Development of modifiable bidentate amino oxazoline directing group for Pd-catalyzed arylation of secondary C-H bonds

Article abstract of DOI:10.1002/chem.201406528

Abstract A novel bidentate α-amino oxazolinyl directing group has been developed. Different from previous directing groups, this newly designed directing group was easily prepared from amino acids and modified in structure. This auxiliary preferentially effects functionalization at secondary C(sp³)-H bonds, rather than at aryl C(sp²)-H bonds. The diastereoselectivity of direct arylation between geminal secondary C(sp³)-H bonds in linear molecules has also been realized for the first time with a chiral directing group by remote chirality relay. Two diastereoisomers are produced with the same chiral source by changing the substituents of substrates and aryl halides. A new direction: A multifunctional amino oxazoline directing group that is readily available from amino acids, has been developed, which can induce chemo-, regio- and diastereoselectivity in secondary C(sp³)-H arylation reactions. Furthermore, this directing group is removable and modifiable. Steric control and counterions play important roles in the relayed chirality transfer.

Full text of DOI:10.1002/chem.201406528

DOI: 10.1002/chem.201406528
Communication
&
Directing Groups
Development of Modifiable Bidentate Amino Oxazoline Directing
Group for Pd-Catalyzed Arylation of Secondary CÀH Bonds
Kang Chen,[a] Zhao-Wei Li,[a] Peng-Xiang Shen,[a] Hong-Wei Zhao,[a] and Zhang-Jie Shi*[a, b]
C(sp3)ÀH functionalization.[8] For example, these directing
Abstract: A novel bidentate a-amino oxazolinyl directing
groups have been applied in alkoxylation,[9] amination,[10] al-
group has been developed. Different from previous direct-
kynylation,[11] alkylation,[12] and oxidative borylation reactions.[13]
ing groups, this newly designed directing group was
Inspired by these important discoveries, chemists have made
easily prepared from amino acids and modified in struc-
great efforts in recent years to design new chelating auxiliaries
ture. This auxiliary preferentially effects functionalization
to promote C(sp3)ÀH activation.[14] The groups of Chatani,[15]
at secondary C(sp3)ÀH bonds, rather than at aryl C(sp2)ÀH
Chen,[16] Carretero,[17] Sahoo,[18] Shi,[19,20] Ackermann,[21] Ma,[22]
bonds. The diastereoselectivity of direct arylation between
and Zhao[23] have all provided innovative contributions to the
geminal secondary C(sp3)ÀH bonds in linear molecules has
design of auxiliaries. Besides Pd, other transition metals were
also been realized for the first time with a chiral directing
also applied in such C(sp3)ÀH bond functionalization reac-
group by remote chirality relay. Two diastereoisomers are
tions.[24]
produced with the same chiral source by changing the
Nevertheless, several challenges remain in this field: 1) al-
substituents of substrates and aryl halides.
though many currently known directing groups can promote
direct functionalization of primary CÀH bonds, only a limited
number of directing groups are efficient for secondary C(sp3)À
H bond fuctionalization;[25] 2) most of the current effective bi-
Direct functionalization of CÀH bonds has attracted much at-
tention in the past several decades, because it affords the
most straightforward pathway to producing valuable chemicals
with higher atom- and step-economy compared to traditional
synthetic methods, by avoiding the need for prefunctionaliza-
tion.[1] Although many exciting achievements have been made
in C(sp2)ÀH functionalization,[2] in comparison, direct function-
alization of inert C(sp3)ÀH bonds is still challenging, as a result
not only of the lack of interaction between aliphatic CÀH
bonds and metal catalysts, but also of the difficulty in control-
ling chemo-, site-, and stereoselectivities.[3] However, directing-
group introduction has proven to be a successful strategy for
solving such problems in aliphatic CÀH bond activation.
dentate directing groups contain heteroaryl rings that act as
one of the coordinating sites (Scheme 1a). Although such
In 2004, Sanford and co-workers developed the first Pd-cata-
lyzed acetoxylation of aliphatic CÀH bonds with O-methyl
oximyl as the directing group.[4] Later on, a similar strategy was
applied by Dong and co-workers.[5] Yu’s group reported their
pioneering works on the use of oxazoline rings and arylamides
as unique directing groups for C(sp3)ÀH functionalization.[6,7]
Since 2005, Daugulis and co-workers have reported new biden-
tate directing groups that have proven significant in studies of
Scheme 1. Examples of previously reported bidentate directing groups (a)
and design of the bidentate a-amino oxazoline directing group for diaste-
reoselective arylation of secondary CÀH bonds (b).
groups can be removed under different conditions, especially
after modifications of the rings,[16] they offer few opportunities
for useful structural modification or transformation into other
moieties in the product molecules; 3) due to the planar struc-
ture of the heteroarenes, it seems impossible to meet the re-
quirement of stereochemical control in secondary CÀH func-
tionalization.[26] In light of all of these limitations, novel auxilia-
ries that demonstrate easy removability, potential transform-
ability, and the ability to simultaneously control chemo-, regio-,
and stereochemistry are highly appealing.
[a] K. Chen, Z.-W. Li, P.-X. Shen, Dr. H.-W. Zhao, Prof. Dr. Z.-J. Shi
Beijing National Laboratory of Molecular Science (BNLMS) and
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of the
Ministry of the Education, College of Chemistry and Green Chemistry Center
Peking University, Beijing, 100871 (China)
E-mail: zshi@pku.edu.cn
[b] Prof. Dr. Z.-J. Shi
State Key Laboratory of Organometallic Chemistry
Chinese Academy of Science, Shanghai, 200032 (China)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201406528.
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Oxazoline has been identified as a competent removable di-
recting group in primary C(sp3)ÀH functionalization, indicating
that it is a promising surrogate for pyridine or quinoline moiet-
ies.[6] Furthermore, chiral oxazoline rings are readily prepared
from the corresponding amino alcohols, which can potentially
control the diastereoselectivity in the secondary C(sp3)ÀH func-
tionalization. As reported, the geminal dimethyl structural unit
may be important to control the bite angle with Pd according
to the Thorpe–Ingold’s effect,[27] which may enhance the chela-
tion effect and the stability of metallacycles. Inspired by those
previous successes, we now design the a-amino oxazolinyl
moiety to promote both reactivity and selectivity in secondary
CÀH arylation (Scheme 1b). In this development, chemo-,
regio- as well as diastereoselectivity are well controlled by the
newly designed bidentate directing group.
catalyst, the substrate was completely converted and the opti-
mal result was obtained at a higher reaction temperature
(Table 1, entries 10–12). To investigate the critical effect of the
geminal dimethyl groups, we replaced the dimethyl linkage of
1a with different aliphatic rings. As predicted, none of these
substrates were comparable with 1a and the yields decreased
dramatically. The lack of methyl groups also led to inferior re-
sults in the arylation reaction (see the Supporting Information).
We further investigated the scope of aryl iodides under the
optimal conditions (Scheme 2). Various protected iodophenols
Our initial studies concerned the screening of reaction con-
ditions for the coupling between substrate 1a and phenyl
iodide 2a (Table 1). As expected, 1a was arylated at the sec-
ondary CÀH bonds in presence of Pd(OAc)2 as the catalyst
Table 1. Optimization of reaction conditions.
Entry
Additive
Solvent
Yield [%][a]
1
AcOH
t-AmylOH
28
2
PivOH
t-AmylOH
32
3
4
5
6
7[b]
8
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
(BnO)2PO2H
t-AmylOH
t-BuOH
CF3CH2OH
HFIP
43
48
52
55
58
68
47
72
HFIP
HFIP/DMSO (9:1)
HFIP/DMSO (8:2)
HFIP/DMSO (9:1)
HFIP/DMSO (9:1)
HFIP/DMSO (9:1)
9
10[c]
11[d]
12[c,d]
76
80 (66)[e]
[a] Unless otherwise stated, reactions were carried out at 0.1 mmol scale.
Yields were determined by 1H NMR spectroscopy with anisole as the in-
ternal standard; [b] 5.0 equiv of DMSO was added; [c] T=1208C,
[d] Pd(OPiv)2 was the catalyst; [e] yield of isolated product of a 0.2 mmol-
scale reaction in 1.0 mL solvent. AcOH=acetic acid; PivOH=pivalic acid;
Scheme 2. Pd-catalyzed secondary C(sp3)ÀH arylation of substrate 1a with
different aryl iodides 2b–m. Reactions were carried out at 0.2 mmol scale in
1.0 mL solvent for 12 h unless otherwise specified. Yields of isolated product
are given. [a] HFIP/DMSO (1.8 mL:0.2 mL); [b] HFIP/DMSO (1.8 mL:0.3 mL);
[c] HFIP/DMSO (0.9 mL:0.15 mL); [d] t=24 h.
(BnO)2PO2H=dibenzyl
phosphate;
t-AmylOH=2-methyl-2-butanol;
DMSO=dimethyl sulfoxide; HFIP=hexafluoro-2-propanol.
(Table 1, entry 1). Inspired by the results of Chen’s group,[28] we
also tested dibenzyl phosphate ((BnO)2PO2H) as an additive,
finding it to be more effective than carboxylic acids (entries 1–
3). In screening of solvents, we found that fluoroalcohols, par-
ticularly hexafluoro-2-propanol (HFIP), led to improved yields
(Table 1, entries 3–6). Further investigations revealed that addi-
tion of DMSO to the solvent was also critical for this reaction
(Table 1, entries 7–9). Finally, when we used Pd(OPiv)2 as the
gave moderate to good yields (3b–f). The acetamide-substitut-
ed aryl iodide was also tolerated, leaving the aryl CÀH bonds
unaffected (3g). The reaction was quite sensitive to steric hin-
drance. For example, 4-iodotoluene reacted smoothly with 1a,
whereas 2-iodotoluene completely failed to give the desired
product (3h and 3i). Reactions with electron-deficient aryl io-
dides gave reasonable results, albeit with low substrate con-
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version (3j–l). To our delight, other functional groups, such as
ester and bromide substituents, survived in the reaction
system, offering opportunities for further orthogonal transfor-
mations. Besides phenyl iodide derivatives, 2-iodonaphthalene
was also verified as an efficient coupling partner, giving 3m in
reasonable yield.
substrate with a longer carbon chain was also a successfully
arylated, albeit with a decreased yield (4i). Surprisingly, this
newly designed directing group was completely ineffective in
C(sp2)ÀH arylation of an aryl amide derivative and only the cor-
responding starting material (1j) was recovered. This specific
feature in C(sp3)ÀH bond chemoselectivity was distinct from
many other reported directing groups.
Next, we examined different amide derivatives (Scheme 3).
4-Arylbutanamide derivatives reacted smoothly with phenyl
iodide to generate 3,4-diarylbutanamides, leaving the more
active benzylic position unaffected. Either electron-donating or
Owing to the multiple active sites of the a-amino oxazoline
auxiliary, it was possible to carry out different transformations
upon it after the C(sp3)ÀH arylation. Actually, this directing
group was successfully removed by hydrolysis under acidic
conditions. The corresponding acid 5 was obtained in an excel-
lent yield (Scheme 4). Alternatively, the oxazoline ring could be
opened under very mild conditions to afford the amine trifluo-
roacetate intermediate 6. This intermediate easily underwent
different transformations, such as benzoylation, in one pot
(Scheme 4). These results might be built upon to create future
designs of transformable directing groups.
Scheme 4. Auxiliary cleavage and transformation.
As designed, the introduction of the oxazolinyl group afford-
ed the capability to input chiral elements. Thus, we set out to
prove our concept by exploring chiral oxazolines to control
the diastereoselectivity of secondary C(sp3)ÀH arylation. From
commercially available l-amino alcohols, substrates containing
chiral auxiliaries were prepared. Unfortunately, the diastereose-
lectivity was very low under the developed conditions (see the
Supporting Information). According to the substrate structure,
we considered that the chiral center was rather far away from
the reactive site; too far in principle to directly control the dia-
stereoselectivity by steric hindrance.
Scheme 3. Pd-catalyzed secondary C(sp3)ÀH arylation of amide derivatives
1b–j with phenyl iodide 2a. Reactions were carried out at 0.2 mmol scale
for 12 h unless otherwise specified. Yields of isolated product are given.
[a] 4-iodoanisole was used as the coupling partner and the reaction time
was 24 h; [b] 76% of starting material was recovered.
According to the previous studies, the concerted metala-
tion–deprotonation (CMD) pathway was proposed to facilitate
CÀH activation.[29] We hypothesized that the orientation of the
counterion participating in the CMD pathway could be in-
duced by the chirality of the oxazoline ring, which would help
to overcome the long distance between the directing group
and the secondary CÀH bond. The resultant enhancement in
the steric hindrance of the counterions would thus lead to
better diastereoselectivity. Indeed, when we used substrate 8
(Scheme 5), product 10a was obtained with good diastereose-
lectivity (d.r.=90:10) after the addition of NaOPiv. In agree-
ment with the former result, the arylation only took place at
electron-withdrawing groups located on the phenyl group
gave comparable yields (4b–e). Halides also survived the reac-
tion well (4d and 4e). Phthaloyl-protected 5-aminopentan-
amide was also a suitable substrate and an acceptable yield of
4 f was obtained. b-Arylpropanamide showed a relatively lower
reactivity (4g). The monoamide of a 1,4-diacid derivative ex-
hibited poor reactivity, although a sole regioisomer was isolat-
ed, showing the importance of the directing group (4h). A
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In conclusion, we have devel-
oped a modifiable amino oxazo-
line directing group to facilitate
the
Pd-catalyzed
secondary
C(sp3)ÀH arylation of amides.
This auxiliary exhibited multiple
functionalities to promote both
reactivity and site selectivity.
Chiral auxiliaries were used to
achieve the asymmetric sec-
ondary C(sp3)ÀH arylation by re-
layed chirality transfer. The de-
signed directing group could be
simply removed or converted
into other useful functional
groups. Efforts into improving
both the reactivity and diaste-
reoseletivity of this auxiliary-as-
sisted secondary C(sp3)ÀH func-
tionalization are currently under-
way in our laboratory.
Scheme 5. Exploration of diastereoselective secondary C(sp3)ÀH arylation by chiral directing groups. All reactions
were carried out at 0.1 mmol scale. The d.r. values of the products were determined from the e.r. values of corre-
sponding esters, which were obtained after the cleavage of the chiral auxiliaries and esterification.
the benzylic C(sp3)ÀH position, while the phenyl group on the
chiral auxiliary remained unaffected.
When we used 4-bromo-1-iodobenzene as the coupling re-
agent, we assigned the absolute configuration at the benzylic
site as S in the major diastereoisomer by comparing the analyt-
ical data with references (10b).[30] This result was beneficial for
us to understand the stereochemical process in the arylation
reaction. Furthermore, we could also prepare the product with
R configuration at the benzylic site with the same chiral auxili-
ary by simply exchanging the aryl groups between the sub-
strate and aryl iodide (10c). Notably, this reaction represents
the first case in which diastereoselective intermolecular cou-
pling takes place between two secondary geminal C(sp3)ÀH
bonds in linear molecules without any chiral center adjacent to
the reaction site.[31]
In light of previous studies and our observations on diaste-
reoselective control, we propose the mechanism depicted in
Scheme 6. The substrate first coordinates to Pd, positioning
the Pd center close to the corresponding C(sp3)ÀH bond to
form the intermediate A, which determines the diastereoselec-
Scheme 6. Proposed mechanism.
tivity of the whole reaction process. In the CÀH bond cleavage
step, the chiral space formed by the chiral auxiliary induces
the orientation of ligands on the Pd center. Thus, the sterically
Acknowledgement
hindered pivalate anion participates in the CMD process, coor-
dinating to Pd on the opposite side to the R’ group to mini-
This work was supported by the “973” Project from the Chi-
nese Ministry of Science and Technology (2009CB825300) and
the NSFC (Nos. 20925207 and 21002001). We also gratefully ac-
knowledge Prof. Qing-Hua Fan’s group in the Institute of
Chemistry, Chinese Academy of Science, Beijing for help with
chiral HPLC analysis.
mize steric repulsion. For the same reason, the R group adja-
cent to the secondary C(sp3)ÀH bond is oriented away from
the pivalate anion. This relayed effect facilitates chirality trans-
fer from the remote auxiliary to the reaction site and eventual-
ly leads to the observed diastereoselectivity.[32] The aryl iodide
then undergoes oxidative addition to the intermediate B to
generate the PdIV species C. Finally, reductive elimination takes
place to form the desired product and the Pd catalyst is regen-
erated to complete the catalytic cycle.
Keywords: arylation · directing groups · diastereoselectivity ·
oxazolines · palladium
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Received: December 17, 2014
Revised: February 16, 2015
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Published online on && &&, 0000
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
&
&
These are not the final page numbers! ÞÞ

Communication
COMMUNICATION
&
Directing Groups
K. Chen, Z.-W. Li, P.-X. Shen, H.-W. Zhao,
Z.-J. Shi*
&& – &&
Development of Modifiable Bidentate
Amino Oxazoline Directing Group for
Pd-Catalyzed Arylation of Secondary
CÀH Bonds
A new direction: A multifunctional
amino oxazoline directing group that is
readily available from amino acids, has
been developed, which can induce
chemo-, regio- and diastereoselectivity
in secondary C(sp3)ÀH arylation reac-
tions. Furthermore, this directing group
is removable and modifiable. Steric con-
trol and counterions play important
roles in the relayed chirality transfer.
&
&
Chem. Eur. J. 2015, 21, 1 – 6
www.chemeurj.org
6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÝÝ These are not the final page numbers!