Palladium-catalyzed aerobic oxidative C-H olefination with removable 1,2,3-triazole directing group

Article abstract of DOI:10.1021/ol5019807

Ortho-olefination of arenes was achieved with removable 1,2,3-triazole auxiliary through Pd-catalyzed C-H activation. Excellent yields were received even when molecular O₂ (1 atm) was used as the terminal oxidant. Other heterocyclic directing groups, such as pyridine and quinoline, gave poor reactivity under this aerobic oxidative condition, which highlighted the unique reactivity of triazole in promoting directed C-H activation.

Full text of DOI:10.1021/ol5019807

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Aerobic Oxidative C−H Olefination with
Removable 1,2,3-Triazole Directing Group
Xiaohan Ye and Xiaodong Shi*
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown, West Virginia 26506, United States
S
* Supporting Information
ABSTRACT: Ortho-olefination of arenes was achieved with
removable 1,2,3-triazole auxiliary through Pd-catalyzed C−H
activation. Excellent yields were received even when molecular
O2 (1 atm) was used as the terminal oxidant. Other
heterocyclic directing groups, such as pyridine and quinoline,
gave poor reactivity under this aerobic oxidative condition,
which highlighted the unique reactivity of triazole in
promoting directed C−H activation.
uring the past decade, transition metal catalyzed C−H
functionalization has been utilized as an efficient
directing group (formation of triazole amide) in promoting
selective C−H olefination. This new triazole DG not only gives
the desired products in excellent yields (up to 95%), but also
allows molecular oxygen (1 atm) to be used as terminal oxidant
under “open-flask” conditions, emphasizing the high efficiency
of this new triazole DG in promoting inactive C−H
functionalization.
D
approach in complex molecule synthesis.1 The Pd-mediated
C−H olefination of arenes has been reported since 1960s
(Fujiwara-Moritani oxidative Heck reaction).2 However, poor
selectivity remains a challenge for this transformation, since
selectivity usually relies on the reactivity of different C−H
bonds for given substrates.3 To achieve selective C−H
functionalization, various directing groups (DGs), such as
OR, COOH and pyridine, have been developed (Scheme 1).4,5
During the last several years, our group has been working on
triazole ligand promoted transition metal catalysis.10 Recently,
we reported 1,2,3-triazole (TA) as a new versatile removable
directing group in promoting sp2 and sp3 C−H activation using
PhI(OAc)2 as the oxidant.11 Impressively, the triazole DGs
indicated excellent chemoselectivity, achieving selective C−N
reductive elimination (cyclization) or C−O reductive elimi-
nation (substitution) through alternating the triazole DG
coordination patterns (TA(Bn) vs TA-Py, Figure 1A).
Encouraged by the result that TA-Py DG successfully avoided
cyclization, we put our attention on directed C−H activation,
namely, C−H olefination. This is because A) as mentioned
above, directed C−H olefination is a very useful transformation
with few economic methods available in literature, and B) this
Heck-type transformations will not only provide a good
platform to evaluate the performance of TA-directing group
under Pd(0)−Pd(II) conditions, but also create the possibility
of using molecular O2 as the oxidant to substitute the expensive
PhI(OAc)2. The TA-Py modified amide 1 was then prepared to
react with n-butyl acrylate (Figure 1B).
Scheme 1. Selective C−H Olefination Using Directing
Groups
As amine is usually not an effective directing group, one
interesting approach is the removable amide protecting group
as chelating directing group.6 Among literature reported
examples, picolinic acid (PA) and quinaldic acid (QA) moieties
were the most successful precursors.7 Interestingly, neither
compound has been used as a viable directing group for C−H
olefination under oxidative heck conditions.8 In fact, our later
studies (vide infra) confirmed that PA and QA could not
promote effective C−H olefination due to the rapid Pd
decomposition (formation of palladium black). The only
successful example of C−H olefination using the removable
DG strategy was the -NHTf system reported by Yu and co-
workers.9 However, in that case, excess silver salts (2.5 equiv)
were required as the oxidant to facilitate the reaction. Herein,
we report the 1,2,3-triazole-4-carboxylic acid as the removable
Unfortunately, under previous standard conditions (PhI-
(OAc)2 as the oxidant, 100 °C), no C−H olefination was
observed, though the undesired cyclization was successfully
prevented (complete recovery of starting material). Interest-
Received: July 8, 2014
© XXXX American Chemical Society
A
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Letter
a,b
Table 1. Selected Optimization of Reaction Conditions
variations from the “standard”
conversion of 1a
yield of 2a
entry
conditions
(%)
(%)
1
w/o Pd(OAc)2
0
24
0
22
2
w/o HOAc and Cu(OTf)2
w/o Cu(OTf)2
3
30
28
4
w/o HOAc
50
48
5
CuCl2 instead of Cu(OTf)2
Cu(OAc)2 instead of Cu(OTf)2
HOAc as solvent
<5
<5
6
65
61
7
33
31
8
toluene as solvent
PdCl2 instead of Pd(OAc)2
air
78
75
9
<10
75
<10
60
10
11
no O2 (Ar protection)
trace
trace
a
Reaction conditions: 1(0.1 mmol), n-butyl acrylate (0.4 mmol),
catalyst, additives, and solvent (0.2 M) in a 20 mL Schlenk tube with
b
1
O2 balloon. Determined by H NMR using 1,3,5 trimethoxybenzene
as internal standard;
Figure 1. Triazole group directed C−H activation.
shown in Figure 2, poor yields were obtained in all tested cases,
including PA- and QA-modified substrates. These results
ingly, a brief screening revealed AgOAc (2.5 equiv) as effective
oxidant to promote this C−H olefination, giving the desired
alkene 2 in good yield (51% conversion and 49% yield).
Moreover, cyclization product was not observed even with the
bidentate TA(Bn) as the directing group under this new
conditions (AgOAc as oxidant). In fact, the desired C−H
olefination product 2 was obtained in 31% yield along with
olefination on the triazole C−H bond (4, 35% yield). Thus, Pd-
catalyzed direct triazole C−H activation, which has been
reported by Ackermann, Jiang and others12 is the main problem
for achieving C−H olefination with good selectivity. We then
postulated that the 4,5-disubsituted triazoles TA(Ph) shown in
Figure 1C, should be of effective DG to promote this C−H
olefination by blocking the reactive triazole C−H bond. As
expected, reaction of TA(Ph) modified 1a under the standard
condition gave the desired C−H olefination product 2a in
excellent yield (94%, Figure 1C).
This result was crucial since it confirmed the possibility of
using triazole DG to promote C−H activation under Pd(0)−
Pd(II) conditions. Considering the low redox potential
between Pd(0) and Pd(II), we put our effort into exploring
the feasibility of using molecular O2 as the terminal oxidant.13,14
The screening of conditions is summarized in Table 1.
First, the TA(Ph) amide alone could give the desired C−H
olefination with O2 as oxidant (entry 2), though in low yield
(22%). Addition of HOAc (2.5 equiv) slightly improved the
reaction performance (entry 3) with a significant amount of 1a
leftover. Finally, addition of Cu(OTf)2 cocatalyst (10 mol %)
led to complete 1a conversion, giving the desired C−H
olefination product 2a in excellent isolated yield (95%).15 To
the best of our knowledge, this is the first successful example of
removable directing group promoted C−H olefination using O2
as the terminal oxidant.16
Figure 2. Evaluation of other directing groups.
highlighted the unique reactivity of 1,2,3-triazole directing
groups in promoting C−H activation. Triazole ester and N-
methyltriazole amide gave no reactions, which was consistent
with the chelation model (for successful C−H activation) as
reported in other similar systems. To evaluate the reaction
scope, various TA(Ph)-modified substrates were prepared and
treated under the optimal conditions.
As shown in Figure 3, this new TA-directing group tolerated
a large number of substrates, furnishing the corresponding
olefination in good to excellent yields. Both EDG (2b) and
EWG (2c) modified arenes were suitable for this reaction.
Notably, substrates with ortho-halides (2c, 2d) could survive
the reaction, giving the desired C−H activation (over oxidative
addition) in good yields. Good regioselectivity was obtained for
the meta-substituted benzenes, with substitution occurring
primarily at the less hindered ortho-carbons position (2e−g).
Typically, the selectivity of mono- and diolefination would be
poor when both ortho-C−H’s were present (2j and 2k). This
problem was overcome by increasing the steric bulkiness at the
benzylic position. As shown in 2l, incorporation of a methyl
group effectively improved the m:d selectivity to >20:1.
Meanwhile, use of an excess amount of alkene (12 equiv)
gave the diolefination in good yields (2m,o). The scope of
Substrates containing other common directing groups were
also prepared and evaluated under the same conditions. As
B
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Letter
Kinetic isotope studies were also performed to probe the
reaction mechanism. A primary KIE was observed (KH/KD =
2.1) as shown in Figure 4A, suggesting a C−H activation over a
Figure 4. Kinetic Isotope effect and derivatization.
Lewis acid catalyzed Friedel−Crafts-type mechanism. Removal
of TA directing group was demonstrated in Figure 4B using the
general protocol reported by Chen.16a The Boc protected
alkene−amine was obtained in excellent yield. Finally, treating
the resulting acrylate−amide product (3a) with NaH gave the
tetrahydroisoquinoine in excellent yield (Figure 4C), further
highlighting the efficiency and potential application of this
method in complex molecules synthesis.
In conclusion, we have unveiled 1,2,3-triazole as an effective
directing group in promoting aerobic C−H oxidative
olefination. This study not only revealed a new efficient and
economic approach (using 1 atm of O2 as the terminal oxidant)
in achieving selective C−H olefination but also confirmed the
versatile reactivity of 1,2,3-triazole in promoting metal catalyzed
C−H activation. Other synthetic applications using this new
TA-directed C−H activation strategy are currently under
investigation.
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details and NMR data. This material is available
free of charge via the Internet at http://pubs.acs.org.
Figure 3. Substrate scope. General reaction conditions: 1 (0.2 mmol),
alkene (0.8 mmol), HOAc (5.0 mmol), and catalyst in 1,4-dioxane (1.0
mL). Conditions A: 7.5 mol % of Pd(OAc)2 and 10 mol % of
Cu(OTf)2, O2 balloon, 105 °C, 20 h. Conditions B: 10 mol % of
Pd(OAc)2 and 10 mol % of Cu(OTf)2, 1 atm of O2 charged in sealed
tube, 115 °C, 20 h. Conditions C: 15 mol % of Pd(OAc)2 and 10 mol
% of Cu(OTf)2, 2.4 mmol of n-butyl acrylate, 1 atm of O2 charged in
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: xiaodong.shi@mail.wvu.edu.
Notes
The authors declare no competing financial interest.
a
sealed tube, 115 °C, 20 h. Isolated yield. The ratio of mono and di
1
substitution was determined by HNMR.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-0844602) for financial support. We
also thank NSF-MRI (CHE-1228336) for the supports on the
new NMR instruments.
alkene was also evaluated. Besides acrylate, most of other
activated alkenes, such as acrylonitrile (3c), acrylamide (3d),
vinyl phosphate (3e), and vinyl sulfone (3f), are suitable for
this transformation, giving the desired olefins in excellent yields.
Impressively, nonactive olefins, such as styrene derivatives,
could also undergo this transformation with good to excellent
yields (3g−i). However, similar to other reported Heck-type
reactions, α- or β-substituted alkenes failed to give the desired
products due to steric hindrance on either alkene insertion or
β-hydride elimination steps. Nevertheless, the broad substrate
scope, simple reaction conditions and use of oxygen as the
oxidant highlighted the advantages of this new triazole-directing
group in promoting selective C−H olefination.
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