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Synlett 2024; 35(13): 1572-1576
DOI: 10.1055/a-2216-4882
letter

Sulfur-Mediated ipso-Cyclization of 4-(p-Methoxyaryl)alk-1-ynes Leading to 3-Thiospiro[4.5]deca-1,6,9-trien-8-ones

Meng Han
,
Pingfan Li  ∗

This work is supported by the Natural Science Foundation of Beijing Municipality (2202040).
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Abstract

A new method for the intramolecular electrophilic ipso-cyclization of alkynes with triflic anhydride-activated sulfoxides, followed by demethylation with triethylamine in one pot, is described for the synthesis of 3-thiospiro[4.5]-decatrienones in moderate to good yields. This method provides a facile strategy for assembling the sulfur-substituted spirocyclic compounds.


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Key words

alkynes - sulfoxides - ipso-cyclization - spiro compounds - dearomatization

Spirocyclic substructures are core synthetic targets for many carbocyclic skeletons.[1] Among the various spirocycles, the spiro[4.5]decane skeleton is widely found in many natural products and pharmacologically active compounds such as an ACAT inhibitor,[2] β-vetivone,[3] the alkaloids spirocalcaridine A and B,[4] the steroid carijodienone,[5] stepharine (with antihypertensive activity),[6] and the well-known antibiotic drug candidate platensimycin (Figure [1]).[7]

For these reasons, considerable efforts have been devoted to developing useful synthetic methods for the construction spiro[4.5]decatrienones.[8] In 2005, Zhang and Larock developed a general protocol for the construction of spiro[4.5]decatrienones by intramolecular ipso-cyclization of 4-(p-methoxyaryl)-1-alkynes using the ICl, I2/NaHCO3, or Br2 as competent electrophilic halogenating reagents (Scheme [1a]).[9] In recent years, inspired by Larock’s studies, great efforts have been devoted to developing electrophiles to construct a variety of 3-functionalized spiro[4.5]decatrienones through either a radical or an electrophilic cyclization process.[10] New additional functional groups, such as halo,[10d] [h] [i] [11] carbonyl,[10f,12] selenyl,[13] phosphoryl,[14] nitro,[15] or silyl,[10b] can be introduced onto an azaspiro[4.5]decatrienone framework.

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Figure 1 Natural products and medicines containing a spiro[4.5]decane skeleton
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Scheme 1 Intramolecular electrophilic cyclization reactions

Sulfur-containing molecules are extremely important in the pharmaceutical industry and natural-product chemistry,[16] as well as being useful synthetic intermediates.[17] Several strategies have been reported for using sulfur-containing reagents as electrophiles to construct various 3-thioazaspiro[4.5]trienones.[18] Li and co-workers developed a novel copper-catalyzed radical ipso-cyclization of propynamides to assemble 2-(arylsulfanyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-diones with disulfides as the sulfur sources.[18c] Wang and co-workers describe a visible-light-mediated method, catalyzed by a metal-free organic dye, for the synthesis of 3-sulfonyl- and 3-sulfenyl-1-1azaspiro[4.5]decatrienones.[18e] Du and co-workers report an intramolecular electrophilic cyclization of N-arylpropynamides to selectively construct 3- methylthioquinolin-2-one and 3-methylthiospiro[4.5]trienone skeletons by using DMSO as a sulfur source and SOCl2 as an activating agent.[18f] We recently reported the reaction of 4-arylalkynes with triflic anhydride-activated sulfoxides for the synthesis of 3-sulfenyl-1,2-dihydronaphthalenes by intramolecular electrophilic cyclization (Scheme [1b]).[19] As part of our continued interest in the C–H functionalization of alkynes or alkenes,[19] [20] we report a convenient and efficient method for accessing a series of 3-thiospiro[4.5]trienones by the intramolecular electrophilic ipso-cyclization of 4-(p-methoxyaryl)-1-alkynes.

The reaction design involves the use of a triflic anhydride-activated sulfoxide as the sulfur source and takes advantage of the intramolecular ipso-cyclization reactivity of 4-(p-methoxyaryl)-1-alkynes for the construction of spiro[4.5]decatrienones (Scheme [1c]). First, the triflic anhydride-activated sulfoxides should react with the C≡C triple bond to generate a vinylic cation intermediate A, which could be captured by the tethered aryl ring through ipso-cyclization to give intermediates B. The desired product is then formed after demethylation with Et3N as a nucleophile by an SN2 process. Through this strategy, new C–S, C–C, and C=O bonds would all be formed in a single step. Therefore, should be able to construct spirocyclic or dihydronaphthalene skeletons selectively by ipso- or ortho-cyclization using different substituted alkyne substrates and a single sulfur source.

Initially, we chose 1-methoxy-4-(4-phenylbut-3-yn-1-yl)benzene (1a) and methyl phenyl sulfoxide (2a) as model substrates to explore the reaction conditions (Table [1]). 1a and 2a were dissolved in CH2Cl2 and Tf2O was added at –78 °C. The mixture was then warmed to room temperature and Et3N was added. However, the desired 1-phenyl-2-(phenylsulfanyl)spiro[4.5]deca-1,6,9-trien-8-one (3aa-1), was not obtained, but instead, the two dihydronaphthalenes 3aa-2 and 3aa-3 were obtained in yields of 55 and 21%, respectively, as a mixture (Table [1], entry 1).

Table 1 Optimization of the Reaction Conditionsa

Entry

Base

PhS(=O)Me (equiv)

Temp (°C)

Yieldb (%)

3aa-1

3aa-2

3aa-3

 1

–

1.2

RT

–

55

21

 2

2-chloropyridine

1.2

RT

–

–

72

 3

2-chloropyridine

1.2

–78

43

–

–

 4

–

1.2

–78

15

–

–

 5

2-fluoropyridine

1.2

–78

45

–

–

 6

2,6-lutidine

1.2

–78

34

–

–

 7

2-chloropyridine

1.5

–78

52

–

–

 8

2-chloropyridine

1.8

–78

74

–

–

 9

2-chloropyridine

2

–78

76

–

–

10

2-fluoropyridine

2

–78

56

–

–

11

2,6-difluoropyridine

2

–78

60

–

–

12

2,6-dichloropyridine

2

–78

74

–

–

a Reaction conditions: A solution of 1a and 2a in CH2Cl2 (2 mL) was treated with the base and Tf2O at –78 °C for 1 h under N2, and then Et3N was added.

b Isolated yield.

We suspected that the formation of byproduct 3aa-2 was due to the presence of triflic acid in the reaction, which initiated protonation–cyclization and electrophilic substitution. Therefore, we added 2-chloropyridine as an acid scavenger. This time, the pure byproduct 3aa-3 (see Scheme1b) was obtained in 72% yield (Table [1], entry 2). It turned out that the reaction temperature had a major influence. When we carried out the reaction at –78 °C, the target spirocyclic product 3aa-1 was obtained in 43% yield (entry 3). It seems that the intramolecular ipso-cyclization is a kinetically favored process, whereas the dihydronaphthalene might be the thermodynamic product at higher temperatures.

Table 2 Substrate Scope of the Sulfoxidea

Entry

Product

R

Yieldb (%)

1

3ca

H

88

2

3cb

NO2

83

3

3cc

Br

63

4

3cd

CN

83

5

3ce

Me

48

6

3cf

OMe

52

a Reaction conditions: 1c (0.15 mmol), 2 (0.3 mmol), 2-chloropyridine (0.3 mmol), Tf2O (0.3 mmol), CH2Cl2 (2 mL), –78 °C, then Et3N (1.5 mmol), RT; N2 atmosphere.

b Isolated yield.

In addition, we attempted to obtain the target product 3aa-1 at –78 °C without an acid scavenger. However, the reaction efficiency was markedly lower in the absence of a base (Table [1], entry 4). The presence of an acid scavenger is therefore beneficial in improving the yield. A series of bases were examined for this reaction (entries 3–6), and 2-chloropyridine was found to be the best base for the formation of production 3aa-1 (entry 3). Subsequently, the amount of activated sulfoxide was tested. When we increased the amount of activated sulfoxide to 1.5, 1.8, or 2.0 equivalents, the yield increased to 52, 74, and 78%, respectively (entries 7–9). Other bases (2-fluoropyridine, 2,6-difluoropyridine, and 2,6-dichloropyridine) were tested again under the conditions of 2.0 equivalents activation of the sulfoxide, but none gave a better result than 2-chloropyridine (entries 10–12).

With the optimized reaction conditions in hand, the effects of substituents on various aryl methyl sulfoxides 2 were investigated (Table [2]). The reaction of alkyne 3c proceeded well with various sulfoxides 2 containing various electron-withdrawing groups (NO2, Br, or CN) on the aromatic ring, giving the corresponding products 3cb–cd in moderate to good yields. For substrates bearing electron-donating groups (Me or OMe), the reaction gave the corresponding product 3ce and 3cf in lower yields of 48 and 52%, respectively.

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Scheme 2 Substrate scope of the alkyne. Reaction conditions A: 1 (0.15 mmol), 2a (0.3 mmol), 2-chloropyridine (0.3 mmol), Tf2O (0.3 mmol), CH2Cl2 (2 mL), –78 °C, 1 h, under N2, then Et3N, –78 °C. Isolated yields after column chromatography are reported. a Reaction conditions B: 1 (0.15 mmol), 2a (0.3 mmol), 2-chloropyridine (0.3 mmol), Tf2O (0.3 mmol), CH2Cl2 (2 mL), –40 °C, 5 min, under N2, then 1:1 MeOH–H2O (1.2 mL), 15 min, then Et3N (1.5 mmol), –40 °C.

In addition, the effect of substituents on the aromatic ring on the terminal alkyne was surveyed (Scheme [2]). For certain substrates, it was found that adding an appropriate amount of methanol and water was beneficial in improving the yield. Therefore, a series of spirocyclic products were synthesized under either conditions A or conditions B (Scheme [2]). Several electron-donating substituents (p-OMe, p-Me, p-Et) were compatible with the optimal conditions affording the corresponding spirocyclic products 3ba, 3ca, and 3fa in good yields. Substrates bearing a p-Cl or p-Br group gave the corresponding products 3da and 3ga in moderate yields. The 1-naphthyl alkyne 1e was also a viable substrate, furnishing product 3ea in 69% yield. The nitrogen-tethered alkyne 1h gave product 3ha in 57% yield. Notably, the corresponding six-membered-ring product 3ia was formed in 58% yield when using substrate 1i. When the o-Br- or o-I-substituted derivative was employed, the desired products 3ja and 3ka were obtained in low yields. The o-methyl- or p-methyl-substituted terminal alkynes gave the corresponding product 3la and 3ma in moderate to good yields. Substrate 1n could also be used in this reaction under the optimized conditions to give product 3na in 85% yield. However, none of the desired products were obtained from substrates bearing electron-withdrawing groups.

Further transformations of the spirocyclic product 3aa-1 were carried out (Scheme [3]). The corresponding sulfoxide and sulfone were obtained in yields of 98 and 95%, respectively, by using 1.1 and 3.0 equivalents of m-CPBA as the oxidant, respectively.

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Scheme 3 Oxidation of the sulfide to a sulfoxide and a sulfone

In conclusion, a simple and convenient strategy has been established for the synthesis of various 3-thiospiro[4.5]decatrienones from 4-(p-methoxyaryl)-1-alkynes and triflic anhydride-activated sulfoxides as sulfur sources.[21] This method achieves alkyne difunctionalization through an ipso-cyclization process, which complements our previous synthesis of 3-sulfenyl-1,2-dihydronaphthalenes.


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Conflict of Interest

The authors declare no conflict of interest.

Supporting Information

    Supporting information for this article is available online at https://doi-org.accesdistant.sorbonne-universite.fr/10.1055/a-2216-4882.
  • Supporting Information

Corresponding Author

Pingfan Li
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, College of Chemistry, Beijing University of Chemical Technology
Beijing 100029
P. R. of China   

Publication History

Received: 30 October 2023

Accepted after revision: 22 November 2023

Accepted Manuscript online:
22 November 2023

Article published online:
11 January 2024

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   Permissions and Reprints All articles of this category
Zoom Image
Figure 1 Natural products and medicines containing a spiro[4.5]decane skeleton
Zoom Image
Scheme 1 Intramolecular electrophilic cyclization reactions
Zoom Image
Scheme 2 Substrate scope of the alkyne. Reaction conditions A: 1 (0.15 mmol), 2a (0.3 mmol), 2-chloropyridine (0.3 mmol), Tf2O (0.3 mmol), CH2Cl2 (2 mL), –78 °C, 1 h, under N2, then Et3N, –78 °C. Isolated yields after column chromatography are reported. a Reaction conditions B: 1 (0.15 mmol), 2a (0.3 mmol), 2-chloropyridine (0.3 mmol), Tf2O (0.3 mmol), CH2Cl2 (2 mL), –40 °C, 5 min, under N2, then 1:1 MeOH–H2O (1.2 mL), 15 min, then Et3N (1.5 mmol), –40 °C.
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Scheme 3 Oxidation of the sulfide to a sulfoxide and a sulfone