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Abstract

Synthesis of phenanthroindolizidine core was efficiently achieved through a pathway involving hetero Diels-Alder reaction of α-allenylchalcogenoketenes, generated in situ by thermal [3,3] sigmatropic rearrangement of alkynyl propargyl sulfides or selenides, with cyclic imines and the subsequent iodine-assisted photochemical cyclization.

Keywords

alkynyl propargyl sufide alkynyl propargyl selenide α-allenylthioketene α-allenylselenoketene hetero Diels-Alder reaction indolizidine phenanthroindolizidine

Tylophorine (1) was first isolated as a constituent of Tylophora asthmatica in 1935, and since then, a variety of phenanthro-indolizidine and phenanthroqunolizidine alkaloids, such as antofine (2), tylocrebrine (3), putative hypoestestatines (4), and cryptopleurine (5) as shown in Scheme 6, were found from the natural sources, such as Onychopetalum amazonicum, Guatteria dielsiana, and Cleistopholis patens.^{1

-15} Especially, it is widely recognized that these compounds possess a variety of biologically important activities, and therefore, a lot of research works have been endeavored for the synthesis of tylophorine (1) and the related derivatives within this several decades.^{16

-39} However, these previous procedures commonly required the long-step procedure and the synthetic efficiency was not enough, and especially selective construction of polysubstituted fused-indolizidine core still remains the problem in the synthetic research work on these compounds.

In the course of our research work on the synthesis of chalcogen-containing heteroaromatic compounds by using the reactivity of chalcogenocarbonyl functionalities, we have previously reported a conversion of alkynyl propargyl chalcogenides into quinolizidine and indolizidine rings via α-allenylchalcogenoketenes by using a sequential [3,3] sigmatropic rearrangement and the subsequent hetero Diels-Alder reaction with cyclic imines.^40

-45 These successful results urged us to the new synthesis of polysubstituted fused-indolizidine skeletons, i e, phenanthroindolizine alkaloid cores. It is expected that these target compounds I would be accessible through a combination of in situ generation of α-allenylchalcogenoketenes B, hetero Diels-Alder reaction with cyclic imines, and intramolecular biaryl coupling, and 3 different synthetic strategies for the construction of phenathroindolizidine ring would be proposed as shown in Scheme 1.

Scheme 1

Synthetic strategies for phenanthrolindolizidine alkaloid skeleton I via hetero Diels-Alder reaction of in situ generated α-allenylchalcogenoketene intermediates B.

The synthetic strategy I involves the formation of 2,3-diaryl-4-methylenecyclobutene-1-chalcogenones C and the subsequent intramolecular oxidative biaryl coupling to form phenanthrocyclobutenone derivatives D prior to the hetero Diels-Alder reaction of in situ generated α-allenylchalcogenolketenes B with cyclic imines E,^46
-48 and both synthetic strategies II and III involve hetero Diels-Alder reaction of in situ generated α-allenylchalco-genoketenes B with cyclic imines E forming indolizidine core. In strategy II, the subsequent intramolecular oxidative biaryl coupling of synthetic intermediates G,^49

-55 structurally related to some unfused quinolizidine alkaloids as septicines,^56

-59 is required, and synthetic strategy III requires the hetero Diels-Alder reaction of alkynyl propargyl chalcogenides A bearing a functionalized biphenyl moiety at the R² substituent in advance in order to achieve the subsequent photochemical ring closure to form phenanthroindolizidine core I.^60
-62 Especially, we have previously reported the formation of 2,3-disubstituted 4-methylenecyclo-butene-1-chalcogenones through thermal [3,3] sigmatropic rearrangement of alkynyl propargyl chalcogenides A, and compounds A are expected to behave as novel intermediates of ketenes bearing a conjugation system at the α-position through retro [2 + 2]-type cycloreversion. It is worth noting that trimethylsilyl group at the R¹ substituent is expected to enhance the nucleophilicity of the α-allenyl part of α-allenylchalcogenoketenes B toward imines in addition to the role of stabilization of chalcogenoketenes by introducing a silyl group.^40

-45 In this paper, we report a novel and efficient construction of phenathroindolizidine core by the combination of hetero Diels-Alder strategy of α-allenylchalcogeno-ketenes with cyclic imines and a photochemical ring closure.

At first, 3,4-dimethoxybenzaldehyde (7) and piperonal were converted into terminal acetylenes 8 and 9 by using Corey-Fuchs reaction,^63,64 and 9 was converted into propargyl bromides 12 by using a 2-step procedure: (i) EtMgBr or n-butyllithium, paraformaldehyde; (ii) Ph₃P-CCl₄ or Ph₃P-CBr₄.^65,66 Compound 8 or phenylacetylene (10) was then treated with elemental sulfur and 12 to form alkynyl propargyl sulfides 14a-b bearing 2 aryl moieties at the R¹ and R² positions according to our previous reports.^40

-45 On the other hand, a similar treatment of 9 with 12 only gave a complex mixture.

Subsequently, alkynyl propargyl sulfides 14a-b were converted into 4-methylene-2-cyclobutene-1-thiones 15a-b in high yields by heating in hexane and the subsequent S-O exchanging was carried out by treating with m-chloroperbenzoic acid (mCPBA) to afford the corresponding 4-methylene-2-cyclobuten-1-ones 16a-b as shown in Table 1. However, all attempts for intramolecular oxidative biaryl coupling of compounds 16a-b by using a variety of oxidizing agents,^67

-72 such as FeCl₃, mCPBA-FeCl₃, and MnO₂, resulted in the formation of complex mixtures. Therefore, we must abandon synthetic route I by regarding these unsuccessful results.

Table 1

Preparation of Alkynyl Propargyl Sulfides 14a-b, 2,3-Diaryl-4-methylene-2-cyclobutene-1-thiones 15a-b, and 2,3-Diaryl-4-methylene-2-cyclobuten-1-ones 16a-b.


R¹	R²	Yield (%)
R¹	R²	14^a	15	16
C₆H₅	MDP	68 (14 a)	80 (15 a)	40 (16 a)
3,4-(CH₃O)₂C₆H₃	MDP	76 (14 b)	84 (15 b)	54 (16 b)
MDP	MDP	Complex mixture		-

MDP, 3,4-(methylenedioxy)phenyl group.

^aIsolated yields based on 7 to 9.

On the other hand, alkynyl propargyl chalcogenides 14c-d (X = S) and 17 c (X = Se) bearing a trimethylsilyl group at the R¹ position of the alkynyl terminal were prepared from trimethylsilylacetylene, EtMgBr or n-butyllithium, elemental chalcogen (X = S, Se), and a substituted propargyl bromide 11 or 13 in a similar manner, and the subsequent treatment of a benzene solution of 14c-d or 17 c with 2-methylpyrroline (18), prepared from 2-methylpyrrolidone according to Hua’s method,^73,74 at refluxing temperature afforded the corresponding [4 + 2] cycloadducts 19c-d or 20 c, respectively, in moderate to high yields. All the results for the preparation of δ-chalcogenolactams (19c-d, 20 c) are summarized in Table 2.

Table 2

Preparation of δ-Chalcogenolactams (19c-d, 20c) v ia Hetero Diels-Alder Strategy Starting from Alkynyl Propargyl Chalcogenides (14c-d, 17c) and 2-Methylpyrroline (18).


R¹	X	Propargyl halide (11-13)			Yield (%)
R¹	X	R²	L		14, 17^a	19, 20
(CH₃)₃Si	S	C₆H₅	Br	13	69 (14 c)	87 (19 c)
(CH₃)₃Si	S	3,4-(MeO)₂C₆H₃	Cl	11	46 (14 d)	47 (19 d)
(CH₃)₃Si	Se	C₆H₅	Br	13	71 (17 c)	42 (20 c)

^aIsolated yields based on trimethylsilylacetylene.

Model compound 19 c (R² = C₆H₅) was then treated with OsO₄ (cat.) and NaIO₄ by using a general manner, and subsequently, the resulting crude mixture of 1,2-diols 21 c was converted into 5,8-dioxoindolizidine 23 c by 2-step procedure involving oxidative glycol cleavage using H₅IO₆ followed by base-induced desilylation of δ-lactam 22 c by using anhydrous Na₂CO₃ powder as shown in Scheme 2. However, all attempts for the introduction of p-methoxyphenyl group to the C-2 position of 23 c, involving the use of ArMgBr-CuBr-(CH₃)₂S, Ar₂Zn-Ni(acac)₂, ArI-Pd(OAc)₂-Ph₃P-Et₃N, and so on, resulted in the recovery of substrate 23 c at all, and, therefore, we abandoned the synthetic route 1I which requires the subsequent intramolecular oxidative biaryl coupling of two aryl groups of compound 24 in this case.

Scheme 2

Conversion of δ-thiolactam 19c into 5,8-dioxoindolizidine 23c [Procedures: (a) OsO₄ (2.0 mol%), NaIO₄ (2.0 mol amt.), aq. dioxane; (b) H₅IO₆ (2.0 mol amt.), aq. dioxane; and (c) K₂CO₃ (2.0 mol amt.), CH₃OH].

In order to realize the synthesis via route III, preparation of propargyl halides bearing a functionalized biphenyl moiety at the acetylenic terminal was necessary prior to the construction of indolizidine skeleton by using hetero Diels-Alder reaction with cyclic imines. Therefore, we chose m-bromoanisole and 2-bromo-4,5-dimethoxybenzaldehyde (25) as starting materials, and these compounds were efficiently converted into propargyl chloride 30 bearing a functionalized biphenyl moiety in several steps involving Suzuki coupling, Corey-Fuchs reaction,^63,64 hydroxymethylation, and chlorination of propargyl alcohol 29 by using Ph₃P-CCl₄.^65,66 Trimethylsilylacetylene was then treated with n-butyllithium, elemental sulfur or selenium, and propargyl chloride 30 to afford the corresponding alkynyl propargyl sulfide 14e and alkynyl propargyl selenide 17e, respectively, in moderate yields as shown in Scheme 3.

Scheme 3

Preparation of alkynyl propargyl chalcogenides (14e, 17e) via Suzuki coupling of 25 and 26 [Procedures: (a) Br₂, AcOH; (b) (i) n-BuLi (1,2 mol amt.), (ii) B(OCH₃)₃ (1.2 mol amt.), (iii) aq. HCl; (c) Pd(OAc)₄ (10 mol%), Ph₃P (20 mol%), Et₃N (excess), DMF; (d) CBr₄ (2.0 mol amt.), Ph₃P (2.0 mol amt.), CH₂Cl₂; (e) (i) n-BuLi (2.0 mol amt.), THF, (ii) (CH₂O)_n (1.0 mol amt.); (f) Ph₃P (1.1 mol amt.), CCl₄ (excess); and (g) trimethylsilylacetylene (2.0 mol amt.), n-BuLi (2.1 mol amt.), elemental sulfur or selenium (2.0 mol amt.)].

When a benzene solution of sulfide 14e was treated with 2-methylpyrroline (18, 2.3 mol amt.) at refluxing temperature for 12 hours, the desired δ-thiolactam 19e was obtained only in low yield. On the other hand, the yield of 19e was raised up to 47% by heating 14e and 18 in a similar manner in the presence of Yb(OTf)₃ (10 mol%). Furthermore, reaction of alkynyl propargyl selenide 17e with 18 in a similar manner even in the absence of Yb(OTf)₃ also afforded the corresponding δ-selenolactam 20e in 50% yield. These results were summarized in Table 3. Subsequent conversion of 19e and 20e into 5,8-dioxoindolizidine 23e was carried out by the 2-step procedure mentioned above in the model reactions as summarized in Scheme 4.

Table 3

Preparation of δ-Chalcogenolactams (19e, 20e) from Alkynyl Propargyl Chalcogenides (14e, 17e) and 2-Methylpyrroline (18).


Substrate		Additive	Solvent	Condition		Yield of 19e, 20e
14e, 17e^a	X	(mol%)	Solvent	Temp (°C)	Time (h)	(%)
14e	S	-	Benzene	Reflux	12	9 (19 e)
14e	S	Yb(OTf)₃ (10)	ClCH₂CH₂Cl	Reflux	12	47 (19 e)
17e	Se	-	Benzene	Reflux	20	50 (20 e)

^aAr = 2-(3-methoxyphenyl)-4,5-dimethoxyphenyl.

Scheme 4

Conversion of δ-chalcogenolactams (19e, 20e) into 5,8-dioxoindolizidine 23e [Procedures: (a) (i) OsO₄ (2 mol%), NaIO₄ (4.0 mol amt.), aq. dioxane, (ii) H₅IO₆ (2.0 mol amt.), aq. dioxane; (b) anhydrous K₂CO₃ (2.0 mol amt.), CH₃OH, reflux].

The final ring closure of 5,8-dioindolizidine 23e was efficiently achieved by using photochemical reactions by UV irradiation in dichloromethane in the presence of catalytic amount of I₂ to afford 9,14-dioxophenanthroindolizidine 31 in 44% yield^75

-83 as shown in Scheme 5. Especially, the pentacyclic structure of 31 was supported by the characteristic low-field shift of 2 aromatic protons in the ¹H NMR spectrum of 31 in comparison with those of 23e, i e, 8.81 ppm (1H, s) assignable to the C-1 proton located near to the carbonyl group at the C-14 position and 9.41 ppm (1H, dd, J = 9.4 Hz) assignable to the C-8 proton located near to the lactam carbonyl group in the spectrum of 31, along with the disappearance of 2 proton signals of 23e. It is worth noting that the same photoirradiation of 23e in methanol, in place of dichloromethane as the solvent, also gave 31 in 42% yield, and we cannot find any solvent effects for the photochemical cyclization reaction. However, all attempts for the further reduction of 31 using LiAlH₄, Red-Al, or BH₃·THF resulted in the formation of complex mixture containing a small amount of uncharacterized products having a hydroxyl group along with the recovery of substrate 31, and the further attempts would be required for the selective reduction of lactam carbonyl functionality of 31.

Scheme 5

Synthesis of 9,14-dioxophenanthroindolizidine 31 by photocyclization of 5,8-dioxoindolizidine 23e

In conclusion, we found a new synthetic method of phenanthroindolizidine core via hetero Diels-Alder reaction of in situ generated α-allenylchalcogenoketenes with cyclic imines and the subsequent photochemical ring closure. Our hetero Diels-Alder methodology for the regioselective access to functionalized and fused indolizidine cores are highly flexible concerning the substitution patterns, and further applications of our new synthetic protocol to the synthesis of various phenanthroindolizidine derivatives having a variety of biological activities are expected in our laboratory.

Scheme 6

Phenanthroindorizidine and phenanthroquinolizidine alkaloids.

Experimental

Instruments

The melting points were determined with a Barnstead International MEL-TEMP. ¹H NMR spectra were recorded on a Bruker DRX-400P (400 MHz) spectrometer or a Bruker AVANCE III 500 (500 MHz) spectrometer, and the chemical shifts of the ¹H NMR spectra are given in δ relative to internal tetramethylsilane (TMS). ¹³C NMR spectra were recorded on a Bruker DRX-400P (100 MHz) or a Bruker AVANCE III 500 (126 MHz) spectrometer. ⁷⁷Se NMR spectra were recorded on a Bruker DRX-400P (76 MHz) spectrometer. Mass spectra were recorded on a JEOL JMS-700T mass spectrometer with electron-impact ionization at 20 or 70 eV using a direct inlet system. High-resolution mass spectra (HRMS) were also recorded on a JEOL JMS-700T spectrometer. IR spectra were recorded for thin film (neat) or KBr disks on a JASCO FT/IR-7300 spectrometer. Elemental analyses were performed using a Yanagimoto CHN corder MT-5.

A General Procedure for Preparation of Alkynyl Propargyl Chalcogenides (14, 17)

A THF solution of trimethylsilylacetylene was treated with n-butyllithium (1.1 mol amt.) at 0°C for 15 minutes, then with elemental sulfur (1.1 mol amt.) at 0°C for 15 minutes, and then with propargyl bromide (1.0 mol amt.) at room temperature for 1 hour. The reaction was quenched by the addition of water, and the reaction mixture was extracted with benzene. The organic layer was washed twice with water and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain alkynyl propargyl sulfide 14.

Physical and Spectral Data for Alkynyl Propargyl Sulfides 14 and Selenides 17

14a (X = S, R¹ = C₆H₅, R² = 3,4-(methylenedioxy)phenyl):

Yellow oil.

IR (neat): 2898, 2166, 1501, 1487, 1250, 1226, 1039, 756 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.83 (2H, s), 5.97 (2H, s), 6.74 (1H, d, J = 1.6 Hz), 6.89 (1H, d, J = 8.0 Hz), 6.97 (1H, dd, J = 8.0, 1.6 Hz), 7.29-7.31 (3H, m), 7.42-7.44 (2H, m).

¹³C NMR (CDCl₃) δ: 25.9 (t), 78.2 (s), 81.9 (s), 85.0 (s), 95.8 (s), 101.4 (t), 108.4 (d), 111.8 (d), 115.9 (s), 123.2 (s), 126.6 (d), 128.4 (d × 2), 131.7 (d), 147.4 (s), 148.1 (s).

HRMS Calcd for C₁₈H₁₂O₂S: m/z 292.0558. Found: m/z 292.0558.

14b (X = S, R¹ = 3,4-(CH₃O)₂C₆H₃, R² = 3,4-(methylenedioxy)phenyl):

Reddish oil.

IR (neat): 2905, 2155, 1595, 1506, 1448, 1327, 1238, 1135, 1033, 812, 616 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.81 (2H, s), 3.83 (3H, s), 3.88 (3H, s), 5.95 (2H, s), 6.72 (1H, d, J = 8.4 Hz), 6.78 (1H, d, J = 8.4 Hz), 6.88 (1H, d, J = 1.6 Hz), 6.95-6.98 (2H, m), 7.06 (1H, dd, J = 8.4, 1.6 Hz).

¹³C NMR (CDCl₃) δ: 25.9 (t), 55.8 (q), 55.9 (q), 76.3 (s), 82.0 (s), 85.0 (s), 95.8 (s), 101.3 (t), 108.4 (d), 110.9 (d), 111.8 (d), 114.7 (d), 115.3 (s), 116.9 (s), 125.5 (d), 126.5 (d), 147.4 (s), 148.0 (s), 148.5 (s), 149.8 (s).

HRMS Calcd for C₂₀H₁₆O₄S: m/z 352.0769. Found: m/z 352.0770.

14 c (X = S, R¹ = (CH₃)₃Si, R² = C₆H₅)

Yellow oil.

IR (neat): 2960, 2095, 1491, 1250, 833 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.18 (9H, s), 3.77 (2H, s), 7.30-7.31 (3H, m), 7.43-7.46 (2H, m).

¹³C NMR (CDCl₃) δ: 0.20 (q), 25.5 (t), 83.2 (s), 85.0 (s), 93.0 (s), 103.5 (s), 122.5 (s), 128.1 (d), 128.4 (d), 131.7 (d).

MS (m/z): 244 (M⁺; bp), 230 (M⁺-CH₃; 96%).

Calcd for C₁₄H₁₆SSi: C, 68.79; H, 6.60%. Found: C, 68.54; H, 6.48%.

14d (X = S, R¹ = (CH₃)₃Si, R² = 3,4-(CH₃O)₂C₆H₃):

Yellow oil.

IR (neat): 2960, 2092, 1514, 1248 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.17 (9H, s), 3.77 (2H, s), 3.87 (6H, s), 6.79 (1H, d, J = 8.3 Hz), 6.94 (1H, s), 7.05 (1H, dd, J = 8.3, 1.8 Hz).

¹³C NMR (CDCl₃) δ: −0.20 (q), 25.6 (t), 55.7 (q × 2), 81.6 (s), 85.0 (s), 91.3 (s), 103.4 (s), 110.8 (d), 114.4 (d), 114.7 (s), 125.0 (d), 148.4 (s), 149.5 (s).

MS (m/z): 304 (M⁺; 3%), 175 (M⁺-TMSCCS; bp).

Calcd for C₁₆H₂₀O₂SSi: C, 63.11; H, 6.62%. Found: C, 62.94; H, 6.51%.

17 c (X = Se, R¹ = (CH₃)₃Si, R² = C₆H₅):

Pale yellow oil.

IR (neat): 2960, 2088, 1491, 1250, 860, 844, 758 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.18 (9H, s), 3.78 (2H, s), 7.25-7.31 (3H, m), 7.42-7.44 (2H, m).

¹³C NMR (CDCl₃) δ: −0.10 (q), 15.4 (t), 84.4 (s), 85.3 (s), 110.5 (s), 122.7 (s), 128.2 (d), 128.4 (d), 131.8 (d).

⁷⁷Se NMR (CDCl₃) δ: 260.0.

MS (m/z): 292 (M⁺; bp, ⁸⁰Se), 277 (M⁺-CH₃; 74%, ⁸⁰Se), 195 (C₆H₅CCCH₂Se; 60%).

Calcd for C₁₄H₁₆SeSi: C, 57.72, H, 5.54%. Found: C, 57.80, H, 5.59%

A General Procedure for the Synthesis of 2,3-Disubstituted 4-Methylene-2-cyclobutene-1-thiones 15

A hexane solution of alkynyl propargyl sulfide 14 was heated at refluxing temperature for 12 hours. The reaction mixture was then subjected to evaporation i n vacuo, and the crude products were purified by column chromatography on silica gel to obtain 2,3-disubstituted 4-methyl-2-cyclobutene-1-thione 15.

Physical and Spectral Data for 4-Methylene-2-cyclobutene-1-thiones 15

15a (X = S, R¹ = C₆H₅, R² = 3,4-(methylenedioxy)phenyl):

Red oil.

IR (neat): 2899, 1610, 1478, 1244, 1099, 1037, 756 cm⁻¹.

¹H NMR (CDCl₃) δ: 5.06 (1H, s), 5.40 (1H, s), 6.08 (2H, s), 6.74 (1H, d, J = 8.0 Hz), 6.89 (1H, d, J = 1.6 Hz), 6.95 (1H, d, J = 8.0 Hz), 7.32 (1H, s), 7.38-7.46 (3H, m), 7.49 (1H, d, J = 8.0 Hz), 7.90 (1H, d, J = 8.0 Hz).

¹³C NMR (CDCl₃) δ: 94.6 (t), 102.0 (t), 107.8 (d), 109.2 (d), 124.6 (d), 124.8 (s), 128.1 (d), 128.6 (d), 129.7 (s), 129.8 (d), 148.4 (s), 151.2 (s), 153.9 (s), 157.7 (s), 171.4 (s), 225.8 (s).

HRMS Calcd for C₁₈H₁₂O₂S: m/z 292.0558. Found: m/z 292.0561.

15b (X = S, R¹ = 3,4-(CH₃O)₂C₆H₃, R² = 3,4-(methylenedioxy)phenyl):

Red powder.

MP: 160.5°C-161.7°C

IR (KBr) 2929, 1590, 1510, 1445, 1368, 1267, 1031, 851 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.86 (3H, s), 3.93 (3H, s), 4.99 (1H, d, J = 1.6 Hz), 5.34 (1H, d, J = 1.6 Hz), 6.09 (2H, s), 6.92 (1H, d, J = 8.4 Hz), 6.96 (1H, d, J = 8.4 Hz), 7.37 (1H, d, J = 1.6 Hz), 7.51 (1H, dd, J = 8.4, 1.6 Hz), 7.57-7.60 (2H, m).

¹³C NMR (CDCl₃) δ: 54.9 (q × 2), 92.3 (t), 101.0 (t), 106.7 (d), 108.1 (d), 110.0 (d × 2), 120.5 (d), 121.5 (s), 123.3 (d), 124.0 (s), 147.3 (s), 147.7 (s), 149.4 (s), 149.9 (s), 153.0 (s), 156.2 (s), 169.0 (s), 225.2 (s).

HRMS Calcd for C₂₀H₁₆O₄S: m/z 352.0769. Found: m/z 352.0781.

A General Procedure for the Synthesis of 2,3-Disubstituted 4-Methylene-2-cyclobuten-1-ones 16

A dichloromethane solution of 4-methylene-2-cyclobutene-1-thione 15 was treated with mCPBA (1.2 mol amt.) at 0°C for 30 minutes. The reaction was quenched by the addition of saturated aqueous Na₂SO₃ solution, and the reaction mixture was extracted with dichloromethane. The organic layer was washed with water and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain 4-methylene-2-cyclobuten-1-one 16 as yellow oil.

Physical and Spectral Data for 4-Methylene-2-cyclobuten-1-ones 16

16a (R¹ = C₆H₅, R² = 3,4-(methylenedioxy)phenyl):

Yellow oil.

IR (neat): 2908, 1748, 1548, 1484, 1441, 1351, 1243, 1031, 699 cm⁻¹.

¹H NMR (CDCl₃) δ: 5.01 (1H, s), 5.26 (1H, s), 6.07 (2H, s), 6.94 (1H, d, J = 8.0 Hz), 7.26 (1H, d, J = 1.6 Hz), 7.36-7.42 (4H, m), 7.80 (2H, dd, J = 8.0, 1.6 Hz).

¹³C NMR (CDCl₃) δ: 95.6 (t), 101.9 (t), 107.8 (d), 109.0 (d), 123.7 (d), 125.0 (s), 127.6 (d), 128.8 (d), 129.4 (s), 129.8 (d), 148.2 (s), 150.5 (s), 154.4 (s), 156.9 (s), 171.6 (s), 188.3 (s).

HRMS Calcd for C₁₈H₁₂O₂S: m/z 276.0786. Found: m/z 276.0780.

16b (R¹ = 3,4-(CH₃O)₂C₆H₃, R² = 3,4-(methylenedioxy)phenyl):

Yellow oil.

IR (neat): 2910, 1757, 1595, 1512, 1445, 1359, 1256, 1032 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.86 (3H, s), 3.92 (3H, s), 4.94 (1H, d, J = 1.6 Hz), 5.20 (1H, d, J = 1.6 Hz), 6.08 (2H, s), 6.88 (1H, d, J = 8.4 Hz), 6.95 (1H, d, J = 8.4 Hz), 7.30 (1H, s), 7.37-7.41 (2H, m), 7.48 (1H, dd, J = 8.4, 1.6 Hz).

¹³C NMR (CDCl₃) δ: 55.9 (q), 94.4 (t), 101.9 (t), 107.8 (d), 108.8 (d), 110.2 (d), 111.1 (d), 121.2 (d), 122.2 (d), 123.4 (d), 125.2 (s), 148.2 (s), 148.9 (s), 150.2 (s), 150.5 (s), 154.1 (s), 156.9 (s), 169.8 (s), 188.6 (s).

HRMS Calcd for C₂₀H₁₆O₅: m/z 336.0998. Found: m/z 336.0994.

A Typical Procedure for the Synthesis of δ-Chalcogenolactams (19, 20)

A benzene solution of alkynyl propargyl sulfide 14 was treated with 2-methylpyrroline 18 (1.5 mol amt.) at refluxing temperature for 14 hours. The reaction mixture was then subjected to evaporation in vacuo, and the crude products were purified by column chromatography on silica gel to obtain δ-thiolactam 19 as yellow needles.

Physical and Spectral Data for δ-Chalcogenolactams (19, 20)

19 c (X = S, R¹ = (CH₃)₃Si, R² = C₆H₅):

Yellow needles.

MP: 155.0°C-156.5°C

IR (KBr): 2971, 2359, 1623, 1246 cm⁻¹.

¹H NMR (CDCl₃) δ: −0.26 (9H, s), 1.48 (3H, s), 2.09-2.30 (4H, m), 3.81 (1H, br. dt, J = 14.1, 9.3 Hz), 4.07 (1H, br. dt, J = 14.1, 2.2 Hz), 4.88 (1H, s), 5.26 (1H, s), 7.14-7.17 (1H, m), 7.28–7.38 (4H, m).

¹³C NMR (CDCl₃) δ: 2.29 (q), 21.4 (t), 26.2 (q), 38.2 (t), 52.3 (t), 65.3 (s), 118.8 (dd), 127.7 (d), 127.9 (d), 128.5 (d), 130.0 (d), 139.7 (s), 140.9 (s), 147.7 (s), 151.5 (s), 190.4 (s).

MS (m/z): 327 (M⁺−1; 4%), 296 (M⁺-S; bp), 73 ((CH₃)₃Si; 30%).

Calcd for C₁₉H₂₅NSSi: C, 69.67; H, 7.69; N, 4.28%. Found: C, 69.45; H, 7.56; N, 4.33%.

19d (X = S, R¹ = (CH₃)₃Si, R² = 3,4-(CH₃O)₂C₆H₃):

Yellow needles.

MP: 131.5°C-132.6°C

IR (KBr): 3097, 2971, 1602, 1454, 1266, 1246 cm⁻¹.

¹H NMR (CDCl₃) δ = −0.21 (9H, s), 1.47 (3H, s), 2.12-2.27 (4H, m), 3.76 (3H, s), 3.83 (3H, s), 3.80-–4.10 (2H, m), 4.96 (1H, s), 5.26 (1H, s), 6.76-6.83 (3H, m).

¹³C NMR (CDCl₃) δ: 2.11 (q), 2.13 (q), 21.1 (t), 25.7 (q), 37.8 (t), 37.9 (t), 51.8 (t), 51.9 (t), 65.0 (s), 109.9 (d), 110.7 (d), 112.7 (d), 114.4 (d), 118.3 (s), 139.7 (s), 140.1 (s), 146.9 (s), 151.1 (s), 190.1 (s).

MS (m/z): 387 (M⁺; 2%), 327 (M⁺-CH₃; bp), 73 ((CH₃)₃Si; 3%).

Calcd for C₂₁H₂₉NO₂SSi: C, 65.07; H, 7.54; N, 3.61%. Found: C, 64.92; H, 7.44; N, 3.57%.

20 c (X = Se, R¹ = (CH₃)₃Si, R² = C₆H₅):

Red needles.

MP: 142.9°C-133.1°C

IR (KBr): 3074, 2970, 1635, 1519, 1488, 1241, 1176, 861 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.08 (9H, s), 1.48 (3H, s), 2.15-2.36 (4H, m), 3.72-3.80 (1H, m), 4.06-4.12 (1H, m), 5.00 (1H, s), 5.34 (1H, s), 7.16-7.18 (1H, m), 7.32-7.39 (4H, m).

¹³C NMR (CDCl₃) δ: 2.68 (q), 21.4 (t), 25.2 (q), 38.1 (t), 55.9 (t), 65.8 (s), 119.2 (d), 127.7 (d), 128.1 (d), 128.6 (d), 130.1 (d), 131.0 (d), 139.7 (s), 144.0 (s), 145.2 (s), 151.5 (s), 192.2 (s).

⁷⁷Se NMR (CDCl₃) δ: 671.5 (s).

MS (m/z): 375 (M⁺; 18%), 360 (M⁺-CH₃; bp), 83 (C₅H₉N; 95%).

Calcd for C₁₉H₂₅NSeSi: C, 60.94; H, 6.73; N, 3.74%. Found: C, 61.21; H, 6.48; N, 3.51%.

Conversion of δ-Thiolactam 19c Into δ-Lactam 22c

An aqueous dioxane solution (dioxane:H₂O = 4:1) of δ-thiolactam 19 c (300 mg, 0.92 mmol) was treated with NaIO₄ (790 mg, 4.0 mol amt.) at 0°C and then the reaction mixture was treated with an aqueous OsO₄ solution (c = 1 mg/1 mL) (4.7 mL, 2.0 mol%) at room temperature for 20 hours. Then, the reaction mixture was extracted with diethyl ether. The organic layer was washed with an aqueous Na₂S₂O₃ solution and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo to obtain the crude mixture of 21 as brown oil. An aqueous dioxane solution (dioxane:H₂O = 1:1) of the crude mixture of 21 was then treated with H₅IO₆ (419 mg, 2.0 mol amt.) at room temperature for 2 hours, and the reaction mixture was extracted with diethyl ether. The organic layer was washed with an aqueous Na₂S₂O₃ solution and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain the corresponding δ-lactam 22 c (198 mg, 69% yield) as yellow needles.

Physical and Spectral Data for δ-Lactam 22c

22 c (R¹ = (CH₃)₃Si, R² = C₆H₅):

Yellow needles.

MP: 118.6°C-119.4°C

IR (neat): 2974, 1713, 1441, 1243 cm⁻¹.

¹H NMR (CDCl₃) δ: −0.03 (9H, s), 1.35 (3H, s), 1.95-2.20 (4H, m), 3.60-3.70 (1H, m), 3.74-3.81 (1H, m), 7.05-7.20 (2H, m), 7.35-7.40 (3H, m).

MS (m/z): 314 (M⁺+1; 54%), 298 (M⁺-CH₃; bp).

Calcd for C₁₈H₂₃NO₂Si: C, 68.97; H, 7.40; N, 4.47%. Found: C, 68.72; H, 7.34; N, 4.56%.

Desilylation of δ-Lactam 22c

A methanol solution of δ-lactam 22 c (144 mg, 0.46 mmol) was treated with anhydrous K₂CO₃ powder (121 mg, 2.0 mol amt.) at refluxing temperature for 5 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed by evaporation. The residual crude products were subjected to chromatography on silica gel to obtain 5,8-dioxoindolizidine 23 (95 mg, 86% yield) as yellow oil.

Physical and Spectral Data for 5,8-Dioxoindolizidine 23c

23 c (R¹ = H, R² = C₆H₅):

Yellow oil.

IR (neat): 2997, 1694, 1655, 1597, 1433, 1112, 704 cm⁻¹.

¹H NMR (CDCl₃) δ: 1.25 (3H, s), 1.60-1.80 (2H, m), 1.90-2.05 (2H, m), 3.35-3.50 (1H, m), 3.55-3.75 (1H, m), 7.06 (1H, s), 7.10-7.30 (5H, m).

Preparation of Biphenyl Derivative 27

A THF solution of 3-bromoanisole was treated with n-butyllithium (1.2 mol amt.) at −78°C for 30 minutes, and the reaction mixture was treated with B(OCH₃)₃ (1.2 mol amt.) at −78°C for 1 hour and then at room temperature for 2 hours. The reaction was quenched by the addition of aqueous 1 M HCl solution, and the reaction mixture was extracted with diethyl ether. The organic layer was washed with water and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were washed with hexane to obtain boronic acid 26 as colorless needles (822 mg, quantitative yield). Subsequently, a N,N-dimethylformamide (DMF) solution of 2-bromo-4,5-dimethoxybenzaldehyde (25) was treated with boronic acid 26 (1.2 mol amt.), triphenylphosphine (20 mol%), Pd(OAc)₂ (10 mol%), and triethylamine (excess) at 110°C for 5 hours. After removal of DMF by evaporation, the residual mixture was extracted with chloroform. The organic layer was washed twice with water and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain biphenyl aldehyde 27 as yellow solids.

Physical and Spectral Data for Biphenyl Aldehyde 27

Yellow prisms.

MP: 97.5°C-97.9°C

IR (KBr): 2940, 1669, 1506, 1272, 1154, 1042, 991, 757 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.85 (3H, s), 3.95 (3H, s), 3.97 (3H, s), 6.86 (1H, s), 6.91-6.98 (3H, m), 7.30-7.38 (1H, m), 7.53 (1H, m), 9.84 (1H, s).

¹³C NMR (CDCl₃) δ: 55.0 (q), 55.8 (q), 55.9 (q), 108.2 (d), 112.2 (d), 113.1 (d), 115.7 (d), 122.5 (d), 126.7 (d), 129.0 (d), 138.7 (s), 141.0 (s), 148.5 (s), 153.1 (s), 159.2 (s), 190.8 (d).

MS (m/z): 272 (M⁺; bp), 241 (M⁺-OCH₃; 20%).

Calcd for C₁₆H₁₆O₄: C, 70.57; H, 5.92%. Found: C, 70.67; H, 5.85%.

Conversion of Biphenyl Aldehyde 27 Into 1,1-Dibromoalkene 28

A dichloromethane solution of biphenyl aldehyde 27 (2.840 g, 10.4 mmol) was treated with triphenylphosphine (5.472 g, 2.0 mol amt.) and carbon tetrabromide (6.918 g, 2.0 mol amt.) at refluxing temperature for 10 hours. The reaction mixture was then cooled to room temperature, and the reaction was quenched by the addition of saturated aqueous NaHCO₃ solution to the reaction mixture. The reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacu o, and the residual crude products were subjected to column chromatography on silica gel to obtain 1,1-dibromoalkene 28 (4.110 g, 92% yield) as yellow needles.

Physical and Spectral Data for 1,1-Dibromoalkene 28

Yellow needles.

MP: 78.0°C-78.7°C

IR (KBr): 3018, 2936, 1606, 1566, 1488, 1464, 1254, 1137, 1051, 1030, 872, 753 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.85 (3H, s), 3.91 (3H, s), 3.94 (3H, s), 6.86 (1H, s), 6.86 (1H, s), 6.90 (1H, br. d, J = 7.8 Hz), 6.92 (1H, br. d, J = 7.8 Hz), 7.21 (1H, s), 7.28 (1H, s), 7.33 (1H, t, J = 7.8 Hz).

¹³C NMR (CDCl₃) δ: 55.2 (q), 55.9 (q), 56.0 (q), 89.1 (s), 111.8 (d), 112.4 (d), 113.1 (d), 115.0 (d), 121.9 (d), 125.7 (s), 129.2 (d), 134.2 (s), 137.0 (d), 141.3 (s), 147.7 (s), 148.9 (s), 159.2 (s).

MS (m/z): 430 (M⁺; 2%, ⁸¹Br), 428 (M⁺; 3%, ⁸¹Br+⁷⁹Br), 426 (M⁺; 2%, ⁷⁹Br), 320 (M⁺-C₆H₄OCH₃; 3%), 268 (M⁺-Br₂; 39%).

Calcd for C₁₇H₁₆Br₂O₃: C, 47.69; H, 3.77%. Found: C, 47.61; H, 3.72%.

Conversion of 1,1-Dibromoalkene 28 Into Propargyl Alcohol 29

A THF solution of 1,1-dibromoalkene 28 (3.719 g, 8.69 mmol) was treated with n-butyllithium (11.0 mL, 2.0 mol amt.) at −78°C for 30 minutes, and subsequently, the reaction mixture was treated with paraformaldehyde (260 mg, 1.0 mol amt.) at room temperature for 15 hours and then at refluxing temperature for 1 hour. The reaction was quenched by the addition of water at room temperature. The reaction mixture was extracted with chloroform, and the organic layer was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain propargyl alcohol 29 (1.788 g, 69% yield) as yellow oil.

Physical and Spectral Data for Propargyl Alcohol 29

Yellow oil.

IR (neat): 3504, 2920, 2225, 1516, 1496, 1255, 1219, 1152, 1028, 999, 755 cm⁻¹.

¹H NMR (CDCl₃) δ: 1.70 (1H, br. s), 3.86 (3H, s), 3.90 (6H, s), 4.35 (2H, d, J = 5.8 Hz), 6.87 (1H, s), 7.02 (1H, s), 7.10-7.16 (2H, m), 7.16 (1H, s), 7.32 (1H, t, J = 7.9 Hz).

¹³C NMR (CDCl₃) δ: 51.5 (t), 55.2 (q), 55.8 (q), 55.9 (q), 85.2 (s), 88.5 (s), 112.2 (d), 112.5 (s), 112.7 (d), 114.8 (d), 115.3 (d), 121.5 (d), 128.9 (d), 137.0 (s), 141.6 (s), 147.7 (s), 149.3 (s), 159.0 (s).

MS (m/z): 298 (M⁺; 37%), 281 (M⁺-OH; 6%), 267 (M⁺-OCH₃; 7%).

Calcd for C₁₈H₁₈O₄: C, 72.47; H, 6.08%. Found: C, 72.31; H, 6.20%

Conversion of Propargyl Alcohol 29 Into Propargyl Chloride 30

A CCl₄ solution (excess) of propargyl alcohol 29 (1.311 g, 4.39 mmol) was treated with triphenylphosphine (1.267 g, 1.1 mol amt.) at refluxing temperature for 14 hours and then the reaction mixture was cooled to room temperature. The reaction mixture was subjected to suction filtration through a silica gel layer, and the residual solids were washed with a 3:1 mixture of hexane and ethyl acetate. The organic solvents were removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain propargyl chloride 30 (1.159 g, 82% yield) as yellow needles.

Physical and Spectral Data for Propargyl Chloride 30

Yellow needles.

MP: 80.5°C-81.2°C

IR (KBr): 2937, 1602, 1516, 778 cm⁻¹.

¹H NMR (CDCl₃) δ: 3.78 (3H, s), 3.89 (6H, s), 4.25 (2H, d, J = 0.7 Hz), 6.68 (1H, s), 6.89 (1H, d, J = 8.3 Hz), 7.02 (1H, s), 7.07-7.13 (1H, m), 7.32 (1H, t, J = 8.3 Hz).

¹³C NMR (CDCl₃) δ = 31.3 (t), 55.1 (q), 55.8 (q), 55.9 (q), 84.8 (s), 86.2 (s), 111.8 (s), 112.2 (d), 113.1 (d), 114.4 (d), 115.4 (d), 121.4 (d), 128.9 (d), 137.6 (s), 141.3 (s), 147.7 (s), 149.6 (s), 159.0 (s). MS (m/z): 318 (M⁺; 10%, ³⁷Cl), 316 (M⁺; 23%, ³⁵Cl), 281 (M⁺-Cl; 11%), 175 (C₆H₃(OCH₃)₂CCCH₂; bp), 51 (CH₂Cl; 3%, ³⁷Cl), 49 (CH₂Cl; 11%, ³⁵Cl).

Calcd for C₁₈H₁₇ClO₃: C, 68.25; H, 5.41%. Found: C, 68.10; H, 5.42%.

A Typical Procedure for Preparation of Alkynyl Propargyl Chalcogenides (14e, 17e)

A THF solution of trimethylsilylacetylene (930 mg, 2.0 mol amt.) was treated with n-butyllithium (7.0 mL, 2.1 mol amt.) at 0°C for 30 minutes, then with elemental selenium (748 mg, 2.0 mol amt.) at 0°C for 15 minutes, and then with propargyl chloride 30 (1.500 g, 4.74 mmol) at room temperature for 30 minutes. The reaction was quenched by the addition of water, and the reaction mixture was extracted with benzene. The organic layer was washed twice with water and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain alkynyl propargyl selenide 17e (910 mg, 42% yield) as orange oil.

Physical and Spectral Data for 14e and 17e

14e (X = S, R¹ = (CH₃)₃Si, R² = 2-(3-methoxyphenyl)−4,5-dimethoxyphenyl):

Yellow oil.

IR (neat): 2961, 2093, 1602, 1516, 1252, 1029, 880, 845 cm^-1.

¹H NMR (CDCl₃) δ: 0.15 (9H, s), 3.68 (2H, s), 3.84 (3H, s), 3.89 (6H, s), 6.84-6.89 (3H, m), 7.02 (1H, s), 7.11 (1H, s), 7.29-7.34 (1H, m).

¹³C NMR (CDCl₃) δ = −0.22 (q), 25.8 (t), 55.1 (q), 55.7 (q), 55.8 (q), 84.2 (s), 84.8 (s), 93.2 (s), 103.2 (s), 111.8 (s), 112.2 (d), 113.1 (d), 114.4 (d), 115.4 (d), 121.4 (d), 128.9 (d), 137.6 (s), 141.4 (s), 147.7 (s), 149.6 (s), 159.0 (s).

MS (m/z): 410 (M⁺; 12%), 395 (M⁺-CH₃; 7%), 281 (M⁺-C₅H₃SSi; 87%), 73 ((CH₃)₃Si; bp).

Calcd for C₂₃H₂₆O₃SSi: C, 67.28; H, 6.38%. Found: C, 67.11; H, 6.21%.

17e (X = Se, R¹ = (CH₃)₃Si, R² = 2-(3-methoxyphenyl)−4,5-dimethoxyphenyl):

Orange oil.

IR (neat): 2958, 2087, 1712, 1602, 1516, 1250, 860 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.14 (9H, s), 3.70 (2H, s), 3.87 (3H, s), 3.91 (6H, s), 6.85-6.87 (1H, m), 6.90 (1H, d, J = 7.9 Hz), 7.01 (1H, s), 7.10-7.11 (1H, m), 7.17 (1H, d, J = 7.9 Hz), 7.34 (1H, t, J = 7.9 Hz).

¹³C NMR (CDCl₃) δ: −0.12 (q), 15.3 (t), 55.2 (q), 55.8 (q), 55.9 (q), 85.1 (s), 85.3 (s), 85.8 (s), 110.2 (s), 112.2 (d), 112.7 (d), 112.9 (d), 114.5 (d), 115.4 (d), 121.5 (d), 129.0 (d), 137.4 (s), 141.5 (s), 147.7 (s), 149.3 (s), 159.1 (s).

MS (m/z): 458 (M⁺; 8%), 281 (M⁺-C₅H₉SeSi; bp), 250 (M⁺-C₆H₁₂OSeSi; 70%), 73 ((CH₃)₃Si; 19%).

Calcd for C₂₃H₂₆O₃SeSi: C, 60.38; H, 5.73%. Found: C, 60.23; H, 5.82%.

A Typical Procedure for the Synthesis of δ-Chalcogenolactams (19e, 20e)

A benzene solution of alkynyl propargyl selenide 17e (328 mg, 0.72 mmol) was treated with 2-methylpyrroline 18 (2.0 mol amt.) at refluxing temperature for 20 hours. The reaction mixture was then subjected to evaporation in vacuo, and the crude products were purified by column chromatography on silica gel to obtain δ-selenolactam 20e (194 mg, 50% yield) as yellow needles.

Synthesis of δ-Thiolactam 19e by Thermal Reaction of 14e in the Presence of Yb(OTf)₃

A dichloromethane solution of alkynyl propargyl sulfide 14e (4.791 g, 11.7 mmol) was treated with 2-methylpyrroline (18, 2.910 g, 1.0 mol amt.) and Yb(OTf)₃ (940 mg, 10 mol%) at refluxing temperature for 12 hours. The reaction mixture was then subjected to evaporation in vacuo, and the crude products were purified by column chromatography on silica gel to obtain δ-thiolactam 19e (2.708 g, 47% yield) as yellow needles.

Physical and Spectral Data for 19e and 20e

19e (X = S, R¹ = (CH₃)₃Si, R² = 2-(3-methoxyphenyl)−4,5-dimethoxyphenyl):

Yellow needles.

IR (KBr): 2958, 1711, 1602, 1516, 1253 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.21 (9H, s), 0.78 (3H, s), 1.24-1.27 (2H, m), 1.95-2.04 (4H, m), 3.75 (3H, s), 3.88 (3H,s), 3.92 (3H, s), 4.67 (1H, s), 4.86 (1H, s), 6.74-6.79 (4H, m), 7.19-7.32 (2H, m).

¹³C NMR (CDCl₃) δ: 3.33 (q), 20.7 (t), 26.7 (q), 38.5 (t), 52.5 (t), 55.1 (q), 55.9 (q × 2), 65.2 (s), 111.7 (d), 113.4 (d), 115.2 (d), 115.5 (d), 118.9 (d), 121.6 (d), 129.0 (d), 129.9 (s), 133.5 (s), 140.2 (s), 142.7 (s), 147.6 (s), 148.4 (s), 148.8 (s), 149.0 (s), 159.0 (s), 189.4 (s).

MS (m/z): 493 (M⁺; 4%), 478 (M⁺-CH₃; bp), 462 (M⁺-OCH₃; 10%), 31 (CH₃O; 11%).

Calcd for C₂₈H₃₅NO₃SSi: C, 68.11; H, 7.15; N, 2.84%. Found: C, 67.97; H, 7.18; N, 2.81%.

20e (X = Se, R¹ = (CH₃)₃Si, R² = 2-(3-methoxyphenyl)-4,5-dimethoxyphenyl):

Red needles.

MP: 79.9°C-80.6°C

IR (KBr): 2958, 1601, 1521, 1437, 1251, 1173, 842 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.26 (9H, s), 0.86 (3H, s), 2.02-2.04 (4H, m), 3.70-3.74 (1H, m), 3.76 (3H, s), 3.92 (3H, s), 3.94 (3H, s), 4.00-4.06 (1H, m), 4.77 (1H, s), 4.92 (1H, s), 6.77 (1H, d, J = 7.8 Hz), 6.81 (1H, s), 6.87-6.89 (3H, m), 7.20 (1H, t, J = 7.8 Hz).

¹³C NMR (CDCl₃) δ: 3.85 (q), 20.7 (t), 26.0 (q), 38.5 (t), 55.1 (q), 55.9 (q × 2), 56.3 (t), 65.8 (s), 111.7 (d), 113.5 (d), 115.2 (d), 115.4 (d), 119.5 (s), 121.6 (d), 129.0 (d), 129.9 (s), 133.4 (s), 142.7 (s), 143.0 (s), 146.6 (s), 147.6 (s), 148.3 (s), 149.1 (s), 159.0 (s), 190.8 (s).

MS (m/z): 541 (M⁺; 14%), 526 (M⁺-CH₃; bp), 462 (M⁺-Se; 9%), 388 (M⁺-Se-(CH₃)₃Si; 7%).

Calcd for C₂₈H₃₅NO₃SeSi: C, 62.21; H, 6.53; N, 2.59%. Found: C, 62.02; H, 6.63; N, 2.52%

A Typical Procedure for the Conversion of δ-Chalcogenolactams (19e, 20e) Into δ-Lactam 22e

An aqueous dioxane solution (dioxane:H₂O = 4:1) of δ-selenolactam 20e (100 mg, 0.18 mmol) was treated with NaIO₄ (158 mg, 4.0 mol amt.) at 0°C and then the reaction mixture was treated with an aqueous OsO₄ solution (c = 1 mg/1 mL) (0.9 mL, 2.0 mol%) at room temperature for 21 hours. Then, the reaction mixture was extracted with diethyl ether. The organic layer was washed with an aqueous Na₂S₂O₃ solution and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo to obtain the crude mixture of 21 as brown oil. An aqueous dioxane solution (dioxane:H₂O = 1:1) of the crude mixture of 21 was then treated with H₅IO₆ (84 mg, 2.0 mol amt.) at room temperature for 4 hours, and the reaction mixture was extracted with diethyl ether. The organic layer was washed with an aqueous Na₂S₂O₃ solution and was dried over anhydrous Na₂SO₄ powder. The organic solvent was removed in vacuo, and the residual crude products were subjected to column chromatography on silica gel to obtain δ-lactam 22e (89 mg, quantitative yield) as yellow needles.

Physical and Spectral Data for δ-Lactam 22e

22e (R¹ = (CH₃)₃Si, R² = 2-(3-methoxyphenyl)-4,5-dimethoxyphenyl):

Yellow needles.

MP: 74.6°C-75.6°C

IR (KBr): 2977, 1689, 1629, 1604, 1512, 1420, 1251, 1049 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.17 (3H, s), 0.78 (9H, s), 1.90-1.92 (4H, m), 3.55-3.60 (1H, m), 3.67-3.73 (1H, m), 3.77 (3H, s), 3.89 (3H, s), 3.92 (3H, s), 6.64 (1H, s), 6.79 (1H, s), 6.79 (1H, d, J = 8.4 Hz), 6.86 (1H, d, J = 7.2 Hz), 6.87 (1H, s), 7.23 (1H, t, J = 8.4, 7.2 Hz).

¹³C NMR (CDCl₃) δ: 0.58 (q), 20.3 (dd), 25.8 (q), 34.6 (t), 55.0 (q), 55.8 (q), 55.9 (q), 68.3 (s), 112.1 (d), 113.0 (d), 114.5 (d), 115.2 (d), 121.6 (d), 126.0 (s), 129.1 (d), 133.8 (s), 142.3 (s), 147.7 (s), 149.3 (s), 151.4 (s), 152.6 (s), 159.0 (s), 163.9 (s), 198.3 (s).

MS (m/z): 478 (M⁺−1; 50%), 464 (M⁺-CH₃; bp), 448 (M⁺-OCH₃; 6%), 406 (M⁺-(CH₃)₃Si; 36%), 73 ((CH₃)₃Si; 10%).

Calcd for C₂₇H₃₃NO₅Si: C, 67.61; H, 6.93; N, 2.92%. Found: C, 67.25; H, 7.05; N, 3.01%.

Desilylation of δ-Lactam 22e

A methanol solution of δ-lactam 22e (701 mg, 1.46 mmol) was treated with anhydrous K₂CO₃ powder (391 mg, 2.0 mol amt.) at refluxing temperature for 13 hours. The reaction mixture was then cooled to room temperature, and the solvent was removed by evaporation. The residual crude products were subjected to chromatography on silica gel to obtain 5,8-dioxoindolizidine 23e (399 mg, 67% yield) as yellow needles.

Physical and Spectral Data for 5,8-Dioxoindolizidine 23e

23e (R¹ = H, R² = 2-(3-methoxyphenyl)-4,5-dimethoxyphenyl):

Yellow needles.

MP: 75.3°C-76.7°C

IR (KBr): 2976, 1704, 1651, 1516, 1455, 1254, 1161, 1047 cm⁻¹.

¹H NMR (CDCl₃) δ: 0.97 (3H, s), 1.92-1.97 (4H, m), 3.56-3.62 (1H, m), 3.74-3.78 (1H, m), 3.79 (3H, s), 3.90 (3H, s), 3.91 (3H, s), 6.75 (1H, s), 6.78-6.79 (1H, m), 6.83 (2H, d, J = 7.5 Hz), 6.86 (1H, s), 6.88 (1H, s), 7.23 (1H, t, J = 7.5 Hz).

¹³C NMR (CDCl₃) δ: 20.1 (t), 25.6 (q), 34.2 (t), 44.9 (t), 55.2 (q), 55.9 (q), 56.0 (q), 62.6 (s), 112.1 (d), 113.1 (d), 113.4 (d), 115.5 (d), 121.9 (d), 123.7 (s), 129.3 (d), 134.7 (s), 142.4 (s), 145.6 (s), 148.2 (s), 149.6 (s), 159.2 (s), 160.3 (s), 197.6 (s).

MS (m/z): 406 (M⁺−1; bp), 391 (M⁺-CH₃-1; 35%).

Calcd for C₂₄H₂₅NO₅: C, 70.74; H, 6.18; N, 3.44%. Found: C, 70.59; H, 6.02; N, 6.21%.

Synthesis of 9,14-Dioxophenanthroindolizidine 31 by Iodine-Assisted Photochemical Cyclization of 5,8-Dioxoindolizidine 23e

A dichloromethane or a methanol solution of 5,8-dioxoindolizidine 23e (354 mg, 0.836 mmol) and iodine (10 mg) in a Pyrex test tube was subjected to photoirradiation using a high-pressure Hg lamp at room temperature for 72 hours. The reaction mixture was then subjected to evaporation in vacuo, and the crude products were purified by column chromatography on silica gel to obtain 9,14-dioxophenanthroindolizidine 31 (155 mg, 44% yield) as pale yellow needles.

Physical and Spectral Data for 9,14-Dioxophenanthroindolizidine 31

Pale yellow needles.

MP: 218.7°C-219.4°C

IR (KBr): 3119, 2980, 1646, 1614, 1520, 1425, 1260, 1112, 1051 cm⁻¹.

¹H NMR (CDCl₃) δ: 1.47 (3H, s), 2.12-2.18 (3H, m), 2.47-2.50 (1H, m), 3.88-3.92 (2H, m), 4.05 (3H, s), 4.09 (3H, s), 4.14 (3H, s), 7.03 (1H, dd, J = 9.4, 2.6 Hz), 7.86 (1H, d, J = 2.6 Hz), 7.89 (1H, s), 8.81 (1H, s), 9.41 (1H, d, J = 9.4 Hz).

¹³C NMR (CDCl₃) δ: 21.3 (t), 26.2 (q), 34.6 (dd), 46.6 (t), 55.4 (q), 55.7 (q), 55.8 (q), 68.9 (s), 102.8 (d), 103.8 (d), 106.9 (d), 116.0 (d), 122.1 (s), 122.4 (s), 123.2 (s), 126.0 (s), 131.1 (s), 131.9 (d), 134.9 (s), 150.2 (s), 160.2 (s), 161.9 (s), 201.6 (s).

MS (m/z): 406 (M⁺+1; bp), 391 (M⁺-CH₃ + 1; 35%).

Calcd for C₂₄H₂₃NO₅: C, 71.10; H, 5.72; N, 3.45%. Found: C, 71.21; H, 5.85; N, 3.49%.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed no financial support for the research, authorship, and/or publication of this article.

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An Efficient Synthesis of Phenanthroindolizidine Core via Hetero Diels-Alder Reaction of In Situ Generated α-Allenylchalcogenoketenes With Cyclic Imines

Abstract

Keywords

Synthesis of 9,14-dioxophenanthroindolizidine 31 by photocyclization of 5,8-dioxoindolizidine 23e

Experimental

Instruments

A General Procedure for Preparation of Alkynyl Propargyl Chalcogenides (14, 17)

Physical and Spectral Data for Alkynyl Propargyl Sulfides 14 and Selenides 17

A General Procedure for the Synthesis of 2,3-Disubstituted 4-Methylene-2-cyclobutene-1-thiones 15

Physical and Spectral Data for 4-Methylene-2-cyclobutene-1-thiones 15

A General Procedure for the Synthesis of 2,3-Disubstituted 4-Methylene-2-cyclobuten-1-ones 16

Physical and Spectral Data for 4-Methylene-2-cyclobuten-1-ones 16

A Typical Procedure for the Synthesis of δ-Chalcogenolactams (19, 20)

Physical and Spectral Data for δ-Chalcogenolactams (19, 20)

Conversion of δ-Thiolactam 19c Into δ-Lactam 22c

Physical and Spectral Data for δ-Lactam 22c

Desilylation of δ-Lactam 22c

Physical and Spectral Data for 5,8-Dioxoindolizidine 23c

Preparation of Biphenyl Derivative 27

Physical and Spectral Data for Biphenyl Aldehyde 27

Conversion of Biphenyl Aldehyde 27 Into 1,1-Dibromoalkene 28

Physical and Spectral Data for 1,1-Dibromoalkene 28

Conversion of 1,1-Dibromoalkene 28 Into Propargyl Alcohol 29

Physical and Spectral Data for Propargyl Alcohol 29

Conversion of Propargyl Alcohol 29 Into Propargyl Chloride 30

Physical and Spectral Data for Propargyl Chloride 30

A Typical Procedure for Preparation of Alkynyl Propargyl Chalcogenides (14e, 17e)

Physical and Spectral Data for 14e and 17e

A Typical Procedure for the Synthesis of δ-Chalcogenolactams (19e, 20e)

Synthesis of δ-Thiolactam 19e by Thermal Reaction of 14e in the Presence of Yb(OTf)3

Physical and Spectral Data for 19e and 20e

A Typical Procedure for the Conversion of δ-Chalcogenolactams (19e, 20e) Into δ-Lactam 22e

Physical and Spectral Data for δ-Lactam 22e

Desilylation of δ-Lactam 22e

Physical and Spectral Data for 5,8-Dioxoindolizidine 23e

Synthesis of 9,14-Dioxophenanthroindolizidine 31 by Iodine-Assisted Photochemical Cyclization of 5,8-Dioxoindolizidine 23e

Physical and Spectral Data for 9,14-Dioxophenanthroindolizidine 31

Footnotes

Declaration of Conflicting Interests

Funding

References

Synthesis of δ-Thiolactam 19e by Thermal Reaction of 14e in the Presence of Yb(OTf)₃