility as chiral synthetic intermediates or chiral building blocks.3 We envisioned that ortho-benzoquinone monohemiaminal could be a new entry into the group of MOBs used for stereoselective reactions. For example, the Diels−Alder reaction of ortho-benzoquinone monohemiaminal 1 (Scheme 2) is expected to stereoselectively afford 2 because the substituent on the nitrogen atom in 1 effectively hinders one side of the diene. Because the hemiaminal in 2 is a masked carbonyl group that can be removed under acidic conditions, 2 can also be used as a synthetic intermediate. The intramolecular formation of five-membered spiro-rings such as spiro-isooxazolines,4 dioxolanes,5 spiro-tetrahydrofur© 2018 American Chemical Society
dearomatization of 3 (N-cyclization) or 5 (O-cyclization). We first examined the N-cyclization route and found that it afforded the corresponding ortho-benzoquinone monohemiaminal. Moreover, the same reactions of phenols bearing a chiral aminoalcohol as well as the Diels−Alder reactions of their products, orthoReceived: December 7, 2017 Published: January 17, 2018 692
DOI: 10.1021/acs.orglett.7b03824 Org. Lett. 2018, 20, 692−695
Letter
Organic Letters
(TFE)15 at 0 °C did not afford ortho-benzoquinone monohemiaminal 11 but furnished 13 in 39% yield (Table 1, entry 1). The reaction of 10 afforded ortho-benzoquinone monohemiaminal 12 in 32% yield; however, the TFE adduct 14 was also formed in 28% yield (Table 1, entry 2). To prevent the formation of 14, the reaction of 10 was carried out in dichloromethane, but the yield of 12 was reduced to 9% (Table 1, entry 3). The reactions of 9 and 10 in the mixed solvent (TFE/dichloromethane = 1:1) did not improve the yield (Table 1, entries 4 and 5). The reaction of 9 in 1,1,1,3,3,3-hexafluoroisopropanol (HFIP), which is a bulky and less nucleophilic fluoroalcohol,15 afforded a complex mixture of products (Table 1, entry 6), although the reaction of 10 in HFIP afforded 12 in 51% yield (Table 1, entry 7). The use of phenyliodine(III) bis(trifluoroacetate) (PIFA) improved the yield of 12 to 62% (Table 1, entry 8). The low yields in Table 1 (Tables 2 and 3 too) are attributed to the formation of some
benzoquinone monohemiaminals, were found to proceed stereoselectively. MOBs are usually prepared by oxidative dearomatization, but because of their high reactivity, they tend to undergo dimerization. However, phenols bearing a bulky or an electrondonating substituent at the para-position have been reported to yield products that are resistant to dimerization.5a,13 On the basis of those reports, we used phenols bearing a bulky tert-butyl group at the para-position throughout this study. The amino group in the substrates was protected with an electron-withdrawing group to avoid its oxidation under the reaction conditions and also to hinder one side of the diene in the formed ortho-benzoquinone monohemiaminal, for the stereoselective reaction. We first prepared simple achiral substrates 9 and 10 for the oxidative dearomatization (Scheme 4). The preparation of 9 and Scheme 4. Preparation of Achiral Substrates 9 and 10 for NCyclization
Table 2. Stereoselective Oxidative Dearomatization/NCyclization Cascade of 16
entry 1 2 3 4
oxidant
solvent
17, yielda (dr)b
PIDA PIDA PIFA PIFA
TFE/CH2Cl2c
10% (>20:1)d 38% (14:1) 47% (12:1) 45% (14:1)
HFIP/CH2Cl2c HFIP/CH2Cl2c HFIP
a
Isolated yields. bRatio elucidated by 1H NMR. cRatio of 1:1. d8% of 18 was formed.
10 was started from a known compound 6,14 which was subjected to reaction with n-butyllithium, followed by treatment with DMF, Baeyer−Villiger oxidation, and hydrolysis to afford 7.5a Alkylation of 7 with bromoacetonitrile afforded 8, which upon reduction with LiAlH4, treatment of the resultant amine with pivaloyl chloride, and hydrogenolysis of the benzyl ether afforded 9. Compound 10 was also prepared from 8 by the same method. Table 1 summarizes the results of the oxidative dearomatization/N-cyclization cascade of 9 and 10. The reaction of 9 with phenyliodine(III) diacetate (PIDA) in 2,2,2-trifluoroethanol
Table 3. Stereoselective Oxidative Dearomatization/NCyclization Cascade of 20
entry 1 2 3 4 5 6e
Table 1. Oxidative Dearomatization/N-Cyclization Cascade of 9 and 10
oxidant
solvent
PIDA PIDA PIDA PIFA PIFA PIFA
TFE/CH2Cl2c
21, yielda (dr)b c
HFIP/CH2Cl2 HFIP HFIP/CH2Cl2c HFIP HFIP
42% (11:1)d 66% (12:1) 54% (13:1) 78% (3:1) 57% (3:1) 62% (5:1)
a
Isolated yields. bRatio elucidated by 1H NMR. cRatio of 1:1. d22% of 22 was formed. eReaction in the presence of NaHCO3.
a
entry
9, 10
oxidant
solvent
resultsa
1 2 3 4 5 6 7 8
9 10 10 9 10 9 10 10
PIDA PIDA PIDA PIDA PIDA PIDA PIDA PIFA
TFE TFE CH2Cl2 TFE/CH2Cl2b TFE/CH2Cl2b HFIP HFIP HFIP
11 (0%); 13 (39%) 12 (32%); 14 (28%) 12 (9%) 11 (0%); 13 (59%) 12 (25%); 14 (29%) complex mixture 12 (51%) 12 (62%)
structurally unidentified products. The results in Table 1 confirm that the p-toluenesulfonyl group on the nitrogen atom is a suitable protecting group for the amine.9 Next, we examined the N-cyclization of substrates bearing a chiral substituent. On the basis of the results in Table 1, ptoluenesulfonyl was selected as the protecting group. To study the stereoselective reaction, we prepared compound 16, which possesses a stereogenic center bearing a nitrogen atom (Scheme 5). Compound 16 was easily obtained by the reaction of Ntosylaziridine 1516 with 7 under basic conditions and subsequent removal of the benzyl group by hydrogenolysis.
Isolated yields. bRatio of 1:1. 693
DOI: 10.1021/acs.orglett.7b03824 Org. Lett. 2018, 20, 692−695
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Organic Letters
acid (TFA) generated from PIFA. The yield and stereoselectivity were slightly improved, indicating that TFA could make a small contribution to the drop in stereoselectivity (Table 3, entry 6). The reason for the reduced stereoselectivity in the reaction with PIFA is not clear at this stage. The high stereoselectivity observed in the N-cyclizations of 16 could be explained by transition-state models TS1 and TS2 in Scheme 7.18 Based on molecular modeling, the energetically
Scheme 5. Preparation of 16
The results of the oxidative dearomatization/N-cyclization cascade of 16 are summarized in Table 2. The reaction of 16 with PIDA in the mixed solvent (TFE/dichloromethane = 1:1) at 0 °C afforded desired ortho-benzoquinone monohemiaminal 17 (Table 1, entry 1). The yield of 17 was 10%, but the stereoselectivity was high (dr = >20:1). Since formation of the side-product 18 (8%) was presumably due to the reaction of the active species with TFE, the reaction was carried out in less nucleophilic HFIP. Accordingly, 17 was obtained in 38% yield with a diastereomeric ratio of 14:1 (Table 1, entry 2). The sideproduct 18 was not formed. The reaction with PIFA in the mixed solvent (TFE/dichloromethane = 1:1) improved the yield of 17 to 47% with almost the same stereoselectivity (dr = 12:1) (Table 1, entry 3). The same results (45%, dr = 14:1) were obtained by the reaction using PIFA in HFIP (Table 1, entry 4). The configuration of 17 was elucidated by the analysis of its NOESY spectrum. Compound 20, possessing a stereogenic center bearing an oxygen atom, was also prepared to examine the stereoselective reaction (Scheme 6). It was easily prepared by the reaction of Ntosylaziridine 1917 (racemate) with 7 in the presence of BF3·OEt2 and subsequent removal of the benzyl group by hydrogenolysis.
Scheme 7. Proposed Rationale for the Stereoselective Formation of 17
favorable transition states of the reaction of 16 could be TS1 and TS2, which are envelope-forms with an equatorial isopropyl group. However, TS2, which leads to the formation of 17′, a diastereomer of 17, would be unfavorable because of the steric strain between the pseudoaxial hydrogen atom of the methylene group and the oxygen lone pair of the phenol. Hence, TS1 would be energetically more favorable, so that 17 was preferentially formed. The stereoselectivity observed in the reaction of 20 could also be explained by envelope-form transition-state models (Scheme 8). The energetically favored transition-state models would be
Scheme 6. Preparation of 20
Scheme 8. Proposed Rationale for the Stereoselective Formation of 21
The reaction of 20 with PIDA in the mixed solvent (TFE/ dichloromethane = 1:1) at 0 °C afforded 21 in 42% yield with a diastereomeric ratio of 11:1, along with the formation of the adducts of TFE, 22 (22%) (Table 3, entry 1). The mixture of crude products (Table 3, entry 1) was treated with PPTS in refluxing acetone to afford 21 in 82% yield with a diastereomeric ratio of 11:1. It was obtained as an inseparable mixture with its diastereomer but was isolated as a single isomer by recrystallization. Its structure was successfully elucidated as shown in Table 3 by the analysis of its NOESY spectrum. To suppress the formation of 22, the reaction of 20 with PIDA was carried out in a mixed solvent using HFIP (HFIP/dichloromethane = 1:1), and 21 was obtained in 66% yield with a diastereomeric ratio of 12:1 (Table 3, entry 2). The reaction in only HFIP as the solvent decreased the yield to 54% and the selectivity was almost unchanged (dr = 13:1) (Table 3, entry 3). Interestingly, the reaction of 20 with PIFA in the mixed solvent (HFIP/dichloromethane = 1:1) improved the yield of 21 to 78%; however, the stereoselectivity decreased (dr = 3:1) (Table 3, entry 4). The reaction of 20 with PIFA in HFIP afforded 21 with the same stereoselectivity (dr = 3:1), but the yield decreased to 57% (Table 3, entry 5). In the stereoselectivity of the reaction of 16, no difference between PIDA and PIFA was observed (Table 2). However, in the case of 20, the reaction with PIFA afforded the product with reduced stereoselectivity. We carried out the reaction of 20 with PIFA in the presence of sodium bicarbonate to trap trifluoroacetic
TS3 and TS4, which are envelope-forms with an equatorial phenyl group. TS4, which leads to the formation of 21′, would be unfavorable because of the steric strain between the pseudoaxial hydrogen atom at the benzylic position and the oxygen lone pair of the phenol. Hence, TS3 would be energetically more favorable, and 21 was preferentially formed. Since 21 was obtained as a pure compound by recrystallization, its Diels−Alder reactions with alkenes were examined (Table 4). The reaction of 21 with n-butyl vinyl ether gave no products even at 90 °C and 21 gradually decomposed, indicating that the Diels− Alder reaction of this compound with an eletron-rich alkene would require harsh reaction conditions (Table 4, entry 1). On 694
DOI: 10.1021/acs.orglett.7b03824 Org. Lett. 2018, 20, 692−695
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Table 4. Diels−Alder Reactions of 21
entry
alkene (equiv)
temp (°C)
time (h)
23, 24 (yielda)
1 2 3 4 5
n-butyl vinyl ether (10) methyl acrylate (30) methyl vinyl ketone (3.0) acrolein (45) N-phenyl maleimide (3.0)
90 130b 80 130b 90
19 24 25 44 14
0 23a (89%)c 23b (94%)c 23c (92%)c 24 (96%)c
a
the other hand, the reaction with electron-deficient alkenes, methyl acrylate, methyl vinyl ketone, acrolein, and N-phenyl maleimide afforded 23a (Table 4, entry 2), 23b (Table 4, entry 3), 23c (Table 4, entry 4), and 24 (Table 4, entry 5) as single products, respectively. The yield was high in all the cases and structural analyses by NOE studies revealed that all the reactions took place stereoselectively at the sterically less-hindered side of 21, as depicted in Scheme 2.19 In summary, we found that the oxidative dearomatization of phenols bearing amino alcohol groups induced N-cyclization to afford ortho-benzoquinone monohemiaminals. The N-cyclization stereoselectively afforded the product when a chiral amino alcohol was used as the substituent. The chiral orthobenzoquinone monohemiaminal underwent stereoselective Diels−Alder reactions with electron-deficient alkenes, as expected, confirming the promising utility of ortho-benzoquinone monohemiaminals.
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b03824. Experimental procedure and characterizations of the substrates and products (PDF)
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REFERENCES
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Isolated yields. bReaction in a sealed tube. cSingle isomer.
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Masahisa Nakada: 0000-0001-6081-5269 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We acknowledge support of the Materials Characterization Central Laboratory, Waseda University, for characterization of new compounds. This work was financially supported in part by the Grant-in-Aid for Scientific Research on Innovative Areas 2707 Middle Molecular Strategy from MEXT and a Waseda University Grant for Special Research Projects. 695
DOI: 10.1021/acs.orglett.7b03824 Org. Lett. 2018, 20, 692−695
