1,2,3-Triazoles as versatile directing group for selective sp2 and sp3 C-H activation: Cyclization vs substitution

Article abstract of DOI:10.1039/c3sc51211h

Selective cyclization and substitution was achieved with designated 1,2,3-triazole acid auxiliary groups under Pd catalyzed C-H activation conditions. Both sp² and sp³ C-H bonds were effectively activated, giving the desired products

Full text of DOI:10.1039/c3sc51211h

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1
,2,3-Triazoles as versatile directing group for selective
2
3
sp and sp C–H activation: cyclization vs substitution†
Cite this: DOI: 10.1039/c3sc51211h
a
b
a
a
a
Xiaohan Ye, Zhengrong He, Tonia Ahmed, Keith Weise, Novruz G. Akhmedov,
a
a
Jeffrey L. Petersen and Xiaodong Shi*
Selective cyclization and substitution was achieved with designated 1,2,3-triazole acid auxiliary groups
Received 3rd May 2013
Accepted 2nd July 2013
2
3
under Pd catalyzed C–H activation conditions. Both sp and sp C–H bonds were effectively activated,
giving the desired products in good yields. This result revealed the first successful example of exclusive
substitution using 1,2,3-triazole ligands, while another triazole-containing directing group dominantly
gave cyclization under identical conditions.
DOI: 10.1039/c3sc51211h
www.rsc.org/chemicalscience
During the last decade, transition metal catalyzed C–H func- cyclization and substitution products are prepared in good to
tionalization has been utilized as an efficient and versatile excellent yields.
1
approach in complex molecule synthesis. Among the reported
To be synthetically useful, the designed auxiliary group
methods, the directing group (DG) approach is particularly needs to be readily removable aer C–H functionalization. As
2
important since it can selectively activate specic C–H bonds.
demonstrated in Scheme 2A, the 1,2,3-triazole 4-carboxylic acid
7
Recently, Yu, Daugulis, and Chen groups reported the applica- can gave facile hydrolyzation under relatively mild conditions.
tion of protected amides (HN-PG) as the directing group in Pd However, the 1,2,3-triazoles are highly electron-decient
3–5
catalyzed C–H activation. (Scheme 1A). This practical and
conceptually novel strategy greatly enriches the reaction scope.
Although signicant progresses have been achieved with this
2
3
strategy, such as effective functionalization of sp and sp C–H
bonds, one challenge is the chemoselectivity between cycliza-
tion and substitution. As shown in Scheme 1B, with the pico-
linic acid (PA) or quinaldic acid (QA) protecting groups, the
cyclization products were dominant, even in the formation of
highly strained azetidine rings. Recently, Chen and coworkers
reported the application of alcohols as the co-solvents to
4j
promote the substitution over the cyclization. Although this
work provided one successful example for O-substitution upon
C–H activation using this auxiliary strategy, the requirement of
an alcohol as a co-solvent limited the potential application for
the incorporation of other functional groups due to the crucial
6
competition from the alcohol solvent. Thus, alternative versa-
tile directing/protecting groups that render effective chemo-
selectivity control are highly desired. Herein, we report the rst
example of the application of 1,2,3-triazole-4-carboxylic acid
derivatives as the alternative auxiliaries in adjusting the Pd
2
3
catalyzed C–H activation (Scheme 1C). Effective sp and sp C–H
activations can be successfully achieved and the desired
a
C. Eugene Bennett Department of Chemistry, West Virginia University, Morgantown,
WV 26506, USA. E-mail: xiaodong.shi@mail.wvu.edu; Fax: +1 304 293 4904; Tel:
+
1 304 293 0179
b
Hubei Engineering University, Hubei, China
†
Electronic supplementary information (ESI) available. See DOI:
0.1039/c3sc51211h
1
Scheme 1 Protecting/directing group promoted C–H activation.
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picolinic acid (PA) directing groups. To the best of our knowl-
edge, this is the rst example of 1,2,3-triazole directed arene
C–H activation with Pd catalysts. Interestingly, other tested
hetero aromatic compounds, such as imidazole, furan and
pyrazole, could not promote this reaction at all, despite being
more electron-rich than triazole. Various TAA derivatives were
prepared to investigate the reaction scope.
As shown in Table 1, the triazole amide auxiliary effectively
2
promoted the C–H activation sp C–H bonds, furnishing the
corresponding cyclization products in good to excellent yields.
This transformation tolerated a large group of substrates. With
2
3
the presence of both sp and sp C–H at the g-positions, the
reaction occurred exclusively on the sp carbon (4b). Both EDG
Scheme 2 Challenge in triazole-directed C–H activation.
2
(4g, 4j) and EWG (4d, 4i, 4l) substituted benzene were suitable
for this reaction. Remarkably, with halides present on the ortho
aromatic compounds and therefore have been overlooked as positions (4c–4e), the directed C–H activation occurred prefer-
potential ligands in transition metal coordination due to the entially over oxidative addition, even for the aryl iodide (4e).
assumed “poor” electron donating ability. In the last several Excellent regioselectivity was observed for the meta-substituted
years, our group has been working towards the development of benzenes (4h, 4i), giving the single cyclization products on the
new metal catalysts with 1,2,3-triazole ligands. Several stable less sterically hindered ortho-carbon.
triazole complexes were successfully prepared and character-
Similarly to PA-directed C–H activation, the reaction selec-
ized, revealing the good binding ability of 1,2,3-triazole towards tively occurred on the primary carbon (CH ) over the secondary
3
8
3
12
transition metal cations, unlike the previous assumption.
2
carbon (CH , 4o) for the sp C–H bonds (Table 2). Formation of
Thus, we wondered whether 1,2,3-triazole-4-carboxylic acid azetidines was observed in all cases, even with the presence of
derivatives (TAA) could be used as suitable auxiliaries in Pd C–H at the d-position (4o, for the synthesis of pyrrolidine). TAA
catalyzed C–H activation.
amide from tert-octylamine were prepared and tested as a
One potential problem associated with our proposed strategy substrate that could undergo cyclization to form a pyrrolidine
9
is the acidic C–H proton on 1,2,3-triazole. Ackermann and (CH3 at the d-position, formation of a 5-member ring). The
13
coworkers have done comprehensive studies regarding the cyclization product was observed with 84% isolated yield.
metal catalyzed C–H activation of conjugated triazole-phenyl Good to excellent diastereoselectivity was observed. Notably, for
2
3
compounds. Based on their results, under the Pd catalyzed both sp and sp substrates, cyclization products were the
conditions, C–H activation exclusively occurred on the triazole
10
C–H bond (instead of the arene C–H, Scheme 2B). Later, the
same group reported Ru catalyzed C–H activation with 1,2,3-
11
triazole directing group as part of the molecule. So far, no Pd
catalyzed triazole-directed C–H activation has ever been repor-
ted in the literature.
2
ac
Table 1 Reaction scope for TAA-directed sp C–H activation
To test our hypothesis, triazole amide 2a was prepared along
with several other similar heteroaromatic amides. These
substrates were screened under identical conditions, (Pd(OAc)
2
ꢀ
and PhI(OAc)
2
in DCE, 80 C).
As shown in Fig. 1, the TAA directing group could effectively
promote arene C–H activation, giving the cyclization product 3a
in 83% isolated yield, similar to quinaldic acid (QA) and
a
The reactions were carried out with Pd(OAc)
2
(5 mol%) and PhI(OAc)
2
ꢀ
(2 equiv.) in 1,2-dichlorethane at 80 C under Ar, unless otherwise
b
ꢀ
c
Fig. 1 TAA-directed C–H activation.
mentioned. Run at 100 C. Isolated yield.
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abd
Table 2 Reaction scope for TAA-directed sp C–H activation
a
The reactions were carried out with Pd(OAc)
2
(5 mol%), PhI(OAc)
2
(2.5
ꢀ
equiv.), AcOH (2 equiv.) in 1,2-dichlorethane at 120 C under Ar, unless
b
otherwise mentioned. TAA ¼ N1-p-methyoxyphenyl-1,2,3-triazole-4-
c
1
d
carboxylic acid. Determined by H NMR analysis. Isolated yield.
dominant products observed with the TAA directing/protecting
group.
Encouraged by the TAA-directed C–H activation, we then Fig. 2 TA-Py controlled selective substitution.
focused on the more challenging substitution reaction. PA, QA,
and TAA directing groups all gave dominant cyclization prod-
ucts, which is consistent with a favored in-plane reductive
elimination (Scheme 3A). We wondered whether the use of a Fig. 2B). With the addition of AgOAc (0.5 equiv.) as the co-
tridentate directing group could force the Pd–C bond into the oxidant, the reaction achieved essentially 100% conversion,
axial position (Scheme 3B), thereby favoring the out-of-plane giving the substitution product 6a (mixture of mono-OAc and
C–O bond-forming reductive elimination pathway (Scheme 3A, di-OAc, m : d ¼ 1 : 0.8) in excellent yields (85% isolated
1
4–16
17
bottom arrow).
The triazole-pyridine amide (TA-Py, 5a) and yields). Notably, no cyclization product was observed under
0
pyridine-triazole acid (Py-TA, 5a ) were prepared and charged these conditions at all. To the best of our knowledge, the
with the standard oxidation conditions.
exclusive substitution (for the substrates that gave dominant
cyclization reaction with PA, QA and TAA directing groups)
0
As shown in Fig. 2A, the tridentate Py-TA directing group 5a
successfully blocked the cyclization reaction path. However, revealed the rst example of directing group controlled (over
under the standard reaction conditions, no substitution substrate controlled) selective C–H functionalization through
product was obtained. Interestingly, when switching the pro- designated protecting group tuning. Notably, both TA-Py ester
tecting group from Py-TA to TA-Py, effective arene C–H activa- and N-methyl TA-Py amide gave no reaction under identical
tion was achieved and the substitution product 6a was reaction conditions (Fig. 2C). These results clearly indicated the
successfully obtained in 56% isolated yield (67% conversion, required binding of amide nitrogen as the X-type ligand for the
substitution reaction. Although it remains uncertain whether
the reaction proceeds through the tridentate coordination
mode at this moment, the successful substitution over cycliza-
tion provides a new strategy in achieving chemoselective C–H
activation through simple directing group control.
Various TA-Py amides were prepared to evaluate the reaction
scope. The results are summarized in Table 3. Similar to TAA,
the TA-Py directing group could effectively promote the Pd
3
2
catalyzed C–H activation for both sp and sp C–H bonds. A
wide substrate scope was observed with this TA-Py protecting
2
group. For sp -substrates, reactions occurred selectively on the
ortho-C–H over the ortho-halides, including aryl iodide (7c, 7d,
7f). Both EDG (7e) and EWG (7d) modied arenes were suitable
under the reaction conditions. Typically, mixtures of mono and
di-acetoxylation products were observed when both ortho-C–Hs
were present. Good yields were obtained for di-substitution in
the present of excess oxidants (7m–7o). Excellent regiose-
lectivity was received with the meta-substituted benzene, with
substitution occurring at the less hindered carbons (7g–7i).
Scheme 3 Proposed TA-Py directing group for selective substitution.
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2
ae
Table 3 Reaction scope for TA-Py directed sp C–H activation
starting materials did not epimerize under the reaction condi-
tions, which suggests potential applications of this strategy in
complex molecule synthesis.
Conclusions
In conclusion, we have developed a directing/protecting group
controlled selective substitution or cyclization with designated
2
1
,2,3-triazole directing/protecting groups in the Pd catalyzed sp
3
and sp C–H activation. This work provided the rst example of
Pd catalyzed C–H activation with the 1,2,3-triazole directing
group. The success in the challenging substitution with the TA-
Py directing group provided the opportunity for other C–H
functionalization through the Pd catalyzed C–H activation by
overcoming the inherent cyclization pathway. In addition, the
sequence dependent directing group effect (TA-Py over Py-TA)
further emphasized the unique reactivity of 1,2,3-triazoles as
ligands in Pd catalyzed reactions, which will open the door for
further developments.
Notes and references
1
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The reactions were carried out with Pd(OAc)
2
(10 mol%), AgOAc (0.5
ꢀ
equiv.) and PhI(OAc)
Ar, unless otherwise mentioned. Run at 100 C. PhI(OAc)
equiv.) was used at 100 C. The ratio of the mono-substitution to di-
substitution was determined by H NMR analysis. Isolated yield.
2
(2.5 equiv.) in 1,2-dichloroethane at 80 C under
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ꢀ
c
2
(3
ꢀ
d
1
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(
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ac
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The reactions were carried out with Pd(OAc)
2
(10 mol%), AgOAc (1.5
ꢀ
equiv.) and PhI(OAc)
under Ar, unless otherwise mentioned. The ratio of the mono-
2
(3.0 equiv.) in 1,2-dichloroethane at 140
C
b
1
substitution to di-substitution was determined by H NMR analysis.
c
Isolated yield.
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7
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1
1
5 For mechanistic studies on Pd-catalyzed acetoxylation: (a)
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7 See ESI† for detailed condition screening for Pd-catalyzed
acetoxylation.
1
1
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