Nickel-catalysed C–O bond reduction of 2,4,6-triaryloxy-1,3,5-triazines in 2-methyltetrahydrofuran

Article abstract of DOI:10.1016/j.cclet.2018.09.009

A nickel-catalysed reduction of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine (TCT) in ecofriendly 2-methyltetrahydrofuran (2-MeTHF) is described. The phenol-TCT derivatives were readily prepared using grinding method in short time without further purification. This catalytic system allowed the facile C–O cleavage of phenol-TCT derivatives under mild reaction conditions with high efficiency and good functional group tolerance. Gram-scale reaction was also achieved. Particularly, sequential functionalization of phenol-TCT derivatives followed by C–O bond reduction could also be realized, affording the high value-added products in moderate to good yields.

Full text of DOI:10.1016/j.cclet.2018.09.009

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Title: Nickel-catalysed C<ce:glyph name="sbnd"/>O bond
reduction of 2,4,6-triaryloxy-1,3,5-triazines in
2-methyltetrahydrofuran
Authors: Yaoyao Wang, Jun Shen, Qun Chen, Liang Wang,
Mingyang He
PII:
DOI:
Reference:
S1001-8417(18)30357-7
https://doi.org/10.1016/j.cclet.2018.09.009
CCLET 4651
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Chinese Chemical Letters
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3-9-2018
10-9-2018
Please cite this article as: Wang Y, Shen J, Chen Q, Wang L, He M,
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Nickel-catalysed C<ce:glyph name=sbnd/>O bond reduction of 2,4,6-triaryloxy-
1,3,5-triazines in 2-methyltetrahydrofuran, Chinese Chemical Letters (2018),
https://doi.org/10.1016/j.cclet.2018.09.009
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Nickel-catalysed C-O bond reduction of 2,4,6-triaryloxy-1,3,5-triazines in 2-
methyltetrahydrofuran
Yaoyao Wang, Jun Shen, Qun Chen, Liang Wang*, Mingyang He*
School of Petrochemical Engineering, Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, Changzhou University, Changzhou 213164,
China
*Corresponding authors.
E-mail addresses: liangwang@cczu.edu.cn (L. Wang) hemingyangjpu@yahoo.com (M. He)
ARTICLE INFO
Article history:
Received 8 June 2018
Received in revised form 3 September 2018
Accepted 6 September 2018
Available online
Graphical abstract
A nickel-catalysed reduction of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine (TCT) in ecofriendly 2-
methyltetrahydrofuran (2-MeTHF) is described.
ABSTRACT
A nickel-catalysed reduction of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine (TCT) in ecofriendly 2-methyltetrahydrofuran (2-
MeTHF) is described. The phenol-TCT derivatives were readily prepared using grinding method in short time without further purification. This
catalytic system allowed the facile C-O cleavage of phenol-TCT derivatives under mild reaction conditions with high efficiency and good functional
group tolerance. Gram-scale reaction was also achieved. Particularly, sequential functionalization of phenol-TCT derivatives followed by C-O bond
reduction could also be realized, affording the high value-added products in moderate to good yields.
Keywords:
Nickel catalysis
Phenol derivatives
C-O bond cleavage
Green solvent
The use of phenol derivatives instead of aryl halides as aryl electrophiles in cross-coupling reactions has received considerable
attention in recent years [1-9]. They are generally cost-effective, readily available and environmentally friendly since no halogen-
containing waste is generated during the coupling reactions. Among the phenol derivatives, substrates bearing 2-pyridyloxy group
(OPy) showed wide applications in C-H activation reactions due to the strong coordination ability of the nitrogen atom and their
chemical stability [10]. A very important feature of such phenol derivatives lies in that the Py or OPy group can be selectively removed
after C-H functionalization, thereby facilitating the formation of high value-added products. For example, the Py group could be
removed in MeOTf/MeONa system [11]. Our group achieved a palladium-catalysed regioselective C-H acetoxylation of 2-
aryloxypyridines [12]. After removal of the Py group, a series of poly-substituted phenols were obtained. Recently, the removal of OPy
group has also been disclosed. Chatani et al. developed a rhodium [13] or nickel [14] catalysed borylation of 2-aryloxypyridines,
providing a facile approach to introduce multiple functional groups into an aromatic ring. Wang et al. reported a nickel-catalysed
amination of 2-aryloxypyridines after initial C-H activations [15] (Scheme 1, a).

Despite these significant progress, the reductive deoxygenation of phenol derivatives has received less attention. It was worth
noting that reductive deoxygenation of phenol derivatives is also of significant importance in synthetic chemistry, enabling the use of
oxygen-based auxiliaries as removable directing groups [16]. It can also be applied to synthesize deoxygenated analogs of phenol-
based natural products [17]. During the past decades, phenol mesylates, triflates, tosylates, sulfonates, and even aryl alkyl ethers were
successfully reduced in the presence of transition metal catalysts as well as the reductants [18]. Just recently, Wang et al. [19] reported
a nickel-catalysed C-O bond reduction of aryl and benzyl 2-pyridyl ethers using simple alkoxide [20] as the reductant. However, most
of these reactions were carried out in a hazardous solvent such as DMF and toluene under harsh reaction conditions.
2-MeTHF is recognized as an eco-friendly solvent which can be obtained from renewable resources. It is also an attractive solvent
in organometallic reactions due to its stronger Lewis basicity compared with THF and Et2O [21], which may facilitate its coordination
to metal center. Moreover, 2-MeTHF is only partially miscible with water, making the separation process simplified. Inspired by these
pioneering works, herein we report a nickel-catalysed reduction of 2,4,6-triaryloxy-1,3,5-triazines (TAT) in 2-MeTHF (Scheme 1, b ).
Scheme 1. Applications of phenol derivatives through C−O bond cleavage.
Initially, 2,4,6-triaryloxy-1,3,5-triazine 1 were chosen as the substrate since such compound could be readily prepared in the
presence of a base. The phenols and TCT are also readily available and cost-effective. Moreover, the TAT structure is similar with 2-
aryloxypyridine. Notably, all of the three aryl groups in TAT can be utilized [22]. To further simplify the preparation of substrate 1, we
tried the grinding method under solvent-free condition. Pleasingly, most of the reactions proceeded smoothly to provide the
corresponding products in moderate to excellent yields within 30 mins (Scheme 2 and Supporting information). The pure products
could be obtained by washing with water and hexane, and no further purification was required.
Scheme 2. Preparation of 2,4,6-triaryloxy-1,3,5-triazines 1.
Then we started to explore the reductive deoxygenation reaction using 2,4,6-triphenoxy-1,3,5-triazine 1a as the model substrate and
i-PrONa as the reductant in 2-MeTHF at 80 oC (Table 1). The tentative reaction using Ni(cod)2 as the catalyst, 1,3-
bis(diphenylphosphino)propane (dppp) as the ligand led to the failure of the reaction (entry 1). Switching the ligands to 1,1'-
bis(diphenylphosphino)ferrocene (dppf), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and Ph3P afforded the desired
products in only trace amount (<5%, entries 2~4). The addition of PCy3, which was reported as the most the effective ligand [18c-e,
18g] for reductive deoxygenation reactions, provided the desired product in 43% yield (entry 5). Pleasingly, when the reaction was
performed by employing 1,3-bis-(2,6-diisopropylphenyl)imidazolinium chloride (IPr·HCl) as the ligand, the yield increased up to 92%
(entry 6). Some bidentate nitrogen ligands were also checked, but no reaction occurred at all (entries 7 and 8). Different nickel
precatalysts such as NiBr2 and Ni(acac)2 were also tried, however, no reaction was observed. Only trace amount of the desired products
were detected in the presence of zinc (entries 9 and 10). The solvent also had a significant influence on the reaction. Comparable yields
were obtained when the reaction took place either in THF or dioxane (entries 13 and 14). Reaction in other solvents such as DMF and
toluene only gave 67% and 28% yields, respectively (entries 15 and 16). Other reductants such as EtONa and HCOONa were also
evaluated, however, only trace amount of desired product was observed. Reduce the amount of i-PrONa to 1 equiv. (relative to phenyl
group) resulted in a slightly decreased yield (84%). No further increase in the yield was noticed in the presence of 3 equiv. of i-PrONa

(entry 17). Finally, attempt reaction with lower catalyst loading (2.5 mol%) also gave a lower yield (75%), and 80 oC was turned out to
be the optimum.
Table 1
Optimization of reaction conditions.a
Entry
1
2
3
4
5
6
7
8
[Ni] (mol%)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
NiBr2 (5)
Ligand (mol%)
dppp (5)
dppf (5)
Xantphos (5)
Ph3P (10)
PCy3 (10)
IPr·HCl (5)
1,10-phen (5)
2,2'-bipy (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (5)
IPr·HCl (2.5)
IPr·HCl (5)
Solvent
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
2-MeTHF
THF
Dioxane
DMF
Toluene
2-MeTHF
2-MeTHF
2-MeTHF
Yield (%)b
0
<5
<5
<5
43
96(92)
0
0
9
0
10
11
12
13
14
15
16
17
18
19
NiCl2 (5)
NiBr2 (5)
0
0, <5c
0, <5c
86
89
67
Ni(acac)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (5)
Ni(cod)2 (2.5)
Ni(cod)2 (5)
28
<5d,e, 84f, 93g
75
83h, 90i
a Reaction conditions: 1a (0.1 mmol), i-PrONa (0.6 mmol), Ni catalyst (5 mol%), ligand (5 mol% or 10 mol%), solvent (2 mL), 80 oC, 12 h.
b GC yields with dodecane as an internal standard. Yield in parentheses is isolated yield.
c 15 mol% of Zn was used.
d EtONa or HCOONa were used instead of i-PrONa.
f 0.3 mmol i-PrONa was used.
g 0.9 mmol i-PrONa was used.
h Reaction at 60 oC.
i Reaction at 100 oC.
With the optimized conditions in hand, a series of 2,4,6-triaryloxy-1,3,5-triazines were utilized to explore the scope of this
protocol (Fig. 1). Generally, all of the investigated substrates underwent the reductive deoxygenation reaction smoothly to provide the
corresponding products in moderate to excellent yields (71%~92%). Among para-substituted substrates, diverse functional groups
including alkyl, methoxyl, fluoro, nitro, cyano, and acyl were all well tolerated. However, substrates with chloro and bromo group (2f
and 2g) did not survive the reaction conditions, and dehalogenation products followed by C-O bond reduction were obtained as the
major products. The meta-substituted substrates also exhibited good reactivities to deliver the corresponding products 2k and 2l in
excellent yields. Importantly, although ortho-methyl substituted substrate 1m gave relatively lower yield which was probably due to
the hindrance effect, the yield was still satisfactory. Compared with 2-naphthol TAT substrate, relatively lower yield was obtained for
1-naphthol TAT substrate due to the steric hindrance. This protocol is also applicable for heterocyclic substrates, giving the
corresponding product 2p in 71% yield. For substrate 1q, 91% yield was obtained. The benzyloxy group which can be easily reduced
by catalytic hydrogenolysis, was kept intact under the present reaction conditions.

o
Fig. 1. Reaction conditions: 1 (0.1 mmol), i-PrONa (0.6 mmol), Ni(COD)2 (5 mol%), IPr·HCl (5 mol%), 2-MeTHF (2 mL), 80 C, 12 h.
Isolated yields. aDehalogenation product followed by C-O reduction was obtained as the major product.
Scale-up experiment was also performed using compound 1s as the model substrate (5 mmol scale, Scheme 3). This reaction also
proceeded smoothly to provide the desired product 2q in 83% yield, indicating the practicability of the present protocol.
Scheme 3. Scale-up experiment.
Since the 2,4,6-triaryloxy-1,3,5-triazines have similar structure with 2-aryloxypyridines, the good coordination ability of the sp2
nitrogen atoms can facilitate a number of ortho C-H functionalization reactions. After C-O reduction, a series of substituted arenes
could be obtained. Thus, sequential C-H functionalization/C-O reduction reactions were carried out (Scheme 4). For example, the Pd-
catalyzed arylation [10b] and Ru-catalyzed oxidative olefination [23] could introduce an ortho aryl and vinyl, respectively, on the
aromatic ring. After C-O bond reduction, products 3 and 4 were obtained in moderate yields. Notably, the ester group in compound 4
was not affected under this reaction conditions.
Scheme 4. Sequential C-H functionalization/C-O bond reduction.
Deuterium experiment was then performed to gain preliminary mechanistic information about this reaction (Scheme 5 and
Supporting information). When the reaction was carried out with a deuterated sodium isopropoxide, the corresponding deuterated
product 2b-D was obtained in 82% yield with 96% deuteration, indicating that sodium isopropoxide was the hydrogen donor of the
reduction reaction. Also, acetone was detected after the reduction reaction by GC-MS.
Scheme 5. Deuterium experiment.
A plausible reaction mechanism was also proposed in Scheme 6. Initially, the nickel catalyst coordinates with ortho nitrogen atom
of substrate 1, then C-O oxidative addition of 1 to Ni(0) catalyst gives intermediate A [22]. Subsequently, intermediate C is generated
via anion exchange with i-PrO-, which releases acetone and intermediate D. Finally, intermediate D undergoes reductive elimination to
give the desired product 2 with simultaneous regeneration of Ni(0) species.

Scheme 6. Proposed mechanism.
In summary, we have developed a nickel-catalysed reduction of phenol derivatives activated by 2,4,6-trichloro-1,3,5-triazine in
ecofriendly 2-MeTHF. The phenol-TCT derivatives were readily prepared using grinding method in a short time without further
purification. Caryl-O bond was selectively cleavaged while no products formed via CPy-O bond cleavage were observed. The reactions
proceeded under mild reaction conditions with high efficiency and good functional group tolerance. Gram-scale reaction was also
achieved on a 5 mmol scale. Particularly, the success of sequential C-H functionalization of phenol-TCT derivatives followed by C-O
bond reduction provided a new way to access functionalized arenes.
Acknowledgment
We gratefully acknowledge financial support from the National Natural Science Foundation of China (No. 21302014 and 21676030),
the Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology (No. BM2012110), the Priority Academic Program
Development (PAPD) of Jiangsu Higher Education Institutions, the Advanced Catalysis and Green Manufacturing Collaborative
Innovation Center of Changzhou University, and Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (No.
PPZY2015B145).
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