One pot synthesis of pyrrolo[3,2,1-de]phenanthridines from 7-phenylindoles via tandem C–H olefination/aza-Michael addition

Abstract

An unprecedented one-pot C–H olefination/aza-Michael addition tandem process has been developed for the synthesis of pyrrolo[3,2,1-de]phenanthridines from 7-phenylindoles and alkenes using a [Cp*RhCl₂]₂/AgOAc/Me₄NOAc catalytic system. A relatively wide range of functional groups are tolerated, and a variety of pyrrolo[3,2,1-de]phenanthridines are obtained in good to excellent yields.

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Introduction

The indole skeleton is unarguably one of the most important structural moieties in innumerable natural and unnatural compounds.¹ In particular, fused tetracyclic ring systems containing indole units attracted synthetic chemists due to their prevalent occurrence in many biologically active molecules.² As the synthesis of these fused tetracyclic indoles usually requires multistep procedures,³ efficient, simple, and divergent production of these molecules remains an important challenge for synthetic organic chemists.

In recent years, the transition-metal-catalyzed cross-dehydrogenative-coupling (CDC) has emerged as an attractive and ideal strategy to synthesize complex heterocyclic molecules, as it permits the building of C–C bonds by directly connecting two C–H bonds. The benefits of CDC include atom and step economy, lower cost, and less waste.⁴ CDC tools were realized for the preparation of 2,3-fused (Scheme 1a) or 1,2-fused tetracyclic indoles (Scheme 1b). For example, the CDC reaction of 2-arylindoles with alkynes, alkenes, ketenes, diazo compounds, and carbon monoxide leading to indolo[2,1-a]isoquinolines,⁵ indole-indolones,⁶ benzo[a]carbazoles,⁷ 5H-benzo[a]carbazol-5-ones⁸and 6H-isoindolo[2,1-a]indol-6-ones⁹ has been developed. The synthesis of indolo[3,2-c]coumarins,¹⁰ indolo[3,2-c]quinolinones,¹¹ and indole[3,2-c]pyrones¹²via the intramolecular CDC reaction was also uncovered. Greaney and co-workers disclosed a palladium-catalyzed intramolecular CDC reaction between the aromatic ring and the indolyl moiety producing a set of indole-containing seven-and eight-membered rings.¹³ Inspired by those advances and as part of our continued interest in the NH-indole-directed C–H functionalization,^9,14 we herein present a protocol for the rhodium-catalyzed C–H alkenylation and subsequent intramolecular aza-Michael reaction of 7-arylindoles with alkenes leading to diverse biologically important pyrrolo[3,2,1-de]phenanthridines (Fig. 1).¹⁵ To the best of our knowledge, the synthesis of such attractive 1,7-fused tetracyclic indoles via the CDC reaction has yet to be described (Scheme 1c).

Scheme 1 Approaches of CDC reactions: synthesis of fused tetracyclic indoles.

Fig. 1 Some biologically active pyrrolo[3,2,1-de]phenanthridine derivatives.

Results and discussion

Our initial studies involved the intermolecular Fujiwara–Moritani reaction of 7-phenyl-1H-indol (1a) with ethyl acrylate (2a) employing the conditions of [Cp*RhCl₂]₂ (2.5 mol%) and AgOAc (2 equiv.) in ethyl acetate (EtOAc) at 100 °C. This leads to the generation of mono-ortho-alkenylated product 3a in 35% (Table S1,† entry 1) with complete E-stereoselectivity. No di-alkenylated or C3-alkenylated product was found in the reaction mixture. We were delighted to find that changing the solvent from EtOAc to acetone could lead to a dramatic increase of the yield of 3a to 84% (Table S1,† entry 2). The optimum reaction temperature is 80 °C, thus affording near quantitative yield (Table S1,† entry 8). Notably, this transformation can also be performed under an air atmosphere; the isolated yield of 3a is 97% (Scheme 2, eqn (1)). Treating 3a with 30 mol% KO^tBu in dichloromethane (DCM) resulted in an intramolecular aza-Michael reaction. The aza-Michael product 7H-pyrrolo[3,2,1-de]phenanthridine 4a is obtained in quantitative yield in pure form directly after workup without the need for column chromatography (Scheme 2, eqn (2)). Replacing KO^tBu with other bases such as KOH, DMAP, Et₃N, KOAc, NaOAc, CsOAc, and LiOAc failed to furnish the desired products, and starting material 3a was recovered (Table S2†). Encouraged by the above results, one-pot synthesis of 7H-pyrrolo[3,2,1-de]phenanthridine 4a by combining intermolecular C–H olefination and intramolecular aza-Michael addition of 7-phenyl-1H-indole (1a) with ethyl acrylate (2a) was surveyed (Table 1). KO^tBu had a detrimental effect on the [Cp*RhCl₂]₂/AgOAc catalyst system, and the starting material 1a was recovered totally (Table 1, entry 1). Other bases such as DBU, DMAP, KOH, and KPF₆ also gave unsatisfactory results (entries 2–5). Interestingly, employing quaternary ammonium salts such as ⁿBu₄NOAc and Me₄NOAc in acetone at 80 °C for 24 h, the desired product 4a can be obtained in 35% and 28% yields, respectively (entries 6 and 7). When the amount of Me₄NOAc was increased from 2 equiv. to 10 equiv., the yield of 4a improved to 58% NMR yield (entry 9). No significant change in the yield of 4a was observed on using 10 equiv. of ⁿBu₄NOAc (entry 8). When 10 equiv. of other acetate salts such as KOAc, NaOAc, CsOAc, and LiOAc was employed, the reaction stopped after olefination and intramolecular aza-Michael addition product 4a was not formed totally. After an extensive screen of solvents, we found that the use of CH₃CN gave the best result of 99% yield of 4a after 24 h (entry 15, 97% isolated yield). MeOH as the solvent gave 3a selectively, and other solvents such as EtOH, DCE, DCM, 1,4-dioxane, and EtOAc led to complete reaction shutdown. Finally, a decrease in the loading of Me₄NOAc (5 equiv.) resulted in a lower yield of 4a (88%, Table 1, entry 17).

Scheme 2 Rhodium-catalyzed ortho C–H olefination of 7-arylindoles (eqn (1)); KO^tBu-catalyzed intramolecular aza-Michael addition (eqn (2)).

Table 1 Optimization of reaction conditions of one-pot synthesis of 7H-pyrrolo[3,2,1-de]phenanthridine^a

Entry	Base	Solvent	Yield^b (%)
a Conditions: 1a (0.3 mmol), 2a (0.75 mmol), [Cp*RhCl2]2(2.5 mol%), AgOAc (2 equiv.), base, solvent(2 mL), 80 °C, 24 h. b ^1H NMR Yield on the basis of the amount of 1a used; the number in parentheses is the isolated yield. c Other acetate salts = KOAc, NaOAc, CsOAc, and LiOAc.
1	KO^tBu (2 equiv.)	Acetone	Trace
2	DBU (2 equiv.)	Acetone	Trace
3	DMAP (2 equiv.)	Acetone	Trace
4	KOH (2 equiv.)	Acetone	Trace
5	KPF6 (2 equiv.)	Acetone	Trace
6	nBu4NOAc (2 equiv.)	Acetone	35
7	Me4NOAc (2 equiv.)	Acetone	28
8	nBu4NOAc (10 equiv.)	Acetone	30
9	Me4NOAc (10 equiv.)	Acetone	58
10^c	Other acetate salts (10 equiv.)	Acetone	0
11	Me4NOAc (10 equiv.)	Xylene	Trace
12	Me4NOAc (10 equiv.)	DCE	Trace
13	Me4NOAc (10 equiv.)	DCM	Trace
14	Me4NOAc (10 equiv.)	1,4-Dioxane	Trace
15	Me4NOAc (10 equiv.)	EtOAc	Trace
16	Me 4 NOAc (10 equiv.)	MeCN	99 (97)
17	Me4NOAc (5 equiv.)	MeCN	88

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With optimized reaction conditions in hand, we then investigated the scope and generality of the present processes (Table 2). Under condition A, a broad range of 7-phenylindoles could be transformed to the ortho-mono-alkenylated products with up to 97% yield. Many functional groups, such as fluoro (3i), cyano (3j), nitro (3k), chloro (3l, 3o), ester (3m), methoxy (3n), and naphthyl (3p), were well tolerated. The positions of substituents plays an important role in the reaction efficiency and regioselectivity. 7-Phenyl-1H-indoles with the substituents on 4,5-positions of the indole ring or meta- and para-positions of the benzene ring were transformed easily to ortho-alkenylated 7-phenyl-1H-indoles in excellent yields (3b–3d, 3i–3n). However, the reaction of 3-methyl-7-phenyl-1H-indole 1e with 2a provided the corresponding product 3e in a low yield (30%), while 2-methyl-7-phenyl-1H-indole 1f led to complete reaction shutdown. When 6-methyl-7-phenyl-1H-indole (1g) or 7-(o-tolyl)-1H-indole (1h) was employed, a low yield of the 3-alkenylated 7-phenyl-1H-indole was formed selectively (3g, 16%; 3h, 13%). No ortho-alkenylated product was formed. On the other hand, the experimental results showed that the electronic properties of the substituents had no discernible effect on the reaction efficiency. As expected, other acrylates such as 2-methoxyethyl acrylate (2b), tert-butyl acrylate (2c), n-butyl acrylate (2d), and 2-(dimethylamino)ethyl acrylate (2e) all smoothly reacted with 1a to afford the desired products 3q–3t in good yields. Furthermore, ethyl vinyl ketone (2f), N,N-dimethylacrylamide (2g), or acrylonitrile (2h) also efficiently reacted with 1a yielding ortho-alkenylated products 3u–3w in 78%, 56%, and 64% yields, respectively. However, methyl methacrylate is less reactive than ethyl acrylate 2a in this system. Almost no desired product 3 was obtained.

Table 2 Substrate scope^a

Entry	7-Aryl-1H-indole 1	Alkene 2	Product 3	Yield of 3^b (%)	Product 4	Yield of 4^b (%)
						Condition B	Condition C
a Conditions A: 1a (0.3 mmol), 2a (0.75 mmol), [Cp*RhCl2]2 (2.5 mol%), AgOAc (2 equiv.), acetone (2 mL), 80 °C, air, 24 h; Conditions B: 3a (0.2 mmol), KO^tBu (30 mmol%), DCM (2 mL), rt, air, 5 h; Conditions C: 1a (0.3 mmol), 2a (0.75 mmol), [Cp*RhCl2]2 (2.5 mol%), AgOAc (2 equiv.), Me4NOAc (10 equiv.), MeCN (2 mL), 80 °C, Ar, 24 h. b Isolated yields reported.
1				97		100	99
2		2a		75		93	80
3		2a		78		92	76
4		2a		79		90	80
5		2a		30		87	45
6		2a		NR
7		2a		16
8		2a		13
9		2a		88		93	82
10		2a		73		93	80
11		2a		73		92	72
12		2a		64		91	90
13		2a		80		72	77
14		2a		77		95	74
15		2a		79		93	81
16		2a		87		91	89
17	1a			92		90	93
18	1a			78		88	97
19	1a			81		89	73
20	1a			75		90	80
21	1a			78		72	63
22	1a			56		87	67
23	1a			64		86	63

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Next, we turned our attention to the synthesis of annulated product 7H-pyrrolo[3,2,1-de]phenanthridines. To our delight, under condition B, the KO^tBu-catalyzed intramolecular aza-Michael reaction proceeded quite well to give the desired products 4 in high yield. The reaction seems to be insensitive to the electronic and steric effects of substituents. Under condition C, a great variety of 7-phenyl-1H-indoles can be converted into the corresponding 7H-pyrrolo[3,2,1-de]phenanthridines through a one-pot C–H olefination/aza-Michael addition sequence. The yield of the product mainly depends on the efficiency of the C–H olefination step. It is worth noting that the first equilibrium reaction (C–H olefination) will be shifted to the right, according to Le Châlelier's principle, as intermediate 3 undergoes the aza-Michael reaction efficiently. Consequently, the yield of the one-pot reaction is higher than the overall yield of the two-step procedure. For example, 3-methyl-7-phenyl-1H-indole 1e provided the product 4e in a synthetically useful yield via the one-pot procedure (45%). In contrast, the two-step route to 4e was hampered by the low yielding step and provided 4e in only 29% overall yield. In addition, when compound 4a is resubjected to reaction conditions B and C, no reaction occurred, and compound 4a was recovered. This result likely indicates that the intramolecular aza-Michael addition is irreversible.

Conclusions

In conclusion, we have successfully developed [Cp*RhCl₂]₂/AgOAc-catalyzed regioselective ortho C–H olefination of 7-phenylindoles and KO^tBu-catalyzed intramolecular aza-Michael addition leading to pyrrolo[3,2,1-de]phenanthridines. More importantly, the tandem C–H olefination/aza-Michael addition can proceed in one-pot under mild reaction conditions using the [Cp*RhCl₂]₂/AgOAc/Me₄NOAc catalytic system. A relatively wide range of functional groups were tolerated, and a variety of pyrrolo[3,2,1-de]phenanthridines were obtained in good to excellent yields. The developed efficient and straightforward synthesis of pyrrolo[3,2,1-de]phenanthridines will be useful for the establishment of compound libraries for drug discovery.

Experimental

General

7-Phenyl-1H-indoles were synthesized from 7-bromo-1H-indoles and phenylboronic acid via Suzuki coupling.¹⁶¹H NMR spectra and ¹³C NMR spectra were recorded at 400 MHz and 100 MHz, respectively. ¹H chemical shifts (δ) were referenced to TMS, and ¹³C NMR chemical shifts (δ) were referenced to internal solvent resonance. ESI-HRMS spectra were recorded by using a Q-TOF mass spectrometer. Data collection and structural analysis of the crystal were performed on a Single Crystal Diffractometer equipped with graphite monochromatic Cu K_α radiation (λ = 1.54184 Å).

General procedure for the ortho C–H olefination reaction (condition A)

Under an air atmosphere, 7-phenyl-1H-indoles 1 (0.3 mmol), alkenes 2 (0.75 mmol, 2.5 equiv.), [Cp*RhCl₂]₂ (4.7 mg, 0.0075 mmol, 2.5 mol%), AgOAc (100.1 mg, 0.6 mmol, 2 equiv.), and acetone (2 mL) were placed in a 50 mL sealed tube. The mixture was heated in an oil bath at 80 °C for 24 h and then cooled to room temperature. The mixture was diluted with CH₂Cl₂ to 5 mL, filtered through a Celite pad, and then washed with CH₂Cl₂. The volatiles were removed under reduced pressure, and the residue was subjected to silica gel column chromatography [eluting with petroleum ether/ethyl acetate] to afford the corresponding product (3a–3w).

Ethyl (E)-3-(2-(1H-indol-7-yl)phenyl)acrylate (3a). 85 mg (97%); white solid; mp 123–124 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.82–7.78 (m, 1H), 7.68 (d, J = 7.9 Hz, 1H), 7.58 (d, J = 16.0, 1H), 7.53–7.42 (m, 3H), 7.23–7.15 (m, 2H), 7.04 (dd, J = 7.2, 1.0 Hz, 1H), 6.62 (dd, J = 3.2, 2.1 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 142.9, 139.6, 134.4, 133.3, 130.7, 130.1, 128.1, 127.0, 124.4, 123.7, 123.0, 120.6, 119.9, 119.4, 103.0, 60.3, 14.2. HRMS (ESI) calcd for C₁₉H₁₇NO₂ [M + Na]⁺ 314.1151, found 314.1151.

Ethyl (E)-3-(2-(4-methyl-1H-indol-7-yl)phenyl)acrylate (3b). 69 mg (75%); yellow solid; mp 126–127 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.07 (s, 1H), 7.79 (d, J = 7.3 Hz, 1H), 7.61 (d, J = 16.0 Hz, 1H), 7.54–7.38 (m, 3H), 7.13 (t, J = 2.7 Hz, 1H), 7.03–6.94 (m, 2H), 6.63 (t, J = 2.7 Hz, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 2.64 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 143.1, 139.8, 133.9, 133.2, 130.7, 130.1, 130.0, 127.9, 127.8, 126.9, 123.9, 123.8, 120.6, 120.1, 119.0, 101.4, 60.3, 18.8, 14.2. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1308.

Ethyl (E)-3-(2-(1H-indol-7-yl)-4-methylphenyl)acrylate (3c). 72 mg (78%); white solid; mp 189–190 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.67 (dt, J = 8.0, 1.0 Hz, 1H), 7.55 (d, J = 16.0 Hz, 1H), 7.32 (s, 1H), 7.28–7.24 (m, 1H), 7.03 (dd, J = 7.2, 1.0 Hz, 1H), 6.61 (dd, J = 3.2, 2.1 Hz, 1H), 6.36 (d, J = 16.0 Hz, 1H), 4.12 (qd, J = 7.1, 2.4 Hz, 2H), 2.42 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.8, 142.8, 140.5, 139.6, 134.4, 131.3, 130.4, 129.0, 128.0, 126.9, 124.4, 123.6, 123.1, 120.5, 120.0, 118.3, 102.9, 60.2, 21.4, 14.2. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1308.

Ethyl (E)-3-(2-(1H-indol-7-yl)-5-methylphenyl)acrylate (3d). 72 mg (79%); white solid; mp 148–149 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.67 (dt, J = 7.8 Hz, 1H), 7.62–7.53 (m, 2H), 7.40 (d, J = 7.8 Hz, 1H), 7.32–7.28 (m, 1H), 7.22–7.15 (m, 2H), 7.02 (dd, J = 7.2, 1.0 Hz, 1H), 6.61 (dd, J = 3.2, 2.1 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 2.46 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 143.1, 137.8, 136.8, 134.5, 133.0, 131.1, 130.5, 128.0, 127.4, 124.4, 123.8, 123.0, 120.4, 119.9, 119.0, 102.9, 60.3, 21.2, 14.2. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1307.

Ethyl (E)-3-(2-(3-methyl-1H-indol-7-yl)phenyl)acrylate (3e). 27 mg (30%); yellow solid; mp 133–134 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.81–7.77 (m, 1H), 7.71 (s, 1H), 7.64–7.56 (m, 2H), 7.52–7.41 (m, 3H), 7.21 (dd, J = 8.0, 7.2 Hz, 1H), 7.04 (dd, J = 7.2, 1.0 Hz, 1H), 6.94 (dd, J = 2.3, 1.2 Hz, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.13 (dd, J = 7.1 Hz, 2H), 2.37 (m, J = 1.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 143.1, 139.7, 134.8, 133.3, 130.7, 130.1, 128.5, 128.0, 126.9, 123.7, 122.9, 122.0, 119.3, 119.2, 118.7, 112.0, 60.4, 14.2, 9.8. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1299.

Ethyl (E)-3-(6-methyl-7-phenyl-1H-indol-3-yl)acrylate (3g). 15 mg (16%); yellow solid; mp 119–120 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (s, 1H), 7.61 (d, J = 16.0 Hz, 1H), 7.56–7.38 (m, 6H), 7.07 (dd, J = 8.1, 0.6 Hz, 1H), 6.81 (d, J = 2.1 Hz, 1H), 6.01 (d, J = 16.0 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 2.29 (s, 3H), 1.30 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.8, 137.3, 137.0, 134.2, 133.1, 131.8, 129.6, 129.1, 127.7, 126.4, 124.7, 123.8, 120.3, 114.9, 109.3, 60.5, 19.8, 14.3. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + H]⁺ 306.1489, found 306.1488.

Ethyl (E)-3-(7-(o-tolyl)-1H-indol-3-yl)acrylate (3h). 12 mg (13%); yellow solid; mp 101–102 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.66–7.60 (m, 2H), 7.39–7.31 (m, 4H), 7.21–7.17 (m, 1H), 7.13 (dd, J = 7.2, 1.2 Hz, 1H), 6.87 (d, J = 2.1 Hz, 1H), 6.09 (d, J = 16.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 2.18 (s, 3H), 1.31 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 137.4, 136.5, 136.3, 134.1, 133.5, 130.7, 129.8, 128.3, 128.1, 126.2, 125.3, 125.1, 120.7, 120.5, 115.6, 109.1, 60.5, 20.0, 14.3. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + H]⁺ 306.1489, found 306.1489.

Ethyl (E)-3-(2-(5-fluoro-1H-indol-7-yl)phenyl)acrylate (3i). 82 mg (88%); white solid; mp 153–154 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (s, 1H), 7.79 (dd, J = 7.6, 2.0 Hz, 1H), 7.55–7.44 (m, 4H), 7.33 (dd, J = 9.3, 2.4 Hz, 1H), 7.21 (t, J = 2.9 Hz, 1H), 6.84 (dd, J = 9.7, 2.4 Hz, 1H), 6.58 (dd, J = 3.2, 2.1 Hz, 1H), 6.41 (d, J = 16.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 157.6 (d, ¹J_C–F = 250.5 Hz), 142.3, 138.3, 133.2, 131.1, 130.6, 130.2, 128.5, 128.3 (d, ³J_C–F = 10.3 Hz), 126.9, 126.2, 123.8 (d, ³J_C–F = 9.5 Hz), 119.7, 111.8 (d, ²J_C–F = 26.6 Hz), 105.2 (d, ²J_C–F = 23.4 Hz), 103.1 (d, ³J_C–F = 4.8 Hz), 60.4, 14.1. ¹⁹F NMR (376 MHz, CDCl₃) δ −124.83 (t, J = 9.0 Hz). HRMS (ESI) calcd for C₁₉H₁₆FNO₂ [M + Na]⁺ 332.1057, found 332.1057.

Ethyl (E)-3-(5-cyano-2-(1H-indol-7-yl)phenyl)acrylate (3j). 69 mg (73%); yellow solid; mp 152–153 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.05 (d, J = 1.6 Hz, 1H), 7.98 (s, 1H), 7.73 (dq, J = 7.9, 1.2 Hz, 2H), 7.64 (dd, J = 7.9, 0.5 Hz, 1H), 7.49 (d, J = 16.0 Hz, 1H), 7.24–7.19 (m, 2H), 7.02 (dd, J = 7.2, 1.0 Hz, 1H), 6.64 (dd, J = 3.2, 2.0 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.15 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 144.0, 140.6, 134.7, 133.7, 132.7, 131.6, 130.8, 128.5, 124.9, 123.6, 121.7, 121.1, 120.0, 118.2, 112.1, 103.3, 60.7, 14.1. HRMS (ESI) calcd for C₂₀H₁₆N₂O₂ [M + H]⁺ 317.1285, found 317.1285.

Ethyl (E)-3-(2-(1H-indol-7-yl)-5-nitrophenyl)acrylate (3k). 74 mg (73%); yellow solid; mp 153–154 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.65 (d, J = 2.3 Hz, 1H), 8.31 (dd, J = 8.5, 2.3 Hz, 1H), 7.94 (s, 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.54 (d, J = 16.0 Hz, 1H), 7.25–7.19 (m, 2H), 7.05 (dd, J = 7.2, 1.1 Hz, 1H), 6.66 (dd, J = 3.2, 2.0 Hz, 1H), 6.57 (d, J = 16.0 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.24 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 165.9, 147.5, 145.8, 140.6, 134.8, 133.7, 131.8, 128.5, 124.9, 124.2, 123.7, 122.1, 122.1, 121.9, 120.9, 120.1, 103.4, 60.8, 14.1. HRMS (ESI) calcd for C₁₉H₁₆N₂O₄ [M + H]⁺ 337.1183, found 337.1183.

Ethyl (E)-3-(5-chloro-2-(1H-indol-7-yl)phenyl)acrylate (3l). 62 mg (64%); white solid; mp 180–181 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.94 (s, 1H), 7.77 (t, J = 1.0 Hz, 1H), 7.69 (dt, J = 7.9, 1.0 Hz, 1H), 7.51–7.43 (m, 3H), 7.22–7.16 (m, 2H), 7.00 (dd, J = 7.3, 1.1 Hz, 1H), 6.62 (dd, J = 3.2, 2.0 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.2, 141.5, 137.9, 135.0, 134.3, 134.1, 132.0, 130.0, 128.2, 126.8, 124.6, 123.7, 121.8, 120.9, 120.6, 120.0, 103.1, 60.5, 14.2. HRMS (ESI) calcd for C₁₉H₁₆ClNO₂ [M + Na]⁺ 348.0762, found 348.0762.

Methyl (E)-3-(3-ethoxy-3-oxoprop-1-en-1-yl)-4-(1H-indol-7-yl)benzoate (3m). 84 mg (80%); yellow solid; mp 128–129 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.46 (d, J = 1.7 Hz, 1H), 8.11 (dd, J = 8.0, 1.7 Hz, 1H), 8.04 (s, 1H), 7.71 (dt, J = 7.9, 0.8 Hz, 1H), 7.61–7.54 (m, 2H), 6.63 (dd, J = 3.2, 2.0 Hz, 1H), 6.52 (d, J = 16.0 Hz, 1H), 4.14 (q, J = 7.1 Hz, 2H), 3.98 (s, 3H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.4 (2C), 143.9, 141.9, 134.0, 133.6, 130.9, 130.7, 129.9, 128.3 (2C), 124.7, 123.6, 122.1, 121.2, 120.5, 120.0, 103.1, 60.5, 52.4, 14.2. HRMS (ESI) calcd for C₂₁H₁₉NO₄ [M + Na]⁺ 372.1206, found 372.1206.

Ethyl (E)-3-(2-(1H-indol-7-yl)-5-methoxyphenyl)acrylate (3n). 74 mg (77%); yellow solid; mp 175–176 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.66 (dt, J = 8.0, 1.0 Hz, 1H), 7.55 (d, J = 16.0 Hz, 1H), 7.42 (d, J = 8.5 Hz, 1H), 7.28 (d, J = 2.7 Hz, 1H), 7.21–7.16 (m, 2H), 7.05 (dd, J = 8.5, 2.6 Hz, 1H), 7.01 (dd, J = 7.2, 1.1 Hz, 1H), 6.61 (dd, J = 3.2, 2.1 Hz, 1H), 6.39 (d, J = 16.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 3.90 (s, 3H), 1.21 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 159.2, 143.0, 134.7, 134.3, 132.2, 131.8, 128.0, 124.4, 123.9, 122.8, 120.3, 119.9, 119.4, 116.6, 111.3, 103.0, 60.4, 55.5, 14.2. HRMS (ESI) calcd for C₂₀H₁₉NO₃ [M + Na]⁺ 344.1257, found 344.1257.

(E)-1-(2-(4-Chloro-1H-indol-7-yl)phenyl)pent-1-en-3-one (3o). 77 mg (79%); white solid; mp 133–134 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.09 (s, 1H), 7.84–7.79 (m, 1H), 7.57–7.46 (m, 4H), 7.27–7.21 (m, 2H), 6.99 (d, J = 7.7 Hz, 1H), 6.75 (dd, J = 3.2, 2.2 Hz, 1H), 6.43 (d, J = 16.0 Hz, 1H), 4.17 (q, J = 7.1 Hz, 2H), 1.23 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 142.5, 138.6, 135.0, 133.3, 130.6, 130.2, 128.4, 127.0, 126.8, 126.0, 125.1, 124.3, 121.8, 119.7, 119.6, 101.8, 60.5, 14.2. HRMS (ESI) calcd for C₁₉H₁₆ClNO₂ [M + H]⁺ 326.0942, found 326.0942.

Ethyl (E)-3-(3-(1H-indol-7-yl)naphthalen-2-yl)acrylate (3p). 89 mg (87%); white solid; mp 120–121 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.28 (s, 1H), 8.04 (s, 1H), 7.97 (s, 1H), 7.94 (dd, J = 6.2, 3.4 Hz, 1H), 7.83 (dd, J = 6.2, 3.4 Hz, 1H), 7.71 (dt, J = 7.9, 0.9 Hz, 1H), 7.67 (d, J = 15.5 Hz, 1H), 7.58–7.53 (m, 2H), 7.24 (dd, J = 8.0, 7.2 Hz, 1H), 7.17 (dd, J = 3.2, 2.5 Hz, 1H), 7.12 (dd, J = 7.2, 1.1 Hz, 1H), 6.64 (dd, J = 3.2, 2.1 Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 4.13 (q, J = 7.1 Hz, 2H), 1.22 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 143.2, 136.5, 134.7, 133.9, 132.6, 131.8, 129.4, 128.3, 128.1, 127.6, 127.5, 127.1, 126.8, 124.5, 123.8, 123.0, 120.5, 120.0, 119.7, 103.0, 60.4, 14.2. HRMS (ESI) calcd for C₂₃H₁₉NO₂ [M + Na]⁺ 364.1308, found 364.1314.

2-Methoxyethyl (E)-3-(2-(1H-indol-7-yl)phenyl)acrylate (3q). 89 mg (92%); white solid; mp 85–86 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.01 (s, 1H), 7.84–7.80 (m, 1H), 7.70 (dt, J = 8.0, 0.8 Hz, 1H), 7.62 (d, J = 16.0 Hz, 1H), 7.55–7.45 (m, 3H), 7.24–7.17 (m, 2H), 7.06 (dd, J = 7.2, 1.0 Hz, 1H), 6.64 (dd, J = 3.2, 2.1 Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 4.27–4.23 (m, 2H), 3.60–3.56 (m, 2H), 3.34 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.5, 143.4, 139.7, 134.4, 133.2, 130.7, 130.2, 128.1, 128.0, 126.9, 124.5, 123.7, 122.9, 120.6, 119.9, 118.8, 103.0, 70.4, 63.6, 59.0. HRMS (ESI) calcd for C₂₀H₁₉NO₃ [M + Na]⁺ 344.1257, found 344.1257.

tert-Butyl (E)-3-(2-(1H-indol-7-yl)phenyl)acrylate (3r). 75 mg (78%); white solid; mp 132–133 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (s, 1H), 7.80 (dd, J = 7.4, 1.7 Hz, 1H), 7.68 (dt, J = 7.9, 0.9 Hz, 1H), 7.52–7.41 (m, 4H), 7.21 (dd, J = 7.9, 7.2 Hz, 1H), 7.15 (dd, 1H), 7.06 (dd, J = 7.2, 1.0 Hz, 1H), 6.62 (dd, J = 3.2, 2.1 Hz, 1H), 6.35 (d, J = 16.0 Hz, 1H), 1.40 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 166.0, 141.8, 139.5, 134.4, 133.3, 130.6, 129.9, 128.0, 126.7, 124.4, 123.6, 123.0, 121.0, 120.5, 119.8, 102.9, 80.3, 28.0. HRMS (ESI) calcd for C₂₁H₂₁NO₂ [M + Na]⁺ 342.1465, found 342.1465.

Butyl (E)-3-(2-(1H-indol-7-yl)phenyl)acrylate (3s). 78 mg (81%); white solid; mp 94–95 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.83–7.77 (m, 1H), 7.69 (dt, J = 7.9, 1.0 Hz, 1H), 7.57 (d, J = 16.0 Hz, 1H), 7.52–7.42 (m, 3H), 7.20 (dd, J = 7.9, 7.2 Hz, 1H), 7.14 (dd, J = 3.2, 2.4 Hz, 1H), 7.05 (dd, J = 7.2, 1.0 Hz, 1H), 6.62 (dd, J = 3.2, 2.1 Hz, 1H), 6.40 (d, J = 16.0 Hz, 1H), 4.06 (t, J = 6.6 Hz, 2H), 1.59–1.51 (m, 2H), 1.34–1.24 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 142.8, 139.6, 134.4, 133.2, 130.6 (2C), 130.1, 128.0, 126.8, 124.4, 123.6, 122.9, 120.5, 119.8, 119.2, 102.9, 64.2, 30.6, 19.1, 13.7. HRMS (ESI) calcd for C₂₁H₂₁NO₂ [M + H]⁺ 320.1645, found 320.1644.

2-(Dimethylamino)ethyl (E)-3-(2-(1H-indol-7-yl)phenyl)acrylate (3t). 75 mg (75%); white solid; mp 95–96 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (s, 1H), 7.79 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 7.9 Hz, 1H), 7.56 (d, J = 16.0 Hz, 1H), 7.51–7.42 (m, 3H), 7.21–7.15 (m, 2H), 7.03 (d, J = 7.2 Hz, 1H), 6.61 (dd, J = 3.2, 2.1 Hz, 1H), 6.44 (d, J = 16.0 Hz, 1H), 4.17 (t, J = 5.6 Hz, 2H), 2.53 (t, J = 5.6 Hz, 2H), 2.21 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 166.6, 143.2, 139.7, 134.5, 133.2, 130.7, 130.2, 128.2, 128.1, 126.9, 124.5, 123.7, 123.0, 120.6, 119.9, 119.0, 103.0, 62.2, 57.6, 45.5. HRMS (ESI) calcd for C₂₁H₂₂N₂O₂ [M + H]⁺ 335.1754, found 335.1754.

(E)-1-(2-(1H-Indol-7-yl)phenyl)pent-1-en-3-one (3u). 64 mg (77%); yellow solid; mp 125–126 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.02 (s, 1H), 7.80 (dd, J = 7.6, 1.7 Hz, 1H), 7.71 (dt, J = 7.9, 1.0 Hz, 1H), 7.54–7.44 (m, 3H), 7.39 (d, J = 16.5 Hz, 1H), 7.22 (dd, J = 7.9, 7.2 Hz, 1H), 7.19–7.15 (m, 1H), 7.06 (dd, J = 7.2, 1.0 Hz, 1H), 6.63 (dd, J = 3.2, 2.1 Hz, 1H), 6.64 (d, J = 16.5 Hz, 1H), 2.35 (s, 2H), 0.96 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 201.5, 141.1, 139.7, 134.4, 133.3, 130.7, 130.3, 128.2, 128.0, 127.7, 126.9, 124.5, 123.6, 123.0, 120.6, 119.9, 103.0, 32.5, 8.1. HRMS (ESI) calcd for C₁₉H₁₇NO [M + Na]⁺ 298.1202, found 298.1202.

(E)-3-(2-(1H-Indol-7-yl)phenyl)-N,N-dimethylacrylamide (3v). 48 mg (55%); white solid; mp 183–184 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.70–7.66 (m, 1H), 7.64 (dt, J = 7.9, 1.0 Hz, 1H), 7.47–7.40 (m, 4H), 7.20–7.13 (m, 2H), 7.04 (dd, J = 7.2, 1.1 Hz, 1H), 6.58 (dd, J = 3.2, 2.1 Hz, 1H), 6.51 (d, J = 15.7 Hz, 1H), 2.89 (s, 3H), 2.80 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 166.7, 140.0, 138.7, 134.2, 134.2, 131.0, 129.3, 128.2, 128.1, 127.9, 124.5, 123.9, 123.2, 120.3, 120.0, 119.7, 102.8, 37.1, 35.6. HRMS (ESI) calcd for C₁₉H₁₈N₂O [M + Na]⁺ 313.1311, found 313.1311.

(E)-3-(2-(1H-Indol-7-yl)phenyl)acrylonitrile (3w). 47 mg (64%); white solid; mp 111–112 °C. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (s, 1H), 7.75–7.67 (m, 2H), 7.56–7.45 (m, 3H), 7.30 (d, J = 16.7 Hz, 1H), 7.25–7.17 (m, 2H), 7.01 (dd, J = 7.2, 0.9 Hz, 1H), 6.65 (dd, J = 3.2, 2.1 Hz, 1H), 5.83 (d, J = 16.7 Hz, 1H). ¹³C NMR (100 MHz, CDCl₃) δ 149.0, 139.3, 134.3, 132.3, 131.1, 130.9, 128.3, 128.2, 126.0, 124.7, 123.6, 122.3, 120.9, 120.0, 118.1, 103.2, 96.9. HRMS (ESI) calcd for C₁₇H₁₂N₂ [M + Na]⁺ 267.0893, found 267.0891.

General procedure for the aza-Michael reaction (condition B)

Under an air atmosphere, compound 3 (0.2 mmol) and KO^tBu (0.06 mmol, 6.8 mg, 30 mol%) were dissolved in CH₂Cl₂ (2 mL), and the mixture was stirred at room temperature for 5 h. The mixture was diluted with 10 mL of CH₂Cl₂, filtered through a Celite pad and then washed with CH₂Cl₂. The organic phases were washed with saturated NH₄Cl solution (3 × 10 mL) and dried over anhydrous Na₂SO₄. The organic solvent was removed under reduced pressure to furnish compounds which were identified as pyrrolo[3,2,1-de]phenanthridines (4a–4w).

General procedure for the one pot synthesis of Pyrrolo[3,2,1-de]phenanthridines (condition C)

Under an Ar atmosphere, 7-phenyl-1H-indoles 1 (0.3 mmol), alkenes 2 (0.75 mmol, 2.5 equiv.), [Cp*RhCl₂]₂ (4.7 mg, 0.0075 mmol, 2.5 mol%), AgOAc (100.1 mg, 0.6 mmol, 2 equiv.), Me₄NOAc (3 mmol, 400 mg), and CH₃CN (2 mL) were placed in a 50 mL sealed tube. The mixture was heated in an oil bath at 80 °C for 24 h and then cooled to room temperature. The mixture was diluted with CH₂Cl₂ to 5 mL, filtered through a Celite pad, and then washed with CH₂Cl₂. The volatiles were removed under reduced pressure, and the residue was subjected to silica gel column chromatography [eluting with petroleum ether/ethyl acetate] to afford the corresponding product (4a–4w).

Ethyl 2-(7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4a). 58 mg (100%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (dt, J = 7.7, 1.0 Hz, 1H), 7.58 (dd, J = 7.3, 0.8 Hz, 1H), 7.54 (dd, J = 7.9, 0.8 Hz, 1H), 7.42–7.37 (m, 1H), 7.33–7.28 (m, 2H), 7.25 (d, J = 3.1 Hz, 1H), 7.15 (dd, J = 7.9, 7.4 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 6.14 (dd, J = 7.3, 5.2 Hz, 1H), 4.10(q, J = 7.1 Hz, 2H), 2.82–2.71 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 133.6, 132.8, 129.9, 128.2, 127.83, 127.5, 126.7, 126.0, 122.8, 120.8, 120.6, 118.0, 113.7, 103.3, 60.9, 55.3, 46.4, 14.0. HRMS (ESI) calcd for C₁₉H₁₇NO₂ [M + H]⁺ 292.1332, found 292.1337.

Ethyl 2-(3-methyl-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4b). 57 mg (93%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.93 (d, J = 7.7 Hz, 1H), 7.50 (d, J = 7.4 Hz, 1H), 7.40–7.35 (m, 1H), 7.32–7.23 (m, 3H), 6.95 (d, J = 7.4 Hz, 1H), 6.57 (d, J = 3.1 Hz, 1H), 6.13 (dd, J = 7.4, 5.1 Hz, 1H), 4.18–4.06 (m, 2H), 2.82–2.71 (m, 2H), 2.57 (s, 3H), 1.18 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 133.1, 132.5, 130.9, 130.1, 128.1, 127.4, 126.6, 125.4, 122.5, 120.7, 115.8, 114.1, 104.9, 101.9, 60.9, 55.4, 46.3, 18.7, 14.0. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1307.

Ethyl 2-(10-methyl-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4c). 56 mg (92%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.77 (s, 1H), 7.57 (d, J = 7.3 Hz, 1H), 7.52 (d, J = 7.8 Hz, 1H), 7.23 (d, J = 3.2 Hz, 1H), 7.20 (d, J = 7.8 Hz, 1H), 7.16–7.09 (m, 2H), 6.54 (d, J = 3.2 Hz, 1H), 6.10 (dd, J = 7.1, 5.3 Hz, 1H), 4.16–4.04 (m, 2H), 2.80–2.69 (m, 2H), 2.43 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 137.8, 132.9, 130.8, 129.6, 128.7, 127.3, 126.6, 126.0, 123.3, 120.6, 120.5, 118.1, 113.6, 103.2, 60.9, 55.1, 46.5, 21.3, 14.0. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1307.

Ethyl 2-(9-methyl-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4d). 55 mg (90%); yellow solid. ¹H NMR (400 MHz, CDCl₃) δ 7.85 (d, J = 8.0 Hz, 1H), 7.54 (d, J = 7.3 Hz, 1H), 7.50 (dd, J = 8.0, 0.9 Hz, 1H), 7.23 (d, J = 3.1 Hz, 1H), 7.20 (dd, J = 8.0, 1.2 Hz, 1H), 7.15–7.11 (m, 2H), 6.53 (d, J = 3.1 Hz, 1H), 6.10–6.06 (m, 1H), 4.15–4.07 (m, 2H), 2.78–2.74 (m, 2H), 2.38 (s, 3H), 1.16 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 137.7, 133.5, 132.6, 129.0, 127.9, 127.0, 126.5, 125.9, 122.6, 120.5, 120.2, 118.1, 113.3, 103.2, 60.8, 55.3, 46.4, 21.2, 13.9. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1307.

Ethyl 2-(4-methyl-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4e). 53 mg (87%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (d, J = 7.8 Hz, 1H), 7.56 (d, J = 7.3 Hz, 1H), 7.47 (dd, J = 7.9, 0.7 Hz, 1H), 7.40–7.35 (m, 1H), 7.32–7.27 (m, 2H), 7.14 (dd, J = 7.9, 7.3 Hz, 1H), 7.01–6.95 (m, 1H), 6.05 (dd, J = 7.2, 5.3 Hz, 1H), 4.18–4.03 (m, 2H), 2.77–2.66 (m, 2H), 2.34 (s, 3H), 1.16 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.8, 133.8, 133.3, 130.0, 128.1, 127.7, 127.5, 127.2, 123.6, 122.7, 119.9, 119.0, 117.8, 113.7, 113.1, 60.8, 55.2, 46.1, 14.0, 10.0. HRMS (ESI) calcd for C₂₀H₁₉NO₂ [M + Na]⁺ 328.1308, found 328.1307.

Ethyl 2-(2-fluoro-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4i). 57 mg (93%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.87 (d, J = 7.8 Hz, 1H), 7.43–7.38 (m, 1H), 7.36–7.27 (m, 4H), 7.18 (dd, J = 9.7, 2.1 Hz, 1H), 6.50 (d, J = 3.1 Hz, 1H), 6.10 (d, J = 6.3 Hz, 1H), 4.14–4.05 (m, 2H), 2.78–2.73 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 157.2 (d, ¹J_C–F = 233.5 Hz), 134.0, 129.4, 129.1 (d, ³J_C–F = 2.0 Hz), 128.4 (d, ²J_C–F = 11.9 Hz), 127.4 (d, ²J_C–F = 9.0 Hz), 126.6, 126.5, 123.1, 118.7, 118.6, 105.7, 105.4, 103.3 (d, ³J_C–F = 5.0 Hz), 102.7, 102.4, 61.0, 55.3, 46.3, 14.0. ¹⁹F NMR (376 MHz, CDCl₃) δ −123.46 (t, J = 7.5 Hz). HRMS (ESI) calcd for C₁₉H₁₆FNO₂ [M + Na]⁺ 332.1057, found 332.1056.

Ethyl 2-(9-cyano-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4j). 59 mg (93%); yellow solid; mp 88–89 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 8.2 Hz, 1H), 7.65 (dd, J = 8.0, 1.7 Hz, 1H), 7.63–7.58 (m, 3H), 7.25 (d, J = 3.2 Hz, 1H), 7.18 (dd, J = 8.0, 7.4 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 6.11 (dd, J = 7.2, 5.1 Hz, 1H), 4.10 (qd, J = 7.1, 0.8 Hz, 2H), 2.82–2.69 (m, 2H), 1.16 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.9, 134.8, 134.3, 133.1, 131.8, 131.2, 127.0, 126.2, 123.3, 122.8, 120.9, 118.6, 116.1, 115.2, 110.9, 104.0, 61.2, 55.0, 46.0, 14.0. HRMS (ESI) calcd for C₂₀H₁₆N₂O₂ [M + H]⁺ 317.1285, found 317.1285.

Ethyl 2-(9-nitro-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4k). 62 mg (92%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 8.18 (dd, J = 8.6, 2.3 Hz, 1H), 8.12 (dt, J = 2.5, 0.5 Hz, 1H), 7.98 (d, J = 8.6 Hz, 1H), 7.62 (dd, J = 7.9, 0.8 Hz, 1H), 7.58 (dd, J = 7.5, 0.7 Hz, 1H), 7.25 (d, J = 3.2 Hz, 1H), 7.17 (dd, J = 7.9, 7.5 Hz, 1H), 6.59 (d, J = 3.2 Hz, 1H), 6.10 (dd, J = 7.2, 5.1 Hz, 1H), 4.15–4.03 (m, 2H), 2.84–2.72 (m, 2H), 1.15 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.8, 146.7, 136.6, 134.4, 133.2, 127.0, 126.3, 123.4, 123.2, 122.9, 120.9, 115.8, 115.6, 104.0, 61.2, 55.1, 46.0, 13.9. HRMS (ESI) calcd for C₁₉H₁₆N₂O₄ [M + H]⁺ 337.1183, found 337.1183.

Ethyl 2-(9-chloro-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4l). 59 mg (91%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.83 (d, J = 8.4 Hz, 1H), 7.55 (dd, J = 7.9, 0.8 Hz, 1H), 7.51 (d, J = 7.3 Hz, 1H), 7.33 (dd, J = 8.4, 2.2 Hz, 1H), 7.27 (d, J = 2.2 Hz, 1H), 7.22 (d, J = 3.1 Hz, 1H), 7.15 (dd, J = 7.9, 7.3 Hz, 1H), 6.57 (d, J = 3.2 Hz, 1H), 6.03 (dd, J = 7.2, 5.3 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 2.80–2.69 (m, 2H), 1.17 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.3, 135.1, 133.2, 132.6, 128.6, 128.3, 127.4, 126.7, 126.0, 124.0, 121.1, 120.7, 117.0, 113.8, 103.5, 61.0, 55.0, 46.1, 14.0. HRMS (ESI) calcd for C₁₉H₁₆ClNO₂ [M + Na]⁺ 348.0762, found 348.0761.

Methyl 7-(2-ethoxy-2-oxoethyl)-7H-pyrrolo[3,2,1-de]phenanthridine-9-carboxylate (4m). 47 mg (72%); yellow oil. ¹H NMR (400 MHz, DMSO) δ 8.18 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 1.7 Hz, 1H), 7.96 (dd, J = 8.2, 1.7 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H), 7.56–7.51 (m, 3H), 7.10 (t, J = 7.6 Hz, 1H), 6.56 (d, J = 3.1 Hz, 1H), 6.23 (t, J = 5.5 Hz, 1H), 3.88 (s, 3H), 3.83–3.74 (m, 2H), 3.00–2.87 (m, 2H), 0.86 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, DMSO) δ 170.3, 166.7, 135.2, 134.6, 133.8, 129.8, 129.5, 127.8, 127.1, 123.8, 122.7, 121.3, 117.5, 115.7, 103.8, 61.0, 55.3, 53.1, 46.1, 14.4. HRMS (ESI) calcd for C₂₁H₁₉NO₄ [M + Na]⁺ 372.1206, found 372.1206.

Ethyl 2-(9-methoxy-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4n). 61 mg (95%); yellow oil. ¹H NMR (400 MHz, DMSO) δ 7.96 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 7.3 Hz, 1H), 7.42 (dd, J = 3.1, 1.3 Hz, 1H), 7.39 (dt, J = 8.1, 1.0 Hz, 1H), 7.07–6.96 (m, 3H), 6.50 (dd, J = 3.2, 1.5 Hz, 1H), 6.12–6.05 (m, 1H), 3.90–3.81 (m, 5H), 2.97 (ddd, J = 15.6, 4.8, 1.3 Hz, 1H), 2.83 (ddd, J = 15.6, 6.6, 1.3 Hz, 1H), 0.92 (td, J = 7.0, 1.3 Hz, 3H). ¹³C NMR (100 MHz, DMSO) δ 170.6, 160.0, 135.9, 132.9, 127.3, 126.7, 124.9, 123.0, 121.3, 120.2, 118.7, 115.0, 113.9, 113.6, 103.6, 61.0, 56.2, 55.5, 46.2, 14.6. HRMS (ESI) calcd for C₂₀H₁₉NO₃ [M + Na]⁺ 344.1257, found 344.1256.

1-(3-Chloro-7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)butan-2-one (4o). 61 mg (93%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.91 (d, J = 7.8 Hz, 1H), 7.48 (d, J = 7.8 Hz, 1H), 7.41–7.37 (m, 1H), 7.33–7.29 (m, 2H), 7.28 (d, J = 3.2 Hz, 1H), 7.12 (d, J = 7.8 Hz, 1H), 6.62 (d, J = 3.2 Hz, 1H), 6.12 (t, J = 6.2 Hz, 1H), 4.14–4.06 (m, 2H), 2.76 (d, J = 6.3 Hz, 2H), 1.16 (t, J = 7.2 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.5, 133.2, 129.2, 128.5, 128.4, 128.1, 127.5, 126.6, 125.8, 125.4, 122.8, 120.4, 116.9, 114.7, 102.0, 61.0, 55.5, 46.3, 14.0. HRMS (ESI) calcd for C₁₉H₁₆ClNO₂ [M + H]⁺ 326.0942, found 326.0936.

Ethyl 2-(7H-benzo[j]pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4p). 62 mg (91%); yellow solid; mp 116–117 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.41 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.83–7.76 (m, 3H), 7.58 (d, J = 7.7 Hz, 1H), 7.52–7.44 (m, 2H), 7.31–7.19 (m, 2H), 6.59 (s, 1H), 6.27 (t, J = 6.1 Hz, 1H), 4.14–4.04 (m, 2H), 2.81 (d, J = 5.5 Hz, 2H), 1.13 (t, J = 7.1 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.6, 133.2, 133.1, 132.8, 132.5, 128.0, 127.7, 127.6, 127.1, 126.6, 126.4, 126.2, 121.4, 120.8, 120.7, 118.0, 114.1, 103.4, 60.9, 55.4, 46.6, 14.0. HRMS (ESI) calcd for C₂₃H₁₉NO₂ [M + Na]⁺ 364.1308, found 364.1310.

2-Methoxyethyl 2-(7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4q). 58 mg (90%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.99 (d, J = 7.7 Hz, 1H), 7.61 (d, J = 7.3 Hz, 1H), 7.57 (dd, J = 7.9, 0.7 Hz, 1H), 7.44–7.39 (m, 1H), 7.35–7.32 (m, 2H), 7.30 (d, J = 3.1 Hz, 1H), 7.18 (dd, J = 7.9, 7.3 Hz, 1H), 6.58 (d, J = 3.1 Hz, 1H), 6.17 (dd, J = 7.2, 5.2 Hz, 1H), 4.26–4.22 (m, 2H), 3.54–3.50 (m, 2H), 3.36 (s, 3H), 2.90–2.79 (m, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 170.6, 133.4, 132.8, 129.9, 128.2, 127.8, 127.4, 126.7, 126.1, 122.7, 120.7, 120.6, 117.9, 113.7, 103.3, 70.1, 63.9, 58.9, 55.2, 46.2. HRMS (ESI) calcd for C₂₀H₁₉NO₃ [M + Na]⁺ 344.1257, found 344.1257.

tert-Butyl 2-(7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4r). 56 mg (88%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (dd, J = 7.4, 1.0 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.54 (dd, J = 7.9, 1.0 Hz, 1H), 7.41–7.36 (m, 1H), 7.33–7.28 (m, 3H), 7.15 (dd, J = 7.9, 7.3 Hz, 1H), 6.56 (d, J = 3.2 Hz, 1H), 6.11 (dd, J = 6.7, 5.4 Hz, 1H), 2.75–2.71 (m, 2H), 1.34 (s, 9H). ¹³C NMR (100 MHz, CDCl₃) δ 169.9, 133.7, 132.8, 129.9, 128.1, 127.8, 127.5, 126.6, 126.1, 122.6, 120.6, 120.5, 118.0, 113.6, 103.0, 81.2, 55.3, 47.5, 27.8. HRMS (ESI) calcd for C₂₁H₂₁NO₂ [M + Na]⁺ 342.1465, found 342.1465.

Butyl 2-(7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4s). 57 mg (89%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.97 (d, J = 7.8 Hz, 1H), 7.59 (d, J = 7.3 Hz, 1H), 7.56 (dd, J = 7.8, 0.8 Hz, 1H), 7.42–7.36 (m, 1H), 7.33–7.25 (m, 3H), 7.20–7.15 (m, 1H), 6.57 (d, J = 3.1 Hz, 1H), 6.14 (dd, J = 7.3, 5.1 Hz, 1H), 4.12–4.01 (m, 2H), 2.84–2.73 (m, 2H), 1.55–1.47 (m, 2H), 1.33–1.23 (m, 2H), 0.90 (t, J = 7.4 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 170.8, 133.5, 132.7, 129.8, 128.1, 127.8, 127.4, 126.6, 126.0, 122.7, 120.7, 120.6, 117.9, 113.7, 103.3, 64.8, 55.3, 46.3, 30.4, 19.0, 13.6. HRMS (ESI) calcd for C₂₁H₂₁NO₂ [M + H]⁺ 320.1645, found 320.1645.

2-(Dimethylamino)ethyl 2-(7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetate (4t). 60 mg (90%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.96 (d, J = 7.7 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.54 (dd, J = 7.9, 0.7 Hz, 1H), 7.41–7.36 (m, 1H), 7.33–7.27 (m, 3H), 7.15 (dd, J = 7.9, 7.3 Hz, 1H), 6.55 (d, J = 3.1 Hz, 1H), 6.13 (dd, J = 7.2, 5.3 Hz, 1H), 4.14 (t, J = 5.8 Hz, 2H), 2.86–2.75 (m, 2H), 2.47–2.42 (m, 2H), 2.22 (s, 6H). ¹³C NMR (100 MHz, CDCl₃) δ 170.7, 133.5, 132.8, 129.9, 128.2, 127.8, 127.4, 126.7, 126.1, 122.7, 120.7, 120.6, 117.9, 113.7, 103.3, 62.6, 57.4, 55.3, 46.2, 45.6. HRMS (ESI) calcd for C₂₁H₂₂N₂O₂ [M + H]⁺ 335.1754, found 335.1754.

1-(7H-Pyrrolo[3,2,1-de]phenanthridin-7-yl)butan-2-one (4u). 40 mg (72%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.95 (dd, J = 8.0, 1.1 Hz, 1H), 7.58 (d, J = 7.3 Hz, 1H), 7.53 (dd, J = 7.9, 0.8 Hz, 1H), 7.41–7.35 (m, 1H), 7.31–7.23 (m, 2H), 7.21–7.09 (m, 2H), 6.51 (d, J = 3.1 Hz, 1H), 6.23 (dd, J = 8.2, 4.0 Hz, 1H), 2.96 (dd, J = 17.0, 8.2 Hz, 1H), 2.75 (dd, J = 17.0, 4.0 Hz, 1H), 2.29–2.11 (m, 2H), 0.98 (t, J = 7.3 Hz, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 208.9, 134.3, 132.7, 129.8, 128.0, 127.9, 127.4, 126.7, 126.5, 122.7, 120.7, 120.6, 118.1, 113.7, 103.1, 53.8, 37.2, 7.50. HRMS (ESI) calcd for C₁₉H₁₇NO [M + Na]⁺ 298.1202, found 298.1205.

N,N-Dimethyl-2-(7H-pyrrolo[3,2,1-de]phenanthridin-7-yl)acetamide (4v). 51 mg (87%); yellow oil. ¹H NMR (400 MHz, CDCl₃) δ 7.98 (dd, J = 7.7, 1.0 Hz, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.56 (dd, J = 7.9, 0.7 Hz, 1H), 7.43–7.36 (m, 2H), 7.35–7.29 (m, 2H), 7.17 (dd, 1H), 6.55 (d, J = 3.1 Hz, 1H), 6.27 (dd, J = 8.4, 4.4 Hz, 1H), 2.97 (s, 3H), 2.85 (dd, J = 15.1, 8.5 Hz, 1H), 2.65 (dd, J = 15.1, 4.4 Hz, 1H), 2.49 (s, 3H). ¹³C NMR (100 MHz, CDCl₃) δ 169.6, 134.4, 132.6, 129.8, 128.0, 127.8, 127.7, 126.8, 126.7, 122.6, 120.7, 120.5, 118.1, 113.5, 102.7, 55.8, 44.8, 37.1, 35.6. HRMS (ESI) calcd for C₁₉H₁₈N₂O [M + Na]⁺ 313.1311, found 313.1311.

2-(7H-Pyrrolo[3,2,1-de]phenanthridin-7-yl)acetonitrile (4w). 42 mg (86%); white solid; mp 185–186 °C. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (d, J = 7.8 Hz, 1H), 7.60 (dd, J = 15.7, 7.6 Hz, 2H), 7.48–7.43 (m, 1H), 7.37 (t, J = 2.9 Hz, 3H), 7.20 (t, J = 7.6 Hz, 1H), 6.66 (d, J = 3.1 Hz, 1H), 5.89 (t, J = 6.1 Hz, 1H), 2.74 (d, J = 5.7 Hz, 2H). ¹³C NMR (100 MHz, CDCl₃) δ 132.5, 131.0, 129.8, 129.1, 128.1, 127.7, 126.9, 125.5, 123.1, 121.3, 121.2, 117.4, 116.7, 114.4, 104.6, 55.2, 29.2. HRMS (ESI) calcd for C₁₇H₁₂N₂ [M + Na]⁺ 267.0893, found 267.0894.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank Yunbin Li and Prof. Shengchang Xiang (Fujian Normal University) for obtaining X-ray crystal diffraction data. Financial support from the NSFC (Grant No. 21872028), the Natural Science Foundation of Fujian Province (Grant No. 2017J01572), the Foundation of Fujian Educational Committee (Grant No. JZ160424), and the Fujian Province University Fund for New Century Excellent Talents is greatly acknowledged.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available: Experimental, copies of NMR spectra. CCDC 1943455 and 1943456. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c9qo01135h

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