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Synthesis 2024; 56(20): 3191-3198
DOI: 10.1055/a-2359-8967
paper

Silver-Catalyzed Dearomative [3+2] Spiroannulation of Aryl Oxamic Acids with Alkynes

Cheng-An Jin
a   College of Chemical Engineering, State Key Laboratory Breeding Base of Green-Chemical Synthesis Technology, Zhejiang University of Technology, Chaowang Road 18#, Hangzhou 310014, P. R. of China
b   College of Chemistry and Chemical Engineering, Shaoxing University, Shaoxing 312000, P. R. of China
,
Ren-Xiao Liang∗
a   College of Chemical Engineering, State Key Laboratory Breeding Base of Green-Chemical Synthesis Technology, Zhejiang University of Technology, Chaowang Road 18#, Hangzhou 310014, P. R. of China
,
Yi-Xia Jia
a   College of Chemical Engineering, State Key Laboratory Breeding Base of Green-Chemical Synthesis Technology, Zhejiang University of Technology, Chaowang Road 18#, Hangzhou 310014, P. R. of China
c   State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, P. R. of China
› Author Affiliations

We are grateful for the financial support from the National Natural Science Foundation of China (22371255, 22371254, and 22071217), Natural Science Foundation of Zhejiang Province (LY22B020008, LZ23B020006), and the Fundamental Research Funds for the Provincial Universities of Zhejiang (RF-B2023003).
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Abstract

A silver-catalyzed dearomative decarboxylative [3+2] spiroannulation of aryl oxamic acids with alkynes is described. The reaction provides reliable access to a range of azaspiro[4,5]trienones in moderate yields in aqueous media. In addition, the reaction exhibits a broad substrate scope and good functional group compatibility.


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Key words

silver-catalyzed - dearomative - [3+2] spiroannulation - oxamic acid - alkyne - azaspiro[4,5]trienone

Azaspiro[4,5]trienone represents an important substructure widely found in natural products and pharmacologically active compounds (Scheme [1a]),[1] which also constitutes a key intermediate capable for construction of complex alkaloids.[2] Thus the development of efficient and straightforward methods to access this molecular framework is a significant research topic in organic synthesis. Over the past decades, cascade radical[3] or electrophilic[4] intramolecular dearomative ipso-cyclization of N-arylpropiolamides has emerged as a powerful tool to synthesize structurally diverse azaspiro[4,5]trienones (Scheme [1b]). In this regard, methodologies towards azaspiro[4,5]trienones bearing a variety of C3-substituents such as alkyl, benzoyl, sulfonyl, phosphoryl, silyl, halogen, thiocyanato, and seleno were well established. Nevertheless, current transformations mainly relied on the use of N-arylpropiolamides as starting materials. More importantly, it is difficult to synthesize C3-non-substituted azaspiro[4,5]trienones by the established routes. Therefore, the development of a general strategy for the facile synthesis of diversely functionalized azaspiro[4,5]trienones is still highly desirable.

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Scheme 1 Representative pharmacologically active compounds and methods to synthesize azaspiro[4,5]trienones

Recently, transition-metal-catalyzed intermolecular dearomative spiroannulation of (hetero)arenes has become a reliable route to access spirocycles.[5] Among them, aromatic compounds including phenols,[6] N-heteroarenes,[7] and benzene or naphthalene derivatives[8] have witnessed as suitable substrates for the dearomative [3+2] spiroannulation with alkynes by proceeding through multiple carbometallation of aryl–metal species across alkyne and the sequential endocyclic C=C bond of (hetero)arenes. The [3+2] spiroannulation reactions in a radical addition manner still remained underdeveloped. Oxamic acids are an important class of compounds widely used as carbamoyl radical precursors in organic synthesis.[9]

In 2015, Chen and Duan independently developed the decarboxylative alkynylation of oxamic acids with alkynyl benziodoxoles to afford a wide range of propiolamides involving a radical process.[10] In particular, decarboxylative [4+2] radical cyclization reactions of aryl oxamic acids with alkenes have also been well-developed.[11] Inspired by these works, we envisioned that the decarboxylative [3+2] spiroannulation of aryl oxamic acids with alkynes would be possibly realized by a sequence of radical addition of carbamoyl radical across alkyne and the following intramolecular dearomative ipso-cyclization. In continuation of our interest in dearomatization reactions,[7d] [8c] [12] we herein present a silver-catalyzed [3+2] spiroannulation of N-(4-methoxyaryl) oxamic acids with alkynes in aqueous media, which afforded azaspiro[4,5]trienones bearing non-C3-substituents in moderate yields under mild conditions via a radical addition process (Scheme [1c]).

Table 1 Optimization of Conditionsa

Entry

Catalyst (mol%)

Oxidant

Solvent

Yield (%)b

 1

AgNO3 (10)

K2S2O8

MeCN/H2O (2:1)

37

 2

AgNO3 (10)

Na2S2O8

MeCN/H2O (2:1)

44

 3

AgNO3 (10)

(NH4)2S2O8

MeCN/H2O (2:1)

41

 4

AgNO3 (10)

Oxone

MeCN/H2O (2:1)

12

 5

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (2:1)

46

 6

AgOTf (10)

Na2S2O8

MeCN/H2O (2:1)

38

 7

Ag2SO4 (10)

Na2S2O8

MeCN/H2O (2:1)

45

 8

Ag(Phen)OTf (10)

Na2S2O8

MeCN/H2O (2:1)

41

 9

Ag2O (10)

Na2S2O8

MeCN/H2O (2:1)

43

10

Cu(NO3)2·3H2O (10)

Na2S2O8

MeCN/H2O (2:1)

trace

11

CuCl (10)

Na2S2O8

MeCN/H2O (2:1)

trace

12

Fe(NO3)3·9H2O (10)

Na2S2O8

MeCN/H2O (2:1)

13

13

Co(NO3)3·6H2O (10)

Na2S2O8

MeCN/H2O (2:1)

16

14

Ag2CO3 (10)

Na2S2O8

DCE/H2O (2:1)

trace

15

Ag2CO3 (10)

Na2S2O8

DMSO/H2O (2:1)

36

16

Ag2CO3 (10)

Na2S2O8

DMF/H2O (2:1)

trace

17

Ag2CO3 (10)

Na2S2O8

acetone/H2O (2:1)

37

18

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (4:1)

26

19

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (1:1)

48

20

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (1:2)

36

21c

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (1:1)

49

22c,d

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (1:1)

52

23c,e

Ag2CO3 (10)

Na2S2O8

MeCN/H2O (1:1)

50

24c,d

Ag2CO3 (15)

Na2S2O8

MeCN/H2O (1:1)

58

25 c,d,f

Ag2CO3 (15)

Na2S2O8

MeCN/H2O (1:1)

32

26 c,d,g

Ag2CO3 (15)

Na2S2O8

MeCN/H2O (1:1)

40

27c,d

Ag2CO3 (30)

Na2S2O8

MeCN/H2O (1:1)

48

28c,d

–

Na2S2O8

MeCN/H2O (1:1)

18

29c

Ag2CO3 (15)

–

MeCN/H2O (1:1)

–

a Reaction conditions: 1a (0.2 mmol), 2a (0.6 mmol), the indicated loading of catalyst, oxidant (2.0 equiv), and solvent (3.0 mL) at 70 °C for 4 h under argon.

b Isolated yields.

c MeCN/H2O (2.0 mL).

d Oxidant (2.5 equiv).

e Oxidant (3.0 equiv).

At the commence, we chose N-(4-methoxyphenyl)-N-methyl oxamic acid (1a) and phenylacetylene (2a) as the model substrates to investigate the silver-catalyzed decarboxylative [3+2] spiroannulation reaction. In the presence of AgNO3 as a catalyst and K2S2O8 as an oxidant in MeCN/H2O (2:1) at 70 °C for 4 hours, the desired product 3a could be obtained in 37% yield (Table [1], entry 1). Oxidant effect was initially investigated to improve the reaction efficiency. Oxone was proved inferior to the reaction, while Na2S2O8 and (NH4)2S2O8 afforded slightly higher yields of 44% and 41%, respectively (entries 2–4). Next, a series of silver salts including Ag2CO3, AgOTf, Ag2SO4, Ag(Phen)OTf, and Ag2O were screened. Comparable yields were obtained for all of them, where a relatively higher yield of 46% was found for Ag2CO3 (entries 5–9). Other metal catalysts such as Cu(NO3)2·3H2O, CuCl, Fe(NO3)3·9H2O, and Co(NO3)3·6H2O were also screened, however, inferior yields were obtained for all these reactions (entries 10–13). It was worth noting that the reaction yields were significantly influenced by the solvent. DMSO/H2O or acetone/H2O as the solvents resulted in decreased yields of 36% and 37%, respectively (entries 15 and 17). However, only a trace amount of product was detected in the solvents of DCE/H2O or DMF/H2O (entries 14 and 16). Changing the volume ratio of MeCN and H2O from 4:1 to 1:2 revealed that the 1:1 ratio was more effective (entries 18–20). Furthermore, reducing the solvent amount to 2.0 mL slightly improved the reaction, delivering product 3a in 49% yield (entry 21).

Moreover, the reaction yield reached to 52% when increasing the equivalents of oxidant Na2S2O8 to 2.5 (Table [1], entry 22), and was further improved to 58% when raising the amount of catalyst loading to 15% (entry 24). In addition, reducing or elevating the reaction temperature to 60 °C and 80 °C both led to decreased reaction yields (entries 25 and 26). Finally, sharply decreased yield of 18% was obtained in the absence of silver catalyst, while no reaction occurred by removal of the oxidant (entries 28 and 29).

Zoom Image
Scheme 2 Substrate scope. Reagents and conditions: 1 (0.2 mmol), 2 (0.6 mmol), Ag2CO3 (15 mol%), and Na2S2O8 (2.5 equiv) in MeCN/H2O (1:1, 2.0 mL) at 70 °C for 3–24 h under argon. NR: No reaction; ND: Not detected.

With the optimized reaction conditions in hand, the substrate scope of this silver-catalyzed decarboxylative [3+2] spiroannulation reaction was investigated and the results are summarized in Scheme [2]. In general, phenylacetylene derivatives bearing a variety of substituents on the phenyl ring, including cyano (3b), methoxycarbonyl (3c), formyl (3d), nitro (3e), methoxy (3f), halogen (3g and 3h), and methyl (3i) could all react smoothly with N-(4-methoxyphenyl)-N-methyl oxamic acid (1a) under the Ag2CO3/Na2S2O8 reaction system, delivering the corresponding products in 30–51% yields. In addition, other (hetero)aryl groups such as 1-naphthyl, 2-naphthyl, 2-pyridinyl, and 3-thienyl were compatible to the reaction conditions, which led to products 3j–m in 31–53% yields. Of note, terminal alkylalkyne 5-chloro-1-pentyne and internal alkyne 1,3-diphenylprop-2-yn-1-one were also suitable for this reaction, with the corresponding products 3n and 3o being obtained in the yields of 22% and 44%, respectively. On the other hand, variations on the oxamic acids 1 were studied as well. A decreased yield of 45% was obtained when changing the methyl group on the nitrogen atom to benzyl (3p). Additionally, the introduction of substituents on the phenyl ring all gave rise to diminished reaction efficiency, affording products 3q–s in the yields ranging from 32% to 45%.

Notably, when N-(2-methoxyphenyl)-N-methyl oxamic acid was employed as a substrate, the reaction could be performed successfully to give product 3t, albeit in 12% yield. Unfortunately, reactions of diphenylacetylene, and electron deficient alkynes such as ethyl propiolate and 1-phenylprop-2-yn-1-one all failed to give the corresponding products 3u–w under the standard conditions.

To demonstrate the practical utility of this silver-catalyzed decarboxylative [3+2] spiroannulation reaction, a gram-scale reaction was carried out, which led to product 3a in a comparable yield of 51% (Scheme [3a]). Radical-trapping experiments with TMEPO or BHT as the additive were also conducted. It was found that the formation of the corresponding spiroannulation product 3a was almost completely inhibited for both reactions, which suggested a radical intermediate in the reaction (Scheme [3b]). Furthermore, the synthetic transformations of 3a with methoxamine or under NaBH4 conditions were well-performed to form products ketoxime 4 and alcohol 5 in 92% and 67% yields, respectively (Scheme [3c]).

Zoom Image
Scheme 3 Gram-scale reaction and synthetic transformations. ND: Not detected.

On the basis of the aforementioned results and literature reports,[3g] [11c] a possible reaction pathway is elucidated and depicted in Scheme [4]. Initially, Ag(I) is oxidized by Na2S2O8 to give Ag(II), which promotes the generation of carbamoyl radical A from oxamic acid 1a involving a decarboxylative process. Upon the addition of carbamoyl radical A across alkyne 2a, radical intermediate B undergoes intramolecular ipso-cyclization to produce intermediate C. Subsequentially, oxidation of radical intermediate C by Na2S2O8 leads to oxocarbonium D. Finally, the desired product 3a is obtained by nucleophilic attack of H2O to oxocarbonium D followed by methanol elimination and deprotonation.

Zoom Image
Scheme 4 Possible mechanism

In conclusion, we have developed a practical Ag-catalyzed dearomative decarboxylative [3+2] spiroannulation of aryl oxamic acids with alkynes. A series of azaspiro[4,5]trienones were afforded in moderate yields in aqueous media. In addition, the reaction features broad substrate scope and good functional group compatibility.

Aryl oxamic acids were synthesized following the reported method;[9g] [11a] for general experimental details, see the Supporting Information. All alkynes and other chemicals used in this work were purchased from commercial sources and without further purification, unless otherwise noted. Anhyd DCM and DMF were freshly distilled over CaH2. 1H, 13C, and 19F NMR spectra were recorded on Bruker Avance 400 MHz spectrometer, and NMR chemical shifts are expressed in values with reference to the internal standard of TMS. HRMS were recorded on Agilent 6210 TOF LC/MS mass spectrometer. Melting points were determined in open capillary tubes and are uncorrected. The reaction mixture was checked by TLC on silica gel plates (60 F-254) using UV light. Flash column chromatography was carried out using silica gel (200–300 mesh) for purification by using petroleum ether (PE) and EtOAc as the eluent.


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Silver-Catalyzed Dearomative [3+2] Spiroannulation; General Procedure

A Schlenk tube was charged with aryl oxamic acid 1 (0.2 mmol), Ag2CO3­ (15 mol%), and Na2S2O8 (0.5 mmol, 2.5 equiv) under argon atmosphere. Then, alkyne 2 (0.6 mmol, 3.0 equiv), MeCN (1.0 mL), and H2O (1.0 mL) were introduced via syringe. The resulting mixture was then stirred at 70 °C for 3–24 h. After completion of the reaction (monitored by TLC), the solution was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc to afford the desired product 3.


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1-Methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3a)[3b]

Yield: 29.1 mg (58%); pale yellow solid; mp 128–130 °C.

1H NMR (400 MHz, CDCl3): δ = 7.51–7.46 (m, 2 H), 7.43–7.32 (m, 3 H), 6.66 (s, 1 H), 6.62–6.54 (m, 4 H), 2.84 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.2, 170.0, 156.0, 145.9, 132.8, 130.8, 130.6, 129.0, 126.6, 124.1, 66.9, 25.1.


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4-(1-Methyl-2,8-dioxo-1-azaspiro[4.5]deca-3,6,9-trien-4-yl)benzonitrile (3b)

Yield: 28.2 mg (51%); pale yellow solid; mp 170–172 °C.

1H NMR (400 MHz, CDCl3): δ = 7.69–7.63 (m, 2 H), 7.62–7.55 (m, 2 H), 6.77 (s, 1 H), 6.66–6.59 (m, 2 H), 6.58–6.50 (m, 2 H), 2.86 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.6, 169.1, 153.8, 144.9, 134.9, 133.4, 132.8, 127.2, 126.9, 117.8, 114.1, 66.8, 25.2.

HRMS (ESI+): m/z calcd for C17H13N2O2 + ([M + H]+): 277.0972; found: 277.0971.


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Methyl 4-(1-Methyl-2,8-dioxo-1-azaspiro[4.5]deca-3,6,9-trien-4-yl)benzoate (3c)

Yield: 24.7 mg (40%); pale yellow solid; mp 178–180 °C.

1H NMR (400 MHz, CDCl3): δ = 8.04–7.98 (m, 2 H), 7.59–7.53 (m, 2 H), 6.75 (s, 1 H), 6.66–6.52 (m, 4 H), 3.93 (s, 3 H), 2.86 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.9, 169.5, 166.0, 154.9, 145.4, 134.8, 133.1, 131.8, 130.2, 126.6, 125.9, 66.9, 52.4, 25.2.

HRMS (ESI+): m/z calcd for C18H16NO4 + ([M + H]+): 310.1074; found: 310.1081.


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4-(1-Methyl-2,8-dioxo-1-azaspiro[4.5]deca-3,6,9-trien-4-yl)benzaldehyde (3d)

Yield: 21.2 mg (38%); pale yellow solid; mp 177–178 °C.

1H NMR (400 MHz, CDCl3): δ = 9.98 (s, 1 H), 7.87–7.81 (m, 2 H), 7.65–7.60 (m, 2 H), 6.76 (s, 1 H), 6.65–6.50 (m, 4 H), 2.83 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 191.1, 183.8, 169.3, 154.6, 145.3, 137.3, 136.1, 133.2, 130.1, 127.2, 126.6, 66.9, 25.2.

HRMS (ESI+): m/z calcd for C17H14NO3 + ([M + H]+): 280.0968; found: 280.0968.


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1-Methyl-4-(4-nitrophenyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3e)

Yield: 17.8 mg (30%); yellow solid; mp 231–233 °C.

1H NMR (400 MHz, CDCl3): δ = 8.25–8.17 (m, 2 H), 7.67–7.62 (m, 2 H), 6.79 (s, 1 H), 6.67–6.59 (m, 2 H), 6.58–6.52 (m, 2 H), 2.86 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.5, 168.9, 153.5, 148.6, 144.9, 136.7, 133.5, 127.6, 124.2, 66.8, 25.3.

HRMS (ESI+): m/z calcd for C16H13N2O4 + ([M + H]+): 297.0870; found: 297.0871.

4-(4-Methoxyphenyl)-1-methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3f)

Yield: 21. 4 mg (38%); pale yellow solid; mp 111–113 °C.

1H NMR (400 MHz, CDCl3): δ = 7.47–7.39 (m, 2 H), 6.85–6.81 (m, 2 H), 6.60–6.51 (m, 5 H), 3.78 (s, 3 H), 2.79 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.3, 170.4, 161.4, 155.5, 146.4, 132.6, 128.1, 123.2, 121.6, 114.4, 66.7, 55.4, 25.0.

HRMS (ESI+): m/z calcd for C17H16NO3 + ([M + H]+): 282.1125; found: 282.1129.


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4-(4-Fluorophenyl)-1-methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3g)

Yield: 20.5 mg (38%); pale yellow solid; mp 110–112 °C.

1H NMR (400 MHz, CDCl3): δ = 7.51–7.41 (m, 2 H), 7.05–6.98 (m, 2 H), 6.60–6.49 (m, 5 H), 2.80 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.9, 169.8, 163.9 (d, J = 252.8 Hz), 154.85, 145.75, 132.94, 128.7 (d, J = 8.6 Hz), 127.0 (d, J = 3.7 Hz), 123.9, 116.2 (d, J = 22.1 Hz), 66.8, 25.1.

19F NMR (376 MHz, CDCl3): δ = –108.6.

HRMS (ESI+): m/z calcd for C23H18NO3 + ([M + H]+): 270.0925; found: 270.0925.


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4-(4-Chlorophenyl)-1-methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3h)

Yield: 17.7 mg (31%); pale yellow solid; mp 139–141 °C.

1H NMR (400 MHz, CDCl3): δ = 7.45–7.40 (m, 2 H), 7.35–7.31 (m, 2 H), 6.65 (s, 1 H), 6.62–6.52 (m, 4 H), 2.84 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.0, 169.7, 154.7, 145.6, 136.8, 133.0, 129.3, 129.1, 127.8, 124.5, 66.8, 25.1.

HRMS (ESI+): m/z calcd for C16H13ClNO2 + ([M + H]+): 286.0629; found: 286.0630.


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1-Methyl-4-(m-tolyl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3i)

Yield: 21.2 mg (40%); pale yellow solid; mp 123–125 °C.

1H NMR (400 MHz, CDCl3): δ = 7.31–7.19 (m, 4 H), 6.64 (s, 1 H), 6.62–6.52 (m, 4 H), 2.83 (s, 3 H), 2.33 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.2, 170.1, 156.2, 146.0, 138.8, 132.7, 131.4, 130.7, 128.9, 127.4, 123.9, 123.5, 66.9, 25.1, 21.4.

HRMS (ESI+): m/z calcd for C17H16NO2 + ([M + H]+): 266.1176; found: 266.1178.


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1-Methyl-4-(naphthalen-1-yl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3j)

Yield: 31.9 mg (53%); pale yellow solid; mp 219–221 °C.

1H NMR (400 MHz, CDCl3): δ = 7.93–7.83 (m, 3 H), 7.58–7.49 (m, 2 H), 7.41 (dd, J = 8.2, 7.1 Hz, 1 H), 7.29 (dd, J = 7.2, 1.2 Hz, 1 H), 6.71–6.62 (m, 2 H), 6.56 (s, 1 H), 6.43–6.34 (m, 2 H), 2.98 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 183.7, 170.0, 155.3, 144.6, 133.7, 133.3, 131.1, 130.1, 123.0, 128.9, 128.3, 127.1, 126.4, 125.9, 124.4, 124.4, 70.0, 26.1.

HRMS (ESI+): m/z calcd for C20H16NO2 + ([M + H]+): 302.1176; found: 302.1176.


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1-Methyl-4-(naphthalen-2-yl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3k)

Yield: 24.7 mg (41%); pale yellow solid; mp 157–159 °C.

1H NMR (400 MHz, CDCl3): δ = 7.95 (d, J = 1.9 Hz, 1 H), 7.85–7.78 (m, 2 H), 7.76–7.72 (m, 1 H), 7.58 (dd, J = 8.7, 2.0 Hz, 1 H), 7.56–7.48 (m, 2 H), 6.79 (s, 1 H), 6.64 (s, 4 H), 2.87 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.2, 170.1, 155.8, 146.2, 133.9, 132.8, 132.8, 128.9, 128.8, 128.8, 128.0, 127.8, 127.7, 127.1, 126.4, 124.2, 123.7, 66.9, 25.1.

HRMS (ESI+): m/z calcd for C15H13N2O2 + ([M + H]+): 302.1176; found: 302.1181.


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1-Methyl-4-(pyridin-2-yl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3l)

Yield: 15.6 mg (31%); pale yellow solid; mp 168–170 °C.

1H NMR (400 MHz, CDCl3): δ = 8.52 (ddd, J = 4.8, 1.9, 1.0 Hz, 1 H), 7.69 (td, J = 7.8, 1.8 Hz, 1 H), 7.54 (dt, J = 7.9, 1.1 Hz, 1 H), 7.25 (ddd, J = 7.6, 4.8, 1.1 Hz, 1 H), 6.96 (s, 1 H), 6.62–6.47 (m, 4 H), 2.86 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.8, 169.8, 155.3, 149.9, 149.4, 145.5, 136.5, 132.5, 126.3, 124.5, 121.7, 66.5, 25.1.

HRMS (ESI+): m/z calcd for C15H13N2O2 + ([M + H]+): 253.0972; found: 253.0975.


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1-Methyl-4-(thiophen-3-yl)-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3m)

Yield: 25.7 mg (50%); brown solid; mp 203–205 °C.

1H NMR (400 MHz, CDCl3): δ = 7.45 (dd, J = 2.9, 1.4 Hz, 1 H), 7.35 (dd, J = 5.1, 2.8 Hz, 1 H), 7.25 (dd, J = 5.1, 1.3 Hz, 1 H), 6.64–6.50 (m, 5 H), 2.84 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 184.2, 170.3, 150.6, 146.4, 132.8, 131.9, 126.9, 126.1, 124.9, 122.4, 66.6, 25.1.

HRMS (ESI+): m/z calcd for C14H12NO2S+ ([M + H]+): 258.0583; found: 258.0586.


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4-(3-Chloropropyl)-1-methyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3n)

Yield: 11.1 mg (22%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 6.57–6.46 (m, 2 H), 6.40–6.32 (m, 2 H), 6.12 (t, J = 1.8 Hz, 1 H), 3.52 (t, J = 6.2 Hz, 2 H), 2.81 (s, 3 H), 2.22 (ddd, J = 8.2, 6.7, 1.8 Hz, 2 H), 2.03–1.95 (m, 2 H).

13C NMR (100 MHz, CDCl3): δ = 184.0, 170.4, 158.3, 145.5, 133.4, 124.6, 68.9, 43.5, 29.8, 25.9, 23.8.

HRMS (ESI+): m/z calcd for C13H15ClNO2 + ([M + H]+): 252.0786; found: 252.0786.


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3-Benzoyl-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3o)[13]

Yield: 31.3 mg (44%); yellow solid; mp 108–110 °C.

1H NMR (400 MHz, CDCl3): δ = 7.82 (dq, J = 7.9, 1.4, 0.9 Hz, 2 H), 7.50 (ddt, J = 7.8, 6.8, 1.3 Hz, 1 H), 7.36 (t, J = 7.8 Hz, 2 H), 7.23 (ddt, J = 5.6, 4.6, 1.1 Hz, 3 H), 7.19–7.12 (m, 2 H), 6.72–6.63 (m, 2 H), 6.60–6.51 (m, 2 H), 2.90 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 191.3, 183.8, 167.2, 154.5, 144.7, 136.1, 135.6, 134.2, 133.5, 130.5, 130.1, 129.5, 128.8, 128.7, 127.8, 67.2, 25.9.


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1-Benzyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3p)

Yield: 29.5 mg (45%); pale yellow solid; mp 139–141 °C.

1H NMR (400 MHz, CDCl3): δ = 7.47–7.18 (m, 10 H), 6.69 (s, 1 H), 6.52–6.21 (m, 4 H), 4.51 (s, 2 H).

13C NMR (100 MHz, CDCl3): δ = 184.4, 170.2, 156.4, 146.1, 137.8, 132.2, 130.8, 130.6, 129.0, 128.5, 127.7, 126.7, 124.1, 67.4, 43.8.

HRMS (ESI+): m/z calcd for C22H18NO2 + ([M + H]+): 328.1332; found: 328.1334.


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1,7-Dimethyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3q)

Yield: 23.9 mg (45%); pale yellow solid; mp 145–147 °C.

1H NMR (400 MHz, CDCl3): δ = 7.48–7.44 (m, 2 H), 7.41–7.32 (m, 3 H), 6.64 (s, 1 H), 6.60–6.49 (m, 2 H), 6.33 (dt, J = 3.0, 1.4 Hz, 1 H), 2.81 (s, 3 H), 2.00 (d, J = 1.5 Hz, 3 H).

13C NMR (100 MHz, CDCl3): δ = 185.0, 170.1, 156.3, 145.8, 140.7, 139.9, 132.6, 130.9, 130.5, 129.0, 126.6, 123.8, 67.4, 25.0, 15.9.

HRMS (ESI+): m/z calcd for C17H16NO2 + ([M + H]+): 266.1176; found: 266.1179.


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7-Fluoro-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-triene-2,8-dione (3r)

Yield: 22.1 mg (41%); pale yellow solid; mp 161–163 °C.

1H NMR (400 MHz, CDCl3): δ = 7.48–7.35 (m, 5 H), 6.65 (s, 1 H), 6.59 (dd, J = 4.3, 1.6 Hz, 2 H), 6.18–6.10 (m, 1 H), 2.86 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 177.2 (d, J = 22.1 Hz), 169.5, 157.0, 155.6, 154.3, 147.1 (d, J = 2.7 Hz), 131.8 (d, J = 4.0 Hz), 130.8, 130.5, 129.2, 126.5, 124.3, 121.7 (d, J = 13.8 Hz), 68.5 (d, J = 8.3 Hz), 25.1.

19F NMR (376 MHz, CDCl3): δ = –122.3.

HRMS (ESI+): m/z calcd for C16H13FNO2 + ([M + H]+): 270.0925; found: 270.0925.


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1-Phenyl-6,7-dihydro-3H-pyrrolo[2,1-j]quinoline-3,9(5H)-dione (3s)

Yield: 17.7 mg (32%); pale yellow solid; mp 153–155 °C.

1H NMR (400 MHz, CDCl3): δ = 7.42–7.27 (m, 5 H), 6.61–6.41 (m, 3 H), 6.30 (dd, J = 9.8, 1.7 Hz, 1 H), 4.14 (ddd, J = 14.0, 8.9, 1.1 Hz, 1 H), 2.74 (ddd, J = 14.1, 10.6, 7.4 Hz, 1 H), 2.58–2.42 (m, 2 H), 2.08 (dtd, J = 13.1, 9.8, 1.6 Hz, 1 H), 1.90–1.79 (m, 1 H).

13C NMR (100 MHz, CDCl3): δ = 184.9, 174.3, 159.6, 158.2, 147.2, 131.7, 131.4, 130.4, 129.3, 128.8, 127.2, 125.9, 71.6, 36.3, 27.5, 26.3.

HRMS (ESI+): m/z calcd for C18H16NO2 + ([M + H]+): 278.1176; found: 278.1176.


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1-Methyl-4-phenyl-1-azaspiro[4.5]deca-3,7,9-triene-2,6-dione (3t)

Yield: 6.1 mg (12%); yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.39–7.31 (m, 5 H), 7.30–7.24 (m, 1 H), 6.70–6.61 (m, 2 H), 6.39 (dt, J = 9.9, 0.9 Hz, 1 H), 6.16 (ddd, J = 9.4, 1.8, 0.9 Hz, 1 H), 2.75 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 195.1, 171.6, 156.5, 141.9, 139.3, 130.6, 130.3, 128.9, 127.5, 126.4, 126.1, 123.5, 73.0, 25.5.

HRMS (ESI+): m/z calcd for C16H14NO2 + ([M + H]+): 252.1019; found: 252.1022.


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Gram-Scale Reaction

A 100 mL Schlenk flask was charged with aryl oxamic acid 1a (1.045 g, 5 mmol), Ag2CO3 (15 mol%), and Na2S2O8 (12.5 mmol, 2.5 equiv) under argon atmosphere. Then, phenylacetylene (2a; 15 mmol, 3.0 equiv), MeCN (25 mL), and H2O (25 mL) were introduced via syringe. The resulting mixture was then stirred at 70 °C for 14 h. After completion of the reaction (monitored by TLC), the solution was diluted with H2O (20 mL) and extracted with EtOAc (3 × 30 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc to afford the product 3a as a pale yellow solid; yield: 0.64 g (51%).


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Synthetic Transformation of 3a with Methoxyamine Hydrochloride; 8-(Methoxyimino)-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (4)

A Schlenk tube was charged with 3a (0.4 mmol) and MeONH2·HCl (1.0 mmol, 2.5 equiv) under argon atmosphere. Then, pyridine (4 mL) was introduced via syringe. The resulting mixture was then stirred at 115 °C for 20 h. After completion of the reaction, the solution was diluted with H2O (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc to afford the product 4; yield: 103.1 mg (92%); pale yellow solid; mp 164–166 °C.

1H NMR (400 MHz, CDCl3): δ = 7.53–7.48 (m, 2 H), 7.37–7.30 (m, 3 H), 7.24 (dd, J = 10.2, 1.7 Hz, 1 H), 6.65 (dd, J = 9.9, 1.8 Hz, 1 H), 6.56 (s, 1 H), 5.87 (dd, J = 10.1, 2.3 Hz, 1 H), 5.77 (dd, J = 9.9, 2.3 Hz, 1 H), 4.04 (s, 3 H), 2.76 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 169.7, 158.1, 146.1, 135.4, 131.3, 131.3, 130.1, 128.8, 128.0, 126.8, 122.3, 119.9, 67.7, 62.6, 24.7.

HRMS (ESI+): m/z calcd for C22H18NO2 + ([M + H]+): 281.1285; found: 281.1290.


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Reductive Transformation of 3a with NaBH4; 8-Hydroxy-1-methyl-4-phenyl-1-azaspiro[4.5]deca-3,6,9-trien-2-one (5)

A Schlenk tube was charged with 3a (0.4 mmol). MeOH (2 mL) was then introduced via syringe. The resulting mixture was stirred at 0 °C for 30 min. Next, NaBH4 (0.6 mmol, 1.5 equiv) was added to the mixture in portions. After stirring at 0 °C for additional 2 h, the reaction was quenched with H2O and the mixture was extracted with EtOAc. The combined organic phases were dried (Na2SO4) and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel eluting with PE/EtOAc to afford the product 5; yield: 67.9 mg (67%); dr 1:1; pale yellow oil.

1H NMR (400 MHz, CDCl3): δ = 7.65 (dtd, J = 7.4, 4.2, 3.5, 2.1 Hz, 2 H), 7.51–7.44 (m, 2 H), 7.41–7.28 (m, 6 H), 6.51 (d, J = 15.8 Hz, 2 H), 6.47–6.32 (m, 4 H), 5.59–5.47 (m, 4 H), 4.73 (dtt, J = 8.2, 3.4, 1.8 Hz, 2 H), 3.21 (s, 2 H), 2.85 (s, 3 H), 2.73 (s, 3 H).

13C NMR (100 MHz, CDCl3): δ = 170.2, 170.1, 159.9, 159.5 134.2, 133.6, 131.8, 131.4, 130.0, 129.9, 128.6, 127.3, 127.2, 127.2, 126.8, 122.3, 122.0, 66.2, 65.8, 61.7, 61.3, 24.9, 24.4.

HRMS (ESI+): m/z calcd for C16H16NO2 + ([M + H]+): 254.1176; found: 254.1176.


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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-2359-8967.
  • Supporting Information

Corresponding Author

Ren-Xiao Liang
College of Chemical Engineering
State Key Laboratory Breeding Base of Green-Chemical Synthesis Technology, Zhejiang University of Technology, Chaowang Road 18#, Hangzhou 310014
P. R. of China   

Publication History

Received: 03 June 2024

Accepted after revision: 03 July 2024

Accepted Manuscript online:
03 July 2024

Article published online:
24 July 2024

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Zoom Image
Scheme 1 Representative pharmacologically active compounds and methods to synthesize azaspiro[4,5]trienones
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Scheme 2 Substrate scope. Reagents and conditions: 1 (0.2 mmol), 2 (0.6 mmol), Ag2CO3 (15 mol%), and Na2S2O8 (2.5 equiv) in MeCN/H2O (1:1, 2.0 mL) at 70 °C for 3–24 h under argon. NR: No reaction; ND: Not detected.
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Scheme 3 Gram-scale reaction and synthetic transformations. ND: Not detected.
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Scheme 4 Possible mechanism