Green and Rapid Access to Benzocoumarins via Direct Benzene Construction through Base-Mediated Formal [4+2] Reaction and Air Oxidation

Article abstract of DOI:10.1002/adsc.201500771

Benzocoumarin is an important structural motif widely found in natural products and synthetic molecules. Traditional methods for the synthesis of benzocoumarins and their derivatives require multiple steps, typically with an intramolecular ester forming reaction to make the lactone ring as the last step. Another major method involves transition metal-catalyzed coupling or carbon-hydrogen bond activation reactions starting with pre-existing aryl frameworks in the substrates. Here we report a new strategy for the green and rapid access to benzocoumarins and their derivatives. Our method uses readily available unsaturated aldehydes and coumarins as the substrates and air as the green oxidant. The overall reaction proceeds through a formal [4+2] process to construct a new benzene ring and thus to afford benzocoumarins in essentially a single step. No metal catalysts were used; no toxic or expensive reagents were involved. The power of our new approach is further demonstrated in a concise formal total synthesis of cannabinol, a bioactive natural product.

Full text of DOI:10.1002/adsc.201500771

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DOI: 10.1002/adsc.201500771
Green and Rapid Access to Benzocoumarins via Direct Benzene
Construction through Base-Mediated Formal [4+2] Reaction and
Air Oxidation
Chengli Mou,+a,b Tingshun Zhu,+b Pengcheng Zheng,a,b Song Yang,a
Bao-An Song,a,* and Yonggui Robin Chia,b,*
a
Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and
Agricultural Bioengineering, Ministry of Education, Guizhou University, Huaxi District, Guiyang 550025, Peopleꢀs
Republic of China
Fax: (+86)-0851-829-2170; phone: (+86)-0851-829-2171; e-mail: basong@gzu.edu.cn
Division of Chemistry & Biological Chemistry, School of Physical & Mathematical Sciences, Nanyang Technological
b
University, Singapore 637371, Singapore
E-mail: robinchi@ntu.edu.sg
+
These authors contributed equally.
Received: August 17, 2015; Revised: December 4, 2015; Published online: February 11, 2016
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201500771.
Abstract: Benzocoumarin is an important structural
motif widely found in natural products and synthet-
ic molecules. Traditional methods for the synthesis
of benzocoumarins and their derivatives require
multiple steps, typically with an intramolecular
ester forming reaction to make the lactone ring as
the last step. Another major method involves transi-
tion metal-catalyzed coupling or carbon-hydrogen
bond activation reactions starting with pre-existing
aryl frameworks in the substrates. Here we report
a new strategy for the green and rapid access to
benzocoumarins and their derivatives. Our method
uses readily available unsaturated aldehydes and
coumarins as the substrates and air as the green ox-
idant. The overall reaction proceeds through
a formal [4+2] process to construct a new benzene
ring and thus to afford benzocoumarins in essential-
ly a single step. No metal catalysts were used; no
toxic or expensive reagents were involved. The
power of our new approach is further demonstrated
in a concise formal total synthesis of cannabinol,
a bioactive natural product.
compounds and synthetic molecules with interesting
bioactivities. For example, cannabinol (Figure 1a),
which contains a derived dibenzopyran structure from
benzocoumarin, is a family member of the cannabi-
noids[1] that can interact with the G-protein coupled
receptors CB1 and CB2,[2] exhibiting a psychotropic
effect as well as analgestic,[3] antiemetic[4] and anticon-
vulsant[5] properties. Notably, natural cannabinoids
shows poor selectivities in differentiating the two re-
ceptors, and synthetic analogs with better selectivities
are being actively pursued.[6] Other important exam-
ples of bioactive benzocoumarin-type natural prod-
ucts include alternariol,[7] fasciculiferol,[8] autumnar-
iol,[9] and autumnariniol[9] (Figure 1a). In part due to
the potential utilities of these molecules, the synthesis
of benzocoumarins remains a long-standing interest in
organic chemistry. The dominating methods reported
to date require multiple steps with the formation of
the lactone ring (B ring as shown in Figure 1b) as the
key step. Transition metal-catalyzed reactions, such as
carbon-carbon couplings of two aryl rings,[10] CO in-
sertion,[11] and carbon-hydrogen bond activation,[12]
have been widely studied to form the lactone B ring
(Figure 1b). Metal-free approaches have also been ex-
plored, typically through a low yielding process in-
volving condensation of salicylaldehyde and cyclohex-
anone followed by pyran formation and aromatiza-
tion.[13]
Keywords: air oxidative aromatization; arene con-
struction; 3,4-benzocoumarins; cannabinol; cascade
reactions; transition metal-free condiitions
In contrast to the B-ring forming approaches that
involve multiple steps and catalysts/reagents that are
Benzocoumarins constitute a class of unique heterocy- expensive and/or toxic, strategies that focus on the
clic scaffolds widely present in naturally occurring construction of the C ring (the benzene unit) can pro-
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Chengli Mou et al.
Figure 1. Benzocoumarins and their synthesis.
vide new opportunities. Unfortunately, such ap- ing materials. Enals are commercially available or
proaches are rarely studied likely because in organic easily accessible; coumarins are either commercially
synthesis the construction of a new benzene ring is available or can be readily prepared in one step via
often avoided. In 2008, Deiters[14] developed an Ru- condensation of salicylaldehyde and ethyl acetoace-
catalyzed [2+2+2] trimerization method for the syn- tate (see the Supporting information).[20] In our ap-
thesis 3,4-benzocoumarins. In 2010, Bodewell[15] devel- proach,
a
simple base (DBU, 1,8-diazabicy-
oped an amine-catalyzed inverse electron demand clo[5.4.0]undec-7-ene) is used, and no expensive or
[4+2] Diels–Alder reaction for access to these com- toxic catalysts/reagents are involved. Air is used as
pounds.[16]
the green oxidant. The utility of our method is further
Our laboratories are interested in new strategies demonstrated in a concise formal total synthesis of
for the direct construction of aromatic rings that can cannabinol.
provide unusual short synthetic routes for functional
We started by using enal 1a and 3-acetylcoumarin
molecules. We recently report the N-heterocyclic car- 2a as the model substrates (Table 1). To our surprise,
bene–organic catalyst-mediated formal [3+3] reac- under the standard [3+3] benzene construction condi-
tion[17] (Figure 1c) and unsaturated aldehyde d-carbon tions,[17] the desired product 4a was obtained in only
activation[18] for the synthesis of the benzene unit.[19] 31% yield, together with a “demethyl” product 3a in
Here we report a new strategy for the construction of 48% yield (Table 1, entry 1). Use of a stronger base
the benzene framework as the C-ring in benzocou- such as DBU can even decrease the formation of 4a
marins and their derivatives (Figure 1b and d). Our (Table 1, entry 2). Further study showed that the
present method uses enals and coumarins as the start- NHC catalyst was not necessary in the formation of
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Table 1. Optimization of the reaction conditions.[a]
Entry
Catalyst
Oxidant
Base
Yield of 3a [%]
Yield of 4a [%]
1
2
3
4
5
6
7
IMes
IMes
TTBD
TTBD
TTBD
air
air
air
air
air
air
air
Cs2CO3
DBU
Cs2CO3
Cs2CO3
K2CO3
TBD
DBU
DBU
DBU
DBU
48
43
68
10
trace
12
30
61
75
31
14
0
0
0
0
0
0
0
–
–
–
–
–
–
–
–
8[b]
9[b,c]
10[b,c.d]
80
0
[a]
Reaction conditions: 0.1 mmol of 1a, 0.1 mmol of 2a, 0.10 mmol of base. 0.03 mmol of IMes, 0.2 mmol of TTBD, 1.0 mL
of THF. Yields are of isolated products based on 1a.
With CHCl3 as solvent.
0.05 mmol of 1a,0.1 mmol of 2a, 0.15 mmol of DBU, 0.5 mL of CHCl3.
With 50 mg 4Š MS.
[b]
[c]
[d]
3a (Table 1, entry 3). And we were also delighted to
find that air could replace TTBD (3,3’,5,5’-tetra-tert- substrate 2a (released as CH3COOH after the reac-
butyl-[1,1’-bi(cyclohexylidene)]-2,2’,5,5’-tetraene-4,4’- tion) could be replaced with other alkyl or aryl sub-
Notably, the CH3 group in the ketone moiety of
dione) as a cheap and green oxidant in the reaction, stituents, albeit with lower yields under the current
albeit in lower yield (Table 1, entry 4). Under these conditions optimized for substrate 2a (see the Sup-
air oxidation conditions, K2CO3 or Et3N could barely porting Information). The ketone moiety of 2a could
mediate the reaction (Table 1, entries 5 and 6). And also be replaced with an ester unit (see the Support-
in such cases, the substrates (nearly all 1a and most ing Information)
2a) remained unreacted. Strong bases such as TBD
The postulated reaction pathway of the reaction is
(1,5,7-triazabicylo[4.4.0]dec-5-ene) and LDA (lithium illustrated in Scheme 1. Deprotonation of the g-CH of
diisopropylamide) were not a suitable choice and only enal substrate 1a in the presence of a base gives a di-
low yields of 3a could be obtained due to the rapid enolate intermediate I. Michael-type addition of the
hydrolysis of 2a under the reaction conditions enal g-carbon of intermediate I to coumarin 2a forms
(Table 1, entry 6) (for the result with LDA, see the intermediate II that undergoes intramolecular aldol
Supporting Information). After further evaluation of reaction to form tricyclic intermediate III.[21] Subse-
the bases (see the Supporting Information) we found quent intramolecular acetal formation gives IV. Elimi-
that DBU could mediate the reaction with the forma- nation of an acetate[16c,22] from IV affords intermediate
tion of 3a in 30% yield (Table 1, entry 7). Solvents V that then undergoes spontaneous oxidative aroma-
could significantly affect the reaction yields (see the tization (with air as the oxidant) to complete the reac-
Supporting Information) and the use of CHCl3 as sol- tion cycle and give 3,4-benzocoumarin product 3a.
vent could give 3a in 61% yield (Table 1, entry 8). In
We next evaluated the scope of the substrates
all cases, hydrolysis of 2a was the main side reaction. (using conditions as in Table 1, entry 10). With 3-ace-
When two equivalents of 2a were used, product 3a tylcoumarin 2a as the model electrophile, several rep-
could be obtained in 75% yield (Table 1, entry 9). The resentative enal substrates were examined (Table 2).
reaction yield could be further improved to 80% by We first studied enals with an aryl and a methyl sub-
the addition of molecular sieves (Table 1, entry 10).
stituent at the b-carbon (products 3a–c). Different
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Chengli Mou et al.
substituents (3d, 3e) or different substituent patterns
(3f) on the b-phenyl ring of enals could all be tolerat-
ed. Replacement of the phenyl unit of the enal with
a naphthyl (3h, 3i) or heteroaryl (3g) unit worked
well too. In all cases, the E/Z mixture of the enals
could be directly used without affecting the reaction
outcomes. Notably, in addition to enals, aryl alde-
hydes bearing side alkyl substituents with an acidic
proton (such as indole-derived aldehyde) could be
used as well (3j). Next we found that enals with alkyl
substituents at the b-carbon (3k–n) could react effec-
tively as well. For example, the b-phenyl group of 2a
could be replaced with a methyl unit to afford prod-
uct 3k in 75% yield. Enals with a single substituent at
the enal b-carbon (3l–n) could also be used. Notably,
the substituent (R1) on the g-carbon of the enal led to
reduced reactivity of the enal substrate and enhanced
the difficulty of the oxidative aromatization process
(e.g., V to 3a, Scheme 1). For the reaction forming
products 3m and 3n, an elevated reaction temperature
(508C) was used; and the use of DDQ (2,3-dichloro-
5,6-dicyano-1,4-benzoquinone) as an oxidant was nec-
essary for the oxidative aromatization step to finally
form 3m and 3n (the reaction stopped at intermediate
V as illustrated in Scheme 1 when the reaction was
carried out under air).
Scheme 1. Postulated pathway.
Table 2. Scope of aldehydes.[a]
[a]
Reaction conditions as in Table 1 entry 10. Yields are of isolated products.
[b]
Reaction was carried out at 508C to give the dihydride of benzocoumarin, which successively oxidized by DDQ (1 equiv.)
in refluxing CH2Cl2 to give the product, yields are total isolated yields of the two steps, see the Supporting Information
for details.
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Table 3. Scope of the 3-acetylcoumarins.[a]
methylacrolein (enal substrate) via our formal [4+2]
benzene forming process under standard conditions
effectively gave 1.2 grams of adduct 7 in 80% yield.
Adduct 7 could be transformed to cannabinol via a 3-
step protocol (with 71% overall yield) as previously
reported.[12c,14] Our method is operationally simple
and green; and it involves shorter routes when com-
pared to previous methods. For example, Deitersꢀ[14]
elegant total synthesis of cannabionol reported in
2008 used 5 steps, including a Ru-catalyzed [2+2+2]
trimerization process, in transforming substrate 5 to
the adduct 7 (our method involves 2 steps)[12c,15b]
.
In conclusion, we have developed a new approach
for the rapid synthesis of benzocoumarin derivatives.
Instead of functionalizing pre-existing aromatic
frameworks, here we construct a new benzene ring
via a formal [4+2] process. All substrates are com-
mercially available or easily accessible, and air is used
as a green oxidant. The utility of our method was fur-
ther demonstrated in a formal total synthesis of a nat-
ural product cannabionol. The benzocoumarin moiety
is a common scaffold in both natural products and
functional synthetic molecules. Given the operational
[a]
Reaction conditions as in Table 1 entry 10. Yields are of
isolated products.
With enal 1a as a model nucleophile, several substi- simplicity and high efficiency, our synthetic approach
tuted 3-acetylcoumarins were then examined via new benzene formation is expected to find wide
(Table 3). Installing different substituents on the ben- applications for both small and large scale synthesis.
zene ring of substrate 2 was well tolerated (3o–t)
without further optimization of the conditions.
Our reaction provides a new approach for the rapid Experimental Section
synthesis of benzocoumarin-containing functional
molecules. Here we demonstrate the utility of our General Procedure for the Synthesis of 3,4-Benzo-
method through a formal total synthesis of cannabi- coumarins 3
nol,[1] a bioactive natural product that was found to
To a dry Schlenk tube equipped with a magnetic stir bar,
were added aldehyde 1a (0.1 mmol), coumarin 2a
exhibit several interesting bioactivities[3–5] (Scheme 2).
Briefly, Knoevenagel condensation of aldehyde 5 and
methyl acetoacetate efficiently gave 3-acetylcoumarin
6 in 94% yield (gram scale). Reaction of 6 with 3,3-di-
(0.2 mmol), 4Š MS (50 mg) and DBU (0.15 mmol). Freshly
anhydrous CHCl3 (0.5 mL) was added, and the reaction mix-
ture was stirred at room temperature until the aldehyde was
completely consumed (for 12 h, monitored by TLC). The re-
action mixture was concentrated under reduced pressure.
The resulting crude residue was purified via column chroma-
tography on silica gel (hexane/EtOAc) to afford the desired
3,4-benzocoumarin derivative product 3.
Acknowledgements
We acknowledge financial support by the Singapore National
Research Foundation, the Ministry of Education of Singa-
pore, Nanyang Technological University (NTU, Singapore),
Chinaꢀs National Key program for Basic Research (No.
2010CB 126105), “Thousand Talent Plan”, National Natural
Science Foundation of China (No. 21132003; No. 21472028),
Guizhou Province Returned Oversea Student Science and
Technology Activity Program, and Guizhou University
(China).
Scheme 2. Synthesis of cannabinol.
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