A cascade Claisen rearrangement/o-quinone methide formation/electrocyclization approach to 2H-chromenes

Article abstract of DOI:10.1039/c7cc03037a

A new approach has been developed for the synthesis of 8-substituted 2H-chromenes, featuring a novel cascade aromatic Claisen rearrangement/o-quinone methide formation/6π-electrocyclization. This new method was demonstrated with 28 examples tolerating different substitutions at alkenes, allylic and aromatic ring and with total syntheses of three 2H-chromene natural products.

Full text of DOI:10.1039/c7cc03037a

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A Cascade Claisen Rearrangement/o-Quinone Methide
Formation/Electrocyclization Approach to 2H-Chromenes
Liyan Songa*, Fang Huanga, Liwen Guoa, Ming-An Ouyanga and Rongbiao Tongb*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new approach has been developed for the synthesis of 8- All these methods share a common feature: loss of small molecules
substituted 2H-chromenes, featuring a novel cascade aromatic (“H-H”, H2O, MeOH, HOAc, HNR2, etc.) to in-situ generate o-QMs. We
Claisen rearrangement/o-quinone methide formation/6π- conceived that if the loss of these small molecules could not only
electrocyclization. This new method was demonstrated with 28 generate in-situ o-QMs for subsequent 6π-EC but also form a new C-
examples tolerating different substitution at alkenes, allylic and C bond, a new cascade approach involving one C-C bond and one C-
aromatic ring and with total syntheses of three 2H-chromene O bond formations might be developed to provide the 2H-chromenes
natural products.
with aromatic substitutions.
Recently, we reported a new cascade reaction for the synthesis of
spirooliganones A and B.6 The key cascade process was believed to
involve aromatic Claisen rearrangement, in situ generation of o-QM
intermediate via 1,6-elimination of HOAc and intermolecular hetero-
Diels-Alder reaction7 (Scheme 1). We hypothesized that if an alkenyl
2H-chromenes (2H-1-benzopyrans) are very important structural
units of and building blocks for many pharmaceutically significant
compounds and biologically active natural products1 (Figure 1). They
have attracted great interest in the field of organic synthesis to
develop new and improved synthetic methods.2 Among all the
methods of the myriad, 6π-electrocyclization3 (6π-EC) involving
ortho-quinone methide (o-QM) intermediates provides a rapid
access to the privileged functionalized 2H-chromenes.4 The in situ
generation of the non-isolable reactive o-QMs is key to this process
and can be promoted by various methods such as thermolysis,
oxidation, acid- or base-promoted β-elimination, and photolysis.5
group was pre-installed,
a new cascade involving Claisen
rearrangement/o-QM formation/6π-electrocyclization would deliver
2H-chromenes with a variety of substitution at C2 and the versatile
allyl substitution at C8, which have rarely been addressed by prior
synthetic methodologies. Importantly, if this idea works, it not only
constitutes a new synthetic method for the important 8-substituted
2H-chromenes (eg. anthyllisone8 and gaudichaudianic acid,9 Figure
1), but also provides experimental evidence that supports our
previously reported mechanistic hypothesis of the cascade process.
Herein, we describe the development of this new cascade process for
the synthesis of 8-substituted 2H-chromenes and its application to
total synthesis of three 8-substituted 2H-chromene natural products.
Figure 1. Selected compounds containing 2H-chromene motif.
a.State Key Laboratory of Ecological Pest Control for Fujian and Taiwan Crops,
Institute of Plant Virology, Fujian Agriculture and Forestry University, Fuzhou,
Fujian, China. E-mail: songliyan@fafu.edu.cn
b.Department of Chemistry, The Hong Kong University of Science and Technology,
Clearwater Bay, Kowloon, Hong Kong, China. E-mail: rtong@ust.hk
†Electronic Supplementary Information (ESI) available: Detailed experimental
procedures and copies of 1H, 13C-NMR spectra of new compounds. See
DOI: 10.1039/x0xx00000x
Scheme 1. Our Hypothesis of Cascade Approach to 2H-Chromenes
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Our studies began with examination of the heating conditions to corresponding acetates were freshly prepared andVuiesweAdrticfloerOntlhinee
DOI: 10.1039/C7CC03037A
initiate the proposed cascade process using compound 1a as the cascade reactions (see ESI for details).
model substrate (the synthesis of 1a was provided in ESI). A survey
As depicted in Table 2, C2- (and C3-) substituted 2H-chromenes
of different solvents was firstly conducted and both xylene and 1,2- (2b2j) could be efficiently prepared by using the cascade reaction
dichlorobenzene (DCB) were found to be suitable (entries 1-4), from 1b1j bearing different substituents (R2, R3, and R4) on the ∆2,3
probably owing to their high boiling points required for the thermo- alkene in 68-92% yields. Interestingly, the cascade reaction of the
promoted reaction. The concentration had a slight influence on the substrates containing a cyclic ∆2,3 alkene (1f1j) afforded polycyclic
reaction yield (entries 5-7) and 0.02 M in xylene would give the 2H-chromenes (2f2j) in good yields with good to excellent
highest yield (86%) and will be used in subsequent studies. Finally, diastereoselectivies (2i and 2j). The relative stereochemistry was
we attempted to add a base to alleviate the acidity of the reaction established either by 2D NOESY or nuclear Overhauser enhancement
(the acetic acid generated stoichiometrically might limit the (NOE) experiments. Notably, the relatively sensitive enol ether and
substrate scope and potential applications) and accelerate the cyclopropane mioety (2h and 2j) survived in our cascade protocol.
elimination of HOAc. Surprisingly, we found that either organic or The electron-rich and electron-withdrawing substituents (R1) on the
inorganic base was detrimental to the reaction (entries 8-10). In aromatic ring had little effect on the reaction yields, delivering the
addition, all Lewis acids as possible catalysts to lower the reaction corresponding 2H-chromenes (2k2m) in good to excellent yields.
temperature were found to result in decomposition (entries 11-15).
Table 2. Substrate scope of the cascade reaction to 2H-chromenes
Table 1. Optimization of the cascade reaction of 1a to 2H-chromene
(2a)a
entry
conditions
yield (%)b
trace
15
80
83
76
86
84
1
2
3
4
5
6
7
8
9
10
0.05 M, benzene, reflux
0.05 M, toluene, reflux
0.05 M, 1,2-dichlorobenzene, reflux
0.05 M, xylene, reflux
0.1 M, xylene, reflux
0.02 M, xylene, reflux
0.01 M, xylene, reflux
0.02 M, xylene, reflux, 2 eq. NaHCO3
0.02 M, xylene, reflux, 2 eq. py.
0.02 M, xylene, reflux, 2 eq. 2,6-
lutidine
0.02 M, benzene, rt → reflux, 0.2 eq.
AgOTf
0.02 M, benzene, rt → reflux, 0.2 eq.
SnCl4
0.02 M, benzene, rt → reflux, 0.2 eq.
TiCl4
0.02 M, benzene, rt → reflux, 0.2 eq.
BF3-Et2O
c
-
-
-
c
c
c
11
12
13
14
15
-
c
-
c
-
c
-
c
0.02 M, benzene, rt → reflux, 0.2 eq.
Sc(OTf)3
-
aReaction conditions: 1 (0.2 mmol), xylene (10 mL), nitrogen atmosphere,
reflux, 30 min. Isolated yields are shown. b1,2-dichlorobenzene as the solvent.
Note: a Reaction conditions: 1a (0.2 mmol), solvent, nitrogen atmosphere, 30
min. b Isolated yields based on 1a. c Decomposition.
The R5R7 substitution on the allyl groups did not erose the cascade
reaction yields of 2H-chromenes (2a, 2n2q). However, lower yields
were observed when R8 was not hydrogen (2r2s), which might be
attributed to the negative steric effect on Claisen rearrangement. It
was noted that 2s was generated in a stereospecific fashion,
consistent with the high stereocontrol of Claisen rearrangement.11
The alkene geometry of 2o was determined by the large coupling
With the optimized conditions in hand, the substrate scope was
then examined and presented in Table 2. A series of substrates
(1a1s) were prepared by using the modified literature protocols.10
Notably, some substrates (acetates) were unstable for purification by
flash chromatography on silica gel and would decompose completely
overnight even when stored in the refrigerator.In such cases, the
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constant of the trans-alkene protons, while the relative was isolated in 1993 from Piper aduncum and exhibited antimicrobial
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and molluscicidal activities;12 while 8 was obtained from the aerial
DOI: 10.1039/C7CC03037A
stereochemistry of 2s was assigned by NOE experiments.
In order to further expand the substrate scope and provide an parts of Werneria stuebelii.13 Total synthesis of 8 was elegantly
expedite access to aromatic C6 substituted 2H-chromenes, we achieved by Stratakis and co-workers in 2011.2o Anthyllisone (9) was
hypothesize that if there was a non-hydrogen substituent at C8, the isolated in 1996 from Anthyllis hermanniae8 and Jun reported the
para Claisen rearrangement11 (or Claisen-Cope rearrangement) total synthesis of anthyllisone in 2016. Interestingly, Jun and co-
might occur and the subsequent 1,4-elimination of HOAc would workers found that 9 showed potent anti-inflammatory activity
generate the requisite o-QM for the 6π-electrocyclization, providing without cytotoxicity.14 The potent and promising biological acivities
otherwise poorly accessible 2H-chromenes with substitutions at of these 2H-chromene natural products prompted us to undertake
both C6 and C8. To test this idea, we synthesized a small series of their total synthesis (Scheme 3). Herein, we proposed a collective
substrates (1t1zb) with C8 substitution and examine the cascade synthesis of 79 from a common intermediate 2e, which was
process. It was found that the nature of the C8 substituent would obtained by our new cascade approach on a 2.0 mmol scale with
have a significant influence on the reaction. For example, the cascade comparable 71% yield. Initial attempt to formylation of 2e by
reaction of compounds 1t and 1u with fluoride and methoxy at C8 Vilsmeier-Haack reaction proved fruitless, probably due to the strong
gave 2t and 2u in 32% and 0% yield, respectively, while substrates acidic condition. Pleasingly, Duff reaction of 2e in acetic acid15 gave
(1v1zb) with the carbon-based substituents
the desired aldehyde 6 in 61% yield. Noteworthy was that milder acid
(citric acid) should be used instead of sulfuric acid to avoid
Scheme 2. New cascade involving para-Claisen rearrangement/o- decomposition.
quinone methide formation/6π-electrocyclization.
Scheme 3. Total syntheses of 8-substituted 2H-chromene-containing
natural products
Pinnick oxidation16 of 6 completed the total synthesis of 7 in 89%
yield. Alternatively, Horner-Wadsworth-Emmons olefination of 6
furnished 8 in 88% yield. The total synthesis of anthyllisone (9) was
accomplished by two highly yielding steps: lithium diisopropylamide
(LDA)-mediated Claisen-Schmidt condensation and TBAF desilylation.
All spectroscopic data for our synthetic samples were in well
agreement with those reported for the corresponding natural
products.10
a
Reaction conditions: 1 (0.2 mmol), 1,2-dichlorobenzene (DCB, 10 mL),
nitrogen atmosphere, reflux, 30 min; isolated yields are shown. b Containing
inseparable impurities.
In summary, we have developed a new cascade strategy for the
syntheses of substituted 2H-chromenes with high efficiency,
featuring aromatic Claisen rearrangement, o-quinone methide
formation and 6π-electrocyclizaiton. The strategy substantiated by
28 examples is amenable to a broad range of substrate scope
tolerating different substitution. In particular, new cascade reaction
involving para-Claisen rearrangement, o-quinone methide formation
and 6π-electrocyclizaiton allows for an expedite access to 2H-
chromenes with substitutions at C6. It is expected that this new
approach can be extended to the efficient preparation of 2H-
chromenes with substitutions at C2, C3, C6 and C8. Moreover, this
synthetic strategy was successfully applied in the concise collective
synthesis of natural products. Further exploration of the strategy for
the total syntheses of other 2H-chromene-containing natural
products is ongoing in our laboratory.
(methyl, allyl and phenyl) at C8 underwent smoothly the cascade
reaction in 2H-chromenes (2v2zb) with excellent yields. It was
noteworthy that 2x exhibited abnormal chemoselectivity because
the allyl group, not the pre-installed prenyl group at C8, participated
the second Cope rearrangement (3 → 4). This was unusual to our
mechanistic understanding. In addition, the para-Claisen
rearrangement was stereospecific as evidenced by the formation of
2y2zb from the corresponding substrates with E-crotyl group (1y),
prenyl group (1z, 1za) and even 1-methyl allyl group (1zb). Note: ca.
10% unidentified impurities could not be separated from 2y and 2zb,
although many efforts had been made.
Finally, we would like to demonstrate the utility of this new
cascade process by the total syntheses of three 2H-chromene-
containing natural proudcts 79. Natural product 2H-chromene 7
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This research was financially supported by National Natural
Science Foundation of China (21502018), Natural Science Foundation
of Fujian Province of China (2016J05024), Natural Science
Foundation of Department of Education of Fujian Province (JA15148),
Fujian Agriculture and Forestry University Foundation for
Outstanding Youth (XJQ201623) and Research Grant Council of Hong
Kong (GRF 16305314). The authors are also grateful to Prof. Dr.
Xinqiang Fang and Dr. Jinxiang Chen (Fujian Institute of Research on
the Structure of Matter, Chinese Academy of Sciences) for kind
assistance in NMR and IR measurements.
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DOI: 10.1039/C7CC03037A
Graphic TOC
A new approach to 8-substituted 2H-chromenes is developed, featuring a novel cascade
aromatic Claisen rearrangement/o-quinone methide formation/6πꢀelectrocyclization.