4-Dimethylaminopyridine (DMAP), A Superior Mediator for Morita–Balylis–Hillman Reaction-Triggered Annulative Condensation of Salicylaldehydes and Acrylonitrile to Form 3-Cyano-2H-chromenes

Abstract

We unveiled superior base mediators for the annulative condensation of salicylaldehydes and acrylonitrile to give 3-cyano-2H-chromenes, which has been mediated only by 1,4-diazabicyclo[2.2.2]octane (DABCO) over the past two decades. The reactions were most efficiently mediated by 4-dimethylaminopyridine (DMAP), which yielded 3-cyano-2H-chromenes in higher yields than DABCO in most cases. We also confirmed that the reaction remained high yielding in a decagram-scale experiment with a catalytic amount of DMAP. The utility of this reaction was also exemplified by derivatization of an obtained 3-cyano-2H-chromene into a known 2H-chromene-3-carboxylic acid, which was previously synthesized with a non-readily available reagent.

Introduction

2H-Chromenes are skeletons found in a large number of natural products^1–17) and unnatural biologically active compounds.^1–26) They are highly versatile as synthetic intermediates in the preparation of various biologically active compounds and can be obtained by modifying the chromenes’ functional groups, including carbon–carbon double bonds, and other functional groups^27–39) (Chart 1A). For example, 3-cyano-2H-chromenes work as useful building blocks of biologically active molecules with a wide range of skeletons/functional groups by converting their cyano groups,^{18–26,37–39)} carbon–carbon double bonds,^19,37) and chromene rings.^37,39) By transforming these functional groups of 3-cyano-2H-chromenes, we can access various molecules, with a wide variety of structures/functional groups.^{18–23,37,38)} These molecules possess a large number of attractive biological activities/functions, such as anti-cancer,^18,38,39) anti-angeogenesis,¹⁸⁾ anti-oxidant,²³⁾ anti-malarial,²⁴⁾ and aldose reductase 2 inhibitory activities,²⁶⁾ and function as serotonin 1A receptor agonist³⁷⁾ and farnesoid X receptor antagonist.²⁵⁾

Chart 1. (A) 3-Cyano-2H-chromenes as Useful Building Blocks for Biologically Active Compounds; (B) MBH Reaction-Triggered Annulative Condensation of Salicylaldehydes 1 and Acrylonitrile 2: Conventional Synthetic Approach for 3-Cyano-2H-chromenes 3

Given the usefulness of 3-cyano-2H-chromenes, their syntheses have been reported. Their preparation is achieved mostly by the annulative condensation reactions of 2-hydroxybenzaldehydes 1, so-called salicylaldehydes, and acrylonitrile 2^{20,21,23–26,40–45)} (Chart 1B). The reactions involve a base (or a base catalyst) which is believed to induce Morita–Balylis–Hillman (MBH) reactions via the formation of ammonium nitrile anion species.^18,20,23,40) The following intramolecular oxa-Michael addition of the generated MBH adduct and dehydration provide 3-cyano-2H-chromenes 3. Thus far, more than two hundred reports have mentioned this reaction, which is enabled by 1,4-diazabicyclo[2.2.2]octane (DABCO) as a base (or a base catalyst).^{20,21,23–26,40–43)} Many of these reported examples resulted in low or moderate yields,⁴²⁾ presumably because this type of MBH reaction-involved systems suffer from low reaction rates/yields in general.⁴⁶⁾ Despite this issue/problem, reaction conditions with any bases⁴³⁾ other than DABCO, which may improve the reaction performance, have not previously been reported to our knowledge.

Herein, we report the discovery of an alternative reaction condition for the annulative condensation of salicylaldehydes and acrylonitrile to give 3-cyano-2H-chromenes without using DABCO. For the first time, the reaction was efficiently mediated by 4-dimethylaminopyridine (DMAP), which showed superior yields to DABCO in most cases.

Results and Discussion

We began the present study by optimizing the reaction conditions for the annulative condensation of 6-methoxysalicylaldehyde 1a and acrylonitrile 2 to form 3-cyano-5-methoxy-2H-chromene 3a (Table 1; Table S1 in Supplementary Materials). At the beginning of this optimization study, we performed reactions with a large excess amount (5.0 equivalent (equiv.)) of 2, a catalytic amount (0.10 equiv.) of bases, and no solvent at an elevated temperature (70 °C) for 18 h. When performing the reaction with the conventionally used DABCO, 3a was obtained in 51% yield (Table 1, entry 1). Other 2-azabicyclo[2.2.2]octane-type bases, namely, quinuclidine and 3-quinuclidinol, which catalyze MBH reactions, were used to give 3a in improved yields (69 and 60% yields, respectively) (entries 2 and 3). Another quinuclidine-based catalyst, quinine, did not provide any 3a presumably because of its steric hindrance (entry 4). We also investigated 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), which were reported by Aggarwal and Mereu as superior amine catalysts in MBH reaction (entries 5 and 6, respectively).⁴⁶⁾ However they gave only 6% (in both cases) of product 3a with the starting salicylaldehyde 1a significantly recovered (69 or 51%) in the present system. This low reaction rate was rationalized by the high Brønsted basicity of these amidine-type bases. Here, we speculated that DBU and DBN easily deprotonated the acidic phenolic hydroxy group of 1a, which resulted in the low concentration of the ammonium nitrile anion species required for MBH reaction. In accordance with this speculation, the reactions resulted in low yields of 3a when using other bases with higher Brønsted basicity, such as 1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD) and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene (MTBD) (entries 7 and 8, respectively). We also investigated another K₂CO₃, which did not induce MBH reaction. K₂CO₃ mediates a similar annulative condensation of salicylaldehydes and other electron-deficient alkenes instead of acrylonitrile, which is presumably initiated by intermolecular oxa-Michael addition.^47–49) However K₂CO₃ (2.0 equiv.) did not give 1a in the present system. This finding implies that the annulative condensation reaction of acrylonitrile should be triggered by the mentioned MBH reaction pathway.⁴⁰⁾ Finally, we surveyed pyridine-based MBH catalysts, namely, DMAP and 4-pyrrolidinopyridine (PPY), to form 3a in 57 and 48% yields, respectively (entries 9 and 10), which are better or comparable with the yield of the above DABCO-using reaction (entry 1). The above investigation revealed that quinuclidine, 3-quinuclidinol, DMAP, and PPY are also promising base mediators for annulative condensation (entries 1–3, 9, and 10). Next, we ran the reactions with a larger equivalent (2.0 equiv.) of these bases and DABCO to improve the yields. In all cases, yields were improved to 54–81%, and all these bases turned out to be superior mediators to DABCO in terms of the desired annulative condensation (entries 11–15). Especially, DMAP had the best yield (81%, entry 14), which was also better than that of conventionally used DABCO (54%, entry 11), among the bases investigated in this work. This higher yield may be attributed to its higher Lewis basicity.⁵⁰⁾ Baidya and Mayr previously reported that the Lewis basicity of DMAP is significantly higher than that of DABCO. This property will result in the higher concentration of the DMAP-derived ammonium nitrile anion species for MBH reaction.^51,52) With the superior base mediator identified as DMAP, we decreased its equivalent to 1.5 and 1.0 equiv. to give 3a in decreased yields of 77 and 72%, respectively (entries 16 and 17). We then screened other reaction temperatures, equivalents of acrylonitrile, and solvents that result in decreased yields of 3a (Table S1 in Supplementary Materials). Based on the above investigations, we have identified the reaction condition in entry 14 as the optimal one.

Table 1. Optimization of Reaction Conditions for the Annulative Condensation of 6-Methoxysalicylaldehyde 1a and Acrylonitrile 2 to Form 3-Cyano-5-methoxy-2H-chromene 3a^a

Entry	Base	Eq.	Recovered 1a/%b	3a/%b
1	DABCO	0.10	0	51
2	Quinuclidine	0.10	0	69
3	3-Quinuclidinol	0.10	0	60
4	Quinine	0.10	78	0
5	DBU	0.10	69	6
6	DBN	0.10	51	6
7	TBD	0.10	69	6
8	MTBD	0.10	60	9
9	DMAP	0.10	3	57
10	PPY	0.10	0	48
11	DABCO	2.0	0	54
12	Quinuclidine	2.0	0	70
13	3-Quinuclidinol	2.0	0	75
14	DMAP	2.0	0	81 (80)c
15	PPY	2.0	0	78
16	DMAP	1.5	0	77
17	DMAP	1.0	0	72

a Reactions were performed with 6-methoxysalicylaldehyde 1a (1.00 mmol, 1.0 equiv.), 2 (5.00 mmol, 5.0 equiv.), and base (0.100–2.00 mmol, 0.10–2.0 equiv.) at 70 °C (hot plate temperature) for 18 h in capped 4.0 mL screw cap vials. b Yields were determined by crude ¹H NMR using triphenylmethane as an internal standard. c The isolated yield of 2a is shown in parentheses.

With this optimal condition in hand, we next focused on expanding the substrate scope of salicylaldehydes (Table 2). When performing reactions with 6-methylsalicylaldehyde 1b as another 6-substituted salicylaldehyde substrate, the reaction gave 3-cyano-5-methyl-2H-chromene 3b in 29% yield. This decreased yield of 3b from that of 3a might have been caused by the increased steric hindrance around the substrate formyl group by the 6-methyl group. Non-substituted salicylaldehyde 1c gave the corresponding 3-cyano-2H-chromene 3c in 84% yield. The use of DABCO instead of DMAP resulted in decreased yields of 3b and 3c (26 and 56%, respectively). Next, we used a variety of 5-substituted salicylaldehyde substrates 1d–1i with electron-withdrawing and electron-donating substituents, such as chloro (1d), bromo (1e), methoxycarbonyl (1f), methyl (1g), methoxy (1h), and fluoro (1i) groups. The corresponding 6-substituted 3-cyano-2H-chromenes 3d–3i formed in moderate to high yields (3d, 80%; 3e, 80%; 3f, 57%; 3g, 88%; 3h, 80%; 3i, 79%, respectively). In all cases, the use of DABCO instead of DMAP caused the significantly diminished yields of 6-substituted 3-cyano-2H-chromenes 3d–3i (3d, 59%; 3e, 62%; 3f, 6%; 3g, 78%; 3h, 73%; 3i, 58%, respectively). For 7-substituted 3-cyano-2H-chromenes 3j–3n, 4-substituted salicylaldehydes 1j–1n were also investigated. With electron-donating 4-methyl- and 4-methoxy-bearing and electron-withdrawing 4-chloro-bearing substrates 1j–1l, 7-substituted 3-cyano-2H-chromenes 3j–3l were successfully formed in 70, 61, and 85%, respectively. However, 4-substituted salicylaldehydes 1m and 1n with highly electron-donating dimethylamino and free hydroxy groups at the para-position of formyl groups provided 3-cyano-2H-chromenes 3m (20%) and 3n (14%) in lower yields,^53,54) respectively. Similar to the above examples, DABCO gave lower yields of 1j–1l (3j, 59%; 3k, 31%; 3l, 39%, respectively). In the cases of 3m and 3n, DABCO showed a similar and an improved yield compared with those of DMAP (23% 3m and 37% 3n, respectively). When utilizing various 3-subsituted salicylaldehyde substrates 1o–1t, all the reactions gave 8-substituted 3-cyano-2H-chromenes 3o–3t in similar high yields without being affected by the electronically and sterically different substituents (84–89% yields). DABCO was lower yielding in all these cases (3o, 57%; 3p, 41%; 3q, 72%; 3r, 71%; 3s, 59%; 3t, 61%). Finally, we investigated disubstituted substrates 1u–1z with electronically and sterically diverse substituents at 3,4-, 3,5-, 3,6-, and 4,6-positions. The reactions successfully provided the corresponding 3-cyano-2H-chromenes 3u–3z in moderate to high yields (3u, 59%; 3v, 40%; 3w, 65%; 3x, 53%; 3y, 90%; 3z, 63%, respectively). DABCO gave 3-cyano-2H-chromenes (3u and 3w–3z) in significantly lower yields (3u 35%, 3v 39%, 3w 48%, 3x 41%, 3y 55%, 3z 57%, respectively), except for the case of 3v (39%). Based on the above observations, our newly found DMAP-using condition showed a broad substrate scope with higher yields than the conventional DABCO-using condition in many cases. In addition, the new condition⁵⁵⁾ occasionally provided lower yields than the conventional one, which indicates that the two conditions are complementary to each other.

Table 2. Annulative Condensation of Salicylaldehyde 1a–1z and Acrylonitrile 2 Mediated by DMAP and DABCO to Form 3-Cyano-2H-chromene 3a–3z^a

a Reactions were performed with salicylaldehyde 1a–1z (1.00 mmol, 1.0 equiv.), 2 (5.00 mmol, 5.0 equiv.), and DMAP or DABCO (2.00 mmol, 2.0 equiv.) at 70 °C (hot plate temperature) for 18 h in capped 4.0 mL screw cap vials. Yields of 3a–3z were determined by crude ¹H-NMR with triphenylmethane as internal standard. Isolated yields of 3a–3z are shown in parentheses. b Results from Table 1.

We next performed gram- and decagram-scale experiments (Chart 2). When 1.52 g (10.0 mmol) 1a and 1k were used as substrates, the reactions smoothly proceeded to give the corresponding 3-cyano-2H-chromenes in 80 and 58% yields, respectively. The decagram-scale experiment of 1c (10.0 g) was conducted in a slightly modified condition with a catalytic amount of DMAP (0.20 equiv.) at 90 °C to give 3c in a nearly quantitative yield (94%, 12.7 g). Moreover, in this decagram and catalytic system, we confirmed that DABCO resulted in a lower yield (78%).⁵⁶⁾

Chart 2. (A) Gram- and (B) Decagram-Scale Experiments

To exemplify the utility of our method, we focused on the derivatization of 7-chloro-3-cyano-2H-chromene 3l into known 7-chloro-2H-chromene-3-carboxylic acid 4^57,58) (Chart 3). The derivatives of this carboxylic acid are potent drug candidates that function as selective antagonists of CC chemokine receptor 2,⁵⁹⁾ an anticoagulant, and a factor Xa inhibitor.^57,58) We successfully hydrolyzed the cyano group of 3l under basic condition to give 4 in 45% yield (38% overall yield in two steps from 1l) (Chart 3, top). The reported synthetic method^57,58) of 4 was developed by Yoshikawa et al. using the same starting material 1l (Chart 3, bottom). They condensed salicylaldehyde 1l and ethyl 2-diethylphosphonoacrylate 2′ through oxa-Michael addition/intramolecular Horner–Wadsworth–Emmons (HWE) olefination to give 3l′ in 32% yield. The following hydrolysis of 3l′ under a basic condition was performed quantitatively to give 4 in a similar overall yield (32% in two steps from 1l). Although this Yoshikawa’s protocol did not require any elevated temperatures, the key HWE reagent 2 is not inexpensive at the present time⁶⁰⁾ or requires its preparation.^61,62) Thus, we believe that our annulative condensation condition, which utilizes readily available inexpensive reagents, will be more useful for the preparation of 4 and its related carboxylic acid derivatives.

Chart 3. New and Previous Synthetic Methods of Carboxylic Acid 4 from 3-Cyano-2H-chromene 3l

Conclusion

In summary, we discovered superior mediators for the annulative condensation of salicylaldehydes and acrylonitrile to give 3-cyano-2H-chromenes, which were previously mediated only by DABCO. Among the investigated bases, the reactions to yield 3-cyano-2H-chromenes were most efficiently mediated by DMAP, which presented higher yields in most cases than DABCO. In addition, our newly found DMAP-using condition occasionally showed lower yields than the conventional DABCO-using one. This finding indicates that the two conditions are complementary to each other. We also confirmed that the reaction remained high yielding in a decagram-scale experiment with a catalytic amount of DMAP. The obtained 7-chloro-3-cyano-2H-chromene 3l was easily hydrolyzed into known 7-chloro-2H-chromene-3-carboxylic acid 4, which was previously synthesized from a non-readily available reagent. We believe that our annulative condensation condition will spur further medicinal chemistry research and the development of novel synthetic reactions involved in the MBH reaction. Efforts dedicated to the derivatization of 3-cyano-2H-chromenes and the development of other MBH reaction-involving methods are currently underway.

Experimental

General Experimental Details

For reactions that required heating, a hot plate and an oil bath were used as the heat source. Column chromatography was performed on Kanto Kagaku Silica Gel 60 N (spherical, neutral), 100–210 µm. Reactions and chromatography fractions were analyzed by TLC on a Wako Silica gel 70 F254 TLC Plate-Wako, with visualization by UV irradiation at 254 nm, and/or 2,4-dinitrophenylhydrazine staining. ¹H-NMR spectra were recorded on a 400 MHz (101 MHz for ¹³C-NMR) JEOL JNM-ECZ-400S instrument. Chemical shifts and coupling constants are presented in ppm δ (relative to tetramethylsilane (0.00 ppm)), and Hz, respectively. Chloroform-d₁ (δ 77.00 ppm) was used as the internal standards for ¹³C-NMR spectroscopy. High-resolution MS (HR-MS) and low-resolution MS (LR-MS) data were obtained by a JEOL JMS-T100LP instrument for electrospray ionization (ESI) with a JEOL MS-5414DART attachment. HR-MS data were obtained after calibration with polyethylene glycol 400. Fourier transform (FT)-IR spectra were recorded with a ThermoFisher Nicolet iS5 instrument with an iD5 attenuated total reflection (ATR) attachment and are reported in terms of frequency absorption (cm⁻¹). All reagents were purchased from chemical companies and were used as received.

General Procedure of the Annulative Condensation of 6-Methoxysalicylaldehyde 1a and Acrylonitrile 2 to Form 3-Cyano-2H-chromene 3a

Caution: Acrylonitrile is highly flammable and toxic at low doses, so reaction should be carried out in fume food behind safety shield in case! To a solution of 6-methoxysalicylaldehyde 1a (1.00 mmol) in acrylonitrile (0.0656–1.64 mL, 1.00–10.0 mmol) in a 4.0 mL screw cap vial, was added base (0.100–2.00 mmol). After filling the vial with nitrogen gas, capping the vial, and stirring the mixture for 18 h at 70 °C (hot plate temperature), the mixture was quenched with 1 N HCl aq. (3.0 mL), extracted with EtOAc (1.0 mL × 3), washed with water (3.0 mL) and brine (3.0 mL), dried over Na₂SO₄, and concentrated under reduced pressure. Yields of 3a were determined by crude ¹H-NMR with triphenylmethane as internal standard.

General Procedure of the Annulative Condensation of Salicylaldehyde 1a–1z and Acrylonitrile 2 to Form 3-Cyano-2H-chromene 3a–3z

Caution: Acrylonitrile is highly flammable and toxic at low doses, so reaction should be carried out in fume food behind safety shield in case! To a solution of salicylaldehyde 1a–1z (1.00 mmol) in acrylonitrile (328 µL, 5.00 mmol) in a 4.0 mL screw cap vial, was added DMAP (244 mg, 2.00 mmol) or DABCO (224 mg, 2.00 mmol). After filling the vial with nitrogen gas, capping the vial, and stirring the mixture for 18 h at 70 °C (hot plate temperature), the mixture was quenched with 1 N HCl aq. (3.0 mL), extracted with EtOAc (1.0 mL × 3), washed with water (3.0 mL) and brine (3.0 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by silica gel column chromatography (hexane–EtOAc or dichloromethane–EtOAc) to obtain 3-cyano-2H-chromene 3a–3z. Yields of 3a–3z were determined by crude ¹H-NMR with triphenylmethane as internal standard. Isolated yields of 3a–3z are shown in parentheses.

Characterization of Compounds

The analytical data for the known and new compounds are as follows. The NMR data for the known compounds 3a,²⁵⁾ 3b,⁶³⁾ 3c,⁶⁴⁾ 3d,²²⁾ 3e,³⁸⁾ 3g,⁶³⁾ 3h,²⁵⁾ 3i,⁶³⁾ 3j,⁶³⁾ 3k,²⁵⁾ 3q,⁶³⁾ 3s,²⁰⁾ 3t,⁶⁵⁾ 3u,⁶⁶⁾ 3w,²⁰⁾ 3x,²⁰⁾ and 4^57,58) were in good agreement with the literature values (see Supplementary Materials for the spectra).

3-Cyano-5-methoxy-2H-chromene (3a)²⁵⁾

The “General procedure” with 6-methoxysalicylaldehyde 1a (152 mg), and silica gel column chromatography using hexane–EtOAc (4 : 1) gave the title compound (150 mg, 80%) as a pale yellow solid; ¹H-NMR (CDCl₃) δ: 7.54 (1H, br s), 7.22 (1H, t, J = 8.4 Hz), 6.50 (1H, d, J = 8.4 Hz), 6.48 (1H, d, J = 8.4 Hz), 4.75 (2H, d, J = 1.2 Hz), 3.85 (3H, s).

3-Cyano-5-methyl-2H-chromene (3b)⁶³⁾

The “General procedure” with 6-methylsalicylaldehyde 1b (136 mg), and silica gel column chromatography using hexane–EtOAc (10 : 1) gave the title compound (50.1 mg, 29%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.39 (1H, br s), 7.16 (1H, t, J = 7.9 Hz), 6.81 (1H, d, J = 7.9 Hz), 6.73 (1H, d, J = 7.9 Hz), 4.75 (2H, d, J = 1.3 Hz), 2.34 (3H, s).

3-Cyano-2H-chromene (3c)

The “General procedure” with salicylaldehyde 1c (122 mg), and silica gel column chromatography using hexane–EtOAc (15 : 1) gave the title compound (130 mg, 84%) as a pale yellow solid; ¹H-NMR (CDCl₃) δ: 7.30–7.26 (1H, m), 7.18 (1H, s), 7.11 (1H, dd, J = 7.6, 1.6 Hz), 6.97 (1H, td, J = 7.5, 1.0 Hz), 6.87 (1H, d, J = 8.2 Hz), 4.82 (2H, d, J = 1.3 Hz).

6-Chloro-3-cyano-2H-chromene (3d)²²⁾

The “General procedure” with 5-chlorosalicylaldehyde 1d (156 mg), and silica gel column chromatography using hexane–EtOAc (12 : 1) gave the title compound (149 mg, 78%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.22 (1H, dd, J = 8.7, 2.6 Hz), 7.11 (1H, br s), 7.09 (1H, d, J = 2.6 Hz), 6.82 (1H, d, J = 8.7 Hz), 4.83 (2H, d, J = 1.4 Hz).

6-Bromo-3-cyano-2H-chromene (3e)³⁸⁾

The “General procedure” with 5-bromosalicylaldehyde 1e (201 mg), and silica gel column chromatography using hexane–EtOAc (10 : 1) gave the title compound (182 mg, 77%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.36 (1H, dd, J = 8.7, 2.3 Hz), 7.24 (1H, d, J = 2.4 Hz), 7.10 (1H, s), 6.77 (1H, d, J = 8.6 Hz), 4.83 (2H, d, J = 1.4 Hz).

3-Cyano-6-methoxycarbonyl-2H-chromene (3f)

The “General procedure” with 5-methoxycarbonylsalicylaldehyde 1f (180 mg), and silica gel column chromatography using hexane–EtOAc (6 : 1) gave the title compound (123 mg, 57%) as a pale pink solid; mp 125.5–127.0 °C; ¹H-NMR (CDCl₃) δ: 7.96 (1H, dd, J = 8.5, 2.1 Hz), 7.81 (1H, d, J = 2.1 Hz), 7.20 (1H, br s), 6.90 (1H, d, J = 8.5 Hz), 4.92 (2H, d, J = 1.4 Hz), 3.90 (3H, s); ¹³C-NMR (CDCl₃) δ: 165.8, 157.7, 138.0, 134.2, 130.1, 124.4, 119.3, 116.6, 115.9, 104.1, 64.7, 52.2; IR (ATR) cm⁻¹: 3064, 2954, 2920, 2850, 2217, 1723, 1708, 1633, 1435, 1292, 1202; HR-MS (ESI) m/z: 238.0481 (Calcd for C₁₂H₉NNaO₃⁺: 238.0475).

3-Cyano-6-methyl-2H-chromene (3g)⁶³⁾

The “General procedure” with 5-methylsalicylaldehyde 1g (136 mg), and silica gel column chromatography using hexane–EtOAc (8 : 1) gave the title compound (124 mg, 72%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.13 (1H, br s), 7.07 (1H, dd, J = 8.2, 2.0 Hz), 6.90 (1H, d, J = 2.0 Hz), 6.77 (1H, d, J = 8.2 Hz), 4.78 (2H, d, J = 1.3 Hz), 2.27 (3H, s).

3-Cyano-6-methoxy-2H-chromene (3h)²⁵⁾

The “General procedure” with 5-methoxysalicylaldehyde 1h (152 mg), and silica gel column chromatography using hexane–EtOAc (10 : 1) gave the title compound (136 mg, 73%) as a yellow solid; ¹H-NMR (CDCl₃) δ: 7.16 (1H, br s), 6.85 (dd, J = 8.9, 2.5 Hz), 6.82 (d, J = 8.9 Hz), 6.64 (d, J = 2.5 Hz, 1H), 4.76 (d, J = 1.3 Hz, 2H), 3.78 (s, 3H).

3-Cyano-6-fluoro-2H-chromene (3i)⁶³⁾

The “General procedure” with 5-methoxycarbonylsalicylaldehyde 1i (140 mg), and silica gel column chromatography using hexane–EtOAc (8 : 1) gave the title compound (138 mg, 79%) as a white solid; ¹H-NMR ((CD₃)₂SO) δ: 7.56 (1H, br s), 7.21–7.15 (2H, m), 6.98–6.91 (1H, m), 4.89 (1H, d, J = 1.4 Hz).

3-Cyano-7-methyl-2H-chromene (3j)⁶³⁾

The “General procedure” with 4-methylsalicylaldehyde 1j (136 mg), and silica gel column chromatography using hexane–EtOAc (8 : 1) gave the title compound (120 mg, 70%) as a pale yellow solid; ¹H-NMR (400 MHz, (CD₃)₂SO) δ: 7.56 (1H, s), 7.16 (1H, d, J = 7.7 Hz), 6.84 (1H, dd, J = 7.8, 0.8 Hz), 6.74 (1H, s), 4.85 (2H, d, J = 1.3 Hz), 2.27 (3H, s).

3-Cyano-7-methoxy-2H-chromene (3k)²⁵⁾

The “General procedure” with 4-methoxysalicylaldehyde 1k (152 mg), and silica gel column chromatography using hexane–EtOAc (8 : 1) gave the title compound (101 mg, 54%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.14 (1H, s), 7.03 (1H, d, J = 8.5 Hz), 6.53 (1H, dd, J = 8.5, 2.4 Hz), 6.42 (1H, d, J = 2.4 Hz), 4.79 (2H, s), 3.81 (3H, s).

7-Chloro-3-cyano-2H-chromene (3l)

The “General procedure” with 4-chlorosalicylaldehyde 1l (157 mg), and silica gel column chromatography using hexane–EtOAc (6 : 1) gave the title compound (162 mg, 85%) as a white solid; mp 117.2–119.9 °C; ¹H-NMR (CDCl₃) δ: 7.15 (1H, br s), 7.04 (1H, d, J = 8.1 Hz), 6.96 (1H, dd, J = 8.1, 1.9 Hz), 6.90 (1H, d, J = 1.9 Hz), 4.83 (2H, d, J = 1.3 Hz); ¹³C-NMR (101 MHz, CDCl₃) δ: 154.8, 138.0, 137.8, 129.1, 122.8, 118.5, 117.2, 116.2, 103.4, 64.4; IR (ATR) cm⁻¹: 3083, 2958, 2928, 2212, 1727, 1630, 1597, 1562, 1261; MS (DART) m/z: 214 (M + Na⁺).

3-Cyano-7-dimethylamino-2H-chromene (3m)

The “General procedure” with 4-dimethylaminosalicylaldehyde 1m (165 mg), and silica gel column chromatography using dichloromethane–EtOAc (20 : 1) gave the title compound (29.7 mg, 15%) as a yellow solid; mp 81.4–82.9 °C; ¹H-NMR (CDCl₃) δ: 7.11 (1H, br s), 6.95 (1H, d, J = 8.6 Hz), 6.28 (1H, dd, J = 8.6, 2.5 Hz), 6.15 (1H, d, J = 2.5 Hz), 4.75 (2H, d, J = 0.9 Hz), 3.00 (6H, s); ¹³C-NMR (CDCl₃) δ: 156.1, 153.8, 139.4, 129.7, 118.0, 109.5, 106.2, 98.8, 95.6, 64.6, 40.2; IR (ATR) cm⁻¹: 3061, 2918, 2856, 2821, 2194, 1623, 1603, 1533, 1358, 1151; HR-MS (ESI) m/z: 223.0873 (Calcd for C₁₂H₁₂N₂NaO⁺: 223.0842).

3-Cyano-7-hydroxy-2H-chromene (3n)

The “General procedure” with 4-hydroxysalicylaldehyde 1n (138 mg), and silica gel column chromatography using hexane–EtOAc (1 : 1) gave the title compound (23.7 mg, 14%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.14 (1H, br s), 7.00 (1H, d, J = 8.3 Hz), 6.45 (1H, dd, J = 8.3, 2.3 Hz), 6.37 (1H, d, J = 2.3 Hz), 5.30 (1H, s), 4.79 (2H, d, J = 1.2 Hz); ¹³C-NMR (CDCl₃) δ: 159.5, 156.0, 138.8, 129.9, 116.9, 113.6, 109.9, 103.7, 99.4, 64.3; IR (ATR) cm⁻¹: 3327, 3071, 2958, 2924, 2855, 2361, 2342, 2213, 1616, 1575, 1507, 1292, 1159; MS (DART) m/z: 174 (M + H⁺).

3-Cyano-8-fluoro-2H-chromene (3o)

The “General procedure” with 3-fluorosalicylaldehyde 1o (140 mg), and silica gel column chromatography using hexane–EtOAc (15 : 1) gave the title compound (139 mg, 79%) as a white solid; mp 113.8–114.3 °C; ¹H-NMR (CDCl₃) δ: 7.20 (1H, dd, J = 2.9, 1.4 Hz), 7.13–7.08 (1H, m), 6.93–6.91 (2H, m), 4.90 (2H, d, J = 1.4 Hz); ¹³C-NMR (CDCl₃) δ: 150.8 (J = 248.0 Hz), 141.8 (d, J = 11.7 Hz), 138.1 (d, J = 3.6 Hz), 123.5 (d, J = 3.5 Hz), 122.1 (d, J = 6.9 Hz), 122.0 (d, J = 1.8) 119.6 (d, J = 18.2 Hz), 115.9, 104.4, 64.4; IR (ATR) cm⁻¹: 3057, 2921, 2852, 2362, 2219, 1630, 1475, 1341, 1276, 1225; MS (DART) m/z: 198 (M + Na⁺).

8-Bromo-3-cyano-2H-chromene (3p)

The “General procedure” with 3-bromosalicylaldehyde 1p (201 mg), and silica gel column chromatography using hexane–EtOAc (6 : 1) gave the title compound (189 mg, 80%) as a white solid; mp 120.5–121.2 °C; ¹H-NMR (CDCl₃) δ: 7.50 (1H, dd, J = 7.8, 1.5 Hz), 7.16 (1H, t, J = 1.4 Hz), 7.06 (1H, dd, J = 7.8, 1.5 Hz), 6.87 (1H, t, J = 7.8 Hz), 4.95 (2H, d, J = 1.4 Hz); ¹³C-NMR (CDCl₃) δ: 151.0, 138.2, 136.1, 127.5, 123.2, 121.1, 115.9, 110.6, 104.2, 64.9; IR (ATR) cm⁻¹: 3062, 3026, 2956, 2923, 2876, 2854, 2212, 1628, 1447, 1339, 1224, 1194, 1146; MS (DART) m/z: 258 (M + Na⁺).

3-Cyano-8-methyl-2H-chromene (3q)⁶³⁾

The “General procedure” with 3-methylsalicylaldehyde 1q (136 mg), and silica gel column chromatography using hexane–EtOAc (12 : 1) gave the title compound (152 mg, 89%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.17 (1H, br s), 7.14 (1H, dd, J = 7.4, 0.9 Hz), 6.95 (1H, dd, J = 7.4, 0.9 Hz), 6.87 (1H, t, J = 7.4 Hz), 4.84 (2H, d, J = 1.2 Hz), 2.19 (3H, s).

8-tert-Butyl-3-cyano-2H-chromene (3r)

The “General procedure” with 3-tert-butylsalicylaldehyde 1r (178 mg), and silica gel column chromatography using hexane–EtOAc (45 : 1) gave the title compound (113 mg, 53%) as a white solid; ¹H-NMR (400 MHz, CDCl₃) δ: 7.30 (1H, dd, J = 7.7, 1.7 Hz), 7.19 (1H, t, J = 1.1 Hz), 6.99 (1H, dd, J = 7.7, 1.7 Hz), 6.93 (1H, t, J = 7.7 Hz), 4.78 (2H, d, J = 1.1 Hz), 1.35 (9H, s); ¹³C-NMR (CDCl₃) δ: 152.9, 139.8, 138.7, 130.3, 126.7, 122.1, 121.2, 116.7, 103.1, 63.6, 34.6, 29.7; IR (ATR) cm⁻¹: 3056, 2957, 2912, 2870, 2212, 1627, 1591, 1433, 1224, 1193; HR-MS (ESI) m/z: 236.1079 (Calcd for C₁₄H₁₅NNaO⁺: 236.1046).

3-Cyano-8-methoxy-2H-chromene (3s)²⁰⁾

The “General procedure” with 3-methoxysalicylaldehyde 1s (152 mg), and silica gel column chromatography using hexane–EtOAc (4 : 1) gave the title compound (160 mg, 85%) as a pale yellow solid; ¹H-NMR (CDCl₃) δ: 7.18 (1H, br s), 6.94–6.93 (2H, m), 6.76–6.74 (1H, m), 4.88 (2H, d, J = 1.3 Hz), 3.88 (3H, s).

3-Cyano-8-ethoxy-2H-chromene (3t)⁶⁵⁾

The “General procedure” with 3-ethoxysalicylaldehyde 1t (166 mg), and silica gel column chromatography using hexane–EtOAc (6 : 1) gave the title compound (156 mg, 77%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.18 (1H, s), 6.92–6.91 (2H, m), 6.73 (1H, dd, J = 6.1, 3.0 Hz), 4.87 (2H, d, J = 1.3 Hz), 4.10 (2H, q, J = 7.0 Hz), 1.46 (3H, t, J = 7.0 Hz).

5-Bromo-3-cyano-8-methoxy-2H-chromene (3u)⁶⁶⁾

The “General procedure” with 6-bromo-3-methoxysalicylaldehyde 1u (231 mg), and silica gel column chromatography using hexane–EtOAc (6 : 1) gave the title compound (158 mg, 59%) as a yellow solid; ¹H-NMR ((CD₃)₂SO) δ: 7.54 (1H, br s), 7.26 (1H, d, J = 8.8 Hz), 7.06 (1H, d, J = 8.8 Hz), 4.87 (2H, d, J = 1.2 Hz), 3.78 (3H, s).

3-Cyano-5,7-dimethoxy-2H-chromene (3v)

The “General procedure” with 4,6-dimethoxysalicylaldehyde 1v (187 mg), and silica gel column chromatography using hexane–EtOAc (10 : 1) gave the title compound (67.5 mg, 31%) as a white solid; mp 119.8–120.9 °C; ¹H-NMR (CDCl₃) δ: 7.46 (1H, br s), 6.06 (1H, d, J = 2.2 Hz), 6.04 (1H, d, J = 2.2 Hz), 4.73 (2H, d, J = 1.2 Hz), 3.82 (3H, s), 3.80 (3H, s); ¹³C-NMR (CDCl₃) δ: 207.1, 164.2, 157.6, 156.7, 134.7, 117.6, 104.3, 96.3, 93.6, 92.5, 64.2, 55.8, 31.0; IR (ATR) cm⁻¹: 3001, 2952, 2924, 2851, 2359, 2205, 1606, 1575, 1465, 1302, 1207, 1153; HR-MS (ESI) m/z: 240.0660 (Calcd for C₁₂H₁₁NNaO₃⁺: 240.0631).

6,8-Dichloro-3-cyano-2H-chromene (3w)²⁰⁾

The “General procedure” with 3,5-dichlorosalicylaldehyde 1w (191 mg), and silica gel column chromatography using hexane–EtOAc (15 : 1) gave the title compound (146 mg, 65%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.34 (1H, d, J = 2.4 Hz), 7.11 (1H, t, J = 1.4 Hz), 7.02 (1H, d, J = 2.4 Hz), 4.94 (2H, d, J = 1.4 Hz).

8-Bromo-6-chloro-3-cyano-2H-chromene (3x)²⁰⁾

The “General procedure” with 3-bromo-5-chlorosalicylaldehyde 1x (235 mg), and silica gel column chromatography using hexane–EtOAc (15 : 1) gave the title compound (144 mg, 53%) as a white solid; ¹H-NMR (CDCl₃) δ: 7.49 (1H, d, J = 2.4 Hz), 7.09 (1H, t, J = 1.4 Hz), 7.06 (1H, d, J = 2.4 Hz), 4.94 (2H, d, J = 1.4 Hz).

6,8-Di-tert-butyl-3-cyano-2H-chromene (3y)

The “General procedure” with 3,5-di-tert-butylsalicylaldehyde 1y (234 mg), and silica gel column chromatography using hexane–EtOAc (45 : 1) gave the title compound (181 mg, 67%) as a white solid; mp 131.1–133.9 °C; ¹H-NMR (CDCl₃) δ: 7.33 (1H, d, J = 2.4 Hz), 7.20 (1H, t, J = 1.2 Hz), 6.97 (1H, d, J = 2.4 Hz), 4.75 (2H, d, J = 1.2 Hz), 1.36 (9H, s), 1.29 (9H, s); ¹³C-NMR (CDCl₃) δ: 150.6, 144.5, 140.2, 137.7, 127.5, 123.1, 120.5, 116.8, 102.6, 63.4, 34.7, 34.3, 31.3, 29.6; IR (ATR) cm⁻¹: 3054, 2956, 2905, 2869, 2211, 1626, 1475, 1362, 1224, 1203, 1178; HR-MS (ESI) m/z: 292.1641 (Calcd for C₁₈H₂₃NNaO⁺: 292.1672).

3-Cyano-2H-benzo[h]chromene (7,8-Benzo-fused 3-cyano-2H-chromene) (3z)

The “General procedure” with 1-hydroxy-2-naphthaldehyde 1z (172 mg), and silica gel column chromatography using hexane–EtOAc (15 : 1) gave the title compound (125 mg, 60%) as a yellow solid; mp 120.5–121.2 °C; ¹H-NMR (CDCl₃) δ: 7.89 (1H, br d, J = 8.5 Hz), 7.88 (1H, br s), 7.81 (1H, d, J = 9.0 Hz), 7.79 (1H, br d, J = 7.0 Hz), 7.58 (1H, td, J = 8.5, 7.0, 1.2 Hz), 7.44 (1H, td, J = 8.5, 7.0, 1.2 Hz), 7.10 (d, J = 9.0 Hz, 1H), 4.89 (2H, d, J = 1.0 Hz); ¹³C-NMR (CDCl₃) δ: 153.9, 135.3, 133.5, 129.8, 129.4, 128.8, 128.1, 124.8, 121.0, 117.3, 117.0, 113.8, 100.2, 64.1; IR (ATR) cm⁻¹: 3060, 3029, 2953, 2924, 2880, 2852, 2210, 1771, 1623, 1564, 1514, 1229, 1191; HR-MS (ESI) m/z: 230.0547 (Calcd for C₁₄H₉NNaO⁺: 230.0577).

Gram-scale Experiments

Caution: Acrylonitrile is highly flammable and toxic at low doses, so reaction should be carried out in fume food behind safety shield in case! To a solution of salicylaldehyde 1a or 1k (1.52 g, 10.0 mmol) in acrylonitrile (3.28 mL, 50.0 mmol) in a flask, was added DMAP (2.44 g, 20.0 mmol). After filling the flask with nitrogen gas, and stirring the mixture for 18 h at 70 °C (oil bath temperature), the mixture was quenched with 1 N HCl aq. (80 mL), extracted with EtOAc (80 mL × 3), washed with water (80 mL) and brine (80 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by silica gel (50 g) column chromatography using hexane–EtOAc (4 : 1) to obtain 3-cyano-2H-chromene 3a (1.50 g, 80%) or 3k (1.09 g, 58%).

Decagram-scale Experiment

Caution: Acrylonitrile is highly flammable and toxic at low doses, so reaction should be carried out in fume food behind safety shield in case! To a solution of salicylaldehyde 1c (10.0 g, 81.9 mmol) in acrylonitrile (26.8 mL, 410 mmol) in a flask, was added DMAP (2.00 g, 16.4 mmol). After filling the flask with nitrogen gas, and stirring the mixture for 24 h at 90 °C (oil bath temperature), the mixture was quenched with sat. NaHCO₃ aq. (50 mL), extracted with CH₂Cl₂ (150 mL), washed with brine (50 mL), dried over Na₂SO₄, and concentrated under reduced pressure. The crude was purified by silica gel (200 g) column chromatography using hexane–EtOAc (15 : 1) to obtain 3-cyano-2H-chromene 3c (12.7 g, 94%).

Hydrolysis of 3-Cyano-2H-chromene 3l

A mixture of 3-cyano-2H-chromene 3a (3.0 mg, 0.016 mmol), NaOH (3.2 mg, 0.080 mmol), and water (0.10 mL) was stirring at 120 °C (hot plate temperature) for 3h. The mixture was quenched with 1 N HCl aq. (1.0 mL), extracted with EtOAc (1.0 mL), washed with brine (1.0 mL), dried over Na₂SO₄, and concentrated under reduced pressure to obtain 7-chloro-2H-chromene-3-carboxylic acid 4^57,58) (1.5 mg, 45%) as a white solid; ¹H-NMR ((CD₃)₂SO) δ: 7.45 (1H, s), 7.36 (1H, d, J = 8.2 Hz), 7.03 (1H, dd, J = 8.1, 2.1 Hz), 6.97 (1H, d, J = 1.8 Hz), 4.94 (2H, d, J = 1.4 Hz).

Acknowledgments

This work was financially supported by the Tenure Track Support Program of Kobe University (for Bubwoong Kang) and a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI, Grant No. JP21K14792 for Bubwoong Kang). The authors sincerely thank Prof. Atsunori Mori, Prof. Kentaro Okano, and Mei Matsuyama (Kobe University) for helping us to measure mass spectrometry, Prof. Hirosato Takikawa (University of Tokyo) for giving us ideas to revise this manuscript, and Ryo Minatomoto for reproducing the experimental results in this work.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

References and Notes

• 1) For selected examples of natural 2H-chromenes: Kaennakam S., Siripong P., Tip-pyang S., J. Nat. Med., 71, 310–314 (2017).
• 2) Li X., Xuan B., Shou Q., Shen Z., Fitoterapia, 95, 220–228 (2014).
• 3) Yoshihara T., Sakuma T., Ichihara A., Biosci. Biotechnol. Biochem., 56, 1955–1958 (1992).
• 4) Li K., Ji S., Song W., Kuang Y., Lin Y., Tang S., Cui Z., Qiao X., Yu S., Ye M., J. Nat. Prod., 80, 334–346 (2017).
• 5) Mori-Hongo M., Yamaguchi H., Warashina T., Miyase T., J. Nat. Prod., 72, 63–71 (2009).
• 6) Mori-Hongo M., Takimoto H., Katagiri T., Kimura M., Ikeda Y., Miyase T., J. Nat. Prod., 72, 194–203 (2009).
• 7) Cheenpracha S., Karalai C., Ponglimanont C., Kanjana-Opas A., J. Nat. Prod., 72, 1395–1398 (2009).
• 8) Erasto P., Bojase-Moleta G., Majinda R. R. T., Phytochemistry, 65, 875–880 (2004).
• 9) Tanaka H., Hirata M., Etoh H., Sako M., Sato M., Murata J., Murata H., Darnaedi D., Fukai T., Heterocycles, 60, 2767–2773 (2003).
• 10) Yenesew A., Midiwo J. O., Guchu S. M., Heydenreich M., Peter M. G., Phytochemistry, 59, 337–341 (2002).
• 11) Miyase T., Sano M., Nakai H., Muraoka M., Nakazawa M., Suzuki M., Yoshino K., Nishihara Y., Tanai M., Phytochemistry, 52, 303–310 (1999).
• 12) Kitagawa I., Chen W. Z., Hori K., Kobayashi M., Ren J., Chem. Pharm. Bull., 46, 1511–1517 (1998).
• 13) Stevenson P. C., Veitch N. C., Phytochemistry, 28, 2359 (1989).
• 14) Castro O., Vergara L. A., Stermitz F. R., Gardner D. R., J. Nat. Prod., 49, 680–683 (1986).
• 15) Mitscher L. A., Park Y. H., Clark D., Beal J. L., J. Nat. Prod., 43, 259–269 (1980).
• 16) Jurd L., Manners G. D., J. Agric. Food Chem., 25, 723–726 (1977).
• 17) Brink A. J., Rall G. J. H., Engelbrecht J. P., Tetrahedron, 30, 311–314 (1974).
• 18) For selected examples of unnatural bioactive 2H-chromenes, which are synthesized from 3-cyano-2H-chromene: Gudipudi G., Sagurthi S. R., Perugu S., Achaiahd G., Krupadanam G. L. D., RSC Adv., 4, 56489–56501 (2014).
• 19) Pigini M., Brasili L., Cassinelli A., Giardinà D., Gulini U., Quaglia W., Melchiorre C., Eur. J. Med. Chem., 22, 273–276 (1987).
• 20) Baral N., Mohapatra S., Raiguru B. P., Mishra N. P., Panda P., Nayak S., Pandey S. K., Kumar P. S., Sahoo C. R., J. Heterocycl. Chem., 56, 552–565 (2019).
• 21) Kumar K. S., Daniel V., Kaki S. S., Rao C. P., Krupadanam G. L. D., Med. Chem. Res., 25, 2179–2186 (2016).
• 22) Konda S. K., Gutam M., Thalari G., Bhoga S., Nayaki S. R., Mattela K., Krupadanam G. L. D., Synth. Commun., 52, 577–584 (2022).
• 23) Srinivas B., Kumar P. V., Reddy P. N., Venu S., Shyam P., Krupadanam G. L. D., Russ. J. Bioorganic Chem., 44, 244–251 (2018).
• 24) Larsen M., Kromann H., Kharazmi A., Nielsen S. F., Bioorg. Med. Chem. Lett., 15, 4858–4861 (2005).
• 25) Zhang G., Liu S., Tan W., Verma R., Chen Y., Sun D., Huan Y., Jiang Q., Wang X., Wang N., Xu Y., Wong C., Shen Z., Deng R., Liu J., Zhang Y., Fang W., Eur. J. Med. Chem., 129, 303–309 (2017).
• 26) Gopinath G., Sankeshi V., Perugu S., Alaparthi M. D., Bandaru S., Pasala V. K., Chittineni P. R., Krupadanam G. L. D., Sagurthi S. R., Eur. J. Med. Chem., 124, 750–762 (2016).
• 27) For selected examples of 2H-chromenes as synthetic intermediates for natural products and/or bioactive compounds and For normal 2H-chromenes as synthetic intermediates: Umeda M., Sakamoto K., Nagai T., Nagamoto M., Ebe Y., Nishimura T., Chem. Commun., 55, 11876–11879 (2019).
• 28) Chen W. H., Wang R., Shi Y.-P., J. Nat. Prod., 73, 1398–1403 (2010).
• 29) For 3-aroyl-2H-chromenes as synthetic intermediates: Jung Y., Kim I., J. Org. Chem., 80, 2001–2005 (2015).
• 30) For 3-aryl-2H-chromenes as synthetic intermediates: Khupse R. S., Erhardt P. W., Org. Lett., 10, 5007–5010 (2008).
• 31) For 3-bromo-2H-chromenes as synthetic intermediates: Koo J. Y., Oh S., Cho S.-R., Koh M., Oh W.-K., Choi H.-S., Park S. B., Org. Biomol. Chem., 11, 5782–5786 (2013).
• 32) For 3-chloro-2H-chromenes as synthetic intermediates: Kohno Y., Koso M., Kuse M., Takikawa H., Tetrahedron Lett., 55, 1826–1828 (2014).
• 33) Kang B., Oe T., Shimizu Y., Takikawa H., Tetrahedron, 113, 132714 (2022).
• 34) For 3-formyl-2H-chromenes as synthetic intermediates: Parker M. A., Satkiewicz E., Hermann T., Bergdahl B. M., Molecules, 16, 281–290 (2011).
• 35) For 3-formyl-2H-chromenes as synthetic intermediates: Jung Y., Kim I., Org. Biomol. Chem., 13, 4331–4335 (2015).
• 36) For 3-formyl-2H-chromenes and 3-acetyl-2H-chromenes as synthetic intermediates: Brenna E., Gatti F. G., Malpezzi L., Monti D., Parmeggiani F., Sacchetti A., J. Org. Chem., 78, 4811–4822 (2013).
• 37) Pavé P., Chalard P., Viaud-Massuard M.-C., Troinb Y., Guillaumet G., Synthesis, 2004, 121–127 (2004).
• 38) Mokenapelli S., Thalari G., Vadiyaala N., Yerrabelli J. R., Irlapati V. K., Gorityala N., Sagurthi S. R., Chitneni P. R., Arch. Pharm., 353, 2000006 (2020).
• 39) Mokenapelli S., Gutam M., Yerrabelli J. R., Irlapati V. K., Gorityala N., Sagurthi S. R., Chitneni P. R., Russ. J. Bioorganic Chem., 46, 845–855 (2020).
• 40) Kaye P. T., Nocanda X. W., J. Chem. Soc., Perkin Trans. 1, 1318–1323 (2002).
• 41) More than two hundred examples of the DABCO-mediated annulative condensation reactions have been reported, which was checked by the SciFinderⁿ database (accessed on December 15th, 2022).
• 42) Kaye’s pioneering work on the annulative condensation resulted in moderate yields (50–65%).
• 43) Although we were unabled to access the following literature through SciFinderⁿ database as well as Web of Science™ database, it was recorded that piperidine was used as a base in the annulative condensation under microwave irradiation condition, according to the SciFinderⁿ database (accessed on January 14th, 2023): Meenakshi C., Ravichandran S., Int. J. Chem. Sci., 4, 125–126 (2006).
• 44) For unconventional multi-step approaches to synthesize 3-cyano-2H-chromenes: Tanaka M., Abe Y., Tokuyama K., Chem. Pharm. Bull., 26, 1558–1569 (1978).
• 45) Minami T., Suganuma H., Agawa T., Chem. Lett., 7, 285–288 (1978).
• 46) Aggarwal V. K., Mereu A., Chem. Commun., 2311–2312 (1999).
• 47) Brenna et al. reported examples of K₂CO₃-mediated similar annulative condensation reactions of salicylaldehydes and other electron-deficient alkenes instead of acrylonitrile.
• 48) Mishra D. R., Panda B. S., Nayak S., Rauta N. K., Mohapatra S., Sahoo C. R., Padhy R. N., Tetrahedron, 124, 133015 (2022).
• 49) Panda P., Nayak S., Sahoo S. K., Mohapatra S., Nayak D., Pradhan R., Kundu C. N., RSC Adv., 8, 16802–16814 (2018).
• 50) Baidya M., Mayr H., Chem. Commun., 1792–1794 (2008).
• 51) Aggarwal and Mereu observed that the DMAP-catalyzed MBH reaction is 2.4 times faster than that of DABCO when using methyl acrylate as the electron-deficient alkene.
• 52) Although the resulting MBH adduct, a precursor of 1a, was not detected/isolated in the system, it is also speculated that DMAP with higher Brønsted basicity may accelarate the following intramolecular oxa-Michael reaction pathway more than DABCO.
• 53) In the case of free hydroxy-having substrate 1n to give 3n, a littile more basic DMAP (pKa 9.2) than DABCO (pKa 8.9) would be consumed to deprotonate the 4-OH of 1n. The resulting lower concentration of DMAP than DABCO may lead to the less performance of DMAP in the reaction system.
• 54) It is speculated that DMAP-mediated reaction would indicate higher yields than DABCO-mediated one, when using the substrates with the 4-OH group of 1n protected, such as 4-benzyloxysalicylaldehyde as we saw in the case of methyl protected 1k. For such a reaction whish was previously reported: Tsai J.-C., Li S.-R., Chiang M.-Y., Chen L.-Y., Chen P.-Y., Lo Y.-F., Wang C.-H., Lin C.-N., Wang E.-C., J. Org. Chem., 74, 8798–8801 (2009).
• 55) Although the reactions were carried out with methyl acrylate and tert-butyl acrylate instead of acrylonitrile, they only produced their corresponding 2H-chromenes in 4 and 8% yields, respectively.
• 56) For the same DABCO-catalyzed reaction, which was reported to provide 3c in 85% yield: Alami M., Peyrat J.-F., Belachmi L., Brion J.-D., Eur. J. Org. Chem., 2001, 4207–4212 (2001).
• 57) For the reported synthesis of carboxylic acid 4: Yoshikawa K., Kobayashi S., Nakamoto Y., Haginoya N., Komoriya S., Yoshino T., Nagata T., Mochizuki A., Watanabe K., Suzuki M., Kanno H., Ohta T., Bioorg. Med. Chem., 17, 8221–8233 (2009).
• 58) Ohta T., Komoriya S., Yoshino T., Uoto K., Nakamoto Y., Naito H., Mochizuki A., Nagata T., Kanno H., Haginoya N., Yoshikawa K., Nagamochi M., Kobayashi S., Ono M., U. S. Patent US20050020645 A1 (2005). https://patents.google.com/patent/US20050020645A1/en?oq=US20050020645+A1
• 59) Lagu B., Gerchak C., Pan M., Hou C., Singer M., Malaviya R., Matheis M., Olini G., Cavender D., Wachter M., Bioorg. Med. Chem. Lett., 17, 4382–4386 (2007).
• 60) The prices of ethyl 2-diethylphosphonoacrylate 2’ (CAS registry number: 20345-61-3) supplied by Manchester Organics Ltd. at Cheshire, United Kingdom are 145 GBP/5 g and 490 GBP/25 g (on January 11th, 2023). https://www.manchesterorganics.com/J40949
• 61) For the synthetic protocols to prepare ethyl 2-diethylphosphonoacrylate 2’: Kleschick W. A., Heathcock C. H., J. Org. Chem., 43, 1256–1259 (1978).
• 62) Semmelhack M. F., Tomesch J. C., Czarny M., Boettger S., J. Org. Chem., 43, 1259–1262 (1978).
• 63) Merk D., Heitel P., Faudone G., Schmidt J., Schubert-Zsilavecz M., World Patent WO2019057969A1 (2019). https://patents.google.com/patent/WO2019057969A1/en?oq=WO2019057969A1
• 64) Rueda-Zubiaurre A., Yahiya S., Fischer O. J., Hu X., Saunders C. N., Sharma S., Straschil U., Shen J., Tate E. W., Delves M. J., Baum J., Barnard A., Fuchter M. J., J. Med. Chem., 63, 2240–2262 (2020).
• 65) Pattanaik P., Nayak S., Mishra D. R., Panda P., Raiguru B. P., Mishra N. P., Mohapatra S., Mallampudi N. A., Chandra S. P., Tetrahedron Lett., 59, 2688–2694 (2018).
• 66) Danjo T., Yamada H., Nakajima T., World Patent WO2018235926A1 (2018). https://patents.google.com/patent/WO2018235926A1/en