Fe-Catalyzed Intramolecular Cross-Dehydrogenative Arylation (CDA), Efficient Synthesis of 1-Arylnaphthalenes and 4-Arylcoumarins

Article abstract of DOI:10.1002/hlca.202100056

Direct cross-dehydrogenative coupling of different inert C?H bonds is the most straightforward and environmentally benign method to construct C?C bonds. In this paper, we developed an iron-catalyzed intramolecular cross-dehydrogenative arylation (CDA) between benzylic C(sp³)H bond and aromatic C(sp²)H bond. From the readily available linear substrates, 1-arylnaphthalenes and 4-arylcoumarins can be quickly constructed with moderate to good yield (18 examples, up to 73 % yield) in one step. Both symmetrical and unsymmetrical substrates with different functional groups could tolerate this system well to form the anticipated products. A radical initiated dehydrogenative cyclization-dehydrogenation tandem process was proposed.

Full text of DOI:10.1002/hlca.202100056

HELVETICA
chimica acta
Accepted Article
Title: Fe Catalyzed Intramolecular Cross-Dehydrogenative-Arylation
(CDA), Efficient Synthesis of 1-Aryl Naphthalenes and 4-Aryl
Coumarins
Authors: Feng Liu, Haiyan Diao, Changcheng wang, Zhen Zhang, and
Zhangjie Shi
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10.1002/hlca.202100056
Helvetica Chimica Acta
HELVETICA
Fe Catalyzed Intramolecular Cross-Dehydrogenative-Arylation (CDA),
Efficient Synthesis of 1-Aryl Naphthalenes and 4-Aryl Coumarins
Haiyan Diao,a Changcheng Wang,b Zhen Zhang,a Zhangjie Shi,b and Feng Liu*,a,b
a School of Perfume and Aroma Technology, Shanghai Institute of Technology, 100 Haiquan Rd, Shanghai, 201418, China.
b Department of Chemistry, Fudan University, 2005 Songhu Rd, Shanghai, 200438, China. email liufeng@fudan.edu.cn
Dedication to Professor Peter Kündig on the occasion of his 75th birthday.
Direct cross dehydrogenative coupling of different inert C-H bonds is the most straightforward and environmentally benign method to construct C-C bonds.
In this paper, we developed an iron-catalyzed intramolecular Cross-Dehydrogenative-Arylation (CDA) between benzylic C(sp3)H bond and aromatic C(sp2)H
bond. From the readily available linear substrates, 1-aryl naphthalenes and 4-aryl coumarins can be quickly constructed with moderate to good yield (18
examples, up to 73% yield) in one step. Both symmetrical and unsymmetrical substrates with different functional groups could tolerate this system well to
form the anticipated products. A radical initiated dehydrogenative cyclization-dehydrogenation tandem process was proposed
Keywords: Cross-dehydrogenative-arylation, Fe-catalysed, radical, 1- aryl naphthalenes, 4- aryl coumarins.
(3-phenoxypropyl) benzene towards the synthesis of 1-aryl naphthalenes
Introduction
and 4-aryl coumarins (Scheme 1c).
Naphthalenes[1,2] and coumarins[3-6] are ubiquitous structural units in many
natural products, pharmaceutical synthetic intermediates, as well as
functional materials.[7,8] For example, Patentiflorin A[9] is a potent inhibitor
of drug-resistant HIV-1 strains identified from the medicinal plant Justicia
gendarussa. Justicidin B[10] exhibits a wide array of biological properties
ranges from piscicidal to antifungal, antiviral and antibacterial activities.
Mammea- A/AA[11] is the active compound of Mammea Africana stem bark
extract, exhibiting anticancer, antimicrobial, and antioxidant properties.
and MK-0633,[12] is a promising 5-lipoxygenase inhibitor (Scheme 1a). Over
the past decades, many efforts have been made to construct such motifs[13-
18,5,6,19-21]
.
However, the development of general and efficient
methodologies remains challenging and is still highly desired. Transition-
metal-catalyzed C-H bond functionalization could provide a green and
economical solution to synthesize valuable products from simple molecules,
has been employed as a powerful warhead in the pharmaceutical and
chemical industry.[22–34] C−H/C−H coupling reactions, which were well-
featured as cross-dehydrogenative-coupling reactions (CDC), offered a
complementary strategy to construct C−C bonds from two simple C−H
bonds directly.[35–52] Among all of the reported transition metals, Fe was
brought into focus because of its low toxicity, popular price, and
environmentally benign features.[53–60] Many excellent works of iron-
catalyzed CDC reactions involve C(sp3)H bond activation have been
reported.[36,61–71] In 2009, we developed
a Fe catalyzed cross
Scheme 1. a) Naphthalenes and coumarins in pharmaceuticals. b) Fe/DDQ catalyzed
cross dehydrogenative arylation. c) This work.
dehydrogenation coupling reaction of electron-rich aromatic hydrocarbons
and diphenylmethane.[36] (Scheme 1b). Based on our continuous research
on the field of transition-metal-catalyzed oxidative coupling of unactivated
C-H bonds,[36,72,73] we here developed an inexpensive, readily available
FeCl3/DDQ system to efficiently catalyze the tandem cross-
dehydrogenative arylation/oxidation reaction of 1, 4-diphenylbutane and
Results and Discussion
To initiate our study, 1, 4-diphenylbutane 1a was synthesized follow the
reported peocedure[74] as the model substrate (Table 1). At the beginning of
the reaction condition optimization, we found that DDQ (3.0 equiv) could
promote the oxidative coupling in the absence of metal catalyst in DCE at
1
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10.1002/hlca.202100056
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100 oC, to form 2a with 26 % yield (Table 1, entry 1). Different metal salts
were then screened, and FeCl3 gave a relatively high result (Table 1, entries
2-10. Table s1 and s2). The catalyst loading was then identified to 2.5 mol%
(Table 1, entry 12). Other solvents like CH3CN, 1,4-Dioxane, and MeNO2 still
works in this system but not as effective as DCE (Table 1, entries 14-16).
DDQ is essential to this oxidative coupling. No desired product was
monitored in the absence of DDQ, even large amount excess of FeCl3 was
used (Table 1, entry 17). Subsequently, we increased DDQ to 5 equivalents
to give 2a in 77 % yield (Table 1, entry 19).
CO2Me (2e), and -phenyl (2f) were introduced to 1,4-diphenylbutanes and
all could tolerate well to give corresponding 1-phenyl naphthalenes in
medium to good yield. For the electron-withdrawing-group-containing
substances like 1c-1e, a higher temperature (120 oC) was needed. As to 1c
and 1d, 4.5 equiv. of DDQ could give better results, form 2c and 2d with
68 % and 59% yield. The yield of 1,4-di-o-tolylbutane 1g was slightly lower
(45% isolated yield) than its para analog 1b, while they all met the same
over-oxidize issue. Then two asymmetric 1,4-diphenylbutane substrates 1h
and 1i were synthesized[76,77] and introduced to this system. For the reaction
of 1-(tert-butyl)-4-(2-methyl-4-phenylbutyl)benzene 1h, fascinating, good
regio selectively was conducted. This may derive from the highly steric
hindrance of the t-Bu group, which makes the ortho position hardly be
approached, to inhibiting the formation of another product. As to 1-methyl-
2-(4-phenylbutyl)benzene 1i, a 1:3 regio-selectivity was obtained to get 2i
and 2i‘. The results of the above two asymmetric substances 1h and 1i,
revealed that the cross-coupling between the benzylic C-H bond of the
alkyl-substituted benzene and the C(sp2)H bond of the unsubstituted
benzene was favored.
Table 1. Screening conditions.
Entry
Catalyst (mol%)
Oxidant
(equiv)
Solvent
Yield of
2a[b]
1
/
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
DDQ (3)
/
DCE
26
27
2
PdCl2 (5.0)
CuBr (5.0)
CoBr2∙xH2O
RhCl3 (5.0)
FeBr2 (5.0)
FeCl2 (5.0)
FeCl3 (5.0)
FeBr3 (5.0)
Fe(OAc)2 (5.0)
FeCl3 (1.25)
FeCl3 (2.5)
FeCl3 (10.0)
FeCl3 (2.5)
FeCl3 (2.5)
FeCl3 (2.5)
FeCl3 (300.0)
FeCl3 (2.5)
FeCl3 (2.5)
FeCl3 (2.5)
DCE
R1
R3
R2
3
DCE
28
28
29
57
R3
FeCl3 (2.5 mol%), DDQ (5.0 eq.)
DCE, 100 °C, 36 h
R1
4
DCE
R2
H
2
H
1
5
DCE
6
DCE
Me
F
Cl
7
DCE
60
61
32
8
DCE
F
Cl
2d, 59%[c]
Me
[c]
[a]
2a
, 73%
2c
2b
, 66%
, 68%
9
DCE
Me
10
11
12
13
14
15
16
17
18
19
20
DCE
55
Me
Ph
MeOOC
DCE
56
63
26
50
41
Me
DCE
tBu
Ph
2f, 64%
COOMe
[b]
DCE
[a]
[a]
2g
, 45%
2h
, 54%
2e
, 66%
Me
CH3CN
1,4-Dioxane
MeNO2
DCE
+
Me
49
0 c
[a]
[a]
2i'
, 32%
2i
, 9%
2k, 38%
2j
, 54%
DDQ (4)
DDQ (5)
DDQ (6)
DCE
70
Figure 1. Substrate scope for construction of 1-aryl naphthalenes. Reaction
conditions: 1 (0.2 mmol, 1.0 equiv), FeCl3 (2.5 mol%), DDQ (5.0 equiv), DCE (2.0 mL),
100 °C for 36 hours, under N2 atmosphere. [a] with 4.0 equiv DDQ. [b] 120 °C. [c] 1 (0.5
mmol, 1.0 equiv), 120 °C, DDQ (4.5 equiv). [d] Yield of 2i and 2i’ was calculated by 1H-
NMR.
DCE
77/73d
73
DCE
[a] Conditions: 1a (0.2 mmol, 1.0 equiv), catalyst, oxidant, solvent (2.0 mL),
100 °C for 36 hours, under N2 atmosphere. [b] Yield of 2a was determined by
1H-NMR using 1,3,5-trimethoxylbenzene as the internal standard. [c] No 2a
was produced even 3.0 eq. of FeCl3 was used. [d] Isolated yield. [e] More details
about the condition optimization could be found in the SI.
The cross oxidative coupling of 1,4-di(naphthalene-1-yl)butane 1j and 1,4-
di(naphthalene-2-yl)butane 1k ran well to form the corresponding fused
ring compound 2j, 2k. These two products could easily undergo a further
dehydrogenative coupling,[79–81] to form benzo[b]perylene and
dibenzo[de,qr]tetracene, which exhibited intriguingly photoelectric
performance in the functional materials.[82]
With the optimized reaction condition in hand, we then begin to explore the
substrate scope. Firstly, several symmetric 1,4-diphenylbutanes[74,75] were
investigated in this reaction system. While 1,4-di-p-tolylbutane 1b was used
as the starting material, we have to reduce the DDQ loading to 4 equiv. to
inhibit the over-oxidative by-product. To our delight, we still could get 2b in
good yield (66 %). Then different functional groups like -F (2c), -Cl (2d), -
We further extended this reaction system to the (3-phenoxypropyl)
benzene derivatives 3. To our delight, 4-aryl coumarins 4 could be obtained
with moderate yield under the standard reaction condition (Figure 2),
2
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10.1002/hlca.202100056
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accompany with a 3-phenylpropanal by-product, which was produeced
from the phenolic C-O bond cleavage and alcohol oxidation. Halogens like
F (4b, 35%), Cl (4c, 44%), Br (4d, 40%), and phenyl (4e, 51%), tert-butyl (4f,
44%) groups could tolerate the oxidative condition to form corresponding
4-aryl coumarins in one step. The first cross-dehydrogenative-couping step
of 1,2,3-trifluoro-5-(3-phenylpropoxy)benzene 3g ran smoothly, but the
following tandem oxidative process didn’t work well, even under higher
temperature (120 oC). Only 15% yield of 4g was formed, with 55% of 4g’.
Figure 3. Proposed mechanism for the intramolecular CDC reaction.
Conclusions
In summary, an iron-catalyzed tandem intramolecular CDA/oxidation
process for the synthesis of biologically and synthetically important 1-aryl
naphthalenes and 4-aryl coumarins was explored. In this system, DDQ was
essential for this tandem protocol. Polycyclic aromatic hydrocarbons,
which exhibits significant photoelectric performance, could also be
synthesized from this protocol. Further mechanistic exploration and
application investigation was underway in our lab.
Figure 2. 4-aryl coumarins obtained by the iron-catalyzed intramolecular cross-
dehydrogenative coupling of 3. Reaction conditions: 1 (0.2 mmol, 1.0 equiv), FeCl3 (2.5
mol%), DDQ (5.0 equiv), DCE (2.0 mL), 100 °C for 36 hours, under N2 atmosphere. [a]
120 °C.
To get more insight of the mechanism, a model reaction was performed
with 5.0 equiv of TEMPO, and the formation of 2a and 4a were completely
inhibited, which implies that a radical species may be involved in this
reaction (Scheme 2).
Experimental Section
General information
All chemicals were purchased from commercial suppliers and were used
without further purification Melting points were determined with an X-4
apparatus. 1H NMR and 13C NMR spectra were recorded on a Bruker 400
spectrometer operating at 400 MHz for 1H NMR, 101 MHz for 13C NMR with
CDCl3 as the solvent. Chemical shifts are reported relative to CDCl3 as an
internal standard. The 1H NMR data are reported as the chemical shift in
parts per million, multiplicity (s, singlet; d, doublet; dd, doublet of doublet; dq,
doublet of quartet; dt, doublet of quartet; t, triplet; m, multiplet; brs, broad
singlet.), coupling constant in Hertz (Hz), and number of protons. HRMS (EI,
FI, DART) were performed by the State-authorized Analytical Center in
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences. All
reported yields are isolated yields, unless otherwise noted.
Scheme 2. Radical quenching experiment.
Based on the above experimental results and the literature reports,[36,61,83,84]
we proposed a plausible mechanism for the intramolecular CDA reaction
(Fig. 3). Firstly, the benzylic C(sp3)-H bond of 1 or 3 is activated to generate
benzylic radical species A and the complex B; 2) an intramolecular radical
addition occurred to form the radical intermediate C; 3) C is quickly
captured by B to form intermediate D and released DDQH2 and FeCl3. 4)
Finally, D is further oxidized by DDQ to obtain the target product 2 (X = CH2)
General Procedures
To a 25 mL oven-dried Schlenk tube with magnetic stir bar, FeCl3 (2.5 mol%),
DDQ (5.0 equiv) was added, then the substrate (0.2 mmol, 1.0 equiv) and
2.0 mL DCE were added to the reaction mixture successively. Subsequently
the tube was pumped 3 times on the vacuum line with nitrogen. The tube
was sealed and stirred at 100 °C for 36 hours. The reaction mixture was
or 4 (X = O)[85-88]
.
3
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10.1002/hlca.202100056
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Spectroscopy and Molecular Dynamics Simulations Study', ACS Omega. 2019,
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cooled to room temperature, diluted with 10 mL DCM, filtered, and rinse
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purified by flash column chromatography on silica gel.
[12] F. Gosselin, R. A. Britton, I. W. Davies, S. J. Dolman, D. Gauvreau, R. S. Hoerrner,
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See supporting information for specific experimental operations and
structural characterization.
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Acknowledgments
We thank all colleagues and all the authors of the cited publications.
Financial support from NSFC (21988101, 21761132027, 22071029), Science
and Technology Commission of Shanghai Municipality (19XD1400800,
18JC1411300), Shanghai Municipal Education Commission (2017-01-07-00-
07-E00058), Key-Area Research and Development Program of Guangdong
Province (2020B010188001), and Shanghai Gaofeng & Gaoyuan Project
forUniversity Academic Program Development.
[14] S. Xiang, H. Hu, J. Ma, Y. Li, B. Wang, C. Feng, K. Zhao, P. Hu, X. Chen,
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[15] X. Zhang, S. Sarkar, R. C. Larock, ‘Synthesis of Naphthalenes and 2-Naphthols
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Author Contribution Statement
[17] C. Mahecha-Mahecha, F. Lecornué, S. Akinari, T. Charote, D. Gamba-Sánchez,
T. Ohwada, S. Thibaudeau, ‘Sequential Suzuki–Miyaura Coupling/Lewis Acid-
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Naphthalenes’, Org. Lett. 2020, 22, 6267-6271.
Dr. Feng Liu and Prof. Zhangjie Shi led this project. Haiyan Diao did most of
the experiments. Thanks to Changcheng Wang for discovering this subject
and giving suggestions. Zhen Zhang helped expanding the substrate scope
and repeat the experiment.
[18] L.-L. Chen, J.-W. Zhang, W.-W. Yang, J.-Y. Fu, J.-Y. Zhu, Y.-B. Wang, ‘Synthesis
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Alkynylphenyl)acetonitriles and Alkynones’, J. Org. Chem. 2019, 84, 8090-
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Fe Catalyzed Intramolecular Cross-Dehydrogenative-Arylation (CDA), Efficient Synthesis of 1-Aryl Naphthalenes and 4-Aryl
Coumarins
Twitter
From the easily available linear substrates, we developed an iron-catalyzed intramolecular Cross-Dehydrogenative-Arylation (CDA)
between benzylic C(sp3)H and aromatic C(sp2)H, which could easily construct 1-aryl naphthalenes and 4-aryl coumarins in one pot.
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