Skip to main content
NCBI home page
Turkish Journal of Chemistry logoLink to Turkish Journal of Chemistry
. 2023 Oct 11;47(6):1429–1437. doi: 10.55730/1300-0527.3625

Comparison of metal-carbenoid reactions of β-2-five-membered heteroaryl substituted α,β-unsaturated ketones

Kumsal EROĞLU 1, Olcay ANAÇ 1, Füsun Şeyma KIŞKAN 1,*
PMCID: PMC10965174  PMID: 38544711

Abstract

In this study, β-2-heteroaryl substituted (N-methyl 2-pyrrolyl, 2-thiophenyl, 2-furyl) α,β-unsaturated ketones were reacted with two α-diazo carbonyl compounds that had different characteristics (dimethyl diazo malonate and 1-diazo-1-phenyl-propane-2-one) in the presence of both copper and rhodium catalysts. In the case of reactions with N-methyl 2-pyrrolyl α,β-unsaturated ketones, the major product was the insertion derivative. However, in the reactions of 2-thiophenyl and 2-furyl α,β-unsaturated ketones with dimethyl diazomalonate (acceptor-acceptor disubstituted), only dihydrofuran products were formed over carbonyl ylides. When 2-thiophenyl and 2-furyl α,β-unsaturated ketones were reacted with 1-diazo-1-phenyl-propane-2-one (donor-acceptor disubstituted), 1-phenylpropane-1,2-dione was obtained under our reaction conditions.

Keywords: Metal-carbenoid, diazocarbonyl, dihydrofuran, insertion, heteroaryl

1. Introduction

α-Diazocarbonyl compounds are a versatile class of compounds in organic synthesis. They are useful intermediates due to their decompositions under various conditions, especially in the presence of transition metal catalysts, to obtain metal-carbenoids [1–3].

Biological and medicinal chemistry studies with heterocyclic compounds have increased in importance to produce many naturally occurring bioactive compounds and synthetic pharmaceuticals [4,5]. Recently, many synthetic methods involving aromatic heterocycles (especially five-membered) and metal-carbenoids have been developed [6]. Heterocycles containing oxygen, sulfur, and nitrogen atoms are electron-rich compounds that can easily undergo reactions with electrophilic metal-carbenoids [7–10]. Although metal-carbenoid reactions for the modification of pyrrole cores have been reported previously [11–16], the literature offers a limited number of examples of reactions with thiophene/furan derivatives [17–23]. According to the current literature on the metal-carbenoid reactions of 2-substituted heteroaryl compounds, variation of the substituents may alter the reaction pathway deriving from either the heterocyclic core or the substituent [7,20]. In our continuous efforts for the metal-carbenoid transformations of 2-substituted five-membered heterocycles [24], we found that furans with only 2-ene/diene-diester functions smoothly gave the corresponding polymethoxy carboxylate-substituted oxo-polyenes over furyl unraveling in good yields (Schemes 1A and 1B). Continuing our research, this study reports the results of the reactions of β-2-heteroaryl α,β-unsaturated ketone with α-diazo compounds. We compared the reaction mechanisms of N-methyl 2-pyrrolyl, 2-thiophenyl, and 2-furyl derivatives (1–3) that contain the same ene-methylketo function at their 2-positions with two different types of diazo carbonyl compounds (4 and 5) under two catalytic conditions (x and y).

Scheme 1.

Scheme 1

Open in a new tab

Reactions of furyl methylene/allylidene malonates and N-methyl 2-pyrrolylmethylene dimalonate with dimethyl diazomalonate [24].

2. Experimental

2.1. General information

Reactions of diazo compounds and heteroaryl carbonyls were carried out under nitrogen atmosphere. A rotary evaporator equipped with a water condenser and attached to a vacuum system was used to concentrate in vacuo. All solvents and reactants were commercially available. Dimethyl diazo malonate (4) [25] and 1-diazo-1-phenyl-propane-2-one (5) [26] were prepared by literature procedures. 1H NMR and 13C NMR spectra in CDCl3 were recorded on an Agilent VNMRS (Agilent Technologies, Santa Clara, CA, USA) at 500 and 125 MHz, respectively. Chemical shifts (δ) are reported in ppm downfield from tetramethyl silane at ambient temperature. GC-MS analyses were performed on a Thermo Finnigan trace DSQ instrument (Thermo Fisher, Waltham, MA, USA) equipped with a flame ionization detector. A 5% phenyl polyphenylene-siloxane capillary column (TR-5MS, Thermo Fisher) was used with helium as the carrier gas. The temperature program was as follows: start at 100 °C, then 5 min isothermal, ramp at 20 °C/min; final 290 °C, and then 10 min isothermal. Retention times (tR) are given in minutes. HR-MS: Agilent 6230-B TOF LC/MS in m/z.

2.2. Reactions of substrates and diazo compounds

For condition x, to a solution of CuCl (0.15 mmol), AgSbF6 (0.15 mmol), (−)-2,2′-isopropylidene bis[(4S)-4-phenyl-2-oxazoline] (0.15 mmol), and a molecular sieve (4 Å) were added and the mixture was refluxed for 1 h. A heteroaryl carbonyl compound (1–3) (1.7 mmol) was added to the reaction mixture and the mixture was stirred for 5 min. A solution of diazo compound (1.7 mmol) in benzene (3 mL) was added to this mixture over 2.5 h under N2 atmosphere. When the IR spectrum of the reaction mixture indicated the total consumption of the diazo compound (absence of the characteristic diazo band), the mixture was filtered, evaporated, and purified by column chromatography or preparative thin-layer chromatography.

For condition y, to a solution of the heteroaryl carbonyl compound (1–3) (2 mmol) in solvent (benzene if the diazo compound was dimethyl diazomalonate or CH2Cl2 if the diazo compound was 1-diazo-1-phenylpropane-2-one) (20 mL) was added Rh2(OAc)4 (0.01 mmol), and the mixture was heated at reflux. A solution of diazo compound (1.4 mmol) in solvent (2 mL) was added to this solution over 2.5 h under N2 atmosphere. When the IR spectrum of the reaction mixture indicated the total consumption of the diazo compound (absence of the characteristic diazo band), the mixture was filtered, evaporated, and purified by column chromatography or preparative thin-layer chromatography.

2.2.1. Dimethyl 5-methyl-3-(1-methyl-1H-pyrrole-2-yl)furan-2,2(3H)-dicarboxylate (61–4)

61–4 was purified by silica column chromatography with hexane and ethyl acetate (1:1) as an eluent. Orange-brownish oil; yield 25% (with condition x); IR νmax (CH2Cl2): 2957, 2924, 1742, 1435, 1284, 1217, 1187, 915, 719 cm−1; 1H NMR (500 MHz, CDCl3) δ 6.52 (t, J = 2.50 Hz, 1H, pyrrolyl-H), 6.00 (t, J = 3.05 Hz, 1H, pyrrolyl-H), 5.94 (dd, J = 3.65/1.70 Hz, 1H, pyrrolyl-H), 5.15 (t, J = 2.05 Hz, 1H, CH-CH=C), 4.67 (dd, J = 2.30/1.25 Hz, 1H, CH=C-CH3), 3.86 (s, 3H, CO2CH3), 3.63 (s, 3H, CO2CH3), 3.34 (s, 3H, N-CH3), 1.98 (dd, J = 1.95/1.25 Hz, 3H, CH=C-CH3); 13C NMR (125 MHz, CDCl3) δ 168.6 (CO2CH3), 166.9 (CO2CH3), 154.0 (CH=C-CH3), 129.5 (Cpyrrolyl), 122.7 (Cpyrrolyl), 108.8 (Cpyrrolyl), 106.9 (Cpyrrolyl), 98.1 (C=C-CH3), 91.7 (C(CO2CH3)2), 53.5 (CO2CH3), 52.6 (CO2CH3), 46.6 (CH-CH=C), 33.8 (N-CH3), 13.3 (CH=C-CH3); tR: 12.95; EI-MS (m/z): 221 (M+-CH3, 57), 162 (100), 118 (66), 91 (19), 59 (10); HRMS: Calcd for C14H18NO5 [M+H]+ 280.1179, found 280.1185.

2.2.2. Dimethyl 5-methyl-3-(thiophene-2-yl)furan-2,2(3H)-dicarboxylate (62–4)

62–4 was purified by preparative silica thin-layer chromatography with hexane and ethyl acetate (7:1) as a mobile phase. Dark yellow oil, yield 92% (with condition x); IR νmax (CH2Cl2): 2927, 1744, 1433, 1287 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.20 (dd, J = 5.00/1.30 Hz, 1H, thiophenyl-H), 6.94 (dd, J = 5.00/3.50 Hz, 1H, thiophenyl-H), 6.93–6.91 (m, 1H, thiophenyl-H), 5.28–5.27 (m, 1H, CH-CH=C), 4.84–4.83 (m, 1H, CH=C-CH3), 3.87 (s, 3H, CO2CH3), 3.37 (s, 3H, CO2CH3), 2.01 (dd, J = 1.80/1.35 Hz, 3H, CH=C-CH3); 13C NMR (125 MHz, CDCl3) δ 168.3 (CO2CH3), 166.2 (CO2CH3), 155.4 (CH=C-CH3), 141.9 (Cthiophenyl), 126.8 (Cthiophenyl), 126.7 (Cthiophenyl), 125.2 (Cthiophenyl), 99.4 (CH=C-CH3), 92.2 (C(CO2CH3)2), 53.6 (CO2CH3), 52.4 (CO2CH3), 49.7 (CH-CH=C), 13.4 (CH=C-CH3); tR: 12.00; EI-MS (m/z): 282 (M+, 35), 222 (100), 191 (80), 164 (61), 151 (48), 135 (57), 91 (39), 59 (27); HRMS: Calcd for C13H15O5S [M+H]+ 283.0635, found 283.0640.

2.2.3. Dimethyl 5′-methyl-[2,3′-bifuran]-2′,2′(3′H)-dicarboxylate (63–4)

63–4 was purified by preparative silica thin-layer chromatography with hexane and ethyl acetate (1:2) as a mobile phase. Yellow oil; yield 88% (with condition x); IR νmax (CH2Cl2): 2968, 2924, 2855, 1744, 1436, 1237 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.34 (d, J = 1.00 Hz, 1H, furyl-H), 6.30 (dd, J = 3.05/1.90 Hz, 1H, furyl-H), 6.18 (d, J = 3.15 Hz, 1H, furyl-H), 5.14 (t, J = 1.90 Hz, 1H, CH-CH=C), 4.72–4.71 (m, 1H, CH-CH=C), 3.87 (s, 3H, CO2CH3), 3.47 (s, 3H, CO2CH3), 1.99 (bs, 3H, CH=C-CH3); 13C NMR (125 MHz, CDCl3) δ 168.0 (CO2CH3), 166.5 (CO2CH3), 155.3 (Cfuryl), 152.1 (CH=C-CH3), 142.3 (Cfuryl), 110.5 (Cfuryl), 108.4 (Cfuryl), 96.6 (CH-CH=C), 90.9 (C(CO2CH3)2), 53.6 (CO2CH3), 52.8 (CO2CH3), 48.7 (CH-CH=C), 13.4 (CH=C-CH3); tR: 10.85; EI-MS (m/z): 266 (M+, 1), 238 (15), 207 (72), 174 (100), 148 (45), 119 (32), 105 (24), 91 (85), 65 (27), 59 (25); HRMS: Calcd for C13H15O6 [M+H]+ 267.0863, found 267.0875.

2.2.4. Dimethyl (E)-2-(1-methyl-5-(3-oxobut-1-ene-1-yl)-1H-pyrrole-2-yl)malonate (71–4)

71–4 and 81–4 were purified by silica column chromatography with hexane and ethyl acetate (1:1) from the crude mixture. From the mixture of 71–4 and 81–4 (2:1, respectively): 1H NMR (500 MHz, CDCl3) δ 7.42 (d, J = 15.75 Hz, 1H, CH=CH-CO), 6.91 (d, J = 1.7 Hz, 1H, pyrrolyl-H), 6.73 (d, J = 1.7 Hz, 1H, pyrrolyl-H), 6.52 (d, J = 15.75 Hz, 1H, CH=CH-CO), 4.57 (s, 1H, CH(CO2CH3)2), 3.77 (s, 6H, CO2CH3), 3.70 (s, 3H, N-CH3), 2.30 (s, 3H, COCH3); 13C NMR (125 MHz, CDCl3) δ 197.6 (C=O), 167.2 (CO2CH3), 130.5 (CH=CH-CO), 130.1 (Cpyrrolyl), 129.4 (Cpyrrolyl), 127.0 (Cpyrrolyl), 115.6 (Cpyrrolyl), 112.5 (CH=CHCO), 50.4 (CH(CO2CH3)2), 31.3 (N-CH3), 28.3 (COCH3); tR: 12.26; EI-MS (m/z): 279 (M+, 13), 220 (80), 188 (39), 160 (42), 132 (100), 108 (49), 59 (18).

2.2.5. (E)-4-(1-Methyl-5-(2-oxo-1-phenyl propyl)-1H-pyrrole-2-yl)but-3-ene-2-one (71–5)

71–5 and 81–5 were purified by silica column chromatography with hexane and ethyl acetate (1:2) from the crude mixture. From the mixture of 71–5 and 81–5 (1.4:1, respectively): IR νmax (CH2Cl2) (cm−1) 2924, 2857, 1709, 1451, 1358 cm−1; 1H NMR (500 MHz, CDCl3) δ 7.47 (d, J = 15.65 Hz, 1H, CH=CH-CO), 7.38–7.28 (m, 3H, Ar-H), 7.19–7.16 (m, 2H, Ar-H), 6.70 (d, J = 4.10 Hz, 1H, pyrrolyl-H), 6.53 (d, J = 15.65 Hz, 1H, CH=CH-CO), 5.99 (d, J = 4.10 Hz, 1H, pyrrolyl-H), 5.07 (s, 1H, CH(CO2CH3)), 3.47 (s, 3H, N-CH3), 2.30 (s, 3H, COCH3), 2.28 (s, 3H, COCH3); 13C NMR (125 MHz, CDCl3) δ 204.3 (C=O), 197.6 (C=O), 135.9 (CAr), 130.3 (CAr), 128.9 (CAr), 126.8 (CAr), 122.2 (Cpyrrolyl), 121.8 (CH=CHCO), 121.6 (Cpyrrolyl), 112.6 (CH=CHCO), 111.5 (Cpyrrolyl), 109.7 (Cpyrrolyl), 58.0 (CH(CO2CH3)), 34.4 (N-CH3), 29.6 (COCH3), 28.7 (COCH3); EI-MS (m/z): 281 (M+, 8), 238 (M+-COCH3, 100), 194 (37), 91 (8), 77 (10).

2.2.6. (E)-4-(1-Methyl-4-(2-oxo-1-phenylpropyl)-1H-pyrrole-2-yl)but-3-ene-2-one (81–5)

From the mixture of 71–5 and 81–5 (1.4:1, respectively): 1H NMR (500 MHz, CDCl3) δ 7.40 (d, J = 15.70 Hz, 1H, CH=CH-CO), 7.38–7.28 (m, 3H, Ar -H), 7.19–7.16 (m, 2H, Ar-H), 6.67 (d, J = 1.80 Hz, 1H, pyrrolyl-H), 6.56 (d, J = 1.80 Hz, 1H, pyrrolyl-H), 6.46 (d, J = 15.70 Hz, 1H, CH=CH-CO), 4.92 (s, 1H, CH(CO2CH3)), 3.67 (s, 3H, N-CH3), 2.29 (s, 3H, COCH3), 2.21 (s, 3H, COCH3); 13C NMR (125 MHz, CDCl3) δ 206.5 (C=O), 197.6 (C=O), 138.7 (CAr), 130.6 (CAr), 129.0 (CAr), 128.6 (Cpyrrolyl), 127.9 (Cpyrrolyl), 127.3 (CAr), 121.7 (CH=CHCO), 112.4 (CH=CHCO), 110.9 (Cpyrrolyl), 63.7 (CH(CO2CH3)), 31.1 (N-CH3), 29.3 (COCH3), 28.3 (COCH3); EI-MS (m/z): 281 (M+, 9), 238 (M+-COCH3, 100), 194 (46), 91 (8), 77 (18).

3. Results and discussion

In this study, we synthesized β-2-heteroaryl α,β-unsaturated ketone compounds (1–3) according to the literature [27]. Two diazo carbonyl compounds, dimethyl diazomalonate (4) (acceptor-acceptor (A-A) disubstituted) and 1-diazo-1-phenyl-propane-2-one (5) (donor-acceptor (D-A) disubstituted), were reacted with synthesized β-2-heteroaryl α,β-unsaturated ketone compounds (1–3) under two different catalytic conditions. The results are summarized in Tables 1 and 2.

Table 1.

Reactions of (E)-4-(1-methyl-1H-pyrrole-2-yl)but-3-ene-2-one (1) with α-diazocarbonyl compounds.

graphic file with name tjc-47-06-1429f4.jpg
Entry Diazo comp. Conditiona 6 ratio %b (yield)c 7 ratio %b (yield)c 8 ratio %b (yield)c
i 4 x 61–4 29.5 (25) 71–4 70.5 -
ii 4 y 61–4 18 (10.3) 71–4 66.0 81–4 15.5
iii 5 x - 71–5 trace -
iv 5 y - 71–5 + 81–5 54.5 + 45.5 71–5 + 81–5 54.5 + 45.5
Open in a new tab
a

Condition x: CuCl (0.15 mmol)/AgSbF6 (0.15 mmol)/isopropylidenebis(4S)-4-phenyl-2-oxazoline (0.15 mmol), compound 1–3 (1.7 mmol), and diazo compound (1.7 mmol); condition y: Compound 1–3 (2 mmol), Rh2(OAc)4 (0.01 mmol), and diazo compound (1.4 mmol).

b

Relative product ratio based on 1H NMR analysis of crude reaction mixture.

c

Isolated yield of chromatographically pure substances.

Table 2.

Reactions of compounds 2 and 3 with α-diazocarbonyl compounds (4 and 5).

Entry Heteroaryl Diazo comp. Conditiona Dihydrofuran 6 (yield)b
i 2 4 x 62–4 (92)
ii 2 4 y 62–4 (60)
iii 2 5 x -
iv 2 5 y -
v 3 4 x 63–4 (88)
vi 3 4 y 63–4 (40)
vii 3 5 x -
viii 3 5 y -
Open in a new tab
a

Condition x: CuCl (0.15 mmol)/AgSbF6 (0.15 mmol)/isopropylidenebis(4S)-4-phenyl-2-oxazoline (0.15 mmol), compound 1–3 (1.7 mmol), and diazo compound (1.7 mmol); condition y: Compound 1–3 (2 mmol), Rh2(OAc)4 (0.01 mmol), and diazo compound (1.4 mmol).

b

Isolated yield of chromatographically pure substances.

First of all, (E)-4-(1-methyl-1H-pyrrole-2-yl)but-3-en-2-one (1) and α-diazocarbonyl compounds (4, 5) were reacted under two different catalytic conditions (Table 1). In most of our previous studies, we used copper(II) acetylacetonate [Cu(acac)2] as a catalyst in metal-carbenoid reactions [24,28,29]. For this reason, we first tried Cu(acac)2 in the reaction of compound 1 with dimethyl diazomalonate (4). However, we did not encounter any product except carbene dimer. Therefore, we planned to repeat the reactions with different catalysts in pursuit of the formation of possible products.

Zhou et al. reported that [1,5]- or [1,7]-ring closure products can be obtained from ylide intermediate under CuCl/AgSbF6/ligand catalytic conditions in a diastereo-controlled way [30]. Accordingly, we tried to use CuCl/AgSbF6/ligand as a catalyst (condition x) in the reaction of 1 and 4. In this attempt, we obtained an insertion product to the pyrrole ring as a major product and a dihydrofuran derivative as a minor product (Table 1, entry i).

As is known, Rh-complexes have become the most common catalysts in diazo reactions, especially C-H insertion reactions [31–35]. Therefore, we needed to repeat the same reaction of 1 and 4 with Rh2(OAc)4 (condition y) to search for the probable change in the product distribution. It was observed that the yield of dihydrofuran (61–4) decreased. As expected, insertion products (71–4, 81–4) to the pyrrole ring were formed mainly depending on the decreasing steric probabilities.

In our previous study (Scheme 1B) [24], only the dihydrofuran product was obtained from the reaction of N-methyl 2-pyrrolylmethylydene malonate and dimethyl diazomalonate (2) with the Rh2(OAc)4 catalyst. The mechanism of formation of dihydrofuran is initiated by the [1,5]-electrocyclic ring closure of the corresponding carbonyl ylide intermediate, derived from the electron-deficient metal-carbenoid and one of the ester carbonyl oxygens of the malonate function (Scheme 1B) or the α,β-unsaturated keto carbonyl oxygen function (Table 1, compound 6). However, the main insertion mechanism (in Table 1, compounds 7 and 8) preferred the attack of the frontier metal-carbenoid to the pyrrole ring instead of the carbonyl oxygen under the same conditions.

As another attempt, reactions with 1-diazo-1-phenyl-propane-2-one (5) (donor-acceptor disubstituted) were also carried out under the same two conditions (x and y) with 1 (Table 1, entries iii and iv). Interestingly, while no dihydrofuran derivative was formed, sterically more possible insertion products (71–5 and 81–5) into the pyrrole ring were observed.

We also needed to investigate the reactions of β-2-thiophenyl methyleneketone (2) and β-2-furyl methyleneketone (3). The results of reactions 2 and 3 with diazo compounds 4 and 5 under catalytic conditions are summarized in Table 2.

No [1+1] products were observed between 2 or 3 and carbenoid 5 having a donor-acceptor character (Table 2, entries iii, iv, vii, and viii). Instead, a decomposition product (9) was obtained from these attempts (Scheme 2). However, corresponding dihydrofurans (62–4 and 63–4) were obtained as sole products from the reactions of dimethyl diazo malonate (4) with compounds 2 and 3.

Scheme 2.

Scheme 2

Open in a new tab

Heteroaryl C-H insertion of carbenoid (path a) [36] and electrocyclic [1,5]- or [1,3]-ring closure reactions of carbonyl ylide (paths b1 and b2) [7,37].

All products were obtained by two general mechanism pathways over the heteroaryl function (path a)/carbonyl oxygen (paths b1 and b2) (Scheme 2).

As is known, the pyrrole ring is the most reactive species in electrophilic substitution according to thiophene and furan. Recent studies [38–40] have shown that the relative reactivities and regioselectivities of heteroaryl derivatives towards electrophiles are mostly variable, depending on the positions and nature of the substituents and also the types of electrophiles. When we performed the reactions of the N-methyl 2-pyrrolyl derivative (1) and diazo compounds (4, 5), insertion products (7, 8) to the pyrrole core were dominant (Table 1; Scheme 2, path a). The reactivity of the pyrrole core of 1 was effective for this chemoselective reaction. On the contrary, a 2-thiophenyl or 2-furyl-insertion product was not observed in the reactions with 2 and 3 (Table 2; Scheme 2, path b). The sole products from 2 and 3 with dimethyl diazomalonate (4) were dihydrofurans (6) formed via [1,5]-ring closure reactions over carbonyl ylide-intermediates (chemoselective reactions) (Scheme 2, path b1).

In our previous study, polyenone formations were observed by opening reactions of corresponding furan rings from β-2-furyl ene/diene-diesters and dimethyl diazomalonate under catalytic conditions (Scheme 1A). However, the carbonyl ylide was formed from the β-2-furyl ene-ketone function with dimethyl diazomalonate to yield compound 6 (Scheme 2, path b1). Therefore, different chemoselectivities were observed in the catalytic reactions of β-2-furyl ene/diene-diesters and β-2-furyl ene-ketone with dimethyl diazomalonate (4).

On the other hand, dimethyl diazomalonate (4) with acceptor-acceptor substituents directed the reaction to path b1 (Scheme 2), but 1-diazo-1-phenyl-2-propanone (5) with donor-acceptor substituents led to path b2 (Scheme 2).

The only detectable compound was 1-phenylpropane-1,2-dione (9) in the reactions of 2 and 3 with 1-diazo-1-phenyl-2-propanone (5) (Scheme 2, path b2). According to the literature, 1,2-dione compounds such as 1-phenylpropane-1,2-dione (9) were formed by oxygen transfer to the diazo compound in a catalytic environment [41–43]. Yu et al. [44] also synthesized dimethyl 2-oxomalonate by Cu-catalyzed deoxygenation of epoxide with dimethyl diazomalonate. Therefore, we propose that under our reaction conditions, both the formation and decomposition of an epoxide might have occurred successively (Scheme 3).

Scheme 3.

Scheme 3

Open in a new tab

Formation of 1-phenylpropane-1,2-dione (9).

4. Conclusion

In this study, we performed the reactions of β-2-heteroaryl substituted α,β-unsaturated ketones (1–3) with α-diazo compounds (4, 5) under catalytic conditions (x, y). Insertion products (71–4 and 81–4) in the pyrrole ring were obtained as the main product from the reactions of β-N-methyl 2-pyrrolyl α,β-unsaturated ketone (1) with dimethyl diazomalonate (4) under both catalytic conditions. The dihydrofuran derivative (61–4) was also found as a byproduct in these reactions. In the reactions of β-2-thiophenyl and β-2-furyl α,β-unsaturated ketones (2 and 3) with dimethyl diazomalonate (4), no insertion product was observed. Instead, dihydrofurans (62–4 and 63–4) were obtained as single products.

When dimethyl diazomalonate (4) was replaced with 1-diazo-1-phenyl-2-propanone (5) as a carbene source, no dihydrofuran was formed in any reaction, but 1-phenyl-propane-1,2-dione (9) could be obtained. In conclusion, the reactions of three β-2-heteroaryl substituted α,β-unsaturated ketones and two metal-carbenoids with acceptor-acceptor and donor-acceptor groups were carried out under the same conditions. While acceptor-acceptor groups containing the metal-carbenoid preferred to attack the N-methyl 2-pyrrolyl ring, the same carbenoid did not react with the 2-thiophenyl or 2-furyl rings.

Acknowledgment

The authors would like to thank the İstanbul Technical University Research Fund (Project No. TYL-2017-40674) for financial support.

Funding Statement

The authors would like to thank the İstanbul Technical University Research Fund (Project No. TYL-2017-40674) for financial support.

References

  • 1.Doyle MP, McKervey MA, Ye T. Modern Catalytic Methods for Organic Synthesis with Diazo Compounds from Cyclopropanes to Ylides. New York, NY, USA: Wiley; 1998. [Google Scholar]
  • 2.Newman DJ, Cragg GM. Natural products as sources of new drugs from 1981 to 2014. Journal of Natural Products. 2016;79(3):629–661. doi: 10.1021/acs.jnatprod.5b01055. [DOI] [PubMed] [Google Scholar]
  • 3.Su N, Theorell JA, Wink DJ, Driver TG. Copper-catalyzed formation of α-alkoxycycloalkenones from N-tosylhydrazones. Angewandte Chemie International Edition. 2015;54(44):12942–12946. doi: 10.1002/anie.201505993. [DOI] [PubMed] [Google Scholar]
  • 4.Martins P, Jesus J, Santos S, Raposo LR, Roma Rodrigues C, et al. Heterocyclic anticancer compounds: recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules. 2015;20(9):16852–16891. doi: 10.3390/molecules200916852. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Taylor AP, Robinson RP, Fobian YM, Blakemore DC, Jones LH, et al. Modern advances in heterocyclic chemistry in drug discovery. Organic & Biomolecular Chemistry. 2016;14:6611–6637. doi: 10.1039/C6OB00936K. [DOI] [PubMed] [Google Scholar]
  • 6.Pellisser H. Recent developments in the synthesis and reactivity of methylene- and alkylidenecyclopropane derivatives. Tetrahedron. 2014;70(34):4991–5031. doi: 10.1016/j.tet.2014.04.057. [DOI] [Google Scholar]
  • 7.Davies HML, Hedley SJ. Intermolecular reactions of electron-rich heterocycles with copper and rhodium carbenoids. Chemical Society Reviews. 2007;36(7):1109–1119. doi: 10.1039/B607983K. [DOI] [PubMed] [Google Scholar]
  • 8.Hedley SJ, Ventura DL, Dominiak PM, Nygren CL, Davies HML. Investigation into factors influencing stereoselectivity in the reactions of heterocycles with donor-acceptor substituted rhodium carbenoids. Journal of Organic Chemistry. 2006;71(14):5349–5356. doi: 10.1021/jo060779g. [DOI] [PubMed] [Google Scholar]
  • 9.Fu L, Wang H, Davies HML. Role of ortho-substituents on rhodium-catalyzed asymmetric synthesis of β-lactones by intramolecular C-H insertions of aryldiazoacetates. Organic Letters. 2014;16(11):3036–3039. doi: 10.1021/ol5011505. [DOI] [PubMed] [Google Scholar]
  • 10.Lian Y, Davies HML. Rhodium-catalyzed [3+2] annulation of indoles. Journal of the American Chemical Society. 2010;132(2):440–441. doi: 10.1021/ja9078094. [DOI] [PubMed] [Google Scholar]
  • 11.Maryanoff BE. Carbenoid chemistry. Reaction of pyrrole derivatives with ethyl diazoacetate. Journal of Organic Chemistry. 1979;44(24):4410–4419. doi: 10.1021/jo01338a033. [DOI] [Google Scholar]
  • 12.Maryanoff BE. Reaction of dimethyl diazomalonate and ethyl 2-diazoacetoacetate with N-methylpyrrole. Journal of Organic Chemistry. 1982;47(15):3000–3002. doi: 10.1021/jo00136a038. [DOI] [Google Scholar]
  • 13.Yadav JS, Reddy BVS, Satheesh G. InBr3/Cu(OTf)2-catalyzed C-alkylation of pyrroles and indoles with α-diazocarbonyl compounds. Tetrahedron Letters. 2003;44(45):8331–8334. doi: 10.1016/j.tetlet.2003.09.031. [DOI] [Google Scholar]
  • 14.Lian Y, Davies HML. Rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles. Organic Letters. 2010;12(5):924–927. doi: 10.1021/ol9028385. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.Dawande SG, Kanchupalli V, Kalepu J, Chennamsetti H, Lad BS, et al. Rhodium enalcarbenoids: direct synthesis of indoles by rhodium(II)-catalyzed [4+2] benzannulation of pyrroles. Angewandte Chemie International Edition. 2014;53(16):4076–4080. doi: 10.1002/anie.201481671. [DOI] [PubMed] [Google Scholar]
  • 16.Shang H, Wang Y, Tian Y, Feng J, Tang Y. The divergent synthesis of nitrogen heterocycles by rhodium(II)-catalyzed cycloadditions of 1-sulfonyl 1,2,3-triazoles with 1,3-dienes. Angewandte Chemie International Edition. 2014;53(22):5662–5666. doi: 10.1002/anie.201400426. [DOI] [PubMed] [Google Scholar]
  • 17.Davies HML, Clark DM, Alligood DB, Eiband GR. Mechanistic aspects of formal [3+4]. cycloadditions between vinylcarbenoids and furans. Tetrahedron. 1987;43(19):4265–4270. doi: 10.1016/S0040-4020(01)90301-1. [DOI] [Google Scholar]
  • 18.Parr BT, Green SA, Davies HML. Rhodium-catalyzed conversion of furan to highly functionalized pyrroles. Journal of the American Chemical Society. 2013;135(12):4716–4718. doi: 10.1021/ja401386z. [DOI] [PubMed] [Google Scholar]
  • 19.Muthusamy S, Sivaguru M. Atom-economical access to highly substituted indenes and furan-2-ones via tandem reaction of diazo compounds and propargyl alcohols. Organic Letters. 2014;16(16):4248–4251. doi: 10.1021/ol501942y. [DOI] [PubMed] [Google Scholar]
  • 20.Wenkert E, Guo M, Lavilla R, Porter B, Ramachandran K, et al. Polyene synthesis. Ready construction of retinol-carotene fragments, (±)-6(E)-LTB3 leukotrienes, and corticrocin. Journal of Organic Chemistry. 1990;55(25):6203–6214. doi: 10.1021/jo00312a031. [DOI] [Google Scholar]
  • 21.Manning JR, Davies HML. One-pot synthesis of highly functionalized pyridines via a rhodium carbenoid induced ring expansion of isoxazoles. Journal of the American Chemical Society. 2008;130(27):8602–8603. doi: 10.1021/ja803139k. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Manning JR, Davies HML. Efficient route to 2H-1,3-oxazines through ring expansion of isoxazoles by rhodium carbenoids. Tetrahedron. 2008;64(29):6901–6908. doi: 10.1016/j.tet.2008.03.010. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Olson JP, Davies HML. Asymmetric [4+3] cycloadditions between benzofuranyl diazoacetates and dienes: formal synthesis of (+)-frondosin B. Organic Letters. 2008;10(4):573–576. doi: 10.1021/ol702844g. [DOI] [PubMed] [Google Scholar]
  • 24.Gungor FS, Merey G, Anac O. Chemoselective carbenoid reactions of furan/thiophene/pyrrole ring containing carbonyl and conjugated carbonyl at their 2-positions. ChemistrySelect. 2020;5(17):5337–5340. doi: 10.1002/slct.202000584. [DOI] [Google Scholar]
  • 25.Wulfman DS, McGibboney BG, Steffen EK, Thinh NV, McDaniel RS, et al. Metal salt catalyzed carbenoids-XV: the synthetic and structural aspects of copper salt catalyzed additions of bis-methoxycarbonyl carbene to olefins. Tetrahedron. 1976;32(11):1257–1265. doi: 10.1016/0040-4020(76)80080-4. [DOI] [Google Scholar]
  • 26.Kubilay HN, Gungor FS, Anac O. Reactions of (1E)-buta-1,3-dien-1-yl acetate with diazocarbonyl compounds. Helvetica Chimica Acta. 2015;98(9):1245–1253. doi: 10.1002/hlca.201500043. [DOI] [Google Scholar]
  • 27.Hayakawa K, Yodo M, Ohsuki S, Kanematsu K. Novel bicycloannulation via tandem vinylation and intramolecular Diels-Alder reaction of five-membered heterocycles: a new approach to construction of psoralen and azapsoralen. Journal of the American Chemical Society. 1984;106(22):6735–6740. doi: 10.1021/ja00334a044. [DOI] [Google Scholar]
  • 28.Anac O, Gungor FS. Electrocyclization reactions of vinyl, styryl, and butadienyl conjugated carbonyl/azomethine ylides. Tetrahedron. 2010;66(32):5931–5953. doi: 10.1016/j.tet.2010.05.058. [DOI] [Google Scholar]
  • 29.Anac O, Daut A. Reactions of α,β-enones with diazo compounds. Part 2: Synthesis of dihydrofuran derivatives. Liebigs Annalen/Recuil. 1997;6:1249–1254. doi: 10.1002/jlac.199719970630. [DOI] [Google Scholar]
  • 30.Zhou JL, Liang Y, Deng C, Zhou H, Wang Z, et al. Tunable carbonyl ylide reactions: Selective synthesis of dihydrofurans and dihydrobenzoxepines. Angewandte Chemie International Edition. 2011;50(34):7874–7878. doi: 10.1002/anie.201100551. [DOI] [PubMed] [Google Scholar]
  • 31.Paulissen R, Reimlinger H, Hayez E, Hubert AJ, Teyssie P. Transition metal catalysed reactions of diazo compounds-II Insertion in the hydroxylic bond. Tetrahedron Letters. 1973;14(24):2233–2236. doi: 10.1016/S0040-4039(01)87603-6. [DOI] [Google Scholar]
  • 32.Doyle MP, Westrum LJ, Wolthuis WNE, See MM, Bone WP, et al. Electronic and steric control in carbon-hydrogen insertion reactions of diazoacetoacetates catalyzed by dirhodium(II) carboxylates and carboxamides. Journal of the American Chemical Society. 1993;115(3):958–964. doi: 10.1021/ja00056a021. [DOI] [Google Scholar]
  • 33.Taber DF, You KK, Rheingold AL. Predicting the diastereoselectivity of Rh-mediated intramolecular C-H insertion. Journal of the American Chemical Society. 1996;118(3):547–556. doi: 10.1021/ja9515213. [DOI] [Google Scholar]
  • 34.Synder JP, Padwa A, Strengel T, Arduengo AJ, Jockisch A, et al. A stable dirhodium tetracarboxylate carbenoid: crystal structure, bonding analysis, and catalysis. Journal of the American Chemical Society. 2001;123(45):11318–11319. doi: 10.1021/ja016928o. [DOI] [PubMed] [Google Scholar]
  • 35.DeAngelis A, Taylor MT, Fox JM. Usually reactive and selective carbonyl ylides for three-component cycloaddition reactions. Journal of the American Chemical Society. 2009;131(3):1101–1105. doi: 10.1021/ja807184r. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Anac O, Sezer O, Candan O, Gungor FS, Cansever MS. Carbonyl ylide reactions of α-benzylidene-β-dicarbonyl compounds: competitive formation of dihydrofurans and dihydrobenzoxepines. Tetrahedron Letters. 2008;49(6):1062–1065. doi: 10.1016/j.tetlet.2007.11.197. [DOI] [Google Scholar]
  • 37.Schinnerl M, Bohm C, Seitz M, Reiser O. New bis(oxazoline) ligands with secondary binding sites for the asymmetric cyclopropanation of furans. Tetrahedron Asymmetry. 2003;14(7):765–771. doi: 10.1016/S0957-4166(03)00094-6. [DOI] [Google Scholar]
  • 38.Ghomri A, Mekelleche SM. Reactivity and regioselectivity of five-membered heterocycles in electrophilic aromatic substitution: a theoretical investigation. Journal of Molecular Structure: THEOCHEM. 2010;941(1–3):36–40. doi: 10.1016/j.theochem.2009.10.035. [DOI] [Google Scholar]
  • 39.Alvarez Idaboy JR, Gonzalez MC, Montero LA. Influence of the nature of the electrophilic reagent in the electrophilic substitution reaction of furan, thiophene and pyrrole. Folia Chimica Theoretica Latina. 1989;17:39–52. [Google Scholar]
  • 40.Belen’kii LI, Chuvylkin ND, Nesterov ID. Positional selectivity in electrophilic substitution reactions of π-excessive heterocycles. Chemistry of Heterocyclic Comp ounds. 2012;48(2):241–257. doi: 10.1007/s10593-012-0985-3. [DOI] [Google Scholar]
  • 41.Jeong J, Lee D, Chang S. Copper-catalyzed oxygen atom transfer of N-oxides leading to a facile deoxygenation procedure applicable to both heterocyclic and amine N-oxides. Chemical Communications. 2015;51(32):7035–7038. doi: 10.1039/C5CC01739D. [DOI] [PubMed] [Google Scholar]
  • 42.O’Connor NR, Bolgar P, Stoltz BM. Development of a simple system for the oxidation of electron-rich diazo compounds to ketones. Tetrahedron Letters. 2016;57(8):849–851. doi: 10.1016/j.tetlet.2016.01.020. [DOI] [Google Scholar]
  • 43.Yu Y, Sha Q, Cui H, Chandler KS, Doyle MP. Displacement of dinitrogen by oxygen: a methodology for the catalytic conversion of diazocarbonyl compounds to ketocarbonyl compounds by 2,6-dichloropyridine-N-oxide. Organic Letters. 2018;20(3):776–779. doi: 10.1021/acs.orglett.7b03912. [DOI] [PubMed] [Google Scholar]
  • 44.Yu J, Zhou Y, Lin Z, Tong R. Regioselective and stereospecific copper-catalyzed deoxygenation of epoxides to alkenes. Organic Letters. 2016;18(18):4734–4737. doi: 10.1021/acs.orglett.6b02405. [DOI] [PubMed] [Google Scholar]

Articles from Turkish Journal of Chemistry are provided here courtesy of The Scientific and Technological Research Council of Turkey

RESOURCES