Synthesis of 6H-Benzo[c]chromenes via Palladium-Catalyzed Intramolecular Dehydrogenative Coupling of Two Aryl C-H Bonds

Article abstract of DOI:10.1021/acs.orglett.6b03763

The palladium-catalyzed intramolecular C-H/C-H coupling reaction of two simple arenes to generate 6H-benzo[c]chromenes has been reported for the first time. The approach features broad substrate scope and good tolerance of functional groups and uses molecular oxygen as the terminal oxidant. The high efficiency of the approach is verified by concise total synthesis of natural product cannabinol.

Full text of DOI:10.1021/acs.orglett.6b03763

Letter
pubs.acs.org/OrgLett
Synthesis of 6H‑Benzo[c]chromenes via Palladium-Catalyzed
Intramolecular Dehydrogenative Coupling of Two Aryl C−H Bonds
Dong-Dong Guo, Bin Li, Da-Yu Wang, Ya-Ru Gao, Shi-Huan Guo, Gao-Fei Pan,
and Yong-Qiang Wang*
Key Laboratory of Synthetic and Natural Functional Molecule Chemistry of Ministry of Education, Department of Chemistry &
Materials Science, Northwest University, Xi’an 710069, P.R. China
S
* Supporting Information
ABSTRACT: The palladium-catalyzed intramolecular C−H/
C−H coupling reaction of two simple arenes to generate 6H-
benzo[c]chromenes has been reported for the first time. The
approach features broad substrate scope and good tolerance of
functional groups and uses molecular oxygen as the terminal
oxidant. The high efficiency of the approach is verified by concise
total synthesis of natural product cannabinol.
6H-Benzo[c]chromenes are an important class of organic
compounds present in numerous natural products and bioactive
molecules.1 A typical natural product case is cannabinol, which
is a family member of the cannabionoids that can interact with
the G-protein coupled cellular receptors CB1 and CB2,2
exhibiting analgesic, antiemetic, anticonvulsant, antibiotic, and
psychotropic activities.3 Considering the potential utilities of
these molecules, the synthesis of 6H-benzo[c]chromenes
remains of long-standing interest in organic chemistry.4−6 In
view of the structural feature of 6H-benzo[c]chromenes, the
formation of the aryl−aryl bond is undoubtedly the key step.
Classically, the aryl−aryl bond can be reliably achieved by
cross-couplings of organometallic aryls with aryl halides
(Scheme 1, paths a and b).7 In the past decade, an attractive
access 6H-benzo[c]chromenes is the dehydrogenative coupling
of two nonactivated aryl C−H bonds to form the key aryl−aryl
bond (path d), particularly when the coupling can be
performed with molecular oxygen as the terminal oxidant.
But, to the best of our knowledge, there is no report in the
literature on employing the ideal strategy in the construction of
6H-benzo[c]chromene. The major hindrance to the ideal
strategy lies in two challenges:7d (i) the low reactivity of the
aryl C−H bond due to its high bond strength8 and (ii) the
regioselectivity issue especially when there are several reactive
sites; moreover, the dimerization is also unavoidable some-
times. Continuing our interest in the C−H bond activation, we
hypothesized that, in order to accomplish the ideal approach,
an appropriate direct group might be introduced into the arene
substrate to control the regioselectivity, simultaneously
enhancing the reactivity of the aryl C−H bond. Meanwhile
an efficient catalytic system should be sought. Herein, we
demonstrate this hypothesis to develop the first intramolecular
two aryl C−H bonds dehydrogenative coupling to construct
6H-benzo[c]chromenes. The high efficiency of the method is
verified by concise total synthesis of natural product
cannabinol.
Scheme 1. Routes to 6H-Benzo[c]chromenes
We began this study by examining the phenol protecting
group which had potential directing feature for the otho-
functionalization of arenes. A set of protecting groups was
tested with 10 mol % Pd(OAc)2 as the catalyst and oxygen as
the oxidant in dimethyl sulfoxide (DMSO) (Table 1). The
reaction did not occur at all when the protecting group was Ac,
−CONMe2, −CONEt2, or O-(2-pyridyl)carbonyl group,
although they were excellent directing groups in many
functionalization reactions of arenes (entries 1−4). These
experiments indicated the low reactivity of aryl C−H bond
once again. Gratifyingly, when the O-(2-pyridyl)sulfonyl group
alternative to this approach, namely the direct arylation of
nonactivated aryl C−H bonds with aryl halides (path c),4a,5,6
has been greatly developed. The approach often undergoes a
transition-metal-catalyzed coupling5 or a homolytic aromatic
substitution with aryl radicals.6 The advantage of the trans-
formation is obviating the need to work with organometallic
reagents. Nevertheless, the simplest and ideal approach to
Received: December 17, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03763
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Organic Letters
Letter
a
Table 1. Optimization of the Reaction Conditions
Scheme 2. Scope of the Two-Aryl C−H/C−H Coupling
Reaction
b
entry
cat.
PG
solvent
DMSO
yield (%)
1
2
3
4
5
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(OAc)2
−Ac
0
0
−CONMe2
−CONEt2
DMSO
DMSO
DMSO
DMSO
other solvent
HFIP
0
−CO(2-Py)
−SO2(2-Py)
−SO2(2-Py)
−SO2(2-Py)
−SO2(2-Py)
−SO2(2-Py)
−SO2(2-Py)
0
10
trace
85
86
52
0
c
6
7
8
HFIP
d
9
HFIP
e
10
HFIP
a
Reaction conditions: 1a (1 mmol), catalyst (0.1 mmol), and O2 (1
b
c
atm) in solvent (5 mL) for 15 h. Isolated yield. Other solvents:
CH2Cl2, ClCH2CH2Cl, EtOAc, DMF, THF, n-hexane, toluene, xylene,
anisole, acetone, CH3CN, dioxane, Et2O, CHCl3, HCONH2,
d
e
CH3NO2, EtOH, i-PrOH, t-BuOH. Using air as oxidant. Without
catalyst.
used as the protecting group, the desired aryl C−H/C−H
coupling product was generated albeit only in 10% yield (entry
5). We considered that the reactivity of the O-(2-pyridyl)-
sulfonyl group should attribute to its not only being good
directing group but also being a great activating group to
facilitate the formation of a phenyl−Pd complex through the
electrophilic substitution of the ortho C−H bond of phenol.9
Encouraged by the preliminary result, we then carefully
investigated various parameters of the reaction including
solvent, temperature, different metal catalysts, and their
loadings to improve the yield of the C−H/C−H coupling
reaction. It turned out that the solvent was critical for the
reaction efficiency, and 1,1,1,3,3,3-hexafluoro-2-propanol
(HFIP) combined with Pd(OAc)2 at 55 °C afforded the best
yield (85%) (entry 7). Pd(TFA)2 was also equally effective for
the reaction (entry 8). In view of the price concern, we further
carried out studies with Pd(OAc)2 as the catalyst. The reaction
rate and the yield were obviously dropped when air was used as
the oxidant instead of oxygen (entry 9). The reaction could not
happen without Pd(OAc)2 catalyst (entry 10).
With the optimal conditions in hand, we first examined the
effect of the substituent on the right aromatic ring for the aryl
C−H/C−H coupling (Scheme 2, 2b−t). A variety of aryls with
both electron-donating and electron-withdrawing groups could
be engaged in this transformation, providing the desired
benzochromenes in good to excellent yields. It should be noted
that the substrates with electron-withdrawing groups reacted
slightly faster than those with electron-donating groups. The
position of the substituent on the aromatic rings had almost no
effect on the reactivity (2b−d). A series of important functional
groups, including methyl, ethyl, tert-butyl, methoxy, −CF3,−-
OCF3, nitro, and phenyl were compatible with this procedure
(2b−m). Fluoro, chloro, and bromo groups were tolerated
under the reaction conditions (2n−r). This was a synthetically
interesting result because such substituents could be versatile
handles for further transformations. It is worth noting that, for
meta-substituted substrates that bear two potentially reactive
sites, the reactions only occurred at the less sterically hindered
position without the product of other position observed,
indicating that the reaction possessed complete regioselectivity
(2c, 2j, 2p). Disubstituted aryls were also suitable substrates,
affording the desired products 2s and 2t in 80% and 82% yields,
respectively. The structures of 2b, 2k, 2l, 2r, and 2t were
confirmed by single-crystal X-ray diffraction (see the Support-
ing Information).
Next, we investigated the substituents on the left phenol ring
(Scheme 2, 2u−aa). Again, the aryl C−H/C−H coupling
reaction was not insensitive to the steric hindrance and the
electronic property of the substituent groups. A series of
substituent groups with various properties (methyl, ethyl,
methoxy, bromo, CO2Me, and acetyl) tolerated the reaction
conditions, and the corresponding substrates all gave the
desired products in good yields. These results might allow high
diversity in the synthesis of functionalized 6H-benzo[c]-
chromenes. Finally, other heteroatom links were checked
(Scheme 2, 2ab−ad). Under the current reaction conditions,
the substrate replacing the oxygen atom with a sulfur atom did
not react to provide 6H-benzo[c]thiochromene, which was
likely attributed to the toxicity of sulfur to palladium catalyst.
Delightedly, N-methyl-N-phenylbenzamide reacted smoothly to
give 5-methylphenanthridin-6(5H)-one (2ab) in 53% yield
with the same reaction conditions, and the reaction also was
successfully extended to the construction of dibenzo[b,d]furans
(2ac, 2ad).
To gain insight into the reaction mechanism, we carried out a
series of experiments. First, dimethyl maleate ester was
introduced into the reaction system of 1aa in order to trap
the palladium intermediate with a Fujiwara−Moritani-type
alkenylation reaction (Scheme 3, eq 1). Pleasingly, the
alkenylation product (3aa) was obtained in 72% yield,
B
DOI: 10.1021/acs.orglett.6b03763
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Organic Letters
Letter
has also received substantial interest from the synthesis
community.13 Recently, Song et al. accomplished the total
synthesis of cannabinol using an intramolecular pyranone
Diels−Alder cycloaddition reaction as the key step.14 More
recently, Chi et al. developed a base-mediated [4 + 2] reaction
to construct the benzene ring and with it as the key step
finished the total synthesis of cannabinol.15 Our synthesis of
cannabinol started from compound 4, which could be obtained
from commercially available 5-pentyl-1,3-diphenol through two
steps in 78% overall yield (for details, see the Supporting
Information). Then, under our optimized conditions, intra-
molecular two aryl C−H/C−H coupling cyclization of 4
smoothly gave the 6H-benzo[c]chromene 5 in 85% yield
(Scheme 6). The oxidation of ether by PCC afforded lactone 6
Scheme 3. Alkenylation Reaction 1aa
indicating that the palladiation of the aromatic ring first occurs
likely at the ortho-position of the phenol. Subsequently, kinetic
isotope effect (KIE) experiments were performed (Scheme 4,
Scheme 4. Kinetic Isotope Effect
Scheme 6. Total Synthesis of Natural Product Cannabinol
eqs 2 and 3). The KIE value of two parallel competition
reactions of 1a and [D7]-1a was found to be 2.25 (Scheme 4,
eq 2), and the intramolecular KIE value for the reaction of [D]-
1a was 2.38 (Scheme 4, eq 3). These results implied an
electrophilic aromatic palladation mechanism is unlikely, and
the cleavage of the C−H bond on the right aromatic ring could
be involved in the rate-determining step. Furthermore, radical-
trapping experiments illustrated a low possibility for a free-
radical pathway.10
in excellent yield. Removal of the 2-pyridysulfonyl group was
easily achieved by reduction with zinc in NH4Cl (aq)/THF
(1:1) at room temperature in quantitative yield. Dimethylation
with MeLi followed by the treatment of TFA afforded natural
product cannabinol in 88% yield over two steps.
On the basis of the above results and relevant publications,11
a plausible mechanism is proposed in Scheme 5. Initially, the O-
In summary, we have developed the first palladium-catalyzed
intramolecular C−H/C−H coupling between two simple
arenes to construct 6H-benzo[c]chromenes. The approach is
featured by broad substrate scope, good tolerance of functional
groups, and use of molecular oxygen as the terminal oxidant.
Notably, the products are useful synthetic intermediates as
clearly demonstrated by efficient total synthesis of natural
product cannabinol with simple operation in 55% overall yield
from commercially available materials. Further studies to
expand the reaction and their applications as well as
investigations of the reaction mechanism are now in progress.
Scheme 5. Plausible Mechanism
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03763.
Experimental procedures, spectral data for all new
compounds, and crystallographic data (PDF)
X-ray data for compound 2b (CIF)
X-ray data for compound 2k (CIF)
X-ray data for compound 2l (CIF)
X-ray data for compound 2r (CIF)
X-ray data for compound 2t (CIF)
(2-pyridyl)sulfonyl group-directed palladation forms complex I,
which then undergoes a concerted metalation−deprotonation
(CMD) step to afford intermediate II. Finally, reductive
elimination of intermediate II produces the 6H-benzo[c]-
chromene products along with Pd(0), which is reoxidized by
O2 to regenerate the Pd(II) species to complete the catalytic
cycle.
To demonstrate the synthetic application of this method-
ology, we employed it as key step to synthesize natural product
cannabinol. Cannabinol is always a hot molecule in medicinal
chemistry due to its broad biological activities;12 therefore, it
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: wangyq@nwu.edu.cn.
C
DOI: 10.1021/acs.orglett.6b03763
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
ORCID
Letter
(9) (a) García-Rubia, A.; Arrayas
́
, R. G.; Carretero, J. C. Angew.
Chem., Int. Ed. 2009, 48, 6511. (b) García-Rubia, A.; Urones, B.;
Gomez Arrayas, R. G.; Carretero, J. C. Chem. - Eur. J. 2010, 16, 9676.
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Yong-Qiang Wang: 0000-0002-2774-3248
Notes
́
́
́
The authors declare no competing financial interest.
(10) In the presence of 1.0 equiv of 2,2,6,6-tetramethylpiperidine
oxide (TEMPO), the reaction of 1a proceeded well to give 2a in
almost the same yield.
(11) (a) García-Rubia, A.; Urones, B.; Gomez Arrayas, R. G.;
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Carretero, J. C. Chem. - Eur. J. 2010, 16, 9676. (b) Pintori, D. G.;
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ACKNOWLEDGMENTS
■
This research was supported by the National Natural Science
Foundation of China (NSFC-21572178 and -21272185).
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