Palladium-catalyzed aerobic synthesis of: Ortho -substituted phenols from cyclohexanones and primary alcohols

Article abstract of DOI:10.1039/c9cc09347h

Due to the importance of phenols as structural cores and precursors of chemical products, synthesis of site-specific substituted phenols is highly desirable and a significant challenge. An aerobic palladium-catalyzed site-specific synthesis of ortho-substituted phenols from cyclohexanones and primary alcohols via an oxidation/aldol/dehydration/aromatization process has been developed. Various substituted cyclohexanones and primary alcohols are successfully transformed into ortho-substituted phenols. In addition, this catalytic reaction uses air as the terminal oxidant and generates water as the sole by-product. Furthermore, the method can also be extended to polyhydroxyl substituted substrates with high chemoselectivity between primary and secondary alcohols. This method provides a greener tool for synthesizing primary alkyl ortho-substituted phenols.

Full text of DOI:10.1039/c9cc09347h

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Palladium-catalyzed aerobic synthesis of ortho-
substituted phenols from cyclohexanones and
Cite this:DOI: 10.1039/c9cc09347h
primary alcohols†
Huiying Zeng, *a Jianjin Yua and Chao-Jun Li
Received 2nd December 2019,
Accepted 16th December 2019
b
*
DOI: 10.1039/c9cc09347h
rsc.li/chemcomm
Due to the importance of phenols as structural cores and precursors of
chemical products, synthesis of site-specific substituted phenols is highly
desirable and a significant challenge. An aerobic palladium-catalyzed
site-specific synthesis of ortho-substituted phenols from cyclohexa-
nones and primary alcohols via an oxidation/aldol/dehydration/
aromatization process has been developed. Various substituted
cyclohexanones and primary alcohols are successfully transformed
into ortho-substituted phenols. In addition, this catalytic reaction uses
air as the terminal oxidant and generates water as the sole by-product.
Furthermore, the method can also be extended to polyhydroxyl
substituted substrates with high chemoselectivity between primary
and secondary alcohols. This method provides a greener tool for
synthesizing primary alkyl ortho-substituted phenols.
Phenols are common structural motifs and precursors of fine
chemicals, such as pharmaceuticals and polymers. Functionaliza-
tion of phenols at specific sites around the aromatic ring represents
a key synthetic challenge.1 The classical approaches to the synthesis
of substituted phenols are via electrophilic aromatic substitutions
of phenol.2 However, strong electronically directing effects by the
hydroxyl group of phenol associated with these reactions result in
mixture of ortho- and para-substituted derivatives, which greatly
affects the efficiency of synthesis and isolation.3 Therefore, exten-
sive efforts were made to develop new methods to synthesize
substituted phenols, e.g. via C–H oxidation to introduce a hydroxyl
group into an aromatic ring4 and transition-metal-catalyzed alkyla- Scheme 1 Strategies for converting cyclohexanone and cyclohexenone
tion of phenols etc.5 Recently, a new methodology of synthesizing
into substituted arenes and phenols.
substituted phenols via aerobic dehydrogenation of substituted
cyclohexanones was pioneered by Stahl (Scheme 1a).6 More
recently, cyclohexanone or cyclohexenone were reacted with anilines,9 indoles,10 sulfonamides,11 nitroarenes12 and Grignard
different nucleophilic reagents, such as alcohols,7 amines,8 reagents,13 followed by dehydrogenation aromatization to synthe-
size 1-substituted arenes (Scheme 1b). To synthesize 3-substituted
a The State Key Laboratory of Applied Organic Chemistry, Lanzhou University, 222
Tianshui Road, Lanzhou, 730000, P. R. China. E-mail: zenghy@lzu.edu.cn
b Department of Chemistry and FQRNT Centre for Green Chemistry and Catalysis,
McGill University, 801 Sherbrooke St. West, Montreal, Quebec H3A 0B8, Canada.
E-mail: cj.li@mcgill.ca
phenols, a Heck reaction of cyclohexenone with boronic acid
followed by oxidative dehydrogenation was also achieved by the
Stahl group (Scheme 1c).14
As primary alcohols are usually very cheap and abundant
commercially available organic chemicals. Thus, it is highly
desirable to explore methods that can directly react primary
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c9cc09347h
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Table 1 Evaluation of various conditionsa
alcohols with cyclohexanone to generate alpha-substituted phenols.
Strong Lewis acids or Brønsted acids can active the C–OH bond of
alcohols to form carbocation, which can undergo nucleophilic
attack by phenols and serves as alkylation reagent.15 However,
there are still two problems for this reaction: (1) due to the easy
rearrangement of primary carbocation to form the more stable
secondary carbocation, secondary-alkyl substituted phenols are
generally obtained; and (2) ortho- and para-substituted phenols
are generated as a mixture with lower regioselectivity. We
envisioned that primary alcohols can undergo oxidative dehydro-
genation to form aldehydes, which can undergo an aldol-type
reaction with cyclohexanone. Then facile dehydration generates
a,b-unsaturated ketone, which renders the C–OH bond much
more easy to cleave than the C–OH bond of primary alcohols.
Finally, oxidative aromatization forms the ortho-substituted
phenols (Scheme 1d). This strategy can efficiently avoid the
competing para-substituted phenol byproduct. Herein, we report
the aerobic palladium-catalyzed site-specific synthesis of ortho-
substituted phenols from cyclohexanones with primary alcohols
via C–O cleavage and dehydrogenative aromatization.
Entry
Catalyst
Additive
Solvent
T/1C
3ab/[%]
1
2
3
4
5
6
7
8
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/Al2O3
Pd(OH)2/C
Pd(OAc)2
PdCl2
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
t-BuOLi
NaOH
NaH
LiOH
DBU
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Heptane
DMSO
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
150
140
160
170
160
160
160
160
68
35
40
57
n.p.
n.p.
26
TFA
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
t-BuOLi
52
9
n.p.
n.p.
25
60
61
n.p.
n.p.
42
50
65
65
55
75
75
75
27
60
75(70)
10
11c
12d
13
14
15
16e
17f
18g
19h
20
21
22
23i
24j
25i,k
26i,l
H2O
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
We commenced our investigation by examining different bases
to couple cyclohexanone with 1-hexanol (Table 1, entries 1–5).
Fortunately, the highest yield (68%) of 2-hexylphenol was detected
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
Pd/C
1
by H NMR when Pd/C was used as catalyst in toluene at 150 1C
under an air atmosphere for 12 h using lithium tert-butoxide
(12.5 mol%) as base (Table 1, entry 1). Other inorganic bases were
also examined with lower efficiency (Table 1, entries 2–4). When
organic base (DBU) or acid (TFA) was used, no product was
detected (Table 1, entries 5 and 6). Different palladium catalysts
were then examined (Table 1, entries 7–10), and lower yields were
obtained when palladium supported on Al2O3 or Pd(OH)2/C was
used (Table 1, entries 7 and 8). However, negative results were
obtained when Pd(OAc)2 or PdCl2 was used as catalyst (Table 1,
entries 9 and 10). Increasing or reducing the amount of lithium
tert-butoxide led to lower yields (Table 1, entries 11 and 12). Less
polar solvent (heptane) gave a lower yield (Table 1, entry 13). No
a
Reaction conditions: cyclohexanone 1a (0.3 mmol), 1-hexanol 2a
(0.2 mmol), [Pd] (10 mol%), additive (12.5 mol%) and solvent (1.0 mL)
b
at 150 1C for 12 h under an air atmosphere. Yields were determined by
1H NMR with nitromethane as internal standard; yields of isolated
c
d
products were given in parentheses. t-BuOLi (6.25 mol%). t-BuOLi
e
(25 mol%). The reaction was performed under an argon atmosphere.
f
g
The reaction was performed under O2 atmosphere. Cyclohexanone
h
i
j
(0.2 mol). Cyclohexanone (0.4 mol). Pd/C (7 mol%). Pd/C (15 mol%).
k
l
For 5 h. For 24 h.
product was detected when more polar solvent (DMSO or H2O) was primary alcohols at 160 1C under air atmosphere using 7 mol% of
used (Table 1, entries 14 and 15). When this reaction was Pd/C as catalyst and 12.5 mol% of lithium tert-butoxide as base in
performed under an argon atmosphere, the yield is lowered to toluene (1.0 mL) for 24 h. As shown in Table 2, various ortho-
42% (Table 1, entry 16). However, a lower yield (50%) was also alkylation of phenols were obtained with moderate to high yields
obtained when this reaction was performed under oxygen atmo- (Table 2, 3a–p). Both cyclohexanone and cyclohexenone reacted very
sphere (Table 1, entry 17). 1.5 equiv. of cyclohexanone appeared to well with 1-hexanol, to give the same 2-hexylphenol product in high
be optimal for this reaction, as either higher or lower amount of yields (Table 2, 3a). When alcohol was used as solvent, 2-ethylphenol
cyclohexanone resulted in lower yields (Table 1, entries 18 and 19). was formed in moderate yield (Table 2, 3b). With the increasing in
Reducing the reaction temperature to 140 1C gave 55% yield of chain length, the yields of the corresponding ortho-alkylated phenols
product (Table 1, entry 20). In contrast, increasing the temperature were formed with good yields (Table 2, 3c–d). Even though benzyl
to 160 1C improved the yield to 75% (Table 1, entry 21). Further alcohol can be reduced to toluene readily with palladium catalysis
increasing the temperature to 170 1C almost gave the same yield under reductive conditions, 2-benzylphenol was also obtained in
(Table 1, entry 22). A similar yield was obtained when we reduced moderate yield under standard conditions (Table 2, 3e). 3-Phenyl-
the catalyst loading to 7 mol% (Table 1, entry 23). On the other propanol and 4-phenylbutanol were also successfully coupled with
hand, increasing the catalyst loading to 15 mol% gave lowered yield cyclohexanone in good yields (Table 2, 3f–g). Alcohol chain bearing
(Table 1, entry 24). Reducing the reaction time to 5 h lowered the terminal substituents, such as tert-butyl, cyclohexyl and adamantanyl,
product yield (Table 1, entry 25). A 75% yield was obtained when did not adversely affect this transformation and moderate to
prolonging the reaction time to 24 h (Table 1, entry 26).
good yields were obtained (Table 2, 3h–j). The primary alcohol
With the optimized reaction conditions in hand, we next terminal substituted by a heterocycle, such as indole, benzo-
proceeded to explore cyclohexanone (1a) to react with different furan and thiophene, were also effective, giving moderate to
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Table 2 Cross-coupling of cyclohexanone with different primary alcoholsa
Table 3 Cross-coupling of 1-hexanol with different cyclohexanonesa
a
Reaction conditions: cyclohexanone 1 (0.3 mmol), 1-hexanol 2a
(0.2 mmol), Pd/C (7 mol%), t-BuOLi (12.5 mol%) in toluene (1.0 mL)
b
at 160 1C for 24 h under an air atmosphere. 3-methylcyclohexenone
c
(0.3 mmol) was used as starting material. 1-Tetralone (0.2 mmol) and
d
1-hexanol (0.3 mmol) were used as starting materials. 1,2,3,4-
tetrahydrocarbazol-4-one (0.2 mmol) and 1-hexanol (0.3 mmol) were
used as starting materials.
We subsequently proceeded to investigate the generality of
this system with different substituted cyclohexanones (Table 3).
A methyl group substituted at different positions (a-, b-, g-) had
no effect on this transformation, with moderate to good yields
being obtained (Table 3, 3q–s). When 3-methylcyclohexenone
was used as a substrate, the corresponding product 3r was
obtained in moderate yield (Table 3, 3r). With phenyl and tert-
butyl groups substituted at the C-4 position, the corresponding
phenol products were generated with moderate yields (Table 3,
3t and 3u). 1-Tetralone also successfully reacted with 1-hexanol,
to give 80% yield of 2-hexylnaphthalen-1-ol (3v) (Table 3, 3v).
When 1,2,3,4-tetrahydrocarbazol-4-one bearing a free amine was
used as substrates, the corresponding product 3w was formed
with good yield (Table 3, 3w), and no competing N-alkylation
byproduct was formed.16
a
To investigate the reaction mechanism, control experiments
were carried out (Scheme 2). Considering the difficulty to cleave
C–O bond of alcohol directly under our catalytic system, it is
Reaction conditions: cyclohexanone 1a (0.3 mmol), alcohol 2 (0.2 mmol),
Pd/C (7 mol%), t-BuOLi (12.5 mol%) in toluene (1.0 mL) at 160 1C for 24 h
under an air atmosphere. Cyclohexenone (0.2 mmol) and 1-hexanol
(0.3 mmol) were used as starting materials. Ethanol was used as solvent
(1.0 mL). Citronellol (0.2 mmol) was used as starting material.
b
c
d
good yields (Table 2, 3k–m). Citronellol reacted smoothly in good
yield; however, the double bond was also reduced under stan-
dard conditions (Table 2, 3n). It is noteworthy that a free
secondary alcohol group was also tolerated in this system, in
which selective primary C–OH bond cleavage was achieved and
the corresponding product 3o was obtained in good yield
(Table 2, 3o). Interestingly, cholic acid derivative, polyhydroxyl
steroid, was also successfully cross-coupled with cyclohexanone
in good yield, in which three free secondary hydroxyl groups
were not affected in this transformation (Table 2, 3p).
Scheme 2 Control experiments.
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Dr Zemin Wang (Lanzhou University) in this group for reproducing
the compound 3a in Table 2 and 3v in Table 3.
Conflicts of interest
There are no conflicts to declare.
Notes and references
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under our catalytic system, and the corresponding product was
obtained in 64% yield (Scheme 2b).
´
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oxidized by air catalyzed by palladium to form aldehyde B.
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ketone E is isomerized to endocyclic double bond to generate
ketone F, which tautomerizes to enol G. Finally, enol G under-
goes oxidative aromatization to give the product phenol H.6d,8e,g
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cyclohexanones and primary alcohols via a tandem oxidation/
aldol/dehydration/dehydrogenation process. Various primary
alkyl ortho-substituted phenols were generated by cross-coupling
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