Scandium (III)-Catalyzed Cycloaddition of in situ Generated ortho-Quinone Methides with Vinyl Azides: An Efficient Access to Substituted 4H-Chromenes

Article abstract of DOI:10.1002/adsc.201800565

A convenient and practical synthesis of 4H-chromenes from the readily accessible o-hydroxybenzhydryl alcohols and vinyl azides has been achieved. The transformation proceeds through a cascade that involves formation of an ortho-quinone methide, [4+2]-cycloaddition and elimination of hydrazoic acid. The reaction is well tolerated with respect to both the o-hydroxybenzhydrols and the vinyl azides and affords the products in moderate to good yields. (Figure presented.).

Full text of DOI:10.1002/adsc.201800565

Title: Scandium (III)-Catalyzed Cycloaddition of In Situ Generated
ortho-Quinone Methides with Vinyl Azides: An Efficient Access to
Substituted 4H-Chromenes
Authors: Nuligonda Thirupathi, Chen-Ho Tung, and Zhenghu Xu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800565
Link to VoR: http://dx.doi.org/10.1002/adsc.201800565

10.1002/adsc.201800565
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Scandium (III)-Catalyzed Cycloaddition of In Situ Generated ortho-Quinone
Methides with Vinyl Azides: An Efficient Access to Substituted 4H-Chromenes
Nuligonda Thirupathi,a Chen-Ho Tunga and Zhenghu Xu a,b*
a
Key Lab for Colloid and Interface Chemistry of Education Ministry, Department of Chemistry, Shandong University
No. 27 South Shanda Road, Jinan, 250100 (China), E-mail: xuzh@sdu.edu.cn
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
b
Sciences, Shanghai, 200032, China
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######
complex naturally occurring oxo cycles in the
Abstract. A convenient and practical synthesis of 4H- presence of organocatalysts and transition-metal
chromenes
from
the
readily
accessible
o-
hydroxybenzhydryl alcohols and vinyl azides has been
achieved. The transformation proceeds through a cascade
that involves formation of an ortho-quinone methide,
[4+2]-cycloaddition and elimination of hydrazoic acid. The
reaction is well tolerated with respect to both the o-
hydroxybenzhydrols and the vinyl azides and affords the
products in moderate to good yields.
Keywords: Cycloaddition; ortho-quinone methides; Vinyl
azides; Chromene
Figure 1. Natural products containing a 4H-chromene.
Chromenes are ubiquitous heterocycles,
frequently found in various biologically significant
natural products and in key pharmaceuticals.[1,2,3] In
particular, 4H-chromene motifs are commonly found
in a wide variety of bioactive natural products such as
daemoronol, callistenone A and uvafzelic acid
(Figure 1).[2,3] As a consequence, although various
methods have been developed,[4-6] easy and practical
ways to construct chromene derivatives will be of
great interest.
ortho-Quinone methides[7,8] (o-QMs) have been
widely used in organic synthesis as they are easily
accessible and highly reactive transient intermediates.
With aromatization as the driving force, they can
readily react as an electron-deficient 1-oxobutadiene
to participate in various cycloaddition and conjugate
addition reactions.
[4+2]-Cycloaddition
between
ortho-quinone
methides and substituted olefins, an oxa-Diels-Alder
reaction is an expedient and direct approach to
chromanes and chromenes. Various dienophiles such
as electronically rich vinyl ethers, vinyl sulfides,
enaminones, styrenes, dienes, 1,3-dicarbonyl
compounds and “pushpull” enamino ketones have
been efficiently used as 2-π partners in these
transformations to synthesize various simple or
Scheme 1. [4+2] cycloaddition reactions of o-QMs.
catalysts.[6,9,10] Although this approach has been well
explored, it is noteworthy that majority of the reports
are devoted towards synthesis of the chromane
skeleton,[9] (Scheme 1A), and few have produced
chromenes.[6] Employing 1,3 diketones as a nucleo-
philes, Rueping et al. developed an elegant method
1
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10.1002/adsc.201800565
Advanced Synthesis & Catalysis
activation mode. Intrigued by this initial result,
variety of reaction parameters were screened with the
purpose of improving product yield and the results
are summarized in Table 1. Other Lewis acid
catalysts such as Yb(OTf)3, Y(OTf)3, La(OTf)3 were
less productive than Sc(OTf)3 (entries 6-8). Upon
increasing the catalyst loading from 10 to 20 mol%, a
notable increase in the yield, to 60% was observed
(entry 9). Finally, by comparing various solvents
(entries 10-15), we found that dioxane was the most
effective solvent in the intended reaction, and yielded
the desired chromene in 81% yield (entry 12).
for the enantioselective synthesis of tetrahydro-
xanthenones.[6b] Very recently, Osyanin et al. used the
pushpull enamino ketones as 2-π partners in a [4+2]
cycloaddition reaction producing 4H-chromene
derivatives.[6e] Despite significant progress of this sort,
efficient methodologies to construct 4H-chromene
derivatives with different substitution patterns from
easily accessible starting materials are highly
desirable.
Retrosynthetic analysis of substituted chromenes
suggests that one of the most straightforward
pathways is the [4+2] cycloaddition of ortho-quinone
methides with alkynes (Scheme 1B). Recently we
discovered that o-hydroxybenzhydryl alcohol (1a)
could generate an o-QM intermediate in the presence
of lanthanide acid catalysts, and this intermediate
reacts with the in situ formed electron-rich vinyl ether
intermediate catalyzed by another gold catalyst to
build complex spirocycles.[9i] Following this π-acid
and σ metal acid bimetallic catalysis approach, we
proposed to treat o-hydroxybenzhydryl alcohol (1a)
with terminal alkynes in presence of various Lewis
acids and gold catalysts to produce 4H-chromene.
Table 1. Optimization studies for the synthesis of 4H-
chromenesa
Yieldb
(%)
entry
Catalyst
[L.A]
Solvent
1c
2c
IPrAuCl/AgOTf
IPrAuCl/AgSbF6
IPrAuCl/AgNTf2 Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
DCE
DCE
DCE
CH3NO2
CH3NO2
0
0
0
0
30
5
3c
Unfortunately,
nucleophilicity of alkynes, all these reactions
provided inferior results (Table 1, entries 1-4).
because
of
the
diminished
4c
IPrAuCl/AgOTf
Sc(OTf)3
Sc(OTf)3
Yb(OTf)3 CH3NO2
5
6
Reactions of this sort prove to be very challenging
because simple alkynes are not electronically-rich
enough to react with o-QMs. A possible solution to
this could be using an active alkyne surrogate in the
place of terminal alkynes. In this context, we
envisioned that using vinyl azides as a masked alkyne
source which would go through [4+2] cycloaddition
with o-QMs to form an azido chromane intermediate,
concomitant elimination of hydrazoic acid afford the
desired chromenes(Scheme 1B).
7
Y(OTf)3
La(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
CH3NO2
CH3NO2
CH3NO2
THF
6
0
8
9 d
60
42
85
92 (81g)
87
80
0
10 d
11 d
12 d
13 d
14 d
15 d
16 e
17 d,f
18
DCE
Dioxane
Toluene
MeCN
DMSO
Dioxane
Dioxane
Dioxane
88
15
60
Vinyl azides have proved to be easily available
prominent building blocks in organic synthesis.[11]
Most commonly, vinyl azides produce vinyl nitrene
intermediates by thermal decomposition or photolysis
and thus act as a three atom C-C-N synthon in
cycloaddition reactions.[12] In contrast, very limited
literature reports are available in which vinyl azides
acts as two atom C-C synthons.[13] Herein, for the first
time we report the [4+2] cycloaddition reaction of
ortho-quinone methides with vinyl azides for the
synthesis of 4H-chromene derivatives.
[a] Reaction conditions: 1a (0.2 mmol.), 2a (0.3 mmol), catalyst 5 mol%,
Lewis acid catalyst 10 mol%, 4 Å molecular sieves. (30 mg), dry solvent
o
(2 mL), at 80 C, 4 h. [b]NMR yields with 1,3,5-trimethoxy benzene as a
[d]
internal standard. [c]Phenyl acetylene was used instead of vinyl azide.
Lewis acid catalyst 20 mol%. [e] Performed at 90 oC. [f] performed at room
temperature. [g] Isolated yield.
With the optimized conditions in hand (Table 1,
entry 12), we turned out to evaluate the scope and
generality of the method with respect to o-
hydroxybenzhydryl alcohols as well as vinyl azides.
First, a variety of o-hydroxybenzhydryl alcohols (1a-
1o) were synthesized by following published methods,
and exposed to standard conditions. As is evident
from Table 2, a variety of substituents including alkyl,
aryl, halogen, methoxy and trifluoromethyl groups
were well tolerated in the reaction affording the
products in good to excellent yields. Compounds with
various electron deficient (1c, 1d, 1h-1j), or electron
rich (1b, 1e-1g, 1k) substituents at different positions
did not significantly affect the reactivity and yielded
the corresponding products (3ba-3ka) in good to
excellent (68-80%) yields. The heteroaryl (thio-
phenyl) derived substrate (1n) was also well tolerated
To validate our hypothesis, we treated o-
hydroxybenzhydryl alcohol (1a) with vinyl azide (2a)
o
in presence of Sc(OTf)3 at 80 C (Table 1, entry 5),
and isolated the intended chromene (3aa) in 30%
yield. The structure of 3aa was unambiguously
confirmed by single crystal X-ray crystallography.[14]
In attempts to identify possible intermediates formed
in the course of the reaction we failed to observe any
possible product. This indicates that the elimination
of HN3 is a fast reaction under these conditions.
Indeed, a signal from HN3 can be detected by GC-
mass spectral analysis of the reaction mixture. These
results indicated the viability of the proposed alkyne
2
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10.1002/adsc.201800565
Advanced Synthesis & Catalysis
under the standard conditions and was converted into
the corresponding chromene (3na) in 72% yield.
Alkyl variants such as cyclohexyl, methyl, and octyl
substituents in the substrates (2o- 2q) were equally
participated in the reaction affording the
corresponding products (3oa-3qa), with moderate
yields. However, dimethyl substituted substrate 1r,
failed to give the corresponding product 3ra, might
be due to the increased steric barrier. Alkynyl derived
substrate 1s, couldn’t survive under standard
conditions and gave unidentifiable byproducts.
standard conditions and produced the corresponding
chromenes in 85 and 88% yields respectively. The
thiophene substituted vinyl azide (2j) reacted
smoothly under the standard conditions affording the
corresponding chromene (3aj) in moderate yield.
Unfortunately, aliphatic vinyl azides such as 2-
azidooct-1-ene, 1-azidocyclooct-1-ene, and (2-
azidoallyloxy) benzene were not suitable for this
reaction and didn't produce any desired products.
Table 3. Scope of vinyl azides in the synthesis of 4H-
chromene a.
Table 2. Scope of o-hydroxybenzhydryl alcohols in the
synthesis of 4H-chromene a.
aReaction conditions: 1a (0.2 mmol.), 2b-2l (0.3 mmol), Sc(OTf)3 (20
mol%), 4 Å molecular sieves (30 mg), dry dioxane (2 mL), at 80 oC, 4 h.
In conclusion, using vinyl azide as a masked
alkyne source, we have developed an efficient [4+2]
cycloaddition of in situ generated ortho-quinone
methides for the synthesis of 4H-chromene.
Prominent features of this trans-formation include a
three-step cascade in one pot, simple and practical
conditions and broad substrate scope. This type of
masked alkyne strategy can find further applications
in organic synthesis.
Experimental Section:
General procedure for the synthesis of 3aa: o-
Hydroxybenzhydryl alcohol (2a, 0.2 mmol) and azido
vinyl benzene (3a, 0.3 mmol) were added to a
mixture of Sc(OTf)3 (0.04 mmol), and 4 Å moleculr
sieves (60 mg) in dry dioxane (2 mL) under an N2
aReaction conditions: 1a-1o (0.2 mmol.), 2a (0.3 mmol), Sc(OTf)3 (20
mol%), 4 Å M.S. (30 mg), dry dioxane (2 mL), at 80 oC, 4 h.
o
atmosphere. The system was stirred at 80 C for 4 h.
Then the mixture was filtered through celite bed,
evaporated under reduced pressure and purified by
column chromatography (petroleum ether:EtOAc =
50:0.2) to give 3aa (46 mg, 81% yield) as a white
solid.
After successful experiments with the o-hydroxy-
benzhydryl alcohols (1a-1o), we next treated a
variety of vinyl azides under similar conditions aimed
at the synthesis of corresponding chromenes and
results are summarized in Table 3. Initially, the halo
substituted vinyl azides (2b-2e) were subjected to a
[4+2] cycloaddition reaction, and they all produced
the corresponding products (3ab-3ae) in good to high
(65-85%) yields. The alkyl-substituted substrate (2f)
and the naphthyl-substituted substrate (2i) furnished
the corresponding chromenes (3af, 3ai) in good
yields. Even the substrates containing strong electron-
withdrawing groups (2g, 2h) survived well in
Acknowledgements
We are grateful for financial support from the Natural
Science Foundation of China and Shandong province
(no. 21572118，21750110444 & JQ201505), subject
construction funds (104.205.2.5) and Tang scholar
award of Shandong University.
3
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10.1002/adsc.201800565
Advanced Synthesis & Catalysis
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5
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10.1002/adsc.201800565
Advanced Synthesis & Catalysis
COMMUNICATION
Scandium (III)-Catalyzed Cycloaddition of In
Situ Generated ortho-Quinone Methides with
Vinyl Azides: An Efficient Access to Substituted
4H-Chromenes
Adv. Synth. Catal. Year, Volume, Page – Page
Nuligonda Thirupathi, Chen-Ho Tung and Zhenghu
Xu *
6
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