2-Pyridylmethyl ether: A readily removable and efficient directing group for amino acid ligand accelerated ortho-C-H olefination of phenols

Article abstract of DOI:10.1039/c2cc37291f

2-Pyridylmethyl ether-directed ortho-C-H olefination of phenols via a seven-membered cyclopalladated intermediate has been disclosed to construct a variety of ortho-alkenyl phenols and ortho-alkyl phenols.

Full text of DOI:10.1039/c2cc37291f

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2-Pyridylmethyl ether: a readily removable and efficient directing group
for amino acid ligand accelerated ortho-C–H olefination of phenols
Xuefeng Cong, Jingsong You*, Ge Gao and Jingbo Lan*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
respectively.2h,11 Inspired by these pioneering works, we
2-Pyridylmethyl ether-directed ortho-C–H olefination of
50 envisioned that 2-pyridylmethyl might serve as a removable
and highly valuable directing and protecting group of phenols
to achieve the palladium(II)-catalyzed direct ortho-C–H
phenols via a seven-membered cyclopalladated intermediate
has been disclosed to construct a variety of ortho-alkenyl
phenols and ortho-alkyl phenols.
olefination through the formation of
cyclopalladated intermediate.
a seven-membered
10
Direct oxidative cross-coupling between arenes and olefins
through the cleavage of two C–H bonds would be one of the
most ideal strategies to achieve olefination of arenes.1
Recently, a large variety of direct olefinations of aromatic C–
H bonds have been reported.2 Among these transformations,
55
In the initial experiments, 2-(pyridin-2-ylmethoxy)toluene
(1a) was used as a model substrate for evaluating the
feasibility of the hypothesis. The coupling of 1a with N,N-
dimethylacrylamide (2a) was investigated using the ligand
developed by Yu et al.,2h and the ortho-alkenylated product
15 the direct ortho-C–H olefination of phenols is an important
area of research. To control the regioselectivity of olefination
of phenols, directing groups are usually introduced for the
efficient activation of ortho-C–H bond. In spite of significant
progress, the successful directing groups are under-
20 represented so far.3 Moreover, the substrate scope mainly
includes electron-deficient alkenes and styrene-type olefins,
and non-activated linear olefins have been proven to be
notorious substrates. It is highly desirable to develop a new
readily removable directing group for the practical and highly
25 efficient ortho-C–H olefination of phenols.
2-Pyridyl is a common directing group due to its good
coordination ability and compatibility with various transition
metals.4 2-Arylpyridines and benzoquinolines have been
frequently employed as the subject of the chelation-assited C–
30 H bond functionalization, in which the process of C–H bond
activation proceeds via five-membered cyclometalation.4,5
Although such an orientating strategy is very successful, the
directing group is recalcitrant and irremovable, which
constrains further potential synthetic elaboration. Recently,
35 several 2-pyridyl-based directing groups such as 2-pyridoxyl,6
2-pyridyl sulfoxide,7 2-pyridyldiisopropylsilyl8 and 2-
pyridylmethyl9 have been developed to perform C–H bond
activation through a presumed six-membered cyclometalation
transition state, but usually require extra cumbersome steps to
40 be installed and detached, and even are irremovable. The more
than six-membered cyclometalated intermediate has
commonly been considered more unstable than the five- and
six-membered rings.10 As a consequence, the examples of
chelation-directed C–H functionalization reactions through a
45 seven-membered cyclometalated process are fairly rare.
Recently, Yu et al. and Carretero et al. reported the Pd-
catalyzed C–H olefinations of 3-phenylpropionic acids and
60 (3a) was obtained in 17% yield (Table S1, entry 1). It was
gratifying that 3a was obtained in excellent yield (90%) in the
absence of benzoquinone (BQ), and none of para- or meta-
alkenylated products were observed (Table S1, entry 2). The
other amino acid-derived ligands such as Ac-Val-OH, Ac-
65 Leu-OH and Ac-Ile-OH were able to work in this
transformation, but led to a slight decrease of yield (Table S1,
entries 3-5). In controlled experiments, trace of cross-coupling
product was observed in the absence of ligand (Table S1,
entry 6). Apparently, amino acid ligands are competent in
70 accelerating the Pd(II)-catalyzed C–H activation with 2-
pyridylmethyl as a directing group. Of the oxidants screened,
other oxidants such as AgOAc, Cu(OAc)2, PhI(OAc)2, K2S2O8
and air were inferior to molecular oxygen (Table S1, entries 7,
and 10-15).
OCH2Ar
10 mol% Pd(OAc)2
20 mol% Boc-Val-OH
2 equiv KHCO3
O
OCH2Ar
O
NMe2
+
NMe2
t-AmylOH, 90 °C
1 atm O2, 12 h
Ar = 2-pyridyl 92%
Ar = 4-pyridyl trace
2a
1
3
Ar = phenyl
trace
75
Scheme 1 Investigation of directed ortho-olefination of phenol ethers.
Next, the directing role of the 2-pyridylmethyl group was
further examined. As shown in Scheme 1, the coupling of 1,2-
dimethyl-4-(pyridin-2-ylmethoxy)benzene 1c with 2a could
80 afford the ortho-alkenylated product in 92% yield under the
optimized conditions. While the 2-pyridylmethyl group was
replaced by the 4-pyridylmethyl or benzyl group, the
corresponding coupling products were detected hardly.
Therefore, the 2-pyridylmethyl group played an important
85 directing role in the ortho-C–H olefination of phenol ether.
We assumed that the 2-pyridylmethyl group might chelate
palladium(II), and then lead to the formation of a seven-
anilines via
a seven-membered cyclopalladated pathway,
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[journal], [year], [vol], 00–00 | 1

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Page 2 of 3
membered cyclopalladated intermediate.
provide the corresponding alkenylated products in 75% and
Using 2a as the olefin coupling partner, the scope of phenol
ether substrates was investigated as summarized in Scheme 2.
As expected, various methyl, tert-butyl and othor-methoxy
66% yields, respectively (Scheme 3). Although a mixture of
double bond isomerization products (3 and 3′) was given in
both cases, a single ortho-alkyl substituted phenol could be
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5
substituted phenol ethers and 1-naphthol ethers could be 35 obtained after the carbon–carbon double bond was
olefinated to give the ortho-alkenyl phenol ethers in good to
excellent yields (Scheme 2, 3a-3h). The unsubstituted phenol
ether can also be transformed to the ortho-monoalkenylated
product in good yield (Scheme 2, 3i). The chloride and nitro
hydrogenated with simultaneous removal of the protective
group. We speculated that the mixture of the double bond
isomerization products was generated as a consequence of
different β-hydride elimination pathways of the cyclized
10 groups were tolerated under the optimized conditions, but 40 intermediate I or the uncyclized intermediate II (Scheme 3).
gave rise to low yields. When Boc-Val-OH was replaced by
OCH2Py
10 mol% Pd(OAc)2
20 mol% Boc-Val-OH
4 equiv KHCO3
OCH2Py
Ac-Ile-OH considered as an optimal ligand for electron-poor
arenes,2h,2i the ortho-alkenyl phenol ethers were obtained in
good yields (Scheme 2, 3j-3l).
R1
R1
R1
+
t-AmylOH, 90 °C
1atm O2, 20 h
R
O
R
1
2
4
OCH2Py
O
Cl
OCH2Py
OCH2Py
10 mol% Pd(OAc)2
20 mol% Boc-Val-OH
2 equiv KHCO3
R1
R3
R4
R1
+
t-AmylOH, 90 °C
OCH2Py
OCH2Py
1atm O2, 12 h
R2
4a, 73%, R2 = H, R3 = R4
4b, 72%, R2= Me, R3 = R4 = NMe2
R
R
2
1
3
=
NMe2
OCH2Py
O
OCH2Py
O
O
OCH2Py
O
4c, 75%, R2
=
tBu, R3 = R4 = NMe2
4d, 70%, R2= OMe, R3
4e, 80%, R2 = OMe, R3
=
=
R4 = NMe2
R4= OnBu
NMe2
NMe2
NMe2
Cl
4f, 48%, R2= OMe, R3 = NMe2, R4 = OnBua
4g, 55%b
3a, 90%
OCH2Py
3b, 85%
3c, 92%
OCH2Py
OCH2Py
O
O
Scheme 4 Pd(II)-catalyzed diolefination. Reactions were carried out using
1 (0.5 mmol) and 2 (2.5 mmol). Isolated yield. a N,N-Dimethyl-
acrylamide (1.0 equiv) was initially added for 10 h, and then n-butyl
45 acrylate (1.5 equiv) was added for another 10 h. b (±)-1,1'-BINOL.
tBu
tBu
NMe2
NMe2
NMe2
3d, 91%
3e, 94%
tBu
3f, 95%
Divinylphenol derivatives are a class of important structural
motif in organic chemistry and materials science, and their
synthesis has recently aroused great interest of scientists.12
Therefore, we further expanded the scope of our methodology
50 to diolefination of phenols. It was gratifying to find that a
variety of phenol ether substrates reacted smoothly with N,N-
dimethylacrylamide or n-butyl acrylate (5.0 equiv) to yield the
dialkenylated products in good yields (Scheme 4, 4a-4e). The
unsymmetrical dialkenylated product was also successfully
55 obtained in an acceptable yield through a Pd-catalyzed semi-
one-pot procedure (Scheme 4, 4f). Furthermore, BINOL
ethers could couple with 4-chlorostyrene in 55% yield of 3,3′-
bisolefinated product 4g.
O
OCH2Py
O
OCH2Py
OCH2Py
O
O
MeO
NMe2
NMe2
NMe2
3g, 80%a
3i, 62%
OCH2Py
3h, 88%
O
OCH2Py
O
OCH2Py
Cl
Cl
O2N
NMe2
NMe2
NMe2
3k, 72% (Ac-Ile-OH)
Cl
3l, 60% (Ac-Ile-OH)
31% (Boc-Val-OH)
3j , 78% (Ac-Ile-OH)
51% (Boc-Val-OH)
27% (Boc-Val-OH)
R4
R3
OCH2Py
OCH2Py
OCH2Py
O
R5
OR2
3o, 83%, R3 = H
3p, 89%, R3 = Me
3q, 87%, R3 = Cl
3r, 78%, R3 = F
3m, 86%, R2
3n, 75%, R2
=
=
nBu
tBu
3s, 72%, R4 = H, R5 = Clb
3t, 75%, R4 = OCH3, R5 = OCH3
15
Scheme 2 Pd(II)-catalyzed direct C–H ortho-olefination of phenol ethers.
Reactions were carried out using 1 (0.5 mmol) and 2 (0.75 mmol).
Isolated yield. a 24 h. b 3-Chlorostyrene (4.0 equiv). Py = 2-pyridyl.
OCH2Py
OH
R1
R1
Deprotection
R
R
Subsequently, the scope of olefins was examined (Scheme 2,
3 or 4
20 3m-3t). Both n-butyl and t-butyl acrylates readily reacted with
1c to generate the ortho-alkenylated products in good yields
OH
OH
O
OH
O
R3
R2
NMe2
NMe2
(Scheme 2, 3m-3n). Gratifyingly,
a range of styrene
3ca
derivatives, which are usually considered as lowly reactive
substrates, could smoothly undergo the olefination, affording
25 the desired products in good to excellent yields (Scheme 2,
3o-3t).
Pd/C, H2 (1 atm)
BBr3, DCM, -40 °C-rt
Pd/C, H2 (1 atm), 90%
Pd/C, H2 (15 atm), 92%
Mg, MeOH,
3ea, 83%, R2
= -Bu
t
3cb, 78%, R3
3qb, 62%, R3
=
=
CONMe2
4-Cl-C6H4
4aa, 85%, R2= (CH2)2CONMe2
70%
60 Scheme 5 Removal of the directing group.
To demonstrate the synthetic potential of this methodology,
we sought to explore the possibility of removal of the
directing group through using different methods. In view of
the similarity between 2-pyridiylmethyl and benzyl, the
65 catalytic hydrogenation was taken. Not surprisingly, the 2-
pyridiylmethyl group of 3c was removed successfully together
with the hydrogenation of the alkenyl double bond, producing
the ortho-alkyl phenol 3ca in 90% (1atm) and 92% (15 atm)
yields, respectively (Scheme 5). Magnesium could also
70 reductively deblock 2-pyridiylmethyl of 3c in methanol, and
O
N
PdII
O
Py
H
R
R
OH
R
H
O
H
H
Pd/C, H2
3
+
O
I
R
N
Py
O
H
PdII
N
H
3ua, R = n-Hept 90%
3va, R = n-Non 86%
′
3
R
H
′
= n-Hept 75% (3u: 3u =1: 1.5)
= n-Non 66% (3v: 3v = 1: 2.5)
R
R
H
R
PdII
′
II
Scheme 3 Cross-coupling reaction of phenol ether with linear alkenes.
It was worth noting that the more challenging non-activated
30 n-decene and n-dodecene could couple efficiently with 1c to
2
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similarly the carbon–carbon double bond was reduced
10.1039/b000000x/
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importantly, the alkenyl was remained, giving the
corresponding ortho-alkenyl phenols in good yields (Scheme
5, 3cb and 3qb).
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A
plausible mechanism of this transformation was
illustrated in Scheme 6. The presumed seven-membered
cyclopalladated intermediate was formed through the
10 chelation-assisted ortho-C–H cleavage. Subsequently, the
intermediate coordinated with an olefin and then formed the
cyclized intermediate I or the uncyclized intermediate II via
the insertion of alkene, followed by β-hydride elimination to
give the desired product 3 together with the species HPdOAc.
15 HPdOAc was transformed to Pd(0) through reductive
elimination, which was possibly stabilized by the amino acid
ligand, and was then oxidized to Pd(II) by molecular oxygen
to finish the catalytic cycle.
H2
O
O2
HPdOAc
O
Pd(OAc)2
3
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O
N
N
β
-H
R
Elimination
C-H
Cleavage
3
O
O
N
O
4
5
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N
N
PdII
R
PdII
PdII
II
O
R
N
I
PdII
R
R
20 Scheme 6 Plausible mechanism for directed ortho-C–H olefination.
In summary, we have demonstrated that 2-pyridiylmethyl
ether can serve as an efficient directing group for amino acid
ligand accelerated ortho-C–H olefination of phenols via a
seven-membered cyclopalladated intermediate. A wide range
25 of phenols and alkenes could be employed in this
transformation, affording the ortho-alkenyl products with high
regioselectivity in good to excellent yields. Especially, non-
activated linear alkenes can serve as amenable coupling
partners. This methodology can also be applied to the
30 diolefination of phenols, providing symmetrical and
unsymmetrical divinylphenol derivatives. Furthermore, the 2-
pyridylmethyl group can be easily removed through several
different methods, giving the ortho-alkenyl phenols or ortho-
alkyl phenols. We expect that the 2-pyridylmethyl ether
35 directing strategy would be a potential pathway to a variety of
selective ortho-C–H functionalization of phenols.
6
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This work was supported by grants from 973 Program
(2011CB808600), the National NSF of China (Nos 21172155,
21025205 and 21021001), and Sichuan Provincial Foundation
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Notes and references
Key Laboratory of Green Chemistry and Technology of Ministry of
Education, College of Chemistry, and State Key Laboratory of Biotherapy,
West China Medical School, Sichuan University, 29 Wangjiang Road,
45 Chengdu 610064, PR China. Fax: (+86) 28-85412203
E-mail: jingbolan@scu.edu.cn; jsyou@scu.edu.cn
†Electronic Supplementary Information (ESI) available: Detailed
experimental
procedures,
analytical
data.
See
DOI:
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