Directing Group Participated Benzylic C(sp3)-H/C(sp2)-H Cross-Dehydrogenative Coupling (CDC): Synthesis of Azapolycycles

Article abstract of DOI:10.1021/acs.orglett.7b03748

An efficient method to construct azapolycycles via directing group participated benzylic C(sp³)-H/C(sp²)-H cross-dehydrogenative coupling reactions is described. The reaction proceeded through a palladium catalyzed C(sp³)-H activation followed by coupling with a C(sp²)-H bond of quinoline to afford the azapolycyclic compounds. The reaction works with a broad substrate scope affording the products in moderate to good yields with excellent diastereoselectivities. Control experiments further supported the proposed mechanism.

Full text of DOI:10.1021/acs.orglett.7b03748

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Directing Group Participated Benzylic C(sp3)−H/C(sp2)−H Cross-
Dehydrogenative Coupling (CDC): Synthesis of Azapolycycles
Yaojia Jiang,*,† Gongtao Deng,† Shuaishuai Zhang,† and Teck-Peng Loh*,†,‡
†Institute of Advanced Synthesis, School of Chemistry and Molecular Engineering, Jiangsu National Synergetic Innovation Center for
Advanced Materials, Nanjing Tech University, Nanjing 211816, China
‡Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
Singapore 637616, Singapore
S
* Supporting Information
ABSTRACT: An efficient method to construct azapolycycles
via directing group participated benzylic C(sp3)−H/C(sp2)−
H cross-dehydrogenative coupling reactions is described. The
reaction proceeded through a palladium catalyzed C(sp3)−H
activation followed by coupling with a C(sp2)−H bond of
quinoline to afford the azapolycyclic compounds. The reaction
works with a broad substrate scope affording the products in
moderate to good yields with excellent diastereoselectivities.
Control experiments further supported the proposed mecha-
nism.
olycyclic compounds are featured widely in many
pharmaceuticals and advanced materials.1 Many of these
uncovered involving the initial C(sp3)−H bond activation.7
Another strategy employing oxidative single electron transfer
(SET) cross-coupling of C(sp3)−H/C(sp2)−H has also
recently been achieved by Wang (Scheme 1b).8 However, to
the best of our knowledge, there is no report on the use of
C(sp3)−H to construct fused rings in polycycles. During the
course of searching for new C(sp3)−H activation methods by
using amide 1 with 8-aminoquinoline9 as a bidentate directing
group in the presence of a palladium catalyst, we unexpectedly
obtained 2 in 11% yield.10 This result encouraged us to further
optimize the reaction conditions to develop a new method for
the construction of useful aza-polycycles. Herein, we disclose a
straightforward and efficient method for the construction of
aza-tricycles via palladium catalyzed C(sp3)−H/C(sp2)−H
cross-dehydrogenative coupling reactions. The reaction works
with a broad substrate scope affording the products in moderate
to good yields with excellent diastereoselectivities.
P
compounds have fused rings containing sp3/sp2 carbon−carbon
bond linkages.2 A direct and efficient strategy to access this
class of compounds is via an intramolecular C(sp3)−H/
C(sp2)−H cross-coupling reaction to construct the fused
rings.3 This strategy has recently been elegantly exploited by
the Fagnou,4 Shi,5 and Baudoin groups6 for the construction of
polycyclic compounds (Scheme 1a). In all these cases, the
reactions involved the initial C(sp2)−H activation followed by
coupling with a C(sp3)−H bond. There are also some limited
intermolecular CDC coupling examples that have been
Scheme 1. C(sp3)−H/C(sp2)−H Cross-Coupling Reactions
Initially, we explored the palladium catalyzed reactions using
2-(1, 3-dioxoisoindolin-2-yl)-3-phenyl-N-(quinolin-8-yl) prop-
anamide 1a as a substrate under different reaction conditions
(Table 1). As shown in Table 1, we found that when the
reaction was carried out in 10 mol % Pd(OAc)2, 15 mol % 2,2′-
bipyridine, and 2.0 equiv AgOAc in HFIP/HOAc at 160 °C
under N2 atmosphere, the desired product 2a was obtained in
the highest yield (77% isolated yield) (Table 1, entry 17) as a
single diastereomer. The structure of this product 2a was
determined by NMR spectroscopies and further confirmed by a
single crystal X-ray analysis (CCDC: 1579692) (Figure 1).
Received: December 6, 2017
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.7b03748
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
a b
,
Table 1. Reaction Conditions Optimization
Scheme 2. Substrate Scope
b
entry
ligand
PPh3
oxidant
solvent
DCE
yield
1
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
Ag2O
11
8
2
DPPP
DCE
3
1,10-phen
Dp-1,10-phen
Dm-2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
2,2′-bpy
DCE
49
43
49
54
20
30
29
15
−
17
11
60
−
4
DCE
5
DCE
6
DCE
7
DCE
8
AgNO3
AgF
DCE
9
DCE
10
11
13
14
15
16
17
AgOTf
Ag2CO3
AgOAc
AgOAc
AgOAc
AgOAc
AgOAc
DCE
DCE
TCE
PhCl
HFIP
DMSO
HFIP/HOAc
c
80/77
a
Unless otherwise noted, reactions were performed using 1a (0.2
mmol), catalyst (10 mol %), ligand (15 mol %), and oxidant (2.0
equiv) in solvent (0.1 M, 1 mL) at 160 °C for 72 h under a nitrogen
b
c
atmosphere. Yields determined by NMR vs standard. Isolated yield.
1,10-phen = 1,10-phenanthroline, Dp-1,10-phen = 4,7-diphenyl-1,10-
phenanthroline, Dm-2,2′-bpy = 5,5′-dimethyl-2,2′-bipyridine, 2,2′-bpy
= 2,2′-bipyridine, HFIP = hexafluoroisopropanol.
Figure 1. X-ray of 2a.
With the optimized reaction conditions in hand, we further
investigated the substrate scope of the reaction (Scheme 2).
Generally, the reactions tolerated a broad range of function-
alities to afford the substituted 4-phenyl-3,4-2H-1,10-phenan-
throline analogs in good yields with single diastereomers.
Subjecting chiral amino acid derivative 1a in the optimized
reaction conditions afforded 2a in 75% yield with complete
retention of the stereogenicity (99% ee). Substrates with a
halogen (F, Cl, Br, and I) substituted at the para-position of
phenyl ring were explored and found to furnish the desired
products in good yields (2b−2e). It should be noted that the
chloro, bromo, and iodo functionalities are common functional
groups used in coupling reactions,11 and this will allow further
transformation to other useful compounds. The electronic
effect was then studied by changing different substitutions on
the phenyl group. The result revealed that both substrates
containing electron-donating (2f−2i) and electron-withdrawing
(2j−2p) groups proceeded smoothly to afford the desired
products in moderate to good yields. Reactive functional groups
such as CN, ketone, and aldehyde groups are well tolerated
under these reaction conditions to give the corresponding
a
Unless otherwise noted, reactions were carried out using 1 (0.2
mmol), Pd(OAc)2 (10 mol %), 2, 2-bipyridine (15 mol %), and
AgOAc (2.0 equiv) in HFIP/HOAc (0.1 M, 2 mL) at 160 °C under a
nitrogen atmosphere, and the products are obtained as a single
b
c
diastereomer. Isolated yields. The ee value was determined by
HPLC analysis on a chiral stationary phase.
tricycles in 55%, 60%, 60%, and 76% yields, respectively (2n−
2q). Notably, the heterocycles indole group could also be used
in this reaction, affording the desired product in 51% yield (2r).
However, replacing the R = aryl group with an alkyl, alkenyl, or
alkynyl group led to no desired product (2aa−2ac). This result
B
DOI: 10.1021/acs.orglett.7b03748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
is consistent with C(sp3)−H work using the same substrate
A is involved in the reaction (Scheme 4c). On the basis of this
result, we proposed that the reaction first involved the
complexation of the palladium catalyst to the quinolone ring
followed by C(sp3)−H bond activation generating complex A
in a highly stereoselective manner. Coupling with the quinoline
7-site C(sp2)−H bond furnished the desired product.
Considering that 1,10-phenanthroline derivatives can also
function as important ligands in the transition metal catalyzed
reactions, we explored the possibility of oxidizing the obtained
products to substituted 1,10-phenanthroline derivatives
(Scheme 5). To our delight, the desired products were
reported by other groups.12
With these encouraging results in hand, we turned our
attention to the probable reaction pathways of this unique
C(sp3)−H/C(sp2)−H cross-coupling reaction (Scheme 3).
Scheme 3. Proposed Reaction Pathways
a b
,
Scheme 5. Transform to 1,10-Phenanthroline Derivatives
Initially, the reaction proceeded via an AQ directed benzylic
C(sp3)−H bond activation to generate palladium species A in a
stereoselective manner. This step has been well studied by
many different groups.13 Subsequently, this intermediate A
could proceed through two possible pathways leading to the
formation of either β-lactam B or intermediate D. The
intermediate A underwent reductive elimination to β-lactam
B (Scheme 3, pathway A). On the other hand, the palladium
species can also form complex C through C−N bond rotation
and activation of the C(sp2)−H bond of the 8-amino quinoline.
Reductive elimination with retention of the stereochemistry will
lead to the trans-product 4-phenyl-3,4-2H-1,10-phenanthroline
2.
a
Unless otherwise noted, reactions were carried out using 2 (0.2
mmol) and DDQ (1.5 equiv) in DCE (0.1 M, 2 mL) at 100 °C under
b
a nitrogen atmosphere. Isolated yields.
To understand the mechanism, we carried out a series of
control experiments. First, we conducted the reaction with 3.0
equiv of TEMPO. In this reaction, the desired product was
obtained in 21% yield with a 47% yield of the starting material
(Scheme 4a). This result, though not conclusive, showed that
obtained in good yields when DDQ was used as the oxidant.14
Various substituents including F, Br, CF3, and NO2 groups are
well tolerated in this reaction. These versatile functional groups
allow further transformations to other phenanthroline deriva-
tives.
Scheme 4. Control Experiments
In summary, an efficient method for the synthesis of
azapolycles was described. This method involves a palladium-
catalyzed C(sp3)−H bond functionalization followed by an
intramolecular coupling with the arene sp2 carbon to form an
sp3−sp2 carbon−carbon fused ring. This reaction tolerates a
wide range of functional groups (halogens, OMe, NO2, CF3,
CHO, etc.) and the desired products were obtained in
moderate to good yields with excellent diastereoselectivities.
Control experiments were explored, and the results supported
our proposed mechanism. Furthermore, the obtained products
were easily converted to 2-hydroyl-1,10-phenanthrolines which
are useful compounds in coordination chemistry. Further work
on the use of this strategy to construct other fused rings is in
progress.
this reaction may not proceed through a radical pathway.
Subjecting the β-lactam 4 to the reaction conditions led to
recovery of the starting material. Ring-expansion product 2a
was not detected in this reaction, indicating that the compound
4 was not the intermediate of the reaction (Scheme 4b).
However, when phenyl iodide was added into the reaction
mixture, the arylation product 5 was detected in 20% yield. This
further confirms that the C(sp3)−H bond activated Pd complex
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.7b03748.
■
S
Experimental procedures and characterization data for
new compounds (PDF)
C
DOI: 10.1021/acs.orglett.7b03748
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
(6) Shi, J.-L.; Wang, D.; Zhang, X.-S.; Li, X.-L.; Chen, Y.-Q.; Li, Y.-X.;
Shi, Z.-J. Nat. Commun. 2017, 8, 238.
CCDC 1579692 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing data_
request@ccdc.cam.ac.uk, or by contacting The Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge CB2
1EZ, UK; fax: +44 1223 336033.
(7) Examples on initial C(sp3)−H activation followed by
intermolecular cross-coupling with C(sp2)−H bond reactions:
(a) Wasa, M.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
3680−3681. (b) Wu, X.; Zhao, Y.; Ge, H. Chem. Sci. 2015, 6, 5978−
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AUTHOR INFORMATION
Corresponding Authors
■
(8) Wang, R.; Li, Y.; Jin, R.-X.; Wang, X.-S. Chem. Sci. 2017, 8, 3838−
*iamyjjiang@njtech.edu.cn.
*teckpeng@ntu.edu.sg.
ORCID
3842.
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Teck-Peng Loh: 0000-0002-2936-337X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors gratefully acknowledge funding from the National
Natural Science Foundation of China (21502089), Jiangsu
Province Funds Surface Project (BK 20161541), and the
Starting Funding of Research (39837107) from Nanjing Tech
University. We are also thankful for the financial support by
SICAM Fellowship by Jiangsu National Synergetic Innovation
Center for Advanced Materials. Dr. Li Yongxing (NTU) is
thanked for single crystal X-ray diffraction analysis.
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DOI: 10.1021/acs.orglett.7b03748
Org. Lett. XXXX, XXX, XXX−XXX