Clean oxidation of (hetero)benzylic Csp3-H bonds with molecular

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Clean oxidation of (hetero)benzylic Csp3-H bonds with molecular oxygen Kai-Jian Liu, Zhen-Hong Duan, Xiu-Ling Zeng, Meng Sun, Zilong Tang, Si Jiang, Zhong Cao, and Wei-Min He ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.9b00002 • Publication Date (Web): 28 May 2019 Downloaded from http://pubs.acs.org on May 29, 2019

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ACS Sustainable Chemistry & Engineering

Clean oxidation of (hetero)benzylic Csp3-H bonds with molecular oxygen Kai-Jian Liua, Zhen-Hong Duana, Xiu-Ling Zenga, Meng Sunb, Zilong Tangb, Si Jiangc, Zhong Caoc and Wei-Min He*a aDepartment

of Chemistry, Hunan University of Science and Engineering, Yangzi Tang Road No.

130, Yongzhou 425100, China b

School of Chemistry and Chemical Engineering, Hunan University of Science and Technology,

Taoyuan Road No. 9, Xiangtan 411201, China cHunan

Provincial Key Laboratory of Materials Protection for Electric Power and Transportation,

Changsha University of Science and Technology, Wanjiali Road No. 960, 410114, China [email protected] ABSTRACT By employing atmospheric dioxygen as the sole oxidant, an eco-friendly protocol for the clean preparation of various aromatic (cyclic) ketones through phosphinate-promoted oxidation of benzylic Csp3−H bonds under base-, metal-, additive-, organic-solvent free conditions has been developed. Keywords base-free; metal-free; dioxygen; dioxygenation; aromatic ketone

INTRODUCTION (Hetero)aromatic ketones are widely present in natural products, biologically active compounds and artificial drugs.1-4 They also act as useful building blocks and versatile synthetic precursors in organic synthesis and material sciences.5-8 As a consequence, much effort and energy have been dedicated to developing various methodologies for the preparation of such motifs. Among the known protocols, the benzylic Csp3–H bond oxidation reaction is one of the most efficient methods, given the inexpensiveness, abundance and accessibility of alkyl aromatics as industrial materials.9-10 Traditionally, (super)stoichiometric amount of hazardous oxidants (e.g. high valent metal salts, ACS Paragon Plus Environment

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halides and peroxides) were employed for these chemical transformations, generally generating large amounts of chemical waste and unwanted by-products (Scheme 1a).11-17 Therefore, to develop an eco-friendly and general protocol for the oxidation of alkyl (hetero)aromatics using safe and environment friendly oxidants is highly appealing. Compared to conventional inorganic or organic oxidants, molecular oxygen is a perfect oxidant because of its environmental benignancy, low cost and natural abundance.18-39 Over the past decades, significant achievements have been obtained in the oxidation of alkyl aromatics with dioxygen catalyzed by transition metal-ligand complex, uncommercialized metal-supported catalyst, or activated carbon catalyst (Scheme 1b).40-51 Nevertheless, those protocols suffer from limitations of requirement of catalyst, tedious procedures, and meagre substrate generality, and few methods are available for the direct oxidation of heterobenzylic Csp3-H bonds to construct heteroaryl ketones and dioxygenation products. Due to the low threshold of transition-metal residual tolerance for pharmaceuticals, it is highly desirable to synthesize them under transition-metal-free conditions. Recently, Xu, Tan and Wang reported the KOtBu-promoted oxidation of benzylic methylenes to diarylketones with dioxygen under metal-free conditions. Unfortunately, the reaction substrate scope was relatively limited and it only worked with diarylmethanes (Scheme 1c).52 Therefore, developing an eco-friendly and general protocol for the oxidation of alkyl (hetero)aromatics and diarylmethanes using O2 as the sole oxidant would be of great synthetic value in organic chemistry and pharmaceutical industry. In 2012, Xiang’s group reported the Mn(II)/Co(II)/PhP(O)HOnBu co-catalyzed oxidative dimerization of styrenes with dioxygen as the oxidant.53 To the best of our knowledge, there have been no reports of alkyl phenylphosphinate-promoted oxidation of alkyl arenes using O2 as the sole oxidant. In line with our ongoing interest in green chemistry,54-60 herein, we wish to report a eco-friendly protocol for the clean preparation of diverse aromatic ketones through the aerobic oxidation of a series of (hetero)benzylic methylenes with atmospheric dioxygen as the oxidant under metal-, base-, additive- and organic-solvent free conditions (Scheme 1d). This developed ACS Paragon Plus Environment

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catalytic system is general and efficient with remarkable functional-group compatibility even toward 1,4-diacetylbenzene and anthracenedione. Scheme 1. Oxidation of benzylic Csp3–H bonds

(a) (super)stoichiometric amount of harmful oxidants

O

metal salt-oxidants or peroxide-oxidants volatile organic solvent (>100 equiv.) (b) transition-metal catalyzed oxidation with O2

O

metal-complex catalyst, dioxygen volatile organic solvent (>100 equiv.) (c) base-promoted oxidation of diarylmethane with O2

O

strong inorganic base (1-1.5 equiv.) volatile organic solvent (>100 equiv.) (d) Phosphinate-promoted oxidation of arylalkane, diarylmethane

O

dioxygen balloon PhP(O)H(On-octyl) (3 equiv.) oxygen as the sole oxidant base, metal, additive, volatile organic solvent-free tolerance: base-and oxidant-sensitive groups dual role of phosphinate: promoter and reaction media

O

RESULTS AND DISCUSSION Initially, the oxidation of ethylbenzene 1a with atmospheric dioxygen was performed in the presence of 3 equiv. of methyl phenylphosphinate [PhP(O)H(OMe)] at 130 ℃ . To our delight, the expected acetophenone 2a was formed in 32% GC-MS yield (Table 1, entry 1). As anticipated, the oxidation efficiency was found to be strongly dependent on the nature of the promoter (entries 2 - 10). Among all of the promoters analyzed, we found that phenylphosphinate motifs promoted the desired transformation, with n-octyl phenylphosphinate providing the best result (entry 5). Increasing the promoter loading had little influence on the oxidation (entry 11), whereas lower yield was observed when the promoter loading was reduced (entry 12). Replacing dioxygen with air diminished the yield of ACS Paragon Plus Environment


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2a (entry 13). Elevating the reaction temperature did not improve the oxidation outcome (entry 14), whereas decrease in the yield of 2a was detected when the temperature was dropped to 120 ℃ (entry 15). As a blank experiment, no oxidation reaction occurred when the reaction was conducted in the absence of phosphinate promoter (entry 16). Table 1. Optimization of reaction conditionsa

Catalyst O2 balloon, Conditions

Ph

O Ph

1a

Me 2a

Entry

Promoter

Temp.

Yieldb (%)

1

PhP(O)H(OMe) (3 equiv.)

130 ℃

32

2

PhP(O)H(OEt) (3 equiv.)

130 ℃

41

3

PhP(O)H(On-Pr) (3 equiv.)

130 ℃

47

4

PhP(O)H(On-penty) (3 equiv.)

130 ℃

86

5

PhP(O)H(On-octyl) (3 equiv.)

130 ℃

90

6

PhP(O)H(On-decyl) (3 equiv.)

130 ℃

7

PhP(O)(OEt)2 (3 equiv.)

130 ℃

88 N.R.

8

P(OEt)3 (3 equiv.)

130 ℃

N.R.

9

P(O)Et3 (3 equiv.)

130 ℃

N.R.

10

PEt3 (3 equiv.)

130 ℃

N.R.

11


130 ℃

90

12


130 ℃

81

13c


130 ℃

41

14


140 ℃

89

15


120 ℃

80

16

--

130 ℃

N. D.

a

Conditions: 1a (0.3 mmol), promoter, 130℃, O2 balloon, 15h.

b

Yield was determined by GC-MS.

c

Atmospheric air was used instead of O2.

With the optimal reaction conditions in hand (Table 1, entry 5), the substrate scope and limitations of the aerobic oxidation was investigated, where various alkyl aromatics were subjected to the standard conditions and these results were summarized in Table 2. First, ethylbenzenes modified with either electron-rich or electron-poor substituents at the para-position of phenyl ring underwent the oxidation smoothly to afford the expected oxygenation products in good to excellent yields (2a – 2p). Higher ACS Paragon Plus Environment

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steric hindrance of the substituent of ethylbenzene substrate indicated reduced reactivity, hence, a relatively lower yield of oxidation product was obtained (2b vs 2q – 2r). We were pleased to find that the oxidation conditions could tolerate sensitive functional groups, such as base-labile silyl ester group (2f) and oxidizable sensitive aldehyde (2m) groups. In previous reported oxidation reactions, it is hard to construct dioxygenated products because of the electron-withdrawing effect of the carbonyl groups on the monoketones which are less reactive than their dialkyl arene precursors. Pleasingly, the expected double oxidation product (2s) was obtained smoothly in 90% yield under the standard reaction conditions. Both 1-ethylnaphthalene and 2-ethylnaphthalene smoothly underwent the oxidation process to form the products 2t and 2u in 92% and 84% yield, respectively. It should be noted that O-, S-, N-containing heteroaromatic motifs were first applied under the base- and metal-free conditions to yield the desired products (2v – 2x) with good yields. Delightfully, a series of β-substituted alkyl benzenes could be oxidized to generate the desired ketones in good yield. The alkyl chain lengths and isomeric structures did not significantly affect the reaction outcome (2y – 2aa). Furthermore, (haloalkyl)benzenes could be converted exclusively into the desired haloalkylketones (2ab – 2ad). Notably, substituted diarylmethanes were also found to be suitable reaction partners, and the corresponding oxidation products were isolated in good yields (2ae - 2aj). We were pleased to find that various (hetero)aromatic hydrocarbons bearing a methylene moiety in (hetero)cyclic framework underwent oxidation to furnish the aromatic cyclic ketones in good yields (2ak - 2ap), thus further enhancing the reaction scope of the developed transformation. Moreover, the anthracene-9,10-dione (2aq) could be selectively prepared from the readily 9,10-dihydroanthracene raw material. The limitation of the present reaction was also realized. Prolonging the reaction time to 25 h, no double oxidation product was detected in the oxidation of 2,3-dihydro-1H-indene and 1,4-dihydronaphthalene. Treatment of methylbenzene under the optimized reaction conditions could not deliver any oxidation product. When 4-ethylbenzonitrile, 1-ethyl-4-nitrobenzene, 3-ethyl-1H-indole, or 2-ethyl-1H-pyrrole were employed as the substrate, no oxidation reaction occurred. Ethylbenzenes bearing easily oxidized groups, such as methyl sulfide (1ar) and alkene (1as), are not suitable as substrates in the current oxidation reaction. Both the easily oxidized ACS Paragon Plus Environment


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and ethyl groups were oxidized and gave the double oxidation products (2ar and 2s’) in moderate to good yields. Table 2. Reaction Scopea O O2 balloon

R

R


O

1 R = H,

O Me R

2a, 87%

4-Me,

2b, 87%

4-i Pr,

2c, 86%

4-OMe,

2d, 75%

4-OCF3

2e, 71%

4-OTBDMS,

2f,

4-OH,

2g, 82%

4-F,

2h, 85%

4-Cl,

2i,

89%

4-Br,

2j,

88%

4-I,

2k, 86%

4-CF3,

2l,

4-CHO,

2m, 63%

Me

O

73%

R = Et butyl,

O

i-Pr, C2H5Cl, CH2Cl, CH2Br,

R

2ak 81%

Me

Me

2v, 72%

O

N

S

Me

Me

2w, 65%

2x, 72% R = H, Me, OMe, F, Cl Br,

O

2ae, 2af, 2ag, 2ah, 2ai, 2aj,

85% 76% 76% 72% 73% 75%

O

2an, 72%

2am, 80%

O

O

N O 2aq, 61%

2ap, 82%

2ao, 67% O Me

Me

Me

O

O

Me

MeO2S

1ar

Me

O 2u, 84% O

O

O

MeS

2t, 92% O Me O

2y, 78% 2z, 74% 2aa, 65% 2ab, 75% R 2ac, 78% 2ad, 76%

O

Me 2r, 60% O Me

2s, 90% O

2p, 74%

2al, 82%

Me

O

78%

O

O

O

Me 2q, 83%

4-CO2n-octyl, 2n, 77% 2o, 72% 4-NMe2, 4-piperidinyl,

2

O

2ar, 76%

2as

Me 2s', 58%

a

All reactions were carried out in a 5 mL round-bottom flask in the presence of 1 (0.6 mmol), PhP(O)H(On-octyl) (1.8 mmol), O2 balloon, 130 ℃. The reaction time is usually 15h; isolated yields are reported.

To prove the practicality of the developed aerobic oxidation reaction, a scale-up reaction of p-diethylbenzene (1s, 8 mmol) was carried out under the standard reaction conditions (Scheme 2a). ACS Paragon Plus Environment

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Pleasingly, the metal-free oxidation provided the desired p-diacetylbenzene 2s in 89% yield, showing a promising application potential for pharmaceutical industry scale-up. The late-stage structural modification of drugs is an important strategy for pharmaceutical research. Thus, three drug derivatives were submitted to the standard conditions (Scheme 2b). All of them could furnish the corresponding ketones (2at - 2av). Scheme 2. Gram-scale Synthesis and late-stage structural modification Me

(a) Me

PhP(O)H(On-octyl) (3 equiv.) O2 balloon, 130 oC

O

O

Me

Me

2s, 89%, 1.14g

1s, 8 mmol O

(b)

i

PrO2C

O

Me O

Me

Me Me

N Me

O

MeO

Fenofibrate derivative, 2at, 71% N O

CO2Me Indometacin derivative, 2au, 73% O

N O F

O

Me

MeO

Iloperidone, 2av, 65%

Considering that this type of aerobic oxidation of ethylbenzene may involve the α-phenylethanol (3a) intermediate, we attempted to oxidize 3a under standard conditions, and 88% yield of 2a of was detected (Scheme 3a). This result proved that α-phenylethanol is the likely reaction intermediate for the developed oxidation. The addition of radical scavenger (0.1 or 2 equiv. of TEMPO or BHT) to the aerobic oxidation led to no conversion of ethylbenzene, indicating that a radical pathway might be involved in the present oxidation reaction (Scheme 3b). When anhydrous TBHP or H2O2 was applied as the sole oxidant under nitrogen atmosphere, only a trace of acetophenone was observed (Scheme 3c). These results suggested that molecular oxygen played a critical role in the oxidation reaction. By using 18O

2

as the sole oxidant, the oxidation of 1a afforded the

18O-labeled

2a, which confirmed that the

oxygen atom of carbonyl originated from atmospheric dioxygen (Scheme 3d). When the reaction was performed in the presence of 2 equiv. of H218O, no 18O-2a was detected (Scheme 3e). An intermolecular kinetic isotope effect (KIE) of 1.2 was obtained in a 1:1 mixture of ethylbenzene 1a and ACS Paragon Plus Environment


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ethylbenzene-D10 (1a-D10) (Scheme 3f), suggesting that the cleavage of the methylene sp3 C-H bond might not be involved in the rate-limiting step in the present oxidation reaction. Furthermore, the decomposition of n-octyl phenylphosphinate affording phenylphosphinic acid and di-n-octyl phenylphosphonate was observed by using

31P

NMR experiments (Figures S1-2, Supporting

Information). Scheme 3. Control Experiments OH Ph

O

standard conditions

(a)

4h

Me

Ph Me 2a, 88%

3a (b) Ph

(c) Ph

O standard conditions Me radical scavenger (0.1 or 2 equiv.) Me Ph radical scavenger 2a 1a 2a BHT trace TEMPO trace 18

O

PhP(O)H(On-octyl) (3 equiv.) Me Oxidant (2 equiv.) N2 balloon, 130oC 1a 2a Oxidant trace TBHP trace H2O2

Ph

O

Me

H218O (2 equiv.) PhP(O)H(On-octyl) (3 equiv.) O2 balloon, 130oC D

O

Ph Me O-2a, N.D.

D D

Me + D

CD3 D D

1a

18

18

1a

(f) Ph

Ph Me O-2a, M+=122

18

1a (e) Ph

Me

18

PhP(O)H(On-octyl) (3 equiv.) Me 18 O2 balloon, 130oC

(d) Ph

2a

D

standard conditions

2a-H/D

time = 5 h k 1a/k 1a-d10 = 1.2

1a-D10

Based on the above-mentioned observations and previous reports,42,

52

a possible mechanistic

pathway for the developed oxidation reaction was proposed in Scheme 4. Firstly, the phosphorus-centre radical B was generated in situ from the oxidation of alkyl phenylphosphinate A with molecular oxygen. Second, the radical B abstracted a hydrogen atom from the benzylic C–H bond of ethylbenzene 1 to form the radical intermediate C, which was trapped by molecular oxygen to deliver a peroxide radical intermediate D. Then, the intermediate D abstracted a proton from alkyl ACS Paragon Plus Environment

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phenylphosphinate A to yield a molecule of E, which underwent β-H cleavage and elimination of a molecule of water to generate the desired product 2. The compound E may also be converted to the benzyl alcohol F (detected by GC-MS), which was followed by dioxygen oxidation affording the target ketone 2. Scheme 4. Plausible Reaction Mechanism O Ph P OR A O2

R

Me

H OOH

O Ph P OR B

1

A

R

Me C

O

O2 R

O

O

A Me

B

D

R

OH

O

Me

H2O

E

OH R

R

Me

2 [O]

Me F

CONCLUSIONS In conclusion, a facile and eco-friendly protocol for the preparation of various (hetero)aromatic ketones has been developed. In the presence of 3 equiv. of PhP(O)H(On-octyl), 35 examples of (hetero)arylalkyl ketones, 6 examples of diaryl ketones and 7 examples of aromatic cyclic ketones were efficiently prepared with dioxygen as the sole oxidant at 130℃ under metal-, base-, additiveand organic solvent-free conditions. The principal advantages of this process are outlined as follows: (a) the abundance and easy accessibility of raw materials; (b) water as the sole side-product; (c) phosphinate has a dual role: promoter and reaction medium; (d) the oxidation reaction proceeded with excellent functional-group tolerance, as proved by the fact that base- and oxidant-sensitive groups were intact under the optimal reaction conditions and easy construction of dioxygenation products; (e) the present oxidation reaction could be easily scaled up; (f) the general and metal-free oxidation reaction allow for the produce of pharmaceutical and bioactive polycyclic aromatic ketones, xanthenone and dihydroquinolinone from easily available starting materials. The ACS Paragon Plus Environment


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cleanness and simplicity of the present reaction will make it attractive in the area of pharmaceutical industry.

EXPERIMENTAL SECTION General procedure for the synthesis of ketones 2 A mixture of ethylbenzene 1 (0.6 mmol) and n-octyl phenylphosphinate (457 mg, 1.8 mmol) was added to a 5 mL round-bottom flask with an O2 balloon at room temperature, then the contents were stirred at 130 ℃ . The reaction typically took 15 hours. The progress of the reaction was monitored by TLC or GC-MS. Upon completion, the reaction was cooled down to room temperature. The resultant residue was purified by silica gel column chromatography to afford the desired product 2.

ACKNOWLEDGMENT We are grateful for financial support from the Hunan Provincial Natural Science Foundation of China (No. 2019JJ40090 and 2019JJ20008).

Supporting Information: 1H

and

13C

NMR spectra of compounds 2. This material is available free of charge via the Internet at

http://pubs.acs.org.

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Table of Contents Graphic By employing atmospheric dioxygen as the sole oxidant, a base-, metal-, additive-, organic-solvent free protocol for the clean preparation of various (hetero)aromatic (cyclic) ketones through phosphinate-promoted oxidation of (hetero)benzylic Csp3–H bonds was developed. O O2 balloon PhP(O)H(On-octyl) (3 equiv.)

48 Examples; 58-92% Yields; Large-scale synthesis O Oxygen as the sole oxidant Base, Metal, volatile organic solvent-free Tolerance: base-and oxidant-sensitive groups Dual role of Phosphinate: Promoter and Reaction Medium


Clean oxidation of (hetero)benzylic Csp3-H bonds with molecular

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