Synthesis of Divergent Benzo[b]fluorenones through

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Synthesis of Divergent Benzo[b]fluorenones through Cycloaromatization Reactions of 1,5-Enynols and 1,5-Diynols Bingyu Yan, Yang Fu, Hui Zhu, and Zhiyuan Chen J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00231 • Publication Date (Web): 05 Mar 2019 Downloaded from http://pubs.acs.org on March 5, 2019

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The Journal of Organic Chemistry

Synthesis of Divergent Benzo[b]fluorenones through Cycloaromatization Reactions of 1,5Enynols and 1,5-Diynols Bingyu Yan, Yang Fu, Hui Zhu and Zhiyuan Chen*,a a

Key Laboratory of Functional Small Organic Molecules, Ministry of Education, and College of Chemistry & Chemical Engineering, Jiangxi Normal University, Nanchang, Jiangxi 330022, China.

Abstract: A facile and efficient synthesis of divergent benzo[b]fluorenones was described through the use of DDQpromoted oxidative cycloaromatization reactions of acyclic 1,5-enynols and 1,5-diynols. The success of these cascade reactions depends on the chemoselectivity of the initial Meyer-Schuster rearrangement to produce allenol intermediate, which is followed by regioselective Schmittel cyclization and the subsequent Friedal-Crafts alkylation or radical attack at the terminal Ar moiety. Only an oxidant and a solvent were required in the reaction, thus delivering a small library of the expected polycarbocyclic products with excellent functional group tolerance under metal-free conditions. The absorption and photoluminescence properties of the selected benzo[b]fluorenones were also investigated. The results indicated that the compound (2h) which containing an electron-donating 4-OMe group at the phenyl moiety displayed deep green color emission (491 nm). Keywords: cycloaromatization, 1,5-enynol, 1,5-diynol, benzo[b]fluorenone, photoluminescent property.

Introduction The cascade cycloaromatization reaction is a powerful avenue for the production of polycyclic compounds in organic synthesis. By utilizing this strategy, various fused carbo/heterocycles can be atom-economically produced in concise synthetic protocols from readily available starting materials.1 However, there exists potential hassle in chemo- or regioselectivity controlwhich always arises when utilizing alkene or alkyne group as basic synthons. This is simply due to the close similarity in the electronic and steric properties of the multiple unsaturated π-conjugated units in the starting materials. The cyclization reaction of enyne-allene species,2 is a particularly intriguing transformation which was realized as a diradical mechanism as evidenced by experimental and computational studies.3 There are generally two different types of diradical pathways for cascade cycloaromatization of enyneallene systems. Each process corresponds to the controlled “cyclization” of allenyl moiety positioned between different carbon atoms via a selective sequence of transformations. The formation of aromatic rings originating from 6-endo-dig C2-C7 cyclization is favoured for the terminal alkyne substitutions, and this reaction was known as Myers-Saito cyclization (Scheme 1, a).4 However, for the internal alkyne (e.g. R = Ph or TMS), the 5-exo-dig C2-C6 Schmittel cyclization is much more energetically favoured. This is due to the fact that the steric repulstion between terminal substituents does not favor the Myers-Saito cyclization, but conjugation (for R = Ph) or hyperconjugation (for R = TMS) favors the the Schmittel reaction (Scheme 1, b).3,5 The resulting formation of fulvene carbocycles constitutes a powerful tool for the synthesis of polycarbo(hetero)cycles in the Schmittel cyclization, because five-member structural motifs are frequently found in numerous natural products and pharmaceutical agents. 6 We have proposed that the indenone frameworks may be expediently produced in chemo- and regioselective transformations in the Schmittel cyclization of allenol species, which a free hydroxyl group at the terminal of the allenyl moiety. What makes the strategy more interesting is the further potential of the consecutive oxidative annulations to construct the tetracyclic benzo[b]fluorenone derivatives (Scheme 1, c). Although the regioselectivity of the 5-exo-dig cyclization is well controlled by preference of the nonterminal alkynes, the key challenge of the cascade involves achieving chemoselectivity to initiate the alleol species. In addition, the tolerance of the free OH group in this oxidative radical conditions should be taken into account. Fortunately, we have found that Meyer-Schuster rearrangement from propargyl diaryl tertiary alcohol appeares to be an excellent protocol for this purpose. The Meyer-Schuster rearrangement is an efficient approach to form the reactive allenol intermediate. A formal 1,3-hydroxyl shift was proposed in this rearrangement process either by transition-metal-catalyzed conditions7 or electrophile-promoted reactions. 8

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3

6

R

2

7

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H

C2-C7 R=H

1

H (a)

Myers-Saito cyclization

R

enyne-allene C2-C6 R = Ph, TMS... Schmittel cyclization

R1 OH R2 R

H H R

fulvene carbocycle

1,5-enynol or 1,5-diynol Meyer-Schuster rearrangement

O

HO

R1

HO

R1

C2-C6

R2 R allenol species

(b)

R

R2

R1

[O] Oxidative Schmittel cyclization

this work

R2

(c)

R

indenone or benzofluorenone

Scheme 1. Cascade cycloisomerization of enyne-allenes via diradical intermediates.

Benzofluorenes are privileged structural motifs with important pharmacological activities in medicinal studies.9 Families of these hydrocarbon scaffolds, including their oxidized and reduced analogues can be widely found in natural products and biologically active substances.10 Benzofluorenes have recently been applied as a building block in the biosynthesis of Kinamycin atypical angucyclines.11 Furthermore, the aromatic πconjugated benzo[b]fluorene derivatives have been employed as active materials in optoelectronic devices due to their high luminescence quantum efficiency and good chemical stability.12 To date, literature reports for the synthesis of the tetracyclic core structure typically requires multiple steps and high temperature conditions.10-13 As a result, functional group tolerance and chemoselectivity have always emerged as problematic issues. The lack of a straightforward and efficient synthetic protocol hinders the rapid assembly of a structurally diverse chemical library and prevents further applications of these polycarbocycles in medicinal chemistry and material sciences. Thus, advanced methods for the efficient construction of benzo[b]fluorenes is both highly valuable and desirable. In 2001, Echavarren and co-workers developed a thermal cyclization of 1-[2-(trimethylsilylethynyl)phenyl]3-arylpropinones to produce benzo[b]fluorenones; however, benzo[a]fluorenones were also formed as a result of a new rearrangement.14 Alabugin reported a Bu3SnH/AIBN-induced radical cascade reaction of (2alkynylphenyl)propargyl methyl ethers to regioselectively prepare 11-phenyl-11H-benzo[a]fluorenes.15 Tu reported a visible-light induced or base-controlled 1,6-enyne-bicyclization to give divergent synthesis of benzo[b]fluorenones and benzo[b]fluorenols.16 We have developed easy approaches regarding cycloisomerization reactions of 1,n-diynols to chemo- and regioselectively afford various benzo[a]fluorenols17a and benzo[b]fluorenones17b under exceedingly mild conditions. In connection with our recent achievements in the metal-catalyzed cycloisomerization of 1,n-endiynyls,18 we envisioned the Meyer-Schuster rearrangement as a tool to form the aforementioned allenol species offering a facile synthesis of benzo[b]fluorenones.

Results and Discussion We employed compound (E)-1,1-diphenyl-3-(2-styrylphenyl)prop-2-yn-1-ol 1a as a starting materials to explore the proposed cycloaromatization reaction (Table 1).19 After a careful survey of the reaction parameters, the desired tetracyclic product 2a was observed when 2.0 equiv. of dichlorobenzoquinone (DDQ) was utilized in CH3CN at 80 oC. No reaction was observed when benzoquinone (BQ) and electron-rich 2,3,5,6tetramethylbenzoquinone (TMQ) were employed. In contrast, the electron-deficient oxidants such as 2,5dichlorobenzoquinone (DCQ) and 2,3,5,6-tetrachlorobenzoquinone (TCQ) can give moderate yields of product 2a. DDQ proved to be the optimal choice of oxidant, the yield of product 2a was 80% when 2.0 equiv. of DDQ was added (entry 1). Table 1. Optimization of the reaction conditions. a


2

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O

OH Ph Ph DDQ (2.0 equiv.) CH3CN (0.1M) 80 oC, 12 h, N2

Ph O

Me O BQ, n.r.

O

O

Cl Cl

Me Cl

Cl Cl

Cl

O

O

TMQ, n.r.

2a

O

Me

Me

Ph

"Standard conditions"

1a

O

Ph

DCQ, 38%

CN

Cl Cl

CN

O

O

TCQ, 61%

DDQ, 80%

O O OH TBHP, n.r.

Entry 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 a The reaction was carried out with reaction.

Ph

O

O

O BPO, 0%

Ph

Ph

O

O

O TBPB, 0%

Variation of the reaction conditions None Other oxidant H2O2 (2.0 equiv.) instead of DDQ K2S2O8 (2.0 equiv.) instead of DDQ AgOTf (10 mol%) as a catalyst AuCl(PPh3) (10 mol%) as a catalyst H2O (1.0 equiv.) as an additive CsOAc (1.0 equiv.) as an additive tBuOK (1.0 equiv.) as an additive HOAc (1.0 equiv.) as an additive 60 oC for 24 h 100 oC overnight DCE instead of CH3CN Toluene instead of CH3CN THF instead of CH3CN 1,4-dioxane instead of CH3CN CH3CN:toluene (1:1) instead of CH3CN DDQ (2.5 equiv) Under air condition 0.3 mmol of 1a in 3.0 mL CH3CN at 80

2a (%)a 80 see above trace n.r. 41 45 complex 35 30 54 50 73 54 68 30 trace 55 76 42 °C for 10-12 h. Isolated yield. n.r. = no

Although trace yield of the desired product 2a could be observed when H2O2 was employed (entry 3), its peroxide analogues such as TBHP, BPO and TBPB, were shown inert for the transformation. The strong coordination nature of the π-electrophilic coinage metal (Au, Ag) Lewis acids, which were typically employed as activators of the alkyne group in many cyclization reactions,[20] proved to be unproductive for the current reaction (entries 5-6). In addition, this reaction demonstrated sensitivity to moisture, as shown by the addition of 1.0 equiv. of water, which eventually destroyed the whole cyclization (entry 7). The ionic, basic, and acidic conditions were applied, and low yields were observed when CsOAc or tBuOK were added as additives into the reaction. The Brønsted acid was found to be powerful in the Meyer-Schuster rearrangement reaction, with an improved efficiency when HOAc (1.0 equiv.) as added (entries 8-10). Lowering the reaction temperature to 60 oC resulted in a decreased yield of product 2a and prolonged reaction time, while raising the temperature to 100 oC drastically accelerated the transformation. but slightly reduced efficiency (entries 11-12). These results indicated that a thermal radical cycloaromatization of arylacetylene should be involved in the reaction. Despite the initial success, the screening of the common laboratory solvents did not provide any noticeable improvements (entries 13-17). No obvious increase in yield of 2a was observed when increasing the amount of DDQ to 2.5 equivalents (entry 18). In addition, competent yields of 42% were obtained when the reaction was carried out under air conditions (entry 19). It should be noted that the avoidance of using transition-metals in this reaction is significant, as metal species are highly toxic when present in an intrusive limitation in the industrial scale usage, especially in the last synthetic stage of the purification of pharmaceutical ingredients or optoelectronic materials.


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The substrate scope of this DDQ-promoted oxidative cycloaromatization reaction was studied firstly by varying substitutions on the aromatic moieties (Table 2). Good yields were observed for the functional groups with electron-donating properties that attached at the benzonoid core structure of substrate 1,5-enynol 1. The 5Me and 6-OMe substitutions at R1 position were compatible to give the desired benzo[b]fluorenones 2b and 2c in 73% and 60% yields, respectively. Electron-deficient halogenated (F, Cl) benzo[b]fluorenones 2d, 2e, and 2f could also be isolated in moderate to good yields. Table 2. Substrate scope of the DDQ-promoted oxidative cycloisomerization reaction of 1,5-enynols 1.a O

OH 3 R

R3

1

R

4

R DDQ (2.0 equiv.) R1

CH3CN, 80 oC, N2

R4

2

R

R2

1

O

Me

O

O

F

Ph

Ph

2

Ph

MeO Ph

Ph

2b, 73%

Ph

2c, 60%

O

2d, 60% O

O Ph

Ph

Ph

F

Cl Ph

Ph

2e, 56%

Tol

2f, 81%

O

2g, 95%

O

O

Ph

Ph

Tol

Me

Cl

MeO 2h, 82%

2i, 96%

2j, 92% Me

F

OMe

O

O

O

Me

F

OMe 2k, 65%

Cl

2l, 66%

2m, 89% F

OMe O

O

F

OMe Me

Me

2n, 77%

2o, 77% Cl

Me O

O

O

O

Cl

Me 2p+2p', 93% (ratio = 2:1)b

2q+2q', 82% (ratio = 1.7:1)b


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Reaction conditions: 1,5-enynol 1 (0.3 mmol), DDQ (0.6 mmol), CH3CN (3.0 mL) at 80 °C for 10-12 h. Isolated yield based on 1. b Molecular ratio was determined by 1H NMR. Tol = p-tolyl. a

Substituents with different electronic characters on the R2 position of the phenyl ring were well tolerated. Electron-donating substituentss such as Me (2g) and OMe (2h), as well as the weak electron-withdrawing group Cl (2i) all resulted in good to excellent yields of the expected products. The structure of compound 2g was confirmed via X-ray diffraction analysis.21 Further studies revealed that the aromatic substitutions R3 and Ar that were attached at the propargyl alcohol moiety were also productive with good efficiency. When using the structure of R3 = C6H4(R4) group, only one tetracyclic benzo[b]fluoreone product was isolated. The methyl substituted benzo[b]fluorenone 2j was obtained in 92% yield, while the aromatic groups at the position containing OMe and F underwent the reaction smoothly to afford the expected products 2k and 2l in 65% and 66% yields, respectively. However, when the arenes in the propargyl position of 1,5,-enynols were attached with different substituents, two constitutional isomers could be formed in the reaction. Interestingly, we have found that the cyclization process in these cases occurred chemoselectively in the electron-rich phenyl group which was attached at the propargyl moiety of 1. For example, in the cyclization reaction of 1,5-enynol 1p, which contains a moderate electron-donating methyl group and an electron neutral H atom, the products 2p and 2p' were isolated in 93% yield, and had a combined molecular ratio of 2:1 as indicated by 1H NMR. The product 2p, which contains the Me group in the core structure of the tetracyclic ring system, was isolated as the major product in this reaction. Similar results were observed in the case of 1q, in which an electron-neutral phenyl group and an electron-withdrawing halogen group were linked at the propargyl position of the starting material, and the corresponding products 2q and 2q' were isolated in good yield. The product 2q was identified as the major product, and the molecular ratio of these two isomers was 1.7:1. OH Ph Ph

O Ph

DDQ (2.0 equiv.) CH3CN, 80 oC, N2

COOEt

MeO

(1)

MeO EtOOC 2r, 59% yield

1r O

OH Ph

O Ph

Ph DDQ (1.05 equiv.)

Ph (2)

CH3CN, 80 oC, N2 COOEt

EtOOC

EtOOC

1s

2t, 45% yield

2s, 32% yield

DDQ (1.0 equiv.) 92% yield O

OH Ph

DDQ (2.0 equiv.) TEMPO (2.0 equiv)

Ph

CH3CN, 80 oC, N2

Ph (3)

COOEt 1s

EtOOC trace yield ! sluggish conversion 2s

Scheme 2. DDQ-promoted cycloaromatization of enyne acrylates.

In addition to the aryl substitution, an ester group which could attach at the alkenyl terminal moiety could also be compatible in the reaction. Aromatic enynes have recently been found to possess siteselective 5-exo-trig radical closure to afford indene derivatives when initiated by Bu3SnH/AIBN.22 However, we have found herein that the cyclization proceeded selectively to give tetracyclic benzo[b]fluorenones when promoted by stoichimetric excess of DDQ (Scheme 2, eq. 1). For the intramolecular cyclization of compound 1r in the presence of 2.0 equiv of DDQ, the corresponding product 2r was isolated in 59% yield. Interestingly, when 1.05 equiv. of DDQ was utilized in the reaction of 1s, the aromatic product 2s was isolated in a 32% yield and a 45% yield of dihydrobenzo[b]fluorenone 2t. Compound 2t could be further transformed into product 2s in high yield when treated with 1.0 equiv. of DDQ in CH3CN (Scheme 2, eq. 2). The formation of dihydrobenzo[b]fluorenone (2t) strongly supports our hypothesis on the mechanistic elucidation, shown in Scheme 2. Additionally, in the presence of 2.0 equiv of radical scavenger, TEMPO, a sluggish transformation was ACS Paragon Plus Environment

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observed, and product 2s was isolated only in trace yield. These results indicated that a radical pathway would likely be involved as a key step of oxidative cyclization (Scheme 2, eq. 3). The substrate scope of this radical cycloaromatization reaction could be extended to the orthoalkynylphenyl propargyl alcohols. For the intramolecular cyclization of 1,5-diynol 3, only one equivalent of DDQ was found to be sufficient to promote the transformation and benzo[b]fluorenone was again the sole product. Despite being easily synthesized and stable starting materials, these 1,5-diynols 3 were found to be highly reactive when in the DDQ-promoted oxidative annulations, which resulted in the chemo- and regioselectively needed to produce the desired product (2) in good to excellent yields and had excellent functional group tolerance (Table 3). The triphenyl substituted compound 3a, 1,1-diphenyl-3-(2(phenylethynyl)phenyl)prop-2-yn-1-ol, to undergo the treatment of 1.0 equiv. of DDQ, resulting in the product 2a with a 89% yield. The electron-donating Me- (2g), MeO- (2h), and tBu-substutited benzo[b]fluorenones (2v) were formed in 94%, 87% and 94% yields, respectively, when utilizing the corresponding propargyl alcohols (3) as the starting materials. For the electron-withdrawing substituent that attached at the aryl groups of R2 position of 1,5-diynols (3), the highly transformable functional groups such as F (2u), Cl (2i), CN (2w), NO2 (2x), and COOMe (2y) groups were all tolerated in order to give the desired products. Table 3. Synthesis of benzo[b]fluorenones 2 via DDQ-promoted oxidative cycloaromatization reaction of 1,5-diynols 3.a


6

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O

HO R3

R3

R1

Ar DDQ (1.0 equiv.)

R1

CH3CN, 80 oC, 10-12 h

3

R4 2

O

O

O Ph

Ph

Ph

Me

2a, 89%, 85%b

MeO

2g, 94%

O

2h, 87% O

O Ph

Cl

R2

R2

Ph

Ph

F

2i, 94%

tBu

2u, 95%

2v, 94%

O

O

O Ph

Ph

O2N

NC

Ph

MeOOC

2w, 91%

2x, 69%

O

2y, 97% O

O

Ph

Ph

Ph

S 2z, 99%

2aa, 75%

O Ph

Ph

O

F3CO

Ph

F

MeO

Me

Me

2cc, 65%

Me 2dd, 91%

2ee, 97% F

OMe

O

Me

2ff + 2ff', 95% (ratio = 2.9:1)b

OMe

O

O

OMe Me

2bb, 41%

O

O

OMe Me

F

Me

2gg + 2gg', 86% (ratio = 1.6:1)c

a Reaction

conditions: 1,5-diynol 3 (0.2 mmol), DDQ (0.2 mmol), CH3CN (4.0 mL) at 80 °C for 12 h. Isolated yield based on 3. bgrame-scale synthesis (3.0 mmol scale).c Molecular ratio was determined by 1H NMR.

In addition, the heterocyclic and alkyl-substituents at the R2 position were also relatively compatible, producing the desired products 2z, 2aa, and 2bb in moderate to quantitative yields, respectively. No radical clock (ring opening of cyclopropane) was observed in the cycloaromatization reaction of 1,5-diynols at the current stage. We contend that this is due to the ring-opening of this specialized cyclopropyl group, which is not fast enough compared to cyclization with the phenyl group, because the neighboring π-conjugated phenyl group or the elecron-deficient indenone group may stabilize the alkenyl radical D' through resonance.[23]


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The electron-donating 4-OMe group and the electron-withdrawing groups, 4-F and 5-OCF3, which are located at the R1 position of the benzoid ring, participated in the reaction smoothly to give the desired products 2cc, 2dd, and 2ee in good to excellent yields. We have also observed chemoselectivity in the cycloaromatization of the 1,5-diynols. When aryl substituents (R3 and Ar) with different electronic natures were attached in the propargyl moiety of 1,5-diynols 3, the cyclization was always favored the relatively electronrich phenyl group. For example, in the reaction of compound 3f in which an electron-rich 4-OMe phenyl group and an electron-neutral phenyl group were attached at the propargyl position, product 2ff containing the OMe group in the core structure of the tetracyclic ring system was isolated as the major product, as opposed to its isomer 2ff'. The ratio of the 2ff and 2ff' compounds was identified as 2.9:1 as indicated by 1H NMR. Similar phenomenon was obtained in the reaction of substrate 3g. An electron-donating OMe compound and an electron-withdrawing fluorine-substituted phenyl group were linked at the propargyl position of 3g. In this case, the major product 2gg was isolated and confirmed by X-ray crystal analysis as the major product over its constitutional isomer 2gg' in an molecular ratio of 1.6:1.21 Since the Meyer-Schuster rearrangement from propargyl diaryl tertiary alcohols were known to be efficiently transformed into enones under transition-metal-catalyzed or acid-promoted reaction conditions,[7a] we synthesized the ortho-alkynyl enone 6 and the ortho-alkenyl enones 7 and 8, and then subjected these enones to different reactions with an attempt to provide insight into the mechanism of this reaction (Scheme 3). Compound ortho-alkynyl enone (6) was tested under different conditions and the expected product 2a could be isolated in 12% yield in CH3CN at 80 oC under air while in the absence of DDQ (eq 1). However, the yield of product 2a could be modestly raised when an oxidant (DDQ) or an acid (TsOH) were added (eqs. 2-3). In a sharp contrast, for the reactions of ortho-alkenyl enones 7 and 8, the starting materials were unaltered regardless of the presence or absence of an oxidant, and no desired product could be detected (eqs. 4-5). These results indicate that for the generation of benzo[b]fluorenone 2a, the substrates 1,5-enynols and 1,5-diynols proceeded under different mechanistic pathways. For 1,5-diynols, the enone species could be a possible key intermediate. However, for 1,5-enynols, the enone species might not be involved in the key step of cyclization. To better understand the origin of the enone species in our DDQ-mediated reactions, propargyl tertiary alcohol (9) was tested under different conditions. Initially, we observed that the reaction of 9 with DDQ in toluene at 60 oC did not offer any positive reaction (eq. 7). It is known that the weak acidic compound 4,5dichloro-3,6-dihydroxyphthalonitrile (2H-DDQ) is a reduction form of DDQ. Thus, we tried the reaction of 1,1,3-triphenylprop-2-yn-1-ol 9 with DDQ in the presence of 1.0 equiv of 2H-DDQ. However, no reaction was observed under this second condition as well (eq. 8). In the addition of 20mol% of TsOH, a 75% yield of the Meyer-Schuster rearrangement enone 10 was isolated (eq. 9). This reaction indicates that only modest acidity could promote the Meyer-Schuster rearrangement actively, regardless the presence of the oxidant.


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Ph

O

Ph Ph [Pd]/[Cu]

Ph OH Ph AuCl3

[Pd] (cat.)

Ph OtBu

OtBu

Br O

5

4

Ph

O Ph

DCM/EtOH 40%

Br

Ph

O

Ph

6

82%

59%

[Pd] (cat.)

7 O O

Ph 49%

Ph 8

MeCN, 80 oC, air

Ph

(1)

2a

12% yield.

Ph

Ph

O

Ph

DDQ (1.0 equiv)

Ph 6

(2)

2a

MeCN, 80 oC, air 47% yield. TsOH (20 mol%)

(3)

2a

o

MeCN, 80 C, air 50% yield. MeCN, 80 oC, air

Ph

O

no reaction

(4)

no reaction

(5)

Ph OtBu 7 O

DDQ (2.0 equiv) MeCN, 80 oC, N2

O

Ph Ph

8

Ph

DDQ (2.0 equiv) o

MeCN, 80 C, N2

DDQ (1.0 equiv) Ph OH Ph Ph 9

toluene, 60 oC,N2

2a no reaction

(6)

(7)

no reaction

OH DDQ / 2H-DDQ toluene, 60 oC,N2 DDQ / TsOH toluene, 80 oC,N2 75% yield.

no reaction

O Ph

(8)

Ph

10

Ph

Cl

CN

Cl

CN OH 2H-DDQ

(9)

Scheme 3. Mechanistic studies.


9


Ph OH Ph

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O Cl

CN

Cl

CN

Ph

Cl

Cl

Ph O

Ph

OH CN

CN 11 (acidic species)

O DDQ

9

O

Cl Ph Ph

O

O

Ph O

CN CN

HCl (acidic species)

12

Scheme 4. Possible route for the generation of the catalytic acidic species. Based upon these studies, we proposed a possible route for the generation of the catalytic acidic species as depicted in Scheme 4. Since the Brønsted acids were known to be able to promote the Meyer-Schuster rearrangement from tertiary alcohols to enones, the Michael-addition of propargyl alcohol 9 with α,βunsaturated ketone DDQ would produce the phenol derivitive 11, allowing for further elimination of hydrochloride of 11 to product 12. The resulting HCl acidic species should then be able to drive the MeyerSchuster rearrangement in the reaction, especially when heating at a high temperature of up to 80 oC. For this proposed pathway, the electron-deficient benzoquinone derivatives such as DCQ, TCQ and DDQ were apparently more advantageous to produce the Michael-addition reaction, as electron-deficient α,β-unsaturated ketones are favorable substrates in Michael-type conjugate additions with nucleophiles. In contrast, the electron-rich benzoquinone derivatives, such as BQ and TMQ, are not so active in the similar Michael addition reactions (entry 2, Table 1). In addtion, a radical species was further supported by an electron paramagnetic resonance (EPR) experiment in the cycloaromatization of 1,5-diynol 3. When compound 3a was employed as a starting material under the standard conditions for 30 min, we successfully observed signal from the carbon radical as detected by EPR. This result suggested that the organic radical is initially generated by DDQ and then reacts with the 1,5-diynols in the reaction system to induce subsequent oxidative annulation sequences (See supporting information for details).


10

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3

R

HCl species

Ar R

R A O

R2 DDQH Radical Oxidation

O

R3

R3

R2 H D

DDQH

Friedel -Crafts

O

R3

R3

R2

Ar R2 B

C

O

O

R3

DDQH

2

1 Radical Cyclization

DDQ

Ar

Meyer-Schuster Rearrangement

2

O

OH

HO R3

R2 H

DDQH2

F

E Ar R3

[O]

2

R2 G

O

OH

R3

O

R3

R3 2

R2 H D'

R2

R2

3

C'

An alternative [4+2] pathway: Ar R3 OH HCl species

R3

R2

R

Ar R2

Meyer-Schuster Rearrangement 3

A

[4+2]

R3

O

OH

O H R3

H

R2

O R3

DDQ R

R2 H I

R 2

R

2

Scheme 5. Mechanistic elucidation.

We proposed the following mechanism for the cycloaromatization of 1,5-endiynol 1 as shown in Scheme 5 for this cascade cycloaromatization reactions. Under heating conditions, the loss of H2O in Meyer-Schuster rearrangement of a formal 1,3-OH shift of 1,5-enynol 1 to produce allenol species A can be envisioned first.5 Radical oxidation of A by DDQ followed by deprotonation would generate the allenol radical B,24 which would then undergo C2-C6 5-exo-trig ring closure to give the indenone radical C. At this stage, the following radical attack at the pendant phenyl group by the alkyl radical to give the benzo[b]fluorenone radical D is unlikely, because alkyl radicals are not reactive enough to attack at the pendant phenyl moiety or similar systems.25 Alternatively, single-electron oxidation of the alkyl radical by DDQH· radical species would give rise to a resonance-stabilized cation E, which then would undergo Friedel-Crafts alkylation into the phenyl group to form the benzo[b]fluorenone framework F. Finally, deprotonation of F followed by rearomatization would yield the product 2. It can be seen from this mechanism analysis that no less than 2.0 equivalents of oxidants should be necessary to promote the transformation. Otherwise, the dihydro-benzo[b]fluorenone intermediate G would be observed. However, only one equivalent of oxidant was necessary for the cycloaromatization reaction of 1,5-diynol 3, because a vinyl indenone radical C' would be formed from the cyclization sequences, and this


11


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vinyl radical C' has sufficient reactivity to attach the aromatic ring and cyclize to directly give rise to the tetracyclic radical D'. However, an alternative [4+2] cycloaddition pathway in Scheme 5 was also likely, due to the fact that enones were found to be useful intermediate in the cycilzation of 1,5-diynols 3, and more importantly, no radical clock was observed in the synthesis of compound 2bb. In this mechanism, the enone species H could be generated from the enol-ketone tautomerization of the allenol intermediate A, which then underwent concert [4+2] cyclization to give the dihydro-benzo[b]fluorenone I. Finally, oxidation of I would deliver the observed compound 2. According to this rationalization, DDQ should offer two distinct advantages: 1) the conjugate addition of alcohol to DDQ followed by release of HCl species is useful to drive the Meyer-Schuster rearrangement, and 2) oxidation of the dihydro-intermediate provides the final product.26 Fluorene derivatives featured with large and rigid π-conjugated structural motifs have long been known as important optoelectronic active agents.12b, 27 To explore the optical utility of the tetracyclic benzo[b]fluorenone derivatives, we studied the photophysical properties of some of the seleted compounds. The UV-Vis absorption and fluorescence emission properties of compound 2a in different concentrations of dilute CH3CN were shown in Figure 1. The obtained benzo[b]fluorenones are yellow crystals in solid state, whereas they displayed a vivid yellow greenish color when dispersed in dilute CH3CN solution. The UV-Vis absorption peak of compounds 2a in CH3CN solution (

Synthesis of Divergent Benzo[b]fluorenones through

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