Synthesis of Polyheteroaromatic Compounds via Rhodium-Catalyzed Multiple C-H Bond Activation and Oxidative Annulation

Article abstract of DOI:10.1021/acs.orglett.5b02510

Polyheteroaromatic compounds are potential optoelectronic conjugated materials due to their electro- and photochemical properties. Transition-metal-catalyzed multiple C-H activation and sequential oxidative annulation allows rapidly assembling of those compounds from readily available starting materials. A rhodium-catalyzed cascade oxidative annulation of β-enamino esters or 4-aminocoumarins with internal alkynes is described to access those compounds, featuring multiple C-H/N-H bond cleavages and sequential C-C/C-N bond formations in one pot.

Full text of DOI:10.1021/acs.orglett.5b02510

Letter
pubs.acs.org/OrgLett
Synthesis of Polyheteroaromatic Compounds via Rhodium-Catalyzed
Multiple C−H Bond Activation and Oxidative Annulation
Shiyong Peng, Suna Liu, Sai Zhang, Shengyu Cao, and Jiangtao Sun*
School of Pharmaceutical Engineering & Life Science, and Jiangsu Key Laboratory of Advanced Catalytic Materials and Technology,
Changzhou University, Changzhou 213164, P. R. China
S
* Supporting Information
ABSTRACT: Polyheteroaromatic compounds are potential optoelectronic conjugated materials due to their electro- and
photochemical properties. Transition-metal-catalyzed multiple C−H activation and sequential oxidative annulation allows rapidly
assembling of those compounds from readily available starting materials. A rhodium-catalyzed cascade oxidative annulation of β-
enamino esters or 4-aminocoumarins with internal alkynes is described to access those compounds, featuring multiple C−H/N−
H bond cleavages and sequential C−C/C−N bond formations in one pot.
Scheme 1. Strategies toward Polyheteroaromatic
Compounds via Rh-Catalyzed Multiple C−H Activation
olycyclic heteroaromatic compounds have received con-
Psiderable attention due to their electrochemical and
photochemical properties as well as their potential utility as
organic electronics and luminescence materials.1 The prepara-
tion of such conjugated π-systems generally proceeds via a
transition-metal-catalyzed cross-coupling reaction, but multi-
step synthesis is often required.2 Thus, it is of great importance
to develop novel and efficient protocols to access those
compounds from readily available starting materials through
simple operations.
Transition-metal-catalyzed C−H bond activation affords a
powerful way for the rapid construction of structurally diverse
compounds from easily accessible starting materials.3 Following
this strategy, an array of complex polyheterocycles has been
easily prepared through multiple sequential C−H/N−H bond
activations and oxidative annulation from aromatic compounds
and alkynes (Scheme 1).4 For example, Miura and Satoh
described the synthesis of polyarenes and polysubstituted
isoquinolines.5 Li reported polycyclic amides synthesis by Rh-
catalyzed double C−H activation.6 Wang developed a Rh-
catalyzed cascade oxidative annulation of benzoylacetonitriles
with alkynes to afford naphtho[1,8-bc]pyrans.7 Recently,
Glorious demonstrated the preparation of polysubstituted
bisheterocycles from 1,3-diyne via a double Rh-catalyzed C−
H activation.8 Cheng and Chuang reported the synthesis of
highly substituted naphthyridine-based polyheteroaromatic
compounds through Rh-catalyzed procedures.9 Despite these
elegant approaches, the development of novel methodologies to
access polyheteroaromatic compounds is still in high demand.
Herein, we report our strategy on the rhodium-catalyzed
multiple C−H and N−H bond cleavages and sequential
oxidative annulation to prepare polycyclic heteroaromatic
compounds from β-enamino esters and 4-aminocoumarins
(which can be regarded as cyclic β-enamino esters).
Furthermore, although enamides have been widely employed
as valuable precursors in transition-metal-catalyzed C−H bond
activation to produce pyrroles and pyridines,10 to our
knowledge, the use of β-enamino esters in multiple C−H
bond activation has not been reported.11
Initially, we used alkyne 1a and unprotected β-enamino ester
2a as model substrates to test the feasibility of the reaction. To
our delight, the combination of [Cp*RhCl2]2 (5 mol %) and
Received: September 1, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02510
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Letter
Cu(OAc)2 (2 equiv) in DMF at 100 °C for 24 h afforded 3a in
73% yield (Table 1, entry 3). The structure of 3a was
Scheme 2. Scope of Rh-Catalyzed Tandem Oxidative
Annulation of β-Enamino Esters with Alkynes
a,b
a
Table 1. Optimization of the Reaction Conditions
b
entry
catalyst
oxidant
additive
solvent yield (%)
1
2
3
4
5
6
7
[Cp*RhCl2]2
DMF
DMF
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
[Cp*RhCl2]2
Pd(dppf)Cl2
[RhCl(COD)]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMSO
MeCN
DCE
73
<10
<10
Ag2CO3
c
8
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
CsOAc
AgSbF6
d
a
9
57
Reaction conditions: 1 (0.3 mmol), 2 (0.1 mmol), [Cp*RhCl2]2 (5
mol %), Cu(OAc)2 (0.2 mmol), DMF (2.0 mL), 100 °C, 24 h under
10
11
12
13
14
b
c
argon. Yields of isolated products. A mixture of two regioisomers; r:r
<10
61
46
20
48
30
74
1
∼ 3.6:1 based on H NMR analysis.
toluene
dioxane
DMF
DMF
DMF
3j). Subsequently, the unsymmetrical alkyne was examined but
afforded two isomers in a 3.6:1 ratio (3k). Notably, the N-
isobutyl-substituted β-enamino ester also worked well and gave
the desired polyheteroaromatic compound 3l in 67% yield.
Next, to demonstrate the generality of this protocol, we
turned to use 4-aminocoumarins as substrates, and the results
are summarized in Scheme 3. Different from β-enamino esters,
e
15
f
16
g
17
a
Reaction conditions: 1a (0.3 mmol), 2a (0.1 mmol), catalyst (5 mol
%), oxidant (0.2 mmol), solvent (2.0 mL), 100 °C, 24 h under argon.
b
c
d
e
Isolated yield. CsOAc (0.1 mmol). AgSbF6 (10 mol %). 1 mol %
f
of [Cp*RhCl2]2 was used, 48 h. 0.1 mmol of Cu(OAc)2 was used, 48
h. 0.4 mmol of Cu(OAc)2 was used.
g
Scheme 3. Scope of Rh-Catalyzed Tandem Oxidative
a,b
Annulation of 4-Aminocoumarins with Alkynes
confirmed by NMR spectroscopy and its high-resolution mass
spectrum, which had been further proved by X-ray analysis.12 In
the absence of an oxidant or rhodium catalyst, the reaction did
not occur (entries 1 and 2). In addition, the use of Pd(dppf)Cl2
or [RhCl(cod)]2 did not promote this transformation (entries 4
and 5). Other oxidants, such as AgOAc and Ag2CO3, resulted in
low conversion (entries 6 and 7). The effect of additive was also
investigated. The presence of a weak base such as CsOAc
totally deterred the reaction (entry 8). The addition of AgSbF6
was also detrimental and led to moderate yield (entry 9).
Solvent screening disclosed that 1,2-dichloroethane (DCE) and
toluene were also effective but gave 3a in moderate yields
(entries 12 and 13). In contrast, the use of dimethyl sulfoxide
(DMSO), acetonitrile (MeCN), and dioxane gave low yields
(entries 10, 11, and 14). Moreover, low catalyst loading also
resulted in significantly lower yield of 3a (entry 15).
Furthermore, reducing the amount of Cu(OAc)2 to 1 equiv
also led to low yield of 3a (entry 16). In contrast, 4 equiv of
Cu(OAc)2 gave a yield to that of entry 3 (entry 17).
Under the optimal reaction conditions (Table 1, entry 3), the
substrate scope of internal alkynes and β-enamino esters has
been further investigated (Scheme 2). The reaction of 1,2-
diphenylethyne 1a with para-substituted aryl β-enamino esters
gave the corresponding products in acceptable yields (3b−d).
The reaction of 1,2-bis(4-fluorophenyl)ethyne with 2a or para-
substituted aryl β-enamino esters also provided the desired
products in moderate yields (3e−h). 1,2-Di-3-methyl- or 3-
methoxyphenyethyne were also tolerated in this reaction and
gave the corresponding products in moderate yields (3i and
a
Reaction conditions: 1 (0.3 mmol), 4 (0.1 mmol), [Cp*RhCl2]2 (5
mol %), Cu(OAc)2 (0.2 mmol), DMF (2.0 mL), 100 °C, 24 h under
b
argon. Yield of isolated products.
the 4-aminocoumarins contain only one hydrogen atom at the
ortho position of the phenyl moiety. Thus, the reaction pathway
might be quite different. Indeed, under the same reaction
conditions (Table 1, entry 3), the tandem multiple C−H
activation and sequential annulation occurred smoothly to give
the corresponding products in moderate to high yields. The
structure of 5 was determined by NMR and HRMS analysis
B
DOI: 10.1021/acs.orglett.5b02510
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and further confirmed by X-ray diffraction analysis of single
crystals of 5a and 5d.12 Next, the reaction of alkyne 1a with
various substituted 4-aminocoumarins was performed. The
electron-rich 4-aminocoumarins gave the corresponding
products in higher yield than the electron-deficient ones (5b,
5c, 5f, 5g to 5d and 5e). Specially, compound 5c was isolated in
91% yield. Next, the reactions between 4a and various alkynes
were carried out. As observed, the electron-rich alkynes gave
the corresponding products in higher yields than the electron-
deficient alkynes (5h and 5i to 5j and 5k). The 3-methyl- or
methoxy-substituted diphenylalkynes also proceeded well to
give the desired products in moderate yields (5l and 5m).
To better understand the reaction mechanism, control
experiments were conducted (Scheme 4). Under standard
On the basis of the above results, plausible reaction
mechanisms are proposed (Scheme 5). For the reaction of 1a
Scheme 5. Proposed Reaction Mechanisms
Scheme 4. Control Experiments
with 2a, coordination of the enamine N atom of 2a to RhIII
followed by ortho C−H activation generates rhodacycle A.
Next, coordinative insertion of 1a into the Rh−C bond leads to
seven-membered rhodacycle B. Reductive elimination of B
provides intermediate 6′ and the RhI species, which has been
reoxidized to the RhIII species. Further C−H activation of 6′
would likely give rise to Rh−C intermediate C-1 or C-2.7
Insertion of another molecule of 1a into the Rh−C bond
provides seven-membered rhodacycle D-1 or D-2, which
subsequently undergoes reductive elimination to afford 3a as
the final product and regenerate active RhIII species by
Cu(OAc)2.7 Similarly, coordination of the aminocoumarin
(4a) nitrogen atom to RhIII followed by C−H activation of the
phenyl ring affords five-membered rhodacycle E, which
undergoes alkyne insertion into the Rh−C bond to generate
rhodacycle F. Reductive elimination of F then provides
intermediate G. Next, this intermediate would undergo another
C−H and N−H cleavage followed by alkyne insertion and
reductive elimination to afford final product 5a.
The solubility of larger polyheteroaromatic compounds is
often problematic. However, compounds 3 and 5 have very
good solubility in dichloromethane and chloroform at ambient
temperature (>10−3 M). To further understand the physical
properties of these polyheteroaromatic compounds, we
performed the measurement of absorption and emission
spectra of 3a, 3c, 3d, 3i, 5a, 5c, 5k, and 5i in dichloromethane
(Figure 1). The fluorescence spectra of 3a and 3i show
emission maxima at 450−470 nm with broad bandwidths and
weak intensities (see the Supporting Information).
reaction conditions, the reaction of 2a and 1a in a 2:1 ratio led
to the isolation of 6 (72% yield) and 7 (9% yield) in an 8:1
ratio (Scheme 4, a), which indicated that the oxidative cleavage
of the C−H bond of the phenyl ring and N−H bond were
preferred rather than the annulation of C(sp2)−H of the
enamine moiety with the C−H bond of the phenyl ring.
However, treatment of 6 with 1a in the presence of
[Cp*RhCl2]2 (5 mol %) and Cu(OAc)2 (2 equiv) led to a
messy reaction (Scheme 4, b), which indicated the reaction
probably involved the initial formation of 6′ followed by
isomerization to more stable 6. Furthermore, the reaction of 2
equiv of 2e with 1 equiv of 1a provided 3l′ as the major isomer,
which can be further converted to 3l under standard conditions.
Next, when alkyne 8 was used, the pyrrole 9 was obtained in
92% yield (Scheme 4, d).12 Next, the reaction of N-substituted
4-aminocoumarins 10a and 10b with 1a were performed
(Scheme 4, e). The oxidative annulation of N−H bond with
C−H bond of phenyl ring occurred and gave the corresponding
products 11a and 11b in 97% and 82% yield, respectively,
whereas the fused pyrroles were not detected, which is quite
different from the palladium-catalyzed procedure.13 However,
the reaction of 4a with 8 led to the formation of fused pyrrole
12 in 95% yield (Scheme 4, f).
In summary, we have demonstrated the rhodium-catalyzed
multiple C−H bond activation of β-enamino esters and 4-
aminocoumarins and tandem oxidative annulation with internal
alkynes to afford polycyclic heteroaromatic compounds in
moderate to high yields. Plausible reaction mechanisms for the
oxidative tandem annulation have been proposed. We
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DOI: 10.1021/acs.orglett.5b02510
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02510.
■
S
Experimental procedures along with characterization data
and copies of NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jtsun08@gmail.com, jtsun@cczu.edu.cn.
Notes
(11) (a) Ke, J.; He, C.; Liu, H.; Li, M.; Lei, A. Chem. Commun. 2013,
49, 7549. (b) Gao, P.; Liu, J.; Wei, Y. Org. Lett. 2013, 15, 2872.
(c) Senadi, G. C.; Hu, W.-P.; Garkhedkar, A. M.; Boominathan, S. S.
K.; Wang, J.-J. Chem. Commun. 2015, 51, 13795.
(12) See the Supporting Information for the X-ray structure. CCDC
1418480 (3a), 1418481 (5a), 1418482 (5d), and 1418483 (9) contain
the supplementary crystallographic data for this paper. These data can
be obtained free of charge from the Cambridge Crystallographic Data
Centre via www.ccdc.cam.ac.uk/data_request/cif.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF of China (No. 21172023), a project funded
by the Priority Academic Program Development of Jiangsu
Higher Education Institutions, and Jiangsu Key Laboratory of
Advanced Catalytic Materials and Technology (BM2012110)
for their financial support.
(13) Peng, S.; Wang, L.; Huang, J.; Sun, S.; Guo, H.; Wang, J. Adv.
Synth. Catal. 2013, 355, 2550.
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