Synthesis of 2,3-Disubstituted Benzo[b]selenophenes via Electrophilic Cyclization

Abstract

2,3-Disubstituted benzo[b]selenophenes have been prepared by the electrophilic cyclization of various 1-(1-alkynyl)-2-(methylseleno)arenes by Br₂, NBS, I₂, ICl, PhSeCl, PhSeBr and Hg(OAc)₂. This method tolerates a wide variety of functional groups, including alcohol, ester, nitrile, nitro and silyl groups, and proceeds under exceptionally mild reaction conditions.

Introduction

The electrophilic cyclization of alkynes having a nucleophile in close proximity to the triple bond has proven to be an efficient way of constructing a wide array of carbocycles and heterocycles.¹ Recently our group and others have successfully utilized this approach to synthesize benzo[b]thiophenes,² benzofurans,³ furans,⁴ thiophenes,⁵ indoles,^3c,6 isoquinolines,⁷ quinolines,⁸ isocoumarins,⁹ and polycyclic aromatic hydrocarbons.¹⁰ Similar cyclizations have also been reported using transition metal catalysts.¹¹ However, some of these transition metal approaches are either incompatible with functionality or lack regioselectivity. Chalcogens, like sulfur, selenium and tellurium, have seldom been employed in such transition metal-catalyzed cyclizations due to their strong affinity for transition metals.

Benzo[b]selenophenes have received little attention as potential drugs, although their potent biological activity and synthetic utility have been discussed in the literature.¹² Recently Otsubo and co-workers have shown that high performance organic field effect transistors can be developed from benzodiselenophenes.¹³ Their studies suggest that the replacement of sulfur atoms with selenium can enhance the optoelectronic properties of thiophene-containing molecules. Thus, we were encouraged to examine the synthesis of selenium analogs of benzo[b]thiophenes using acetylene cyclization chemistry.

Earlier syntheses of benzo[b]selenophenes have generally required harsh reaction conditions and suffer from poor reaction yields and intolerance of many functional groups.¹⁴ Among the known protocols for the synthesis of 3-halobenzo[b]selenophenes,¹⁵ the reaction of 1-aryl-1-alkynes with SeBr₄ or SeCl₄ is reported to give good yields.¹⁶ Although iodides are more useful than bromides or chlorides for subsequent transition metal-catalyzed cross coupling reactions, no general method is known for the synthesis of 3-iodobenzo[b]selenophenes. Herein, we report a general, high yielding synthesis of 3-iodobenzo[b]selenophenes via iodocyclization, which also gives good yields with several other electrophiles.

Results and Discussion

The expeditious synthesis of benzo[b]selenophenes have been achieved by a two step approach involving the Sonogashira coupling of 2-iodoselenoanisoles with terminal alkynes, followed by electrophilic cyclization using various electrophiles (Scheme 1). The required starting compounds 1 and 2 have been prepared by a two step approach developed by Christiaens and co-worker¹⁷ in 35% and 49% overall yields respectively (Scheme 2).

Scheme 1.

Scheme 2.

Various substituted selenium-containing alkynes have been prepared using standard Sonogashira coupling conditions¹⁸ in order to study the scope and generality of our methodology (Table 1). Although selenium compounds 1 and 2 react slowly with terminal alkynes under standard Sonogashira reaction conditions, the required coupling products are obtained in good to excellent yields after 24–48 h. The slow reaction may be attributed to the strong coordination between selenium and palladium in the key arylpalladium intermediate. Terminal alkynes bearing simple alkyl groups have afforded the expected internal alkynes in high yields (Table 1, entries 1 and 2). The reactions of alkylalkynes bearing cyano, ester and hydroxyl groups also proceed in excellent yields (entries 3–5). Alkynes bearing a triethylsilyl group (entry 6) and a vinylic group (entry 7) furnished the desired products in 79% and 96% yields respectively. The reaction of phenylacetylene was low yielding due to homocoupling of this alkyne (entry 8). Substituted aryl groups on the alkyne were also successfully employed in the coupling reaction (entries 9 and 10). Diyne 13 was prepared from coupling of 1 and 1,4-diethynylbenzene. However, the reaction proceeded rather slowly and afforded only a 47% yield (entry 11). The reaction of 2 and 3-cyclohexyl-1-propyne also proceeded smoothly to furnish the desired product 14 in an excellent yield (entry 12).

Table 1.

Sonogshira coupling of 1-iodo-2-(methylseleno)arenes and terminal acetylenes.^a

entry	substrate	alkyne	time (h)	product	%	isolated yield
1	1		24		3	82
2	1		24		4	88
3	1		24		5	86
4	1		48		6	90
5	1		24		7	95
6	1		24		8	79
7	1		24		9	96
8	1		24		10	68
9	1		48		11	85b
10	1		24		12	95
11	1		48		13	47c
12	2		48		14	92

^aUnless otherwise stated, all reactions were carried out on a 2.0 mmol scale in 12 mL of Et₃N using 1.0 equiv of the 1-iodo-2-(methylseleno)arene, 1.5 equiv of alkyne, 2 mol % of PdCl₂(PPh₃)₂ and 1 mol % of CuI at room temperature for the desired time.

^bThis reaction was carried out in a 1:1 mixture of DMF and Et₃N as the solvent for 48 h.

^cThis reaction was performed using 2.2 equiv of 1-iodo-2-(methylseleno)benzene and 1.0 equiv of alkyne.

We have found that the electrophilic cyclization of 1-(1-decynyl)-2-(methylseleno)benzene (3) with I₂ in CH₂Cl₂ as the solvent at room temperature affords a near quantitative yield of the desired 2,3-disubstituted benzo[b]selenophene 15 after only 30 min reaction time (Scheme 3).

Scheme 3.

The yield of this reaction is not much affected when different solvents are employed (Table 2). THF, Et₂O, CH₃CN and hexanes gave 15 in greater than 90% yields, while the reaction proceeded more slowly and gave a lower yield in MeOH (entry 4). The mild reaction conditions, ease of product isolation and high yields encouraged us to broaden the scope of our methodology by using different 1-(1-alkynyl)-2-(methylseleno)arenes (Table 3).

Table 2.

Effect of the solvent in the reaction of 1-(1-decynyl)-2-(methylseleno)benzene (3) with I₂.^a

entry	solvent	I2 equiv	time (min)	% yield
1	CH2Cl2	1.1	30	98
2	CH2Cl2	2.0	30	97
3	Et2O	1.1	30	91
4	MeOH	1.1	60	82
5	THF	1.1	30	92
6	CH3CN	1.1	30	95
7	Hexanes	1.1	30	90

^aAll reactions were carried out on a 0.25 mmol scale in 5 mL of solvent using 1.0 equiv of 1-(1-decynyl)-2-(methylseleno)benzene (3) and the indicated amount of I₂ at room temperature.

Table 3.

Iodocyclization of various 1-(alkynyl)-2-(methylseleno)arenes.^a

entry	alkyne	electrophile	time (min)	product		% isolated yield
1	3	I2	30		15	98
2	3	ICl	60		15	78
3	10	I2	30		16	90
4	10	ICl	60		16	79
5	9	I2	30		17	92
6	9	ICl	60		17	76
7	5	I2	60		18	87
8	6	I2	60		19	83
9	7	I2	30		20	93
10	8	I2	30		21	91
11	4	I2	30		22	91
12	14	I2	60		23	82
13	11	I2	30		24	94
14	12	I2	30		25	91
15	13	I2	30		26	88b

^aUnless otherwise stated, all reactions were carried out on a 0.25 mmol scale in 5 mL of solvent using 1.0 equiv of 1-(1-alkynyl-2-(methylseleno)benzene and 1.1 equiv of I₂ or ICl at room temperature.

^bThis reaction was carried out on a 0.25 mmol scale in 5 mL of solvent using 1.0 equiv of 1-(1-alkynyl)-2-(methylseleno)benzene and 2.2 equiv of I₂.

The yield of benzo[b]selenophenes was excellent whether the substituent on the alkyne was alkyl, aryl or vinylic (Table 3; entries 1, 3 and 5). In some of our earlier work on the iodocyclization of functionally-substituted alkynes ICl proved to be a better electrophile than I₂ for some substrates. In our current methodology, ICl gave somewhat lower yields compared to I₂ (see entries 2, 4 and 6). The higher yields with I₂ as the electrophile may be attributed to the higher nucleophilicity of an iodide ion than a chloride ion, which facilitates removal of the methyl group present in the cationic intermediate presumably generated during cyclization (see the later discussion of mechanism). Alternatively, the weaker electrophile I₂ may simply be less likely to react directly with the selenium moiety.

Iodocyclization also readily tolerates functionally-substituted alkyl groups (entries 7–9) with little effect on the reaction yield. The sterically hindered triethylsilylalkyne 8 also reacted rapidly to give benzo[b]selenophene 21 in a 91% yield (entry 10). The iodocyclization of 14 proceeded slowly when compared to that of compound 4 (entries 11 and 12); this observation can be attributed to the presence of an ester group para to the selenium, which reduces the electron density on selenium. No such effect is observed when varying the nature of the substituents on the remote aryl group. The presence of an electron-withdrawing nitro group or an electron-donating methoxy group did not make much of a difference and the reaction proceeded with ease giving the desired products in greater than 90% yields (entries 13 and 14). The iodocyclization of 13 resulted in the formation of the dicyclized product in a good yield of 88% (entry 15).

Electrophilic cyclization using other electrophiles, such as Br₂, NBS, PhSeBr, PhSeCl, Hg(OAc)₂ and p-O₂NC₆H₄SCl, has also been examined in order to extend the scope of our methodology (Table 4). The cyclization of alkyne 10 using PhSeBr resulted in a slightly higher yield of the desired product when compared to PhSeCl (entries 1 and 2). PhSeBr was then employed for the cyclization of alkynes bearing alkyl and vinylic groups (entries 6 and 9) and the yields were 84% and 87% respectively. With Hg(OAc)₂ as the electrophile, the reaction was quenched with an aqueous NaCl solution and the chloromercurio derivative 29 was isolated in 92% yield (entry 5). When p-O₂NC₆H₄SCl was used as an electrophile on alkyne 10, the corresponding cyclized product was not observed even after 2 d.

Table 4.

Other electrophilic cyclizations of 1-(1-alkynyl)-2-(methylseleno)arenes.^a

entry	alkyne	Electrophile (equiv)	Time (h)	product		% isolated yield
1	10	PhSeCl (1.5)	2		27	92
2	10	PhSeBr (1.5)	2		27	95
3	10	Br2 (1.1)	12		28	75
4	10	NBS (2.2)	12		28	46
5	10	Hg(OAc)2 (1.1)	1		29	92b
6	3	PhSeBr (1.5)	2		30	84
7	3	Br2 (1.1)	12		31	78
8	3	NBS (2.2)	48		31	43
9	9	PhSeBr (1.5)	2		32	87
10	9	NBS (2.2)	48		33	48

^aUnless otherwise stated, reactions were carried out on a 0.25 mmol scale in 5 mL of CH₂Cl₂ by using 1.0 equiv of 1-(1-alkynyl)-2-(methylseleno)benzene and 1.1 equiv of I₂ or ICl at room temperature.

^bThis reaction was carried out on a 0.25 mmol scale in 5 mL of AcOH using 1.0 equiv of alkyne and 1.1 equiv of Hg(OAc)₂ at room temperature and quenched with satd aq NaCl solution.

The cyclization of alkynes using Br₂ and NBS as electrophiles gave some interesting results. The use of NBS resulted in formation of the desired product in lower yields (entries 4, 8 and 10), contrary to our analogous efforts earlier in preparing benzo[b]thiophenes.^2b Unlike the reactions using NBS, cyclizations employing Br₂ were slower and also resulted in lower yields in comparison with our earlier benzo[b]thiophene methodology^2b (entries 3 and 7). When the bromocyclization of 10 was monitored by TLC, the disappearance of starting compound was observed soon after the addition of Br₂, but formation of the product was not observed. However, after 20 min, the product spot appeared and its intensity increased over a period of 2–3 h. A similar observation was made during the bromocyclization of 3, indicating once again a possible intermediate.

In an attempt to clarify these results, the cyclization of alkyne 10 by Br₂ was carried out in CDCl₃ as the solvent and the reaction was monitored by ¹H NMR spectroscopy. A small peak D was observed at δ 2.5 soon after the addition of Br_2. This peak corresponds to MeBr, the by-product of this overall process (Figure 1). Two more peaks were observed at approximately δ 4.0, which may correspond to a methyl group on an electron-deficient selenium. From the above ¹H NMR studies, a possible stepwise mechanism can be derived for bromocyclization by Br₂. In the first step, the electrophile coordinates with the triple bond, followed by nucleophilic attack by selenium to generate a cationic intermediate 34 (Scheme 4). The peak B (Figure 1) can be attributed to the methyl protons in 34, while peak C corresponds to the methyl group in dibromo compound 35. The formation of dibromo compounds of type 35 on addition of bromine to selenides has been reported earlier.¹⁹ The cationic intermediate 34 can then undergo a facile removal of the methyl group via S_N2 displacement by the counter ion bromide generated in situ during the cyclization (Scheme 4). Selenonium salts analogous to intermediate 34 are known in the literature and have been used for the alkylation of relative acidic carbon nucleophiles.²⁰

Figure 1.

¹H NMR spectra from the reaction of alkyne 10 in CDCl₃ before and after the addition of Br₂.

Scheme 4.

To support this mechanistic hypothesis, we attempted to isolate intermediate 34. The bromocyclization of 10 was performed in nonpolar hexanes at 0 °C, which resulted in the formation of a yellow precipitate soon after the addition of Br₂. The precipitate was filtered, washed with cold hexanes, and isolated in 53% yield (Scheme 5). This precipitate was then dissolved in CDCl₃ and monitored by ¹H NMR spectroscopy, which showed decomposition of this material, assumed to be intermediate 34 (Figure 2). Peak C slowly disappeared over a period of 6 h, which indicated the decay of intermediate 34. The height of peak D increased over this same time period, supporting the formation of methyl bromide. A noticeable change in the aromatic region was also observed, which matched the aromatic peaks of compound 28. Reactions with I₂ as an electrophile proceed much faster, and similar experiments to trap the cationic intermediate failed even at a lower temperature.

Scheme 5.

Figure 2.

¹H NMR spectra following the decomposition of 34 into 28 and MeBr

Our iodobenzo[b]selenophene products can be further functionalized by palladium-catalyzed coupling reactions. 2-(1-Octynyl)-3-phenylbenzo[b]selenophene (36) has been successfully obtained in a 90% isolated yield by the Suzuki cross-coupling of 15 with phenylboronic acid (Scheme 6). In a similar manner, the Sonogashira coupling of 16 with phenylacetylene gave alkyne 37 in 65% yield.

Scheme 6.

Conclusions

2,3-Disubstituted benzo[b]selenophenes have been obtained in good yields from simple starting materials by the electrophilic cyclization of 2-(1-alkynyl)selenoanisoles by Br₂, NBS, I₂, ICl, PhSeCl, PhSeBr and Hg(OAc)₂. This method tolerates many functional groups, including nitrile, hydroxyl, silyl, nitro, methoxy and ester groups. An iodine moiety can be readily introduced into the heterocycle in a position not easily obtained previously. Subsequent functionalization of the resulting heterocycles by palladium-catalyzed coupling reactions leads to a number of interesting substituted benzo[b]selenophenes. With respect to subsequent transition metal-catalyzed reactions, 3-iodobenzo[b]selenophenes are expected to be more effective than the corresponding bromo and chloro derivatives and that augurs well for this new approach to benzo[b]selenophenes. A cationic intermediate in the cyclization with Br₂ has been isolated and studied, providing evidence for a stepwise cyclization process.

Experimental Section

General procedure for the palladium/copper-catalyzed formation of 1-(1-alkynyl)-2-(methylseleno)arenas

To a solution of Et₃N (10 mL), 2.0 mmol of o-iodo(methylseleno)benzene and PdCl₂(PPh₃)₂ (2 mol %) (stirring for 5 min beforehand), CuI (1 mol %) was added and the flask was sealed and flushed with Ar. 3.0 Mmol of terminal acetylene dissolved in 2 mL of Et₃N was then added dropwise and the reaction mixture was allowed to stir at room temperature for the desired time. After the reaction was over, the resulting solution was filtered, washed with satd aq NaCl and extracted with diethyl ether (3 × 15 mL). The combined ether fractions were dried over anhydrous Na₂SO₄ and concentrated under vacuum to yield the crude product. The crude product was purified by flash chromatography on silica gel using ethyl acetate/hexanes as the eluent.

(1-Decynyl)-2-(methylseleno)benzene (3)

The product was obtained as a yellow oil: ¹H NMR (CDCl₃) δ 0.88 (t, J = 6.9 Hz, 3H), 1.28–1.30 (m, 8H), 1.43–1.51 (m, 2H), 1.60–1.69 (m, 2H), 2.31 (s, 3H), 2.47 (t, J = 6.9 Hz, 2H), 7.05–7.11 (m, 1H), 7.16–7.21 (m, 2H), 7.34 (d, J = 8.2 Hz, 1H); ¹³C NMR (CDCl₃) δ 6.0, 14.3, 19.8, 22.9, 28.9, 29.1, 29.3, 29.4, 32.0, 79.2, 96.9, 124.4, 125.1, 127.0, 128.3, 132.3, 136.2; IR (neat, cm⁻¹) 3058, 2926, 2227, 1432; HRMS calcd for C₁₇H₂₄Se 308.10432, found 308.10500.

General procedure for the iodocyclizations

To a solution of 0.25 mmol of the alkyne and 3 mL of CH₂Cl₂, 1.1 equiv of I₂ or ICl dissolved in 2 mL of CH₂Cl₂ was added gradually. The reaction mixture was allowed to stir at room temperature for the desired time. The excess I₂ or ICl was removed by washing with satd aq Na₂S₂O₃. The mixture was then extracted by diethyl ether (3 × 10 mL). The combined ether layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum to yield the crude product, which was purified by flash chromatography on silica gel using ethyl acetate/hexanes as the eluent.

3-Iodo-2-octylbenzo[b]selenophene (15)

The product was obtained as a yellow oil: ¹H NMR (CDCl₃) δ 0.91 (t, J = 6.9 Hz, 3H), 1.31–1.48 (m, 10H), 1.71–1.79 (m, 2H), 3.02 (t, J = 7.8 Hz, 2H), 7.24–7.29 (m, 1H), 7.39–7.45 (m, 1H), 7.77–7.83 (m, 2H); ¹³C NMR (CDCl₃) δ 14.4, 22.9, 29.4, 29.5, 29.6, 31.6, 32.1, 36.1, 83.4, 125.3, 125.5, 125.7, 127.8, 139.1, 143.2, 148.2; IR (neat, cm⁻¹) 3056, 2953, 2923, 1432; HRMS calcd for C₁₆H₂₁ISe 419.98532, found 419.98620.

General procedure for the bromocyclizations

To a solution of 0.25 mmol of the alkyne and 3 mL of CH₂Cl₂, 1.1 equiv of Br₂ or 2.2 equiv of NBS dissolved in 2 mL of CH₂Cl₂ was added gradually. The reaction mixture was allowed to stir at room temperature for the desired time. The excess Br₂ or NBS was removed by washing with satd aq Na₂S₂O₃. The mixture was then extracted by diethyl ether (3 × 10 mL). The combined ether layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum to yield the crude product, which was purified by flash chromatography on silica gel using ethyl acetate/hexanes as the eluent.

3-Bromo-2-octylbenzo[b]selenophene (31)

The product was obtained as a pale yellow oil: ¹H NMR (CDCl₃) δ 0.87 (t, J = 7.1 Hz, 3H), 1.27–1.46 (m, 10H), 1.68–1.78 (m, 2H), 2.99 (t, J = 7.7 Hz, 2H), 7.25–7.31 (m, 1H), 7.39–7.45 (m, 1H), 7.80 (d, J = 8.1 Hz, 2H); ¹³C NMR (CDCl₃) δ 14.3, 22.9, 29.3, 29.4, 29.6, 31.4, 32.1, 32.5, 125.1, 125.2, 125.4, 125.6, 138.0, 140.5, 144.5; IR (neat, cm⁻¹) 3059, 2954, 2925; HRMS calcd for C₁₆H₂₁BrSe 371.99918, found 371.99990.

General procedure for the PhSeCl and PhSeBr cyclizations

To a solution of 0.25 mmol of the alkyne and CH₂Cl₂ (3 mL), 0.375 mmol of PhSeBr or PhSeCl dissolved in 2 mL of CH₂Cl₂ was added dropwise. The mixture was allowed to stir at room temperature for the desired time. The reaction mixture was washed with 20 mL of water and extracted with diethyl ether (3 × 10 mL). The combined ether layers were dried over anhydrous Na₂SO₄ and concentrated under vacuum to yield the crude product, which was further purified by flash chromatography on silica gel using ethyl acetate/hexanes as the eluent.

2-Octyl-3-(phenylseleno)benzo[b]selenophene (30)

The product was obtained as a yellow oil: ¹H NMR (CDCl₃) δ 0.86 (t, J = 6.5 Hz, 3H), 1.23–1.37 (m, 10H), 1.69 (quintet, J = 7.3 Hz, 2H), 3.21 (t, J = 7.4 Hz, 2H), 7.08–7.14 (m, 5H), 7.21–7.34 (m, 2H), 7.83–7.89 (m, 2H); ¹³C NMR (CDCl₃) δ 14.4, 22.9, 29.4, 29.6, 32.1, 32.7, 33.7, 118.8, 124.9, 125.3, 125.5, 126.0, 126.6, 129.0, 129.4,132.9, 139.9, 143.7, 157.8; IR (neat, cm⁻¹) 3058, 2925, 1577; HRMS calcd for C₂₂H₂₆Se₂ 448.03937, found 448.04010.

Supplementary Material

1si20051212_01. Supporting Information Available.

General experimental details, preparation, iodocyclization, bromocyclization, PhSeCl and PhSeBr cyclizations of 1-(1-alkynyl)-2-(methylselenyl)arenes, and copies of ¹H and ¹³C NMR spectra. This material is available free of charge via the Internet at http://pubs.acs.org.