A copper(ii) perchlorate-promoted tandem reaction of internal alkynol and salicyl N-tosylhydrazone: Direct access to isochromeno[3,4-b]chromene

Article abstract of DOI:10.1039/c4cc02862g

A copper(ii) perchlorate-promoted tandem reaction of internal alkynol and salicyl N-tosylhydrazone provides a novel, concise method for constructing isochromeno[3,4-b]chromene in 35-94% yields. The tandem reaction involves cycloisomerization, formal [4+2] cycloaddition and an elimination process. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc02862g

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A copper(II) perchlorate-promoted tandem
reaction of internal alkynol and salicyl
N-tosylhydrazone: direct access to
isochromeno[3,4-b]chromene†
Cite this: Chem. Commun., 2014,
50, 8514
Received 17th April 2014,
Accepted 9th June 2014
Hai Xiao Siyang, Xu Rui Wu, Xiao Yue Ji, Xin Yan Wu and Pei Nian Liu*
DOI: 10.1039/c4cc02862g
www.rsc.org/chemcomm
A copper(II) perchlorate-promoted tandem reaction of internal
alkynol and salicyl N-tosylhydrazone provides a novel, concise
method for constructing isochromeno[3,4-b]chromene in 35–94%
yields. The tandem reaction involves cycloisomerization, formal
[4+2] cycloaddition and an elimination process.
Heteroannular ketals are synthetically and pharmaceutically
important structural motifs present in a wide range of natural
products.1 For example, [3,4-b]ketals form the scaffold of
numerous natural products with useful biological activities,
such as dipyranosides I, key precursors for ansamycins,2 sapo-
Fig. 1 Natural products containing the [3,4-b] ketal moiety.
genin triterpene II, from Emmenospermum pancherianum,3 and making them much more expensive than copper-based methods.
the antimalarial macralstonidine III, from Alstonia (Fig. 1).4
Meanwhile, alternative and novel protocols employing salicyl
Numerous researchers have explored ways to synthesize these N-tosylhydrazones and terminal alkynes were reported for
natural ketal-like derivatives. Although these efforts have led to constructing heterocycles.12 In continuation of our work on the
creative strategies to construct spiroketals,1a,d–g heteroannular development of new synthetic applications based on alkynols,13
ketals such as fused pyranobenzopyrans remain a challenge. we report here a copper perchlorate-promoted tandem reaction
The methodologies reported to date involve cyclization reactions of internal alkynol with salicyl N-tosylhydrazone, which provides
promoted by radicals,5 acid,6 or Me3SiI,7 or conducted under a novel, concise synthetic route to the heteroannular ketal
Diels–Alder,8 Heck,9 or Lewis-acid catalyzed conditions.10 Most of isochromeno[3,4-b]chromene.
these methods require numerous steps and preformed tetra-
As indicated in Table 1, our study started with the Cu(OTf)2-
hydropyran derivatives as substrates, or more than stoichiometric mediated reaction of internal alkynol 1a with salicyl N-tosylhydra-
amounts of Lewis acid is needed. Therefore, developing new zone 2a at 100 1C in dioxane. Using 0.2 equiv. of Cu(OTf)2 resulted
synthetic methods to construct fused pyranobenzoyran deriva- in the corresponding isochromeno[3,4-b]chromene 3a in 40%
tives would be an important advancement.
isolated yield (entry 1). The structure of 3a was confirmed by
The reactivity of alkynol-based systems has made them one single-crystal X-ray diffraction analysis (see ESI,† CCDC number:
of the most prevalent organic synthons for generating diverse 997620). We then screened various reaction conditions to optimize
structures such as furans, pyrans and ketals, as well as many the catalytic process. Among the copper catalysts tested, Cu(ClO4)2Á
other heterocyclic systems and natural products.11 However, 6H2O proved to be the best one, increasing the yield to 43%
most syntheses involving alkynols rely on noble-metal catalysts, (entries 2–7). Among the solvents tested, toluene performed well to
afford the product in 46% yield (entries 8–13). We also carried out
the experiments with different reactant ratios: changing the ratio
of 1a :2a from 1:1.2 to 1:2 increased the yield to 52% (entry 14).
Lowering the temperature to 60 1C further increased the yield to
60% (Table 1, entry 15). The reaction proceeded more efficiently to
give 67% yield at this temperature when we reversed the ratio of
1a :2a to 2 : 1 (entry 16). When the solvent was changed to a 1 : 1
Shanghai Key Laboratory of Functional Materials Chemistry, Key Lab for Advanced
Materials and Institute of Fine Chemicals, East China University of Science and
Technology, Meilong Road 130, Shanghai 200237, China.
E-mail: liupn@ecust.edu.cn; Fax: +86-21-64250552
† Electronic supplementary information (ESI) available: Experimental procedures,
analytical data for all products, crystal data and structure refinement of product 3a,
copies of 1H and 13C NMR spectra of all products. CCDC 997620. For ESI and
crystallographic data in CIF or other electronic format see DOI: 10.1039/c4cc02862g (v/v) mixture of toluene and dioxane and the catalyst load was
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Table 1 Optimization of the reaction between 1a and 2aa
Table 2 Reaction of internal alkynol 1a with various salicyl N-tosylhydrazones 2
in the presence of Cu(ClO4)2Á6H2Oa
Entry Catalyst/mol%
Solvent
T/1C t/h
3ab/%
1
2
3
4
5
6
7
8
Cu(OTf)2/20
CuI/20
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
100
100
100
100
100
100
100
100
100
100
100
100
100
100
60
2
10
18
20
20
5
40
0
CuSO4Á5H2O/20
CuCl2Á2H2O/20
Cu(NO3)2Á3H2O/20
o5
25
18
o5
43
22
46
37
27
35
0
52
60
67
66
78
94
[Cu(CH3CN)4]PF6/20 Dioxane
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/20
Cu(ClO4)2Á6H2O/30
Cu(ClO4)2Á6H2O/30
Dioxane
CH3CN
Toluene
THF
CH3NO2
DCE
DMSO
Toluene
Toluene
Toluene
Toluene–dioxane
Toluene–dioxane
Toluene–dioxane
6
20
9
3.5
20
3.5
3.5
24
0.5
15
20
24
24
11
10
11
12
13
14c
15c
16d
17d,e
18d,e
19d,f
60
60
60
60
a
a
Reactions were conducted at 60 1C for 11 h using 1a (0.6 mmol), 2
Reactions were performed in sealed tubes containing 1a (0.3 mmol),
2a (0.36 mmol), and solvent (2 mL) under Ar, unless noted otherwise.
(0.3 mmol), Cu(ClO4)2Á6H2O (30 mol%), and a 1 : 4 (v/v) mixture of
b
c
d
toluene : dioxane (2 mL). Isolated yields are shown.
Isolated yield. 1a (0.3 mmol) and 2a (0.6 mmol). 1a (0.6 mmol) and
e
f
2a (0.3 mmol). Toluene : dioxane = 1 : 1 (v/v, 2 mL). Toluene : dioxane =
1 : 4 (v/v, 2 mL).
N-tosylhydrazone 2a (Table 3). Internal alkynols 1 bearing
electron-donating Me groups at positions R1, R2, and R3 reacted
increased to 0.3 equiv. of Cu(ClO4)2Á6H2O, the reaction generated well to afford the products 3l–3n in 60–66% yields. A substrate
3a with a better yield of 78% (entries 17 and 18). Altering the carrying a F at position R2 generated 3o in 91% yield, while
solvent ratio of toluene and dioxane to 1 : 4 further improved the alkynols substituted with a Cl group generated 3p in 52% yield.
reaction and 3a was isolated in 94% yield (entry 19).
Substituting the benzylic methylene of the substrate with a Me
Using the optimized reaction conditions (1a : 2a = 2 : 1, 30 group led to formation of 3q in 69% yield. The reaction also
mol% Cu(ClO4)2Á6H2O, 1 : 4 (v/v) mixture of toluene : dioxane, proceeded with (2-(phenylethynyl)phenyl)methanol, giving 3r
11 h, 60 1C), we explored the scope and limitations of the in 51% yield, while using (2-( p-tolylethynyl)phenyl)methanol
tandem vinylation–cyclization coupling. Various substituted gave 3s in 73% yield. Naphthyl and 4-pentylphenyl alkynols also
salicyl N-tosylhydrazones 2 were reacted with 1a to form reacted, though they generated the corresponding products 3t
isochromeno[3,4-b]chromene (Table 2). Salicyl N-tosylhydra- and 3u in only 44% and 45% yields, respectively. Internal
zones with electron-donating groups at the ortho, meta, and alkynols bearing non-benzeniod bridges such as cyclopentene
para positions were effective, affording the corresponding and cyclohexene were also suitable for the reaction, and the
isochromeno[3,4-b]chromenes 3b–d in 64–71% yields. Salicyl products 3v and 3w were generated in 36% and 41% yields,
N-tosylhydrazones bearing the electron-donating Me group or respectively. Moreover, the alkynol containing heterocyclic
electron-withdrawing Br or F groups at position R3 reacted thiophenyl group also worked well to deliver 3x in 75% isolated
smoothly with 1a to furnish products 3e–g in 73–81% yields. yield, although alkynols substituted by an alkyl group such as
However, placing the strongly electron-withdrawing nitro hexyl or alkenyl group such as 1-cyclohexene could not give the
group at position R3 made the reaction sluggish, generating desired products.
3h in only 41% yield. Further examination of the scope of
We propose a tentative mechanism for the copper(II)
N-tosylhydrazones showed that a naphthalene-based substrate perchlorate-promoted tandem reaction of internal alkynol
generated the product 3i in only 52% yield. Disubstituted sub- and salicyl N-tosylhydrazone to generate isochromeno[3,4-
strates hampered the formation of the desired products, and b]chromene (Scheme 1). Coordination between the triple bond
reacting 3,5-disubstituted salicyl N-tosylhydrazone with 1a delivered of 1a and Cu(ClO4)2Á6H2O (A) enhances the electrophilicity of
the corresponding 3j in only 45% yield. Similarly, steric hindrance the alkyne. Intramolecular addition of the hydroxyl group to
in the substrates meant that 3k was generated in only 35% yield.
the electron-deficient alkyne generates vinylcopper species B,
To explore the full scope of the reaction, we examined the based on previous reports of large-scale, Cu(II)-catalyzed prepara-
ability of various substituted alkynols 1 to react with salicyl tion of 2,3-dimethylfuran,14 Pd-catalyzed cycloisomerization15
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Table 3 Reaction of various internal alkynols 1 with salicyl N-tosylhydra-
zone 2a in the presence of Cu(ClO4)2Á6H2Oa
release of a proton. Subsequent cleavage of the carbon–copper
bond18 and acid-promoted elimination of TsNHNH2 affords the
desired isochromeno[3,4-b]chromene 3a and regenerates the
catalytic species.
In summary, we have developed a novel, concise catalytic
tandem reaction that provides direct access to isochromeno-
[3,4-b]chromene from available internal alkynol and salicyl
N-tosylhydrazone using copper(II) perchlorate. This methodo-
logy tolerates a broad array of substitutions on functional
salicyl N-tosylhydrazone, and internal alkynols can be applied
well. The use of inexpensive copper(II) perchlorate makes this
method preferable to standard approaches based on noble-
metal catalysts. This tandem reaction involves cycloisomeriza-
tion, formal [4+2] cycloaddition and an elimination process.
Further investigations focused on expanding our methodology
with alkynols are undergoing in our laboratories.
This work was supported by NSFC/China, NCET (NCET-13-
0798), the Innovation Program of Shanghai Municipal Educa-
tion Commission (Project No. 12ZZ050), the Basic Research
Program of the Shanghai Committee of Sci. & Tech. (Project No.
13NM1400802) and the Fundamental Research Funds for the
Central Universities.
a
Reactions were conducted under Ar at 60 1C for 11 h using 1
(0.6 mmol), 2a (0.3 mmol), Cu(ClO4)2Á6H2O (30 mol%), and a 1 : 4
(v/v) mixture of toluene : dioxane (2 mL), unless otherwise noted.
Notes and references
b
Isolated yields are shown. The reaction was performed at 80 1C for
c
20 h. The reaction was performed at 80 1C in toluene (2 mL) for 4 h.
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