C4-aldehyde of guaiazulene: synthesis and derivatisation

Abstract

Guaiazulene is an alkyl-substituted azulene available from natural sources and is a much lower cost starting material for the synthesis of azulene derivatives than azulene itself. Here we report an approach for the selective functionalisation of guaiazulene which takes advantage of the acidity of the protons on the guaiazulene C4 methyl group. The aldehyde produced by this approach constitutes a building block for the construction of azulenes substituted on the seven-membered ring. Derivatives of this aldehyde synthesised by alkenylation, reduction and condensation are reported, and the halochromic properties of a subset of these derivatives have been studied.

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Introduction

Azulene (1) is a non-alternant bicyclic aromatic hydrocarbon, that has significantly different properties to those of its isomer naphthalene (2).¹ Whereas the HOMO–LUMO gap in naphthalene leads to absorption in the UV region, the corresponding molecular orbitals are closer in energy in azulene, hence leading to an absorption in the visible region. Thus, naphthalene is colourless but azulene is blue. Azulene also displays anomalous fluorescence characteristics, being an exception to Kasha's rule, with the S₂ → S₀ transition being the dominant mode of emission.² Additional interesting optical properties such as halochromism,³ solvatochromism⁴ and barochromism⁵ have also been reported for certain azulenes. Azulene also has a dipole moment of 1.08 D, unusually high for a simple hydrocarbon.⁶ This arises from the contribution of resonance structure 1′, in which both individual rings are 6π aromatic systems (Fig. 1). These notable properties have led to azulenes being used extensively as both colorimetric⁷ and fluorescent⁸ probes for various analytes. Azulenes have also been employed in solar cells⁹ and organic electronics,¹⁰ as well as in medicinal chemistry.¹¹

Fig. 1 Structures of azulene, naphthalene and guaiazulene.

These various applications have been enabled by the development of synthetic routes to substituted azulenes.¹² One approach is to synthesise the azulene ring from a precursor which already incorporates the desired substituents, for example by aromatisation of 1,1-dicyanodihydroazulenes¹³ or by a carbene insertion/ring expansion approach.¹⁴ Another strategy is to employ synthetic methodology that introduces the desired substituents onto a pre-existing azulene ring. Approaches for functionalisation of the 5-membered ring of azulene include S_EAr reactions,¹⁵ cross-coupling¹⁶ and C–H activation.¹⁷ Approaches for functionalisation of the 7-membered ring of azulene are less numerous, but include vicarious nucleophilic substitution¹⁸ and nucleophilic addition/rearomatisation.^16g,19 However, regardless of the diversity of approaches for azulene derivatisation, work in this area is hindered by the high cost of azulene itself – preparation of the parent hydrocarbon requires multistep procedures and/or reagents that are themselves costly.^15a,20 There is therefore a motivation to use an alternative azulene starting material which is abundantly available from natural sources and hence has a much lower cost, namely guaiazulene (3).

Guaiazulene and its derivatives are sesquiterpene natural products produced by various organisms, in particular gorgonian octocorals and the fungal genus Lactarius.²¹ Moreover, guaiazulene may be produced from the essential oils isolated from genera such as Eucalyptus,²²Matricaria (chamomile)²³ and others.²⁴ These processes proceed via the dehydration/dehydrogenation of other sesquiterpenes such as guaiol and occur in high yields, permitting the large scale production of guaiazulene at low cost. The main uses of guaiazulene and its derivative sodium guaiazulene-3-sulfonate are as anti-inflammatory agents and in cosmetics.²⁵

The alkyl groups on guaiazulene do not influence the azulene chromophore significantly, but they impart a much lower melting point (30–33 °C)²⁶ and guaiazulene can undergo very slow decomposition on exposure to air.²⁷ However, derivatives bearing electron withdrawing groups are generally stable. Methods for derivatisation of guaiazulene are not as extensively developed as for azulene itself and in some instances may be hindered by the alkyl substituents. On the other hand, the alkyl substituents of guaiazulene can be seen as handles for further derivatisation themselves.²⁸ One strategy to achieve this exploits the known acidity of the protons on the guaiazulene C4 methyl group.^3h,17n,29 The low pK_a of these protons arises from the resonance stabilisation of the corresponding conjugate base, [3–H]⁻ that may be attributed to resonance structure [3′–H]⁻ (Scheme 1) that comprises an aromatic cyclopentadienide substructure.

Scheme 1 Guaiazulene deprotonates preferentially at the C4 methyl group.

Amide acetals such as dimethylformamide dimethyl acetal (DMFDMA) are versatile reagents able to effect a variety of synthetic transformations.³⁰ Reaction of an amide acetal with aryl methyl groups to give the corresponding enamines was first reported by Meerwein³¹ and was further developed by Bredereck.³² Oxidative cleavage of such enamines is possible using sodium periodate (with no requirement for osmium tetroxide).³³ Taken together, these two procedures allow formation of an aryl aldehyde in two steps from the corresponding aryl methyl group. The reaction mechanism requires that the arene is able to stabilise a benzylic anion, hence electron-poor arene substrates are generally required (Scheme 2a). We reasoned that this synthetic sequence could be applicable to guaiazulene, resulting in a regioselective transformation of the C4 methyl group to an aldehyde, although whether the C4 methyl protons were sufficiently acidic was unclear at the outset. To our knowledge there are three prior reports of azulenyl aldehydes being formed from the corresponding azulene methyl groups in this way. In 2006, Kim, Osuka and co-workers reported the reaction of a 4-methylazulene 4, bearing an electron-withdrawing ester at the 1-position, which would lower the pK_a of the C4 methyl protons (Scheme 2b).³⁴ In 2015, Leino and co-workers reported the reaction of 6-methylazulene 6, which lacks any other substituents (Scheme 2c).³⁵ Most recently, in 2018 Shoji and co-workers reported the reaction of various 2-methylazulenes of type 8, finding that the reaction did not proceed without an electron-withdrawing group at the 1-position (Scheme 2d).³⁶

Scheme 2 (a) Mechanism for transformation of aryl methyl group to aryl aldehyde. (b) Work of Kim, Osuka and co-workers. (c) Work of Leino and co-workers. (d) Work of Shoji and co-workers.

In this paper we describe the first synthesis of guaiazulene-4-carbaldehyde, as well as some further transformations of this compound.

Results and discussion

Treatment of guaiazulene 3 with DMFDMA in DMF gave crude enamine 10 as a green solid after aqueous workup.‡ This proved to be somewhat unstable and could not be purified by chromatography on silica. Thus, 10 was used crude, and was directly subjected to oxidative cleavage with NaIO₄ to give novel aldehyde 11 in 77% yield over two steps (Scheme 3). In contrast to 10, aldehyde 11 could be purified by chromatography on silica, and is stable in pure form. Crystals of 11 were subjected to X-ray diffraction analysis and the resultant structure is shown in Fig. 2.

Scheme 3 Synthesis of guaiazulene-4-carbaldehyde 11.

Fig. 2 ORTEP representation of the X-ray structure of 11. Ellipsoids are shown at 50% probability. Hydrogens are shown as spheres of arbitrary radius. CCDC 2047319.†

We anticipate that aldehyde 11 may find various uses in synthesis, since it is accessible in a concise fashion from a cheap azulenic starting material. Reduction of 11 with NaBH₄ furnished alcohol 12 in sufficient purity that chromatography was not required (Scheme 4a). Alkenylation of 11 by Horner–Wadsworth–Emmons reaction was carried out using a variety of phosphonates (Scheme 4b, Table 1).³⁷ Alkenes 20 and 21 were synthesised from phosphonate reagents containing additional Lewis basic groups, and as such the modified Masamune–Rousch reaction conditions were employed in these instances.³⁸

Scheme 4 (a) Reduction of 11. (b) Horner–Wadsworth–Emmons reaction of 11.

Table 1 Horner–Wadsworth–Emmons reactions of 11

Entry	R	Product	R′	Method^a^,^b	Yield (%)
a Method A: 60% NaH (2 eq.), THF, rt, 2 h. b Method B: LiCl (3 eq.), DBU (3 eq.), THF, 0 °C, 3 h.
1		14	Et	A	38
2		15	Et	A	46
3		16	Et	A	18
4		17	Et	A	56
5		18	Et	A	42
6		19	Et	A	44
7		20	Me	B	41
8		21	Et	B	33
9		22	Et	A	50

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C4-alkenylated guaiazulene derivatives such as 14–22 have been reported previously,^{3h,11j,29c,j,29l–n,29r} although in these cases the C4 methyl carbon reacted as a nucleophile, as opposed to as an electrophile as is the case here. A notable property of certain C4-alkenylated guaiazulenes described previously is their halochromism.^3h,29c Accordingly, selected alkenylated derivatives of 11 and their response to Brønsted acid were studied. 4-Fluorostyrylazulene 19 was titrated against increasing quantities of trifluoroacetic acid in CH₂Cl₂ and UV/vis absorption spectra were acquired (Fig. 3).

Fig. 3 Titration of 19 (0.08 mM) with TFA (1 M in CH₂Cl₂) in CH₂Cl₂.

The absorption maxima at λ = 289 nm and λ = 319 nm decreased in intensity with increasing acid concentration, whereas a new absorption maximum at λ = 447 nm (in the blue region) was seen to increase in intensity; an isosbestic point was observed at λ ≈ 388 nm. ¹H-NMR spectra of 19 in CDCl₃ and in CDCl₃/TFA were acquired (Fig. 4), and show the site of protonation to be the guaiazulene C3 position. Specifically, for the spectrum in CDCl₃, the H-3 resonance is observed as a 1H doublet at 7.46 ppm, whereas in TFA/CDCl₃ it is observed as a 2H broad singlet at 4.08 ppm, this chemical shift being indicative of an sp³-hybridised carbon. Further support for the guaiazulene C3 position being the site of protonation comes from comparison with spectra of similar azulenium cations generated by hydride abstraction from dihydroazulenes.^13d,39

Fig. 4 Top: ¹H-NMR spectrum of 19 in CDCl₃. Bottom: ¹H-NMR spectrum of 19 in TFA/CDCl₃ 1 : 9. Inset: NMR tubes containing 19 in CDCl₃ (left) and 19 in TFA/CDCl₃ (right).

Cyano-substituted 15, chloro-substituted 18 and α,β-unsaturated ester 20 were investigated in a similar fashion, and all were observed by NMR to undergo protonation at the same position (Fig. S1–S3†). Whereas 15 and 18 exhibited similar maxima and isosbestic points to 19 (Fig. S4 and S5†), the isosbestic point for 20 was blue shifted (Fig. S6†). As a further demonstration of the scope for functionalisation of 11, formation of a nitrone was attempted. Azulenyl nitrones are of interest as free radical spin traps with neuroprotective activity and potential clinical utility.⁴⁰ In the present case, condensation of 11 with N-tert-butylhydroxylamine gave nitrone 23 (Scheme 5).

Scheme 5 Synthesis of nitrone 23.

Conclusions

We have described the concise synthesis of an azulene bearing an aldehyde at the 4-position (11). The use of a low-cost, commercially available azulene starting material and the requirement for only one purification step render 11 an attractive building block for the synthesis of more complex azulenes bearing substituents at the 4-position. We have demonstrated the utility of 11 through its use in reduction, alkenylation and condensation reactions.

Experimental

General details

Reactions which required the use of anhydrous, inert atmosphere techniques were carried out under an atmosphere of argon. Reaction solvents were obtained by passing though anhydrous alumina columns using an Innovative Technology Inc. PS-400-7 solvent purification system. In most cases, solvents were purchased as “anhydrous” grade from Fisher Scientific. “Petrol” refers to petroleum spirit b.pt. 40–60 °C. TLC was performed using aluminium backed plates pre-coated with Alugram®SIL G/UV 254 nm. Where needed, visualisation was accomplished by UV light and/or KMnO₄ or using phosphomolybdic acid (PMA) dip followed by gentle warming. Following work up, the organic layers were routinely dried using anhydrous MgSO₄ and evaporated using a Büchi rotary evaporator. When necessary, further drying was facilitated by high vacuum. During purification, flash column chromatography was carried out using 60 angstroms (Å) silica gel (40–75 micron) purchased from Sigma Aldrich. ¹H and ¹³C NMR spectra were acquired on Agilent ProPulse 500 MHz or Bruker Advance 250, 300, 400 or 500 megahertz (MHz) instruments at 298 K. All spectra were referenced to residual solvent peaks; chemical shifts are reported in parts per million (ppm) relative to residual chloroform (δ = 7.26 ppm, ¹H; 77.16 ppm, ¹³C). All ¹³C{¹H} resonances are singlets, unless stated otherwise. Coupling constants, J, reported in Hz, were calculated using MestreNova 9.0 to the nearest 0.1 Hz. The following abbreviations are used to label the multiplicities: s, singlet; d, doublet; t, triplet; q, quartet; quin, quintet; sex, sextet; sep, septet; dd, doublet of doublets; dq, doublet of quartets; td, triplet of doublets; m, multiplet and br, broad. ¹H and ¹³C{¹H} assignments for novel compounds are corroborated though 2D (COSY, HSQC, HMBC). Infrared (IR) spectra were recorded on a PerkinElmer Spectrum 100 ATR-FTIR spectrometer with only selected absorbances quoted as ν in cm⁻¹. For mass spectrometry a microTOF electrospray time-of-flight (ESI-TOF) mass spectrometer (Bruker Daltonik GmbH, Bremen, Germany) was used. Data are reported in the form of m/z. The observed mass and isotope pattern matched the corresponding theoretical values as calculated from the expected elemental formula. Melting points (mp) were determined on an Stanford Research Systems OptiMelt automated capillary melting point apparatus in open capillary tubes and are uncorrected. X-Ray intensity data for 11 were collected at 150(2) K on a Rigaku SuperNova Dual EosS2 single crystal diffractometer using monochromated Cu-Kα radiation (λ = 1.54184 Å). Unit cell determination, data collection data reduction and absorption correction were performed using the CrysAlisPro software (version 1.171.40.43a, Rigaku Oxford Diffraction, 2019). The structure was solved with SHELXT and refined by a full-matrix least-squares procedure based on F2 (SHELXL-2018/3). All non-hydrogen atoms were refined anisotropically. Hydrogen atoms were placed onto calculated positions and refined using a riding model.

7-Isopropyl-1-methylazulene-4-carbaldehyde (11). Under an atmosphere of nitrogen, guaiazulene (0.32 g, 1.6 mmol, 1.0 eq.) was dissolved in degassed anhydrous DMF (5.0 mL), to which N,N-dimethylformamide dimethyl acetal (0.43 mL, 3.2 mmol, 2.0 eq.) was added. The reaction was heated to 140 °C and stirred for 9 h, during which the solution turned from blue to green. The solution was cooled to room temperature and diluted with ethyl acetate (30 mL). The organic mixture was washed with water (30 mL) and 5% LiCl_(aq) solution (2 × 30 mL). The organic phase was dried over MgSO₄ and filtered, and the filtrate was concentrated under reduced pressure to give crude 10, used immediately. Under aerobic conditions, the crude material was re-dissolved in THF/H₂O (30 mL, 1 : 1, v/v), to which NaIO₄ (1.0 g, 4.8 mmol, 3.0 eq.) was added. The solution was stirred room temperature for 2.5 hours, turning from green to blue, then diluted with ethyl acetate (30 mL). The organic phase was washed with water (30 mL) and sat. NaHCO_3(aq) solution (2 × 30 mL), for which the initial aqueous extract was orange and the latter extract was colourless. The organic phase was dried over MgSO₄ and filtered, and the filtrate was concentrated under reduced pressure. The crude material was purified by silica column chromatography, eluting with EtOAc/petrol (5 : 95, R_f = 0.50) to give 7-isopropyl-1-methylazulene-4-carbaldehyde 11 (0.21 g, 62%) as a blue-brown solid. ¹H NMR (500 MHz, CDCl₃) δ 1.40 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.71 (s, 3H, C1–CH₃), 3.15 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 7.56 (d, J = 10.4 Hz, 1H, C5–H), 7.63 (dd, J = 10.5, 1.9 Hz, 1H, C6–H), 7.92 (d, J = 3.6 Hz, 1H, C3–H), 8.08 (d, J = 3.7 Hz, 1H, C2–H), 8.25 (d, J = 1.3 Hz, 1H, C8–H), 10.77 (s, 1H, –CHO) ppm. ¹³C NMR (500 MHz, (CDCl₃) δ 13.0, 24.6, 39.0, 112.4, 123.8, 126.2, 133.9, 134.1, 134.7, 136.2, 141.4, 141.6, 145.1, 195.1 ppm. IR ν_max 701, 761, 1682, 2861, 2924, 2955 cm⁻¹. Melting point 81–84 °C. HRMS (ESI⁺): calculated for C₁₅H₁₆O [M + H]⁺ 213.1274, found 213.1278.

(7-Isopropyl-1-methylazulen-4-yl)methanol (12). To a solution of 11 (75 mg, 0.3 mmol, 1.0 eq.) in EtOH was added NaBH₄ (27 mg, 0.7 mmol, 2.0 eq.). The solution was stirred for 1 h at rt and was then quenched with water (10 mL) and extracted with CH₂Cl₂ (3 × 10 mL), dried over MgSO₄ and filtered, then the filtrate was evaporated under reduced pressure to give (7-isopropyl-1-methylazulen-4-yl)methanol as a turquoise gum (54 mg, 72%). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.37 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.65 (s, 3H, C1–CH₃), 3.14 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 4.57 (t, J = 5.8 Hz, 1H, –OH), 5.18 (d, J = 5.3 Hz, 2H, –CH̲₂OH), 7.25 (d, J = 3.7 Hz, 1H, C3–H), 7.52 (d, J = 10.7 Hz, 1H, C5–H), 7.62–7.59 (m, 2H, C2–H, C6–H), 8.27 (d, J = 2.0 Hz, 1H, C8–H) ppm. ¹³C NMR (500 MHz, (CD₃)₂CO) δ 12.9, 25.0, 39.0, 64.5, 111.3, 121.3, 125.4, 133.9, 135.7, 135.7, 137.2, 138.6, 141.4, 147.4 ppm. IR ν_max 1008, 1386, 2924, 2956, 3316 cm⁻¹. HRMS (ESI⁺): calculated for C₁₅H₁₈O [M + H]⁺ 215.1430, found 215.1438.

General procedure A for Horner–Wadsworth–Emmons reactions

To a stirred solution of 60% NaH (11 mg, 0.3 mmol, 2.0 eq.) in anhyd. THF (3 mL) was added dropwise a solution of the required phosphonate (0.3 mmol, 2.0 eq.) in anhyd. THF (4 mL) under nitrogen. The mixture was stirred for 10 min after which a solution of 11 (30 mg, 0.1 mmol, 1.0 eq.) in anhyd. THF (3 mL) was added dropwise. The mixture was stirred at rt until the starting material was consumed as shown by TLC (approx. 2 h). The reaction mixture was diluted with water (10 mL) and extracted with CH₂Cl₂ (3 × 30 mL). The combined organic fractions were dried over MgSO₄ and filtered, then the filtrate was evaporated under reduced pressure. Purification was achieved by column chromatography to give the desired alkenylazulene.

(E)-4-(4-Iodostyryl)-7-isopropyl-1-methylazulene (14). General procedure A was used with diethyl (4-iodobenzyl)phosphonate (100 mg) to give the product as a green waxy gum (22 mg, 38%) following purification via column chromatography using Petrol (100%, R_f 0.50). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.66 (s, 3H, C1–CH₃), 3.15 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 7.48 (d, J = 16.2 Hz, 1H, C₆H₄–CH̲=CH–), 7.58–7.61 (m, 5H, C3–H, C5–H, C6–H, m–I–Ar–H), 7.67 (d, J = 3.9 Hz, 1H, C2–H), 7.80 (d, J = 8.4 Hz, 2H, o–I–Ar–H), 8.20 (d, J = 16.2 Hz, 1H, C₆H₄–CH=CH̲–), 8.25 (s, 1H, C8–H) ppm. ¹³C NMR (500 MHz, (CD₃)₂CO) δ 13.1, 24.9, 38.9, 94.2, 113.1, 120.8, 126.7, 130.0, 130.9, 133.7, 133.7, 135.6, 137.5, 137.7, 137.8, 138.0, 138.8, 141.0, 142.1 ppm. IR ν_max 763, 950, 2958 cm⁻¹. HMS (ESI⁺): calc. for C₂₂H₂₁I [M + H]⁺ 413.0761, found 413.0771.

(E)-4-(2-(7-Isopropyl-1-methylazulen-4-yl)vinyl)benzonitrile (15). General procedure A was used with diethyl (4-cyanobenzyl)phosphonate (72 mg) to give the product as a green gum (20 mg, 46%) following purification via column chromatography using Petrol (100%, R_f 0.40). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.66 (s, 3H, C1–CH₃), 3.16 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 7.59 (d, J = 15.9 Hz, 1H, C₆H₄–CH̲=CH–), 7.59–7.60 (m, 2H, C5–H, C6–H), 7.63 (d, J = 3.9 Hz, 1H, C3–H), 7.70 (d, J = 3.9 Hz, 1H, C2–H), 7.81 (d, J = 8.4 Hz, 2H, m–CN–Ar–H), 7.98 (d, J = 8.3 Hz, 2H, o–CN–Ar–H), 8.28 (s, 1H, C8–H), 8.33 (d, J = 16.3 Hz, 1H, C₆H₄–CH=CH̲–) ppm. ¹³C NMR (500 MHz, (CD₃)₂CO) δ 13.0, 24.9, 38.9, 112.1, 113.2, 119.4, 120.8, 126.8, 128.7, 133.0, 133.4, 133.7, 133.9, 135.7, 137.7, 138.1, 138.2, 141.4, 141.6, 142.7 ppm. IR ν_max 738, 787, 1262, 2222, 2849, 2917, 2959 cm⁻¹. HRMS (ESI⁺): calc. for C₂₃H₂₁N [M + H]⁺ 312.1747, found 312.1753.

(E)-7-Isopropyl-1-methyl-4-(4-nitrostyryl)azulene (16). General procedure A was used with diethyl (4-nitrobenzyl)phosphonate (77 mg) to give the product as a dark green waxy gum (8.6 mg, 18%) following purification via column chromatography using Petrol (100%, R_f 0.40). ¹H NMR (500 MHz, CDCl₃) δ 1.40 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.70 (s, 3H, C1–CH₃), 3.13 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 7.40 (d, J = 16.2 Hz, 1H, C₆H₄–CH̲=CH–), 7.43 (d, J = 10.9 Hz, 1H, C5–H), 7.45 (br s, 1H, C3–H), 7.54 (dd, J = 10.9, 1.9 Hz, C6–H), 7.72 (s, 1H, C2–H), 7.74–7.77 (m, 2H, m–NO₂–Ar–H), 8.15 (d, J = 16.2 Hz, 1H, C₆H₄–CH=CH̲–), 8.23 (d, J = 1.9 Hz, 1H, C8–H), 8.26–8.30 (m, 2H, o–NO₂–Ar–H). ¹³C NMR (500 MHz, (CD₃)₂CO) δ 13.0, 24.9, 39.0, 113.2, 120.9, 124.8, 126.9, 128.9, 132.6, 133.9, 134.6, 135.7, 137.7, 138.2, 138.3, 141.4, 141.6, 144.8, 148.2 ppm. IR ν_max 744, 1335, 1511, 1592, 2924, 2957 cm⁻¹. HRMS (ESI⁺): calc. for C₂₂H₂₁NO₂ [M + H]⁺ 332.1645, found 332.1653.

(E)-7-Isopropyl-1-methyl-4-(4-(trifluoromethyl)styryl)azulene (17). General procedure A was used with (4-(trifluoromethyl)benzyl)phosphonate (74 mg) to give the product as a green waxy gum (25 mg, 56%) following purification via column chromatography using Petrol (100%, R_f 0.60). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.66 (s, 3H, C1–CH₃), 3.15 (hept, J = 7.0 Hz, 1H, –CH̲(CH₃)₂), 7.59 (d, J = 16.2 Hz, 1H, C₆H₄–CH̲=CH–), 7.61–7.60 (m, 2H, C5–H, C6–H), 7.62 (d, J = 3.9 Hz, C3–H), 7.69 (d, J = 3.8 Hz, 1H, C2–H), 7.76 (d, J = 8.1 Hz, 2H, m–CF₃–Ar–H), 7.99 (d, J = 7.8 Hz, 2H, o–CF₃–Ar–H), 8.27 (s, 1H, C8–H), 8.30 (d, J = 16.2 Hz, 1H, C₆H₄–CH=CH̲–). ¹³C NMR (500 MHz, (CD₃)₂CO) δ 142.2 (q, ⁴J_CF = 1.5 Hz), 141.8, 141.3, 138.1, 138.1, 137.6, 135.7, 133.8, 133.2, 132.9, 130.1 (q, ²J_CF = 32.0 Hz), 128.5, 126.8, 126.5 (q, ³J_CF = 3.9 Hz), 125.4 (q, ¹J_CF = 270.9 Hz), 120.9, 113.2, 38.9, 24.9, 13.0 ppm. IR ν_max 825, 1065, 1106, 1320, 1413, 2960 cm⁻¹. HRMS (ESI⁺): calc. for C₂₃H₂₁F₃ [M + H]⁺ 355.1668, found 355.1655.

(E)-4-(4-Chlorostyryl)-7-isopropyl-1-methylazulene (18). General procedure A was used with diethyl (4-chlorobenzyl)phosphonate (74 mg) to yield a green waxy gum (19 mg, 42%) following purification via column chromatography using Petrol (100%, R_f 0.40). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (d, J = 7.0 Hz, 6H, –CH(CH̲₃)₂), 2.66 (s, 3H, C1–CH₃), 3.15 (hept, J = 6.8 Hz, 1H, –CH̲(CH₃)₂), 7.44–7.48 (m, 2H, m–Cl–Ar–H), 7.54 (d, J = 16.2 Hz, 1H, C₆H₄–CH̲=CH–), 7.59–7.60 (m, 2H, C5–H, C6–H), 7.60–7.62 (m, 1H, C3–H), 7.67–7.68 (m, 1H, C2–H), 7.79–7.84 (m, 2H, o–Cl–Ar–H), 8.19 (d, J = 16.2 Hz, 1H, C₆H₄–CH=CH̲–), 8.26 (s, 1H, C8–H) ppm. ¹³C NMR (500 MHz, (CD₃)₂CO) δ 13.1, 24.9, 38.9, 113.1, 120.7, 126.6, 129.6, 129.7, 130.8, 133.5, 133.7, 134.3, 135.6, 137.1, 137.4, 137.7, 137.8, 141.0, 142.1 ppm. IR ν_max 772, 817, 1011, 1091, 1490, 2923 cm⁻¹. HRMS (ESI⁺): calc. for C₂₂H₂₁Cl [M + H]⁺ 321.1405, found 321.1412.

(E)-4-(4-Fluorostyryl)-7-isopropyl-1-methylazulene (19). General procedure A was used with diethyl (3-fluorobenzyl) phosphonate (70 mg) to give the product as a green waxy gum (19 mg, 44%) following purification via column chromatography using Petrol (100%, R_f 0.30). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.66 (s, 3H, C1–CH₃), 3.15 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 7.21 (dd, ³J_HH = 8.8 Hz, ³J_HF = 8.8 Hz, 2H, o–F–Ar–H), 7.54 (d, J = 16.2 Hz, 1H, C₆H₄–CH̲=CH–), 7.59 (br s, 2H, C5–H, C6–H), 7.60 (d, J = 4.0 Hz, 1H, C3–H), 7.66 (d, J = 4.0 Hz, 1H, C2–H), 7.85 (dd, ³J_HH = 8.6 Hz, ⁴J_HF = 5.5 Hz, 2H, m–F–Ar–H), 8.12 (d, J = 16.2 Hz, 1H, C₆H₄–CH=CH̲–), 8.26 (s, 1H, C8–H) ppm. ¹³C NMR (500 MHz, (CD₃)₂CO) δ 13.1, 25.0, 38.9, 113.1, 116.5 (d, ²J_CF = 21.8 Hz), 120.8, 126.6, 129.9 (d, ⁵J_CF = 2.4 Hz), 130.0 (d, ³J_CF = 8.1 Hz), 133.6, 133.7, 134.8 (d, ⁴J_CF = 3.3 Hz), 135.7, 137.4, 137.7, 138.0, 140.9, 142.4, 163.7 (d, ¹J_CF = 246.5 Hz) ppm. IR ν_max 771, 1215, 1505, 2955 cm⁻¹. HRMS (ESI⁺): calc. for C₂₂H₂₁F [M + H]⁺ 305.1700, found 305.1706.

General procedure B for Horner–Wadsworth–Emmons reactions

To the required phosphonate (0.1 mmol, 1.0 eq.) in anhyd. THF (5 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (60 μL, 0.4 mmol, 3.0 eq.) and lithium chloride (18 mg, 0.4 mmol, 3.0 eq.) under nitrogen. The mixture was stirred for 5 min after which a solution of 11 (30 mg, 0.1 mmol, 1.0 eq.) in anhyd. THF (5 mL) was added dropwise. The mixture was stirred at rt until the starting material was consumed as shown by TLC (approx. 3 h). The mixture was then quenched with water (2 mL) and sat. NH₄Cl. The mixture was then extracted with EtOAC (3 × 20 mL) and the combined organic fractions were washed with water (30 mL) and brine (30 mL), dried over MgSO₄ and filtered, then the filtrate was evaporated under reduced pressure. Purification was achieved by column chromatography to give the desired alkenylazulene.

Methyl (E)-3-(7-isopropyl-1-methylazulen-4-yl)acrylate (20). General procedure B was used with methyl 2-(diethoxyphosphoryl)acetate (26 mg) to give the product as a green waxy gum (15 mg, 41%) following purification via column chromatography using Petrol/EtOAc (95 : 5; R_f 0.5). ¹H NMR (400 MHz, CDCl₃) δ 1.39 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.69 (s, 3H, C1–CH₃), 3.11 (hept, J = 6.8 Hz, 1H, –CH̲(CH₃)₂), 3.87 (s, 3H, –OCH₃), 6.65 (d, J = 15.9 Hz, 1H, –CH=CH̲–COOCH₃), 7.29 (d, J = 10.8 Hz, 1H, C5–H), 7.46 (d, J = 3.9 Hz, 1H, C3–H), 7.50 (dd, J = 10.8, 2.0 Hz, 1H, C6–H), 7.75 (d, J = 3.3 Hz, 1H, C2–H), 8.21 (d, J = 1.9 Hz, 1H, C8–H), 8.53 (d, J = 15.9 Hz, 1H, –CH̲=CH–COOCH₃) ppm. ¹³C NMR (500 MHz, CDCl₃) δ 13.1, 24.8, 38.6, 52.1, 112.6, 120.4, 122.8, 126.6, 133.6, 134.9, 137.3, 137.4, 138.4, 138.5, 141.8, 145.9, 167.3 ppm. IR ν_max 1018, 1169, 1273, 1718, 2958 cm⁻¹. HRMS (ESI⁺): calc. for C₁₈H₂₀O₂ [M + H]⁺ 269.1536, found 269.1535.

(E)-3-(7-Isopropyl-1-methylazulen-4-yl)acrylonitrile (21). General procedure B was used with diethyl (cyanomethyl)phosphonate (25 mg) to give the product as a dark green waxy gum (10 mg, 33%) following purification via column chromatography using Petrol/EtOAc (80 : 20; R_f 0.6). ¹H NMR (500 MHz, CDCl₃) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.69 (s, 3H, C1–CH₃), 3.12 (hept, J = 6.8 Hz, 1H, –CH̲(CH₃)₂), 6.13 (d, J = 16.6 Hz, 1H, –CH=CH̲–CN), 7.15 (d, J = 10.7 Hz, 1H, C5–H), 7.34 (d, J = 3.8 Hz, 1H, C3–H), 7.50 (dd, J = 10.7, 2.0 Hz, 1H, C6–H), 7.78 (d, J = 3.7 Hz, 1H, C2–H), 8.22 (d, J = 1.9 Hz, 1H, C8–H), 8.28 (d, J = 16.7 Hz, 1H, –CH̲=CH–CN) ppm. ¹³C NMR (500 MHz, CDCl₃) δ 13.1, 24.7, 38.6, 101.3, 112.4, 118.0, 119.4, 127.2, 134.0, 134.8, 136.4, 136.9, 137.9, 139.1, 142.5, 151.9 ppm. IR ν_max 721, 787, 918, 976, 1422, 2215, 2959 cm⁻¹. HMS (ESI⁻): calc. for C₁₇H₁₇N [M − H]⁻ 234.1288, found 234.1290.

(E)-3-(7-Isopropyl-1-methylazulen-4-yl)-N-methoxy-N-methylacrylamide (22). General procedure A was used with diethyl (2-(methoxy(methyl)amino)-2-oxoethyl)phosphonate (68 mg) to give the product as a light blue waxy gum (28 mg, 50%) following purification via column chromatography using Petrol (100%, R_f 0.3). ¹H NMR (500 MHz, (CD₃)₂CO) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 2.67 (s, 3H, C1–CH₃), 3.16 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 3.30 (s, 3H, CH₃), 3.84 (s, 3H, CH₃), 7.36 (d, J = 15.7 Hz, 1H, –CH=CH̲–COO–), 7.46 (d, J = 3.9 Hz, 1H, C3–H), 7.50 (d, J = 10.9 Hz, 1H, C5–H), 7.61 (dd, J = 10.9, 1.9 Hz, 1H, C6–H), 7.74 (d, J = 3.9 Hz, 1H, C2–H), 8.30 (d, J = 1.9 Hz, 1H, C8–H), 8.51 (d, J = 15.7 Hz, 1H, –CH̲=CH–COO–) ppm. ¹³C NMR (500 MHz, (CD₃)₂CO) δ 13.0, 24.9, 32.6 (br), 39.0, 62.4, 113.0, 121.2, 122.5, 127.1, 134.2, 135.7, 138.0, 138.4, 138.8, 140.1, 142.2, 143.7, 166.7 (br) ppm. IR ν_max 977, 1001, 1378, 1414, 1652, 2958 cm⁻¹. HRMS (ESI⁺): calc. for C₁₉H₂₃NO₂ [M + H]⁺ 298.1810, found 298.1812.

(Z)-N-tert-Butyl-1-(7-isopropyl-1-methylazulen-4-yl)methanimine oxide (23). To aldehyde 11 (70 mg, 0.3 mmol, 1.0 eq.) was added N-tert-butylhydroxylamine hydrochloride (62 mg, 0.5 mmol, 1.5 eq.) and pyridine (5 mL) under nitrogen. The mixture was stirred at 95 °C until all the starting material was consumed by TLC (3 h). After cooling to rt, the pyridine was evaporated under reduced pressure. The mixture was diluted with water (10 mL) and extracted with EtOAc (3 × 30 mL) and the combined organic fractions were washed with brine and dried over MgSO₄ and filtered. The filtrate was evaporated under reduced pressure to yield a turquoise/green waxy gum (64 mg, 69%). ¹H NMR (500 MHz, (CDCl₃) δ 1.38 (d, J = 6.9 Hz, 6H, –CH(CH̲₃)₂), 1.71 (s, 9H, C(CH₃)₃), 2.68 (s, 3H, C1–CH₃), 3.12 (hept, J = 6.9 Hz, 1H, –CH̲(CH₃)₂), 7.18 (d, J = 3.7 Hz, 1H, C3–H), 7.57 (dd, J = 11.0, 2.0 Hz, 1H, C6–H), 7.67 (d, J = 3.7 Hz, 1H, C2–H), 8.21 (d, J = 1.8 Hz, 1H, C8–H), 8.37 (s, 1H, –CH=N), 8.85 (d, J = 11.0 Hz, C5–H) ppm. ¹³C NMR (500 MHz, (CDCl₃) δ 13.1, 24.7, 28.6, 38.7, 72.6, 109.7, 121.5, 125.4, 129.5, 133.5, 134.0, 135.3, 137.1, 137.4, 138.4, 143.3 ppm. IR ν_max 766, 1131, 1361, 1537, 2958 cm⁻¹. HRMS (ESI⁺): calc. for C₁₉H₂₅NO [M + H]⁺ 284.2009, found 284.2019.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the University of Bath for funding. TDJ wishes to thank the Royal Society for a Wolfson Research Merit Award and the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University for support (2020ZD01).

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2047319. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d0ob02567d

‡ Although 10 has not been reported previously, various substituted analogues have been described, having been formed under Vilsmeier conditions – see ref. 41.

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