Oxidative α-C-C Bond Cleavage of 2° and 3° Alcohols to Aromatic Acids with O2at Room Temperature via Iron Photocatalysis

Acids with O at Room Temperature via Iron Photocatalysis

Letter

Oxidative α‑C−C Bond Cleavage of 2° and 3° Alcohols to Aromatic

Zongnan Zhang, Guoxiang Zhang, Ni Xiong, Ting Xue, Junjie Zhang, Lu Bai, Qinyue Guo,*

and Rong Zeng *

Cite This: Org. Lett. 2021, 23, 2915 −2920

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sı Supporting Information

ABSTRACT: The selective α-C−C bond cleavage of unfunctionalized

secondary (2°) and tertiary alcohols (3°) is essential for valorization of

macromolecules and biopolymers. We developed a blue-light-driven iron

catalysis for aerobic oxidation of 2° and 3° alcohols to acids via α-C−C

bond cleavages at room temperature. The ﬁrst example of oxygenation of

the simple tertiary alcohols was reported. The iron catalyst and blue light

play critical roles to enable the formation of highly reactive O radicals

from alcohols and the consequent two α-C−C bond cleavages.

he catalytic and selective α-C−C bond cleavage of

unfunctionalized secondary and tertiary alcohol has

drawn chemists’ signiﬁcant attention and attracted signiﬁcant

research eﬀorts in recent years. These deconstruction-and-

functionalization protocols provide novel, imperative, and

practical strategies to build useful organic frameworks and also

show great potential for degradation and valorization of

macromolecules and biopolymers such as epoxy resins,

cellulose, and native lignin by selective fragmentation (Figure

a). The direct oxidation of secondary and tertiary alcohols to

carboxylic acids through oxidative C−C bond cleavage using

molecular oxygen (O ) is considered a green and attractive

process. However, while oxidative transformations of the

primary alcohol using O catalyzed by transition metals such as

Pd(II), Pt(II), Au(I), Ag(I), Co(II), and Fe(III)

have been well-reported (Figure 1b, path a), the corresponding

oxidations of the simple secondary/tertiary alcohols remain

challenging and highly required.

In 2012, the Tokunaga group reported the examples of

oxidation of 1-aryl-ethanols to substituted benzoic acid using t-

BuONO as oxidant. The yields are low even using excess

amount of oxidant. The reactions are initiated by α-C−H

oxidation and followed subsequently by ketone oxidation.

Later, O was introduced as a clean and green oxidant by the

Wang, Li, and Han groups, respectively, using Cu(OAc)₂,

Figure 1. (a) Alcohols in macromolecules and biopolymers. (b)

−

Fe(NO ) /I , or NO as catalysts. While eﬃcient, these

Alcohol oxidation to carboxylic acid under O . (c) Strategy and

processes of oxidation of tertiary alcohols.

reactions all required high temperature (110−130 °C) and are

extremely limited to secondary alcohols (Figure 1b, path b).

An intriguing question is whether simple tertiary alcohols can

Received: February 16, 2021

Published: March 26, 2021

be oxidized to form carboxylic acids by O through breaking

two C−C bonds which, to the best of our knowledge, has not

been explored previously. Herein, we describe an inexpensive

and green catalytic aerobic oxidation of simple tertiary alcohols

under mild conditions. Catalyzed by Fe/blue light, this

reaction proceeds at room temperature (rt) and provides a

2021 American Chemical Society

915

Org. Lett. 2021, 23, 2915−2920

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Letter

distinct and unique strategy to synthesize various substituted

benzoic acids through two C−C bonds cleavages (Figure 1b,

path c).

Table 1. Control Experiments

To enable the formation of benzoic acid, taking 1-phenyl-

cyclohexanol 1a as an example, two unreactive C(sp )−

C(OH) single bonds are broken selectively in one oxidation

protocol, while the C(sp )−C(OH) cleavage must remain.

One key concern is the control of selectivity and reactivity.

entry

change from standard conditions

yield of 2a

Given that direct C(sp )−C(OH) cleavage of tertiary alcohols

none

w/o CeCl₃

w/o FeCl₃

72, (73)

−, (45)

under basic conditions or with a transition metal via β-carbon

elimination is known to be eﬃcient (path i, Figure 1c), we

hypothesize that, through the development of a catalytically

highly reactive radical protocol, a selectively catalytic oxidation

no LED

no LED, w/o CeCl₃

w/o TBACl

air instead of O₂

of tertiary alcohol can be achieved under O atmosphere.

Over the past decade, visible-light-promoted catalysis has

emerged as a powerful tool to enable the formation of

heteroatom-centered radicals, providing a prominent platform

for the development of novel transformation in organic

Ce(OTf) instead of CeCl₃

(Bu N) CeCl instead of CeCl

Fe(acac) instead of FeCl₃

synthesis. Encouraged by elegant works by the Zuo group

Fe(OTf) instead of FeCl₃

on photoinduced Ce−O bond homolysis to O radical via

Fe(NO ) ·9H O instead of FeCl

3 3 2 3

Fe (SO ) instead of FeCl

2 4 3 3

9a−e

ligand-to-metal charge transfer (LMCT),

the inexpensive

and readily available ferric compounds under irradiation was

proposed to oﬀer facile and eﬃcient access for the generation

of versatile alkoxy radicals from alcohols, promote α-C−C

FeCl instead of FeCl₃

6 mol % of FeCl instead of 10 mol %

PhH instead of MeCN

THF instead of MeCN

−11

cleavage by homolytic β-scission,

and then oxidize the

formed ketone to acid (path ii, Figure 1c). This has been

shown to be true. After screening (Table 1), the reaction of

MeNO

acetone instead of MeCN

FeCl ·6H O and CeCl ·7H O were used

instead of MeCN

tertiary alcohol 1a in the presence of 10 mol % FeCl and 5

^m^o^l^%^T^B^A^C^lⁱⁿ^M^e^C^N^u^sⁱⁿ^g^a^b^l^u^e^L^E^D⁽³⁹⁰ⁿ^m⁾^uⁿ^d^e^r^O2

atmosphere at rt indeed happened smoothly and showed

superior selectivity to isolate the benzoic acid 2a in 45% yields

The standard reactions were conducted with 1a (0.2 mmol), FeCl

(10 mol %), TBACl (5 mol %), CeCl (2 mol %), and MeCN (1 mL)

in a 20 mL Schlenk tube with 390 nm LED photoirradiation under 1

atm of O at rt. All yields were determined by GC using standard

calibration curves with decane as the internal standard. The yield in

the parentheses is based on isolation. >95% of 1a was recovered. 7%

of 1a was recovered. 27% of 1a was recovered.

(

entry 2). This is the ﬁrst example on Fe/visible-light-induced

radical-based unreactive C−C bond cleavage. While no

byproduct was isolated, dimethyl glutarate was observed on

GC-MS after treating with an excess amount of TMSCHN ,

indicating that two C(sp )−C(OH) single bonds of 1a were

broken. Interestingly, while CeCl₃failed to catalyze the

a−e,12

formation of benzoic acid solely (entry 3), CeCl

substituent (4-PhO, 2b) or an electron-withdrawing group

such as 4-F (2d), 4-CF (2f), or 4-CN (2g) were employed.

could be used as a cocatalyst to increase the yields of GC

and isolate compound to 72 and 73%, respectively (entry 1).

The control experiments were subsequently conducted (Table

While carbon−halogen bonds were tolerated (2e and 2i),

electron-withdrawing groups showed higher reactivity than the

electron-donating groups. The reactions of 3- or 4-phenyl

substituted tertiary alcohols occurred to give 2h, 2k, and 2l in

moderate yields. Using 4-MeO-phenyl cyclohexanol 1c as the

starting material, the 4-(formyloxy)-benzoic acid 2c was

obtained as the only product in 38% yield. The terephthalic

acid derivative 3o was able to be obtained from the

corresponding bis-tert-alcohol through oxidation and then

). Less than 5% of the starting material was consumed in the

absence of blue LED, proving the essential role of light (entries

and 5). While the reaction without TBACl aﬀorded 59% of

the product, the use of air atmosphere instead of O gave

only 42% (entries 6 and 7). Other cerium and ferric catalysts

such as Ce(OTf) , (Bu N) CeCl , Fe(acac) , Fe(OTf) ,

Fe(NO ) ·9H O, and Fe (SO ) showed lower eﬃciency,

4 3

aﬀording 2a in 47−64% yields (entries 8−13). Notably, the

methylation with TMSCHN . Moreover, heteroaryl groups,

use of ferrous compound FeCl was able to result in 2a in 63%

such as pyridinyl (2p), dibenzo[b,d]furanyl (3q), and

dibenzo[b,d]thiophenyl groups (3r) could be tolerated.

The reaction of 1-(naththalen-2-yl)-cyclohexanol 1s or 1-

(naththalen-1-yl)-cyclohexanol 1t under the standard con-

ditions did not observe the naphthoic acid, but the

naphthalene ring was nevertheless oxidized, and phthalic

anhydride 4 was isolated in 53 and 73% yields, respectively.

Moreover, the anthracene ring of 1u could be oxidized, and the

corresponding dioxo product 3u was isolated in 23% yield.

Moreover, 1-(phenylethynyl)-cyclohexanol 1v was oxidized to

benzoic acid 2a in 74% yield. Aliphatic alcohol was

decomposed under the standard conditions. Notably, the

reaction could be scaled up to 1 mmol of 1a to aﬀord 2a in

65% yield, showing potential for application.

yield under oxidative conditions (entry 14). Lowering the

catalyst loading of FeCl to 6 mol % showed lower eﬃciency,

aﬀording 2a in only 57% yield (entry 15). Solvent eﬀect was

also surveyed: while benzene and THF completely decom-

posed the starting material (entries 16 and 17), MeNO and

acetone proved to have low eﬀectiveness, obtaining 2a in 31

and 21% yields, respectively (entries 18 and 19). Interestingly,

the hydrated catalysts FeCl ·6H O and CeCl ·7H O could be

used, leading to only slightly lower yield (entry 20).

The reaction scope was ﬁrst tested using diﬀerent 1-aryl-

cyclohexanols 1 (Table 2). Gratifyingly, moderate to excellent

yields were generally obtained. The reactions proceeded

smoothly when substrates bearing either an electron-donating

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Org. Lett. 2021, 23, 2915−2920

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Letter

Table 2. Synthesis of Aryl Acids from 1-Aryl-Cyclohexanols

Table 3. Synthesis of Benzoic Acids from Alcohols 1

3% of benzophenone was isolated. 69% of phthalic anhydride was

c d

obtained. 26% of acetophenone was isolated. 27% of acetophenone

was isolated.

The yields are calculated after isolation. The reaction was

conducted in 1 mmol scale. 4-MeO-phenyl-cyclohexanol 1c was

used as starting material. The ﬁnal product was treated with

TMSCHN in MeOH.

The scope of the diﬀerent gem-disubstituted benzylic

alcohols was next investigated (Table 3). The reactions all

worked equally well to aﬀord 2a in moderate yields. Compared

to acyclic substrates, the cyclic alcohols observed a higher

reactivity (1aa−1ad vs 1ae−1ag). Interestingly, while 1,2,3-

triphenylpropan-2-ol 1ah was used, an eﬃcient deep oxidation

of the formed fragments was observed to form benzoic acid 2a

in 72% theoretical yield. This deep oxidation was further

conﬁrmed by the reaction of 1ai, while 69% of phthalic

anhydride 4 was obtained as a side product. The reaction of

,1-diphenyl-ethanol 1aj gave only 20% of benzoic acid, while

2% of benzophenone was isolated. Bis-tert-alcohol 1ak and

al were transformed to 52 and 49% of benzoic acid together

Figure 2. (a) Radical-captured experiments. (b) Ketone oxidation.

with 26 and 27% of acetophenone, respectively. Moreover, not

surprisingly, these catalytic conditions were further found to be

compatible with secondary (1am, 1da, and 1ea) and primary

alcohols (1an, 1db, and 1eb), proving this method to be a

powerful tool for the oxidation of all the 1°, 2°, and 3°

alcohols.

To probe the catalytic pathways, controlled experiments

were then conducted. First, the UV−vis absorption showed

iron compounds could be excited by the blue light. Second,

the oxidation of 1a under standard conditions was monitored

by FT-IR, indicating that a carbonyl-group-containing

intermediate 5 was detected to be generated and subsequently

the reaction using CeCl as the sole catalyst obtained no

product, a C−C bond cleavage product 5a was isolated when

using FeCl as catalyst in 46% yield, indicating that a C-radical

intermediate Int 2, which was generated from β-scission of O

radical intermediate Int 1, was involved during the catalytic

protocol. In addition, the reaction using both FeCl and CeCl

aﬀorded 5a in 68% yield, presenting a higher reactivity over the

use of sole FeCl₃.

Consequently, the control experiments on ketone oxidation

16,17

were examined (Figure 2b).

FeCl /blue light were proven

to be an eﬃcient photoinduced system to enable the oxidation

of the ketones 5b−5e with diﬀerent functional groups such as

OH, OOH, or COOH. No reaction happened using

benzophenone/2,2,2-triﬂuoro-1-phenylethanone, indicating

the crucial role of the α-H of the ketones.

consumed to acid during the reaction. Moreover, while the

pure intermediate 5 was hard to isolate and characterize, the

radical-captured experiments were set up by treating 1a with

.0 equiv of TEMPO under Ar (Figure 2a). Interestingly, while

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Org. Lett. 2021, 23, 2915−2920

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as depicted in Figure 3 . The ﬁrst step of the transformation

Letter

Based on the evidence, a plausible mechanism is proposed,

and the consequent two α-C−C bond cleavages, oﬀering new

opportunities for the development of visible light photo-

induced transformation.

ASSOCIATED CONTENT

■

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.orglett.1c00556.

Experimental procedure and spectroscopic data for all

compounds (PDF )

AUTHOR INFORMATION

■

Corresponding Authors

Figure 3. Plausible mechanism.

Qinyue Guo − School of Chemistry, the First Aﬃliated

Hospital of XJTU, MOE Key Laboratory for Nonequilibrium

Synthesis and Modulation of Condensed Matter, Xi’an Key

Laboratory of Sustainable Energy Materials Chemistry, Xi’an

Jiaotong University (XJTU), Xi’an 710049, P.R. China;

Email: guoqinyue@163.com

Rong Zeng − School of Chemistry, the First Aﬃliated Hospital

of XJTU, MOE Key Laboratory for Nonequilibrium Synthesis

and Modulation of Condensed Matter, Xi’an Key Laboratory

of Sustainable Energy Materials Chemistry, Xi’an Jiaotong

University (XJTU), Xi ’an 710049, P.R. China; orcid.org/

0000-0002-2728-7502 ; Email: rongzeng@xjtu.edu.cn

_s_h_o_u_l_d_b_e_a_b_l_u_e_-_l_i_g_h_t_-_i_n_d_u_c_e_d_L_M_C_Ta−e,18 via Fe-alkoxide

and Ce-alkoxide intermediates to generate O radical Int 1 from

the tertiary alcohol 1a. The use of a Ce compound can increase

the reactivity by enhancing the eﬃciency of the LMCT.

Consequently, while an eﬃcient β-scission and radical quench

occur to cleave the ﬁrst C−C single bond of 1a and aﬀord a

ketone intermediate 5, a single electron transfer between

dioxygen and the formed Fe(II) occurred to regenerate Fe(III)

−

and superoxide anion radical (O · ), which is reactive for the

consequent ketone oxidation through α-oxidative functional-

6,17

ization.

Blue light is crucial for both C−C bond cleavages.

The fragment generated from tertiary alcohol was ﬁnally

Authors

oxidized to glutaric acid, whose methylation product with

Zongnan Zhang − School of Chemistry, the First Aﬃliated

Hospital of XJTU, MOE Key Laboratory for Nonequilibrium

Synthesis and Modulation of Condensed Matter, Xi’an Key

Laboratory of Sustainable Energy Materials Chemistry, Xi’an

Jiaotong University (XJTU), Xi’an 710049, P.R. China

Guoxiang Zhang − School of Chemistry, the First Aﬃliated

Hospital of XJTU, MOE Key Laboratory for Nonequilibrium

Synthesis and Modulation of Condensed Matter, Xi’an Key

Laboratory of Sustainable Energy Materials Chemistry, Xi’an

Jiaotong University (XJTU), Xi’an 710049, P.R. China

Ni Xiong − School of Chemistry, the First Aﬃliated Hospital of

XJTU, MOE Key Laboratory for Nonequilibrium Synthesis

and Modulation of Condensed Matter, Xi’an Key Laboratory

of Sustainable Energy Materials Chemistry, Xi’an Jiaotong

University (XJTU), Xi’an 710049, P.R. China

TMSCHN could be observed on GC-MS. A more in-depth

mechanistic study is still ongoing.

In addition, the synthetic potentials of this reaction were

explored: ﬁrst, when the mixture of 1°, 2°, and 3° alcohols (1a,

1am, and 1an) was subjected to the standard conditions, the

reaction worked well to obtain benzoic acid 2a as a single

product in 72% yield, oﬀering a practical process for isolation-

needless upgrading of alcohol mixtures (eq 1 ). Moreover, as a

Ting Xue − School of Chemistry, the First Aﬃliated Hospital

of XJTU, MOE Key Laboratory for Nonequilibrium Synthesis

and Modulation of Condensed Matter, Xi’an Key Laboratory

of Sustainable Energy Materials Chemistry, Xi’an Jiaotong

University (XJTU), Xi’an 710049, P.R. China

Junjie Zhang − School of Chemistry, the First Aﬃliated

Hospital of XJTU, MOE Key Laboratory for Nonequilibrium

Synthesis and Modulation of Condensed Matter, Xi’an Key

Laboratory of Sustainable Energy Materials Chemistry, Xi’an

Jiaotong University (XJTU), Xi’an 710049, P.R. China

Lu Bai − Instrument Analysis Center of XJTU, Xi’an Jiaotong

University (XJTU), Xi’an 710049, P.R. China

model reaction for lignin valorization, the reaction of 2-

phenoxy-1-phenylethanol 1ao with O was examined under

standard conditions; gladly, the reaction proceeded smoothly

and aﬀorded benzoic acid 2a and phenyl formate 6 in 84 and

2% yields, respectively, showing potential for use in the lignin

2,19

industry (eq 2).

In summary, we developed a highly reactive Fe/photo-

catalysis for aerobic oxidation of 1°, 2°, and 3° alcohols to

aromatic acids under mild conditions. This radical-based

protocol provides a green and eﬃcient method for selective α-

C−C bond cleavage of the simple secondary and tertiary

alcohols, showing great potentials for depolymerization and

valorization of macromolecules and biopolymers. The photo-

induced LMCT process involving Fe(III) alkoxide was

proposed to enable the formation of highly reactive O radicals

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.1c00556

Notes

The authors declare no competing ﬁnancial interest.

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Organic Letters

S.; Ishii, Y. Efficient Oxidation of Alcohols to Carbonyl Compounds

Letter

Acids, and Imines Catalyzed by a Ag-NHC Complex. Org. Lett. 2014,

6, 3428−3431. (e) Iwahama, T.; Yoshino, Y.; Keitoku, T.; Sakaguchi,

ACKNOWLEDGMENTS

■

R.Z. and Q.G. are grateful for the ﬁnancial support from the

National Natural Science Foundation of China (Grant

1901197), the Natural Science Basic Research Plan in

Shaanxi Province of China (Grants 2019JM093 and S2018-

JC-YB-1708), and the startup funds from Xi’an Jiaotong

University (XJTU). Prof. Dr. Bin Yang from the School of

Chemistry at XJTU is acknowledged for proofreading the

manuscript. We thank the Instrument Analysis Center of XJTU

for assistance with HRMS analysis.

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