Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation of Enaminones with Vinyl Esters through C-H Bond Functionalization

Article abstract of DOI:10.1021/acs.orglett.8b03284

An expedient [5 + 1] annulation method via Rh(III)-catalyzed C-H bond functionalization of enaminones to synthesize polyaromatic rings is described. The reaction tolerates a broad range of functional groups and offers a new entry to construct polycyclic a

Full text of DOI:10.1021/acs.orglett.8b03284

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Polyaromatic Rings: Rh(III)-Catalyzed [5 + 1] Annulation
of Enaminones with Vinyl Esters through C−H Bond
Functionalization
Gaohui Liang,† Jiaxin Rong,† Wangbin Sun,† Gengjia Chen,† Yaojia Jiang,*,† 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 expedient [5 + 1] annulation method via
Rh(III)-catalyzed C−H bond functionalization of enaminones
to synthesize polyaromatic rings is described. The reaction
tolerates a broad range of functional groups and offers a new
entry to construct polycyclic aromatic compounds with amino
and formyl substituents. A possible reaction mechanism was
proposed based on the results obtained from isotope labeling
experiments.
ransition-metal-catalyzed C−H activation has gained
Twidespread applications in the total synthesis of natural
products1 and materials science research.2 Since the pioneering
work by Fagnou and Guimond in 2010 on the use of
[Cp*RhCl2]2-catalyzed C(sp2)−H functionalization,3 applica-
tion of this method utilizing a nitrogen-containing auxiliary as a
directinggroup coupledwith annulation of the unsaturated C−C
bond to synthesize aza-heterocycles have witnessed remarkable
progress.4 However, it has been a challenging task to construct
carbocyclic compounds by this strategy since heteroatoms in the
directing group may participate in the reaction to form
heterocycles instead.5 To overcome this problem, a less strong
directing group is highly desirable for the Rh(III)-catalyzed
C(sp2)−H functionalization.6
As part of our continued interest in the C−H bond
functionalization of enamines7 as well as in the development of
practical methods to access polyaromatic compounds,8 we
envisioned that using ketones as weak directing groups may be
possible to install functionalized carbocyclic compounds via
multiple sp2 C−H functionalizations. Recently, Zhu’s group has
developed an elegant method to access aromatic rings based on
the [4+ 2] annulation of enaminoneswith either alkynesor diazo
compounds.9 Herein, wedemonstrateforthefirsttimeaRh(III)-
catalyzed [5 + 1] annulation of enaminones and vinyl esters to
construct useful functionalized polyaromatic rings through
multiple C−H bond functionalizations (Figure 1).10 The
obtained 1,4-substituted polyaromatic derivatives carrying an
electron-donating amino group and an electron-deficient formyl
group are located in opposite position of aromatics leading to
push−pull electronic structure; this method could potentially be
applied to the discovery of efficient fluorescent probes in
biological and material science.11
Figure 1. Rhodium-catalyzed C−H functionalization.
Wefirstexploredthepossibilityofannulationofenaminone1a
withvinylpivalate2inthepresenceofRh(III)catalystandKOAc
with different oxidants in DCE at 125 °C (Table 1, entries 1−4).
The annulation product 4-(dimethylamino)-1-naphthaldeh-
hyde 3a was obtained when copper oxidants were employed,
while other commonly used oxidants such as silver and
PhI(OAc)2 failed to promote the reaction. The structure of
this product 3 was determined by NMR spectroscopies and
further confirmed by a single crystal X-ray analysis of 3m
(CCDC: 1524569) (Scheme 1). Screening other bases found
that inorganic bases displayed higher reactivities compared to
organic bases in the reaction (Table 1, entries 5−7). Enamines
normallyaresensitivetoacid,andthereactionmightgeneratethe
Received: October 14, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03284
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
a,b
Table 1. Reaction Conditions Optimization
Scheme 1. Substrate Scope
b
entry
catalyst
oxidant
base
additive yield (%)
1
2
3
4
5
6
7
8
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
[RhCp*Cl2]2
Cu(OAc)2
CuOAc
AgOAc
KOAc
KOAc
KOAc
KOAc
K2CO3
KOH
66
46
0
PIDA
0
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
45
50
0
71
67
56
82
0
TEA
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
LiOH
NaOH
KOH
LiOH
LiOH
LiOH
9
10
11
12
13
c
[RhCp*Cl2]2
0
a
Conditions: a mixture of 1a (0.15 mmol, 1.0 equiv), 2 (0.75 mmol,
5.0 equiv), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (0.225 mmol, 1.5
equiv), KOAc (0.09 mmol, 0.6 equiv), LiOH (0.225 mmol, 1.5
equiv), 4 Å MS (100 mg), and DCE (1.5 mL) was sealed in Schlenk
tube under nitrogen atmosphere, and the mixture was stirred until the
b
c
1a was consumed completely. Isolated yield. 100 mg 4 Å MS was
added.
pivalic acid. Therefore, additional base additives were examined
to modify the pH of the catalytic system (Table 1, entries 8−10).
Remarkably, LiOH effectively promoted the reaction, and the
desired product was obtained in 71% yield (Table 1, entry 8).
Finally, the reaction was carried out with 2.5 mol % of
[RhCp*Cl2]2, 2.0 equiv of Cu(OAc)2, 0.6 equiv of KOAc, 1.5
equivofLiOH, and 100mgof4ÅMSinDCEat 125°CunderN2
atmosphere, and the desired product 3a was obtained in the
highest yield (82%) (Table 1, entry 11). Control experiments
performed in the absence of Rh catalyst or oxidant led to no
desired product 3a (Table 1, entries 12−13).
With the optimized reaction conditions in hand, we proceeded
to screen the substrate scope of the reaction (Scheme 1). Overall,
a broad range of functional groups was tolerated, and the
corresponding products were obtained in moderate to good
yields. Enaminones with aryl groups bearing methyl groups both
at the para and meta positions were subjected to the optimized
reaction conditions, and the corresponding 4-amino-naphthal-
dehydes were obtained in 75% and 60% yields, respectively (3b
and 3c). Unfortunately, ortho-substitued groups failed to react
and recovered the starting material completely (3v−3x).
Halogenic substituents (F, Cl, Br, and I) at the para-position of
thephenylgroups were welltolerated (3d−3g). Itisimportantto
note that the bromo and iodo functional groups could be further
transformed in many known coupling reactions.12 Enaminones
with aryl groups bearing electron-donating and electron-
withdrawing groups were then explored to the standard reaction
conditions to examine the electronic effect. The result revealed
that substrates containing electron-donating groups (3h and 3i)
proceeded more efficiently compared to those containing
electron-withdrawing (3j−3m) groups. Remarkably, when
enaminones with polycyclic aromatic groups as substrates were
employed using this new method, it has the potential to afford
amino polycyclic aromatic aldehyde compounds, which have
a
Conditions: a mixture of 1 (0.20 mmol, 1.0 equiv), 2 (1.0 mmol, 5.0
equiv), [RhCp*Cl2]2 (2.5 mol %), Cu(OAc)2 (0.30 mmol, 1.5 equiv),
KOAc (1.2 mmol, 0.6 equiv), LiOH (0.30 mmol, 1.5 equiv), 4 Å MS
(135 mg), and DCE (2.0 mL) was sealed in a Schlenk tube under a
nitrogen atmosphere, and the mixture was stirred until 1 was
b
consumed completely. Isolated yields.
great applications in material science. Indeed, the corresponding
products could be obtained in synthetically useful yields ranging
from 47% to 54% (3n−3p). Changing N-substituents from
dimethyl to other alkyl and aryl groups, the desired annulation
products were obtained in moderate to good yields, either with
acyclic or cyclic amino substitutions (3q−3u).
With these encouraging results in hand, we carried out a series
of experiments to explore the reaction mechanism (Scheme 2a).
Initially, we carried out the experiment using the γ-carbon 13
C
isotope labeled of enaminone 1a under the optimized reaction
conditions. NMR spectroscopic analysis (DEPT-135, HMQC,
and HMBC) indicated that the 13C labeled carbon is directly
attached to the nitrogen. This result shows that the nitrogen
group of the enaminone has migrated to the γ-carbon. In
addition, when we carried out crossover experiments using
enaminone 1b and 1t, we observed four different products (3b,
B
DOI: 10.1021/acs.orglett.8b03284
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Scheme 2. 13C Labelling and Control Experiments
rhodium in activation C−H bonds of the phenyl group.
Interestingly, we also found that the β−C−H bond of the
enaminone was deuterated in the presence of either D2O or
CH3COOD. To rule out the possibility of enaminone reacting
with the acid, we carried out the reaction in the absence of vinyl
pivalate 2 under the standard conditions (Scheme 3c). No
isotope-labeled β−C−H bond was observed, indicating that the
isotope-labeled product was most probably derived from a C−H
bond functionalization assisted by rhodium (Scheme 4,
Scheme 4. Proposed Reaction Mechanism
3x, 3t, and 3a), indicating that the migration is an intermolecular
reaction (Scheme 2b).
intermediate F). Finally, we employed H218O under the standard
reaction conditions. The 18O labeling product was obtained in
the formyl group. It supports the proposed that the formyl group
may undergo a hydrolysis process.
Next, we carried out the reactions in the presence of D2O and
CH3COOD to probe the sites of the C−H bond functionaliza-
tion. In this experiment, the obtained the products deuterium
labeled at the ortho-position of the enaminone’s phenyl group
3ab and 3ac with 27% and 20% deuterium, respectively (Scheme
3a,b). This result provides evidence of the possibility that the
ketone is functioning as a weak directing group to assist the
On the basis of the above experiments, we propose a possible
reactionpathwayasdepictedin Scheme4. Initially, [RhCp*Cl2]2
activates the ortho-position of the phenyl group via a weak keto
coordination to generate intermediate A. Migratory insertion of
vinyl pivatate 2 via intermediate B to form rhodium complex C
followed by β-H elimination provides intermediate D. After
rotation of the C−C bond, a pivalate-mediated C−H activation
forms complex E. Next, a six-membered cyclic intermediate F is
generated through reductive elimination. The amino group may
then be released with the Rh complex and consequently
condense with the keto group to give G. The desired product
3a is finally obtained through hydrolysis and aromatization.
A large scale experiment was explored to investigate the
potential applications both in academic and industrial
laboratories (Scheme 5). The reaction proceeded efficiently on
5 mmol scale of 1a, albeit in slightly decreased yield (45%). The
obtained 4-(dimethylamino)-1-naphthaldehyde 3a could be
decorated both in the formyl and the amino groups. For example,
theformylgroupcouldbecondensedwithmalonate,13 olefinated
with MePPh3Br,14 and reacted with Grignard reagent15 (78%,
73%, and 82%). Furthermore, the amino group could also be
functionalized to attach NO/NO2.16
Scheme 3. Reaction Mechanism Study
In summary, we have described an expedient [5 + 1]
annulation method to synthesize polyaromatic rings via Rh-
(III)-catalyzed C−H activation of enaminones. The reaction
C
DOI: 10.1021/acs.orglett.8b03284
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Materials. Dr. Li Yongxing (NTU) is thanked for single crystal X-
ray diffraction analysis.
Scheme 5. Transformation of Functional Groups
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ASSOCIATED CONTENT
* Supporting Information
■
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The Supporting Information is available free of charge on the
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Experimental procedures and characterization data for
new compounds (PDF)
Accession Codes
CCDC 1524569 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.
AUTHOR INFORMATION
Corresponding Authors
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*E-mail: iamyjjiang@njtech.edu.cn.
*E-mail: teckpeng@ntu.edu.sg.
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ORCID
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
ProvinceFundsSurfaceProject(BK20161541), andtheStarting
FundingofResearch (39837107)fromNanjingTechUniversity.
We also thank the financial support by SICAM Fellowship by
Jiangsu National Synergetic Innovation Center for Advanced
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