A short synthesis of pyridines from deprotonated α-aminonitriles by an alkylation/RCM sequence

Carina Weber 1 , Marco M. Nebe 1 , Lukas P.V. Kaluza 1 , and Till Opatz 2
  • 1 Johannes Gutenberg-University, Institute of Organic Chemistry
  • 2 Johannes Gutenberg-University, Institute of Organic Chemistry
Carina Weber, Marco M. Nebe, Lukas P.V. Kaluza and Till Opatz

Abstract

α-Aminonitriles can serve as versatile key precursors for the synthesis of nitrogen containing heterocycles. After unsuccessful trials involving the [1,2]-Stevens rearrangement of nitrile-stabilized ammonium ylides, we herein report a simple three-step synthesis of substituted pyridines based on an alkylation/ring-closing metathesis/aromatization sequence.

1 Introduction

Pyridines are an important class of nitrogen heterocycles and find widespread application in pharmacology, crop science and materials science. In the course of our ongoing work on the development of new synthetic methods based on the chemistry of deprotonated α-aminonitriles, we sought for a novel access to polysubstituted pyridines using these versatile intermediates [18]. Herein, we report a modular approach towards 2-arylpyridines using α-aminonitrile chemistry in combination with ring-closing metathesis (RCM) to construct the heterocyclic core. Even though RCM is a frequently used tool in the synthesis of cyclic compounds, its application in pyridine synthesis is exceedingly rare [9, 10].

2 Results and discussion

Based on our previous work on Stevens rearrangements of nitrile-stabilized ammonium ylides for the construction of heterocycles [11, 12], a first attempt was to synthesize substituted pyridines from quaternary ammonium salts 3 derived from N,N-diallyl-α-aminonitriles 2 (Scheme 1). The [1,2]-Stevens rearrangement forming the six-membered ring should be performed on the substituted 3-pyrrolinium triflate 4. Several synthetic approaches (Scheme 1) towards compound 4 involving Strecker reactions and ring-closing metathesis (RCM) were investigated.

Scheme 1:
Scheme 1:

Synthetic approaches towards precursor 4 for the [1,2]-Stevens rearrangement.

Citation: Zeitschrift für Naturforschung B 71, 6; 10.1515/znb-2016-0005

Starting from inexpensive diallylamine and benzaldehyde, a Strecker reaction yielded N,N-diallyl-α-aminonitrile 2 [13, 14] which was N-methylated with methyl triflate to obtain the quaternary ammonium salt 3 [13]. In order to dissolve the triflate salt 3 it was required to use polar solvents, which have previously been applied in RCM reactions on other substrates [15, 16]. In our case, however, these reactions resulted either in no conversion or in decomposition of the starting material (Table 1) in various experiments.

Table 1:

Reaction conditions and results of the ring-closing metathesis experiments with 3 and 5.

SubstrateTemperatureCatalystaCatalyst loading (mol%)SolventReaction timeResult
3r. t.85.0AcOH24 hNo conversionb
3r. t.115.0acetone-H2O (2:1)24 hNo conversionb
3r. t.105.0acetone-H2O (2:1)24 hNo conversionb
350°C105.0DME-H2O (2:1)24 hComplex mixtureb
380°C115.0DME-H2O (4:1)24 hComplex mixtureb
5r. t.81.0CH2Cl224 hIncomplete conversionb
5r. t.80.5CH2Cl224 hIncomplete conversionb
5r. t.82.0CH2Cl22 h99%c

aSee Fig. 1; bmonitored by thin layer chromatography; cisolated yield.

Fig. 1:
Fig. 1:

Ruthenium catalysts used for ring-closing metathesis experiments.

Citation: Zeitschrift für Naturforschung B 71, 6; 10.1515/znb-2016-0005

Based on these results, the reaction sequence was reversed and the ring-closing metathesis with the Grubbs I catalyst on Boc-protected diallylamine 5 was performed first. After acidolytic removal of the Boc group from the resulting 3-pyrroline 6 followed by in situ Strecker reaction with benzaldehyde and potassium cyanide, N-methylation of the so formed α-aminonitrile led to the desired rearrangement precursor 4 in high yield. This route could later be shortened due to the unexpected discovery that α-aminonitrile 2 itself is a suitable substrate for ring-closing metathesis.

In order to generate ammonium ylide 12, which was assumed to undergo an energetically favorable in situ [1,2]-Stevens rearrangement, ammonium triflate 4 was deprotonated by potassium bis(trimethylsilyl)amide (KHMDS) at –78°C and was allowed to slowly warm up to room temperature. The reaction, however, led to a complex mixture of substances from which only the compounds 13, 16, and 17 could be isolated in low yields and were characterized by 1H NMR spectroscopy (Scheme 2).

Scheme 2:
Scheme 2:

Attempted [1,2]-Stevens rearrangement of 4.

Citation: Zeitschrift für Naturforschung B 71, 6; 10.1515/znb-2016-0005

Neither 1,6-dihydropyridine 14 nor the 2-phenylpyridinium salt 15 were detected. 1,2,3,6-Tetrahydropyridine 13 is the desired product of the [1,2]-Stevens rearrangement while the formation of penta-2,4-diene-1-imine 16 can be explained by dehydrocyanation of 13 to intermediate 14 followed by an electrocyclic ring-opening. The unexpected azetidine derivative 17 is assumed to be the product of a [2,3]-rearrangement, which has previously been reported for allyl-substituted ammonium ylides [12]. Since the route via [1,2]-Stevens rearrangement proved inefficient, this synthetic approach was abandoned.

The aforementioned successful ring-closing metathesis of α-aminonitrile 2 was somewhat surprising since compounds of this class can liberate cyanide, which can act as a poison to the ruthenium catalyst. There are also numerous reports that unprotected amines are no suitable substrates for olefin metathesis due to a decreased catalytic activity of the metal complexes employed. Electron withdrawing protecting groups or quantitative protonation with strong acids are frequently used to circumvent this problem [17]. However, already the first attempt of an RCM reaction on the diallylic aminonitrile 2 produced 7 in moderate yield (Scheme 1). Based on these results, we investigated an alternative approach for the preparation of substituted pyridines from α-aminonitriles (Scheme 3).

Scheme 3:
Scheme 3:

Alternative approach towards 2-phenylpyridine including RCM of α-aminonitrile 20.

Citation: Zeitschrift für Naturforschung B 71, 6; 10.1515/znb-2016-0005

Starting from benzaldehyde, allylamine and potassium cyanide, a Strecker reaction was carried out leading to 2-(allylamino)-2-phenylacetonitrile (19) in very high yield. α-Aminonitrile 19 was deprotonated by KHMDS [6] and alkylated with allyl bromide, again in almost quantitative yield. For the key step, the ring-closing metathesis of diallylic α-aminonitrile 20, various reaction conditions were tested (Table 2). The best results were obtained using 10 mol% of Grubbs’ second generation catalyst in dichloromethane at room temperature. Higher temperatures or the use of microwave radiation led to decomposition of the starting material and to an extensive formation of byproducts. Remarkably, 2-phenylpyridine (22) was identified as the sole RCM product while its assumed precursor 2- phenyl-1,2,3,6-tetrahydropyridine-2-carbonitrile (21) could not be detected. Hence, dehydrocyanation and oxidation of 21 both occur spontaneously, the latter reaction presumably is caused by the presence of air during work-up. These results disprove the assumption that cyanide is an efficient poison of the well-known and popular Grubbs II metathesis catalyst.

Table 2:

Optimization chart for the ring-closing metathesis of diallylamine 20.

SubstrateTemperatureCatalystaCatalyst loading (mol%)SolventReaction timeResult
20r. t.910.0CH2Cl218 h48%b of 22
20r. t.1110.0CH2Cl218 hIncomplete conversionc
20r. t.1010.0CH2Cl218 h19%c,d (22)
20r. t.95.0CH2Cl218 h55%c,d (22)
20r. t.92.0CH2Cl218 h21%c,d (22)
20r. t.115.0CH2Cl216 h36%c,d (22)
20r. t.112.0CH2Cl216 h21%c,d (22)
2040°C95.0CH2Cl23 hMixture of productsc
2040°C98.0CH2Cl26 hMixture of productsc
2070–100°Ce95.0CH2Cl21 hMixture of productsc
2090–140°Ce95.0CH2Cl21 hMixture of productsc
20110°C98.0toluene2.5 hMixture of productsc
20100–140°Ce95.0toluene1 hMixture of productsc

aSee Fig. 1; bisolated yield; cmonitored by thin layer chromatography; ddetermined by 1H NMR; emicrowave irradiation.

In order to extend the invented method to pyridines with a different substitution pattern, the sequence was repeated using 1-amino-1-phenylprop-2-ene (26) as the allylamine component. Amine 26 was prepared according to the literature in three steps from cinnamyl alcohol 23 (Scheme 4) [18, 19]. The Strecker reaction of 26, benzaldehyde (18) and potassium cyanide again proceeded in almost quantitative yield. The subsequent alkylation of 27 with allyl bromide was accomplished in a moderate yield of 76%. Using the same conditions for RCM as in the synthesis of 22, 2,6-diphenylpyridine (29) was isolated in 25% yield.

Scheme 4:
Scheme 4:

Preparation of 2,6-diphenylpyridine from α-aminonitrile 28via the alkylation/RCM sequence.

Citation: Zeitschrift für Naturforschung B 71, 6; 10.1515/znb-2016-0005

In contrast, the attempted C-alkylation of the potassium salt of 27 with the less reactive 3-chlorobut-1-ene was unsuccessful.

3 Conclusion

A modular three-step synthesis of pyridines from structurally simple starting materials using deprotonated α-aminonitriles was developed. A ring closing metathesis reaction on an unprotected allylic amine was employed as the key step of the sequence. The substrates for the RCM were conveniently synthesized from readily available allylic halides, allylic amines and aromatic aldehydes.

4 Experimental section

All chemicals were purchased from commercial suppliers and were used without further purification, unless otherwise stated. Reactions involving air- or moisture-sensitive compounds were carried out in oven dried glassware under an inert argon atmosphere. THF was freshly distilled from potassium under an argon atmosphere using benzophenone as an indicator. Dichloromethane used for RCM reactions was dried over CaH2, freshly distilled and degassed by three consecutive freeze-pump-thaw cycles prior to use. Thin-layer chromatography (TLC) was performed on 0.25 mm silica gel plates (60F254). Substance bands were visualized by UV light and by developing with ninhydrine solution (1.5 g of ninhydrine and 15 mL AcOH in 485 mL of MeOH), potassium permanganate solution (2.0 g KMnO4 and 5.5 g Na2CO3 in 250 mL of H2O), or 2,4-dinitrophenylhydrazine (DNPH) solution (4.0 g DNPH in 100 mL of ketone free EtOH, 32 mL of H2O, 20 mL of H2SO4). Flash column chromatography was carried out on 35–70 μm silica gel obtained from Acros Organics eluting with the specified solvent ratios in parts by volume. NMR spectra were recorded on a Bruker Avance-III HD 300 MHz or a Bruker Avance-II 400 MHz spectrometer. Chemical shifts were referenced to the residual solvent signal (δ = 7.26 ppm and 77.16 ppm for CDCl3, δ = 2.05 ppm and 29.84 ppm for [D6]acetone) [20]. FT-IR spectra were recorded on a Bruker Tensor 27 FT-IR spectrometer using a diamond ATR unit. Melting points were determined using open capillary tubes in an electronic apparatus from A. Krüss Optronic GmbH, Hamburg (Germany). Reaction monitoring by LC-MS was carried out with a 1200-series HPLC system from Agilent Technologies with a binary pump and a diode array detector, linked to a Bruker LC/MSD trap mass spectrometer. Ionization was accomplished by electrospray ionization (ESI). High-resolution mass spectrometry was performed on a Waters QTof-Ultima 3-Instrument with a dual electrospray source and an external calibrant.

4.1 Diallylamino(phenyl)acetonitrile (2)

Benzaldehyde (2.65 g, 25.0 mmol, 1.0 eq) was dissolved in water (140 mL) and methanol (35 mL) and sodium bisulfite (2.60 g, 25.0 mmol, 1.0 eq) were added. The mixture was stirred at ambient temperature for 2 h, before diallylamine (2.43 g, 25.0 mmol, 1.0 eq) and potassium cyanide (3.26 g, 50.0 mmol, 2.0 eq) were added at once. After stirring at ambient temperature for 20 h, a constant nitrogen-stream was passed through the mixture in order to remove excess hydrogen cyanide formed during the reaction (CAUTION!). The resulting solution was extracted with CH2Cl2 (4 × 50 mL), the combined organic layers were washed with water (2 × 50 mL) and brine (2 × 50 mL), dried over sodium sulfate and the solvent was removed under reduced pressure to yield 2 as a yellow oil (2.69 g, 12.7 mmol, 85%). – Rf = 0.76 (Cy-EtOAc-NEt3 3:1:1). C14H16N2 (212.3). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 7.58–7.53 (m, 2H, Ph-2,6-H), 7.43–7.35 (m, 3H, Ph-3,4,5-H), 5.80 (dddd, 2H, J = 17.2, 10.1, 8.4, 4.1 Hz, 2 × CH=CH2), 5.36–5.19 (m, 4H, 2 × CH=CH2), 5.12 (s, 1H, CHCN), 3.37 (ddt, 2H, J = 14.0, 4.1, 1.9 Hz, NCH2a), 2.94 (ddt, 2H, J = 14.0, 8.4, 0.8 Hz, NCH2b). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 134.7 (2C, CH=CH2), 134.0 (Ph-C-1), 128.9 (Ph-C-3,5), 128.9 (Ph-C-4), 127.8 (Ph-C-2,6), 119.1 (2C, CH=CH2), 115.8 (CN), 57.6 (CHCN), 53.9 (2C, NCH2). – IR (ATR): v (cm−1 ) = 3082, 2820, 2250, 1644, 1495, 1451, 1421, 1115, 996, 975, 923, 740, 698. – MS (ESI): m/z (%) = 213.1 (100) [M+H]+. – HRMS ((+)-ESI): m/z = 213.1400 (calcd. 213.1392 for C14H17N2, [M+H]+).

4.2 N-[Cyano(phenyl)methyl]-N,N-diallyl-N-methylammonium trifluoromethanesulfonate (3)

Under an argon atmosphere, methyl trifluoromethanesulfonate (0.70 mL, 6.36 mmol, 1.5 eq) was added dropwise at 0°C to a solution of aminonitrile 2 (900 mg, 4.24 mmol, 1.0 eq) in CH2Cl2 (6 mL). The resulting solution was stirred at ambient temperature for 3 days before another portion of methyl trifluoromethanesulfonate (0.43 mL, 3.91 mmol, 0.9 eq) was added. Stirring was continued for further 30 h. A few drops of water were added and the solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO2, CHCl3-MeOH gradient: 0→15% MeOH) to obtain 3 as a yellow oil (1.09 g, 2.88 mmol, 68%). – Rf = 0.18 (CHCl3-MeOH 9:1). C16H19F3N2O3S (376.4). – 1H NMR, COSY (400 MHz, [D6]acetone): δ (ppm) = 7.96–7.93 (m, 2H, Ph-2,6-H), 7.75–7.63 (m, 3H, Ph-3,4,5-H), 6.38–6.23 (m, 3H, 2 × CH=CH2, CHCN), 5.97–5.79 (m, 4H, 2 × CH=CH2), 4.46–4.31 (m, 3H, 3 × H NCH2), 4.17 (dd, J = 13.4, 7.5 Hz, 1H, 1 × NCH2), 3.34 (s, 3H, NCH3). – 13C NMR, HSQC, HMBC (100.6 MHz, [D6]acetone): δ (ppm) = 133.1 (Ph-C-4), 133.0 (Ph-C-2,6), 130.3 (Ph-C-3,5), 130.2 (CH=CaH2), 130.1 (CH=CbH2), 124.8 (Ph-C-1), 124.7 (CaH=CH2), 124.5 (CbH=CH2), 121.5 (q, J = 320.5 Hz, CF3), 113.5 (CN), 65.3 (CHCN), 64.3 (NCaH2), 63.9 (NCbH2), 46.2 (CH3). – IR (ATR): v (cm−1) = 2945, 2210, 1709, 1461, 1432, 1284, 1223, 1167, 1025, 960, 747, 703, 635. – MS (ESI): m/z (%) = 227.1 (100) [M]+. – HRMS ((+)-ESI): m/z = 227.1555 (calcd. 227.1548 for C15H19N2, [M]+).

4.3 tert-Butyl N,N-diallylcarbamate (5)

The title compound was prepared according to a procedure by Stürmer [21]. A solution of di-tert-butyl dicarbonate (14.15 g, 64.83 mmol, 1.0 eq) in cyclohexane (30 mL) was added slowly to diallylamine (7.97 mL, 64.84 mmol, 1.0 eq) in cyclohexane (10 mL) at 10°C. The mixture was allowed to warm to ambient temperature and stirred for 21 h. It was then washed with 0.01 m aq. HCl (4 × 10 mL) and sat. aq. NaHCO3 (3 × 10 mL). The organic phase was dried over sodium sulfate and the solvent was evaporated under reduced pressure to yield 5 as a light yellow liquid (11.70 g, 59.30 mmol, 92%; lit. [21]: 93%). – Rf = 0.61 (Cy-EtOAc 4:1). C11H19NO2 (197.3). – 1H NMR (300 MHz, CDCl3): δ (ppm) = 5.82–5.69 (m, 2H, CH=CH2), 5.13–5.06 (m, 4H, CH=CH2), 3.79 (dt, J = 5.8, 1.5 Hz, 4H, NCH2), 1.45 (s, 9H, C(CH3)3). The spectroscopic data are in accordance with the literature [21].

4.4 tert-Butyl 2,5-dihydro-1H-pyrrole-1-carboxylate (6)

A solution of 5 (807 mg, 4.09 mmol, 1 eq) in degassed dry CH2Cl2 (10 mL) was added to a solution of Grubbs’ first generation metathesis catalyst (8; 68 mg, 0.082 mmol, 2 mol%) in degassed dry CH2Cl2 (70 mL) under an argon atmosphere. The mixture was heated under reflux for 2 h after which the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (SiO2, Cy-EtOAc 3:1) to obtain 6 as a brown oil (683 mg, 4.03 mmol, 99%). – Rf = 0.36 (Cy-EtOAc 3:1). C9H15NO2 (169.2). – 1H NMR (300 MHz, CDCl3): δ (ppm) = 5.76 (s, 2H, CH), 4.11 (s, 4H, CH2), 1.47 (s, 9H, C(CH3)3). The spectroscopic data are in accordance with the literature [21].

4.5 2,5-Dihydro-1H-pyrrol-1-yl(phenyl)acetonitrile (7)

4.5.1 Method A – Deprotection of 6 and in situ Strecker reaction

To a solution of 6 (99 mg, 0.59 mmol, 1.0 eq) in dry CH2Cl2 (2 mL) at 0°C was slowly added trifluoroacetic acid (670 mg, 5.86 mmol, 10.0 eq). The solution was allowed to warm to ambient temperature and stirred for 4 h. Potassium cyanide (76 mg, 1.23 mmol, 2.0 eq), benzaldehyde (6 mg, 0.59 mmol, 1.0 eq), sodium acetate (480 mg, 5.86 mmol, 10.0 eq), and methanol (0.7 mL) were added and the mixture was stirred for an additional 48 h. The mixture was quenched with water (2 mL) and extracted with CH2Cl2 (3 × 2 mL). The combined organic extracts were dried over sodium sulfate and the solvent was evaporated under reduced pressure to yield 7 as a brown oil (69 mg, 0.38 mmol, 64%).

4.5.2 Method B – Ring-closing metathesis of 2

A solution of 2 (14.3 mg, 68 μmol, 1 eq) in degassed dry CH2Cl2 (1.1 mL) was added to a solution of Grubbs-Hoveyda catalyst II (11; 4.2 mg, 6.8 μmol, 10 mol%) in degassed dry CH2Cl2 (0.3 mL) under an argon atmosphere. The mixture was stirred at ambient temperature for 18 h after which the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (SiO2, Cy-EtOAc 4:1) to obtain 7 as a yellow oil (6.6 mg, 36 μmol, 53%). – Rf = 0.45 (Cy-EtOAc 4:1). C12H12N2 (184.2). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 7.58–7.34 (m, 2H, Ph-2,6-H), 7.44–7.34 (m, 3H, Ph-3,4,5-H), 5.79–5.78 (m, 2H, CH), 5.10 (s, 1H, CHCN), 3.69–3.52 (m, 4H, CH2). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 134.2 (Ph-C-1), 129.0 (Ph-C-3,4,5), 127.7 (Ph-C-2,6), 127.1 (2C, CH), 116.8 (CN), 59.5 (CHCN), 56.8 (2C, CH2). – IR (ATR): v (cm−1) = 3066, 3034, 2943, 2889, 2795, 1718, 1494, 1452, 1367, 1271, 1151, 708. – MS (ESI): m/z (%) = 185.1 (100) [M+H]+. – HRMS ((+)-ESI): m/z = 185.1087 (calcd. 185.1079 for C12H13N2, [M+H]+).

4.6 1-[Cyano(phenyl)methyl]-1-methyl-2,5-dihydro-1H-pyrrolium trifluoromethanesulfonate (4)

Under argon atmosphere, methyl trifluoromethanesulfonate (110 mg, 0.68 mmol, 1.5 eq) was added dropwise at 0°C to a solution of compound 7 (83 mg, 0.45 mmol, 1.0 eq) in CH2Cl2 (0.64 mL). The solution was allowed to warm to ambient temperature and stirred for 18 h, after which the solvent was removed under reduced pressure. The crude product was purified by column chromatography (SiO2, CHCl3-MeOH gradient: 0→20% MeOH) to obtain 4 as a light brown solid (184 mg, 0.43 mmol, 94%). – M. p. 86.0–88.3°C (CHCl3-MeOH). – Rf = 0.22 (CHCl3-MeOH 4:1). C14H15F3N2O3S (348.3). – 1H NMR, COSY (300 MHz, [D6]acetone): δ (ppm) = 7.98–7.95 (m, 2H, Ph-2,6-H), 7.77–7.65 (m, 3H, Ph-3,4,5-H), 6.75 (s, 1H, CHCN), 6.17–6.11 (m, 2H, CH), 5.16–5.02 (m, 2H, CH2a,a′), 4.67–4.60 (m, 1H, CH2b), 4.44–4.37 (m, 1H, CH2b′), 3.45 (s, 3H, NCH3). – 13C NMR, HSQC, HMBC (75.5 MHz, [D6]acetone): δ (ppm) = 133.5 (Ph-C-4). 132.3 (Ph-C-2,6), 130.8 (Ph-C-3,5), 126.4 (Ph-C-1), 125.2 (CaH), 125.0 (CbH), 122.0 (q, J = 321 Hz, CF3), 114.2 (CN), 71.3 (2 C, CH2), 66.5 (CHCN), 50.7 (NCH3). – IR (ATR): v (cm−1) = 2944, 2362, 1635, 1460, 1256, 1229, 1169, 1032, 790, 760, 705, 669, 639. – MS (ESI): m/z (%) = 199.0 (100) [M]+. – HRMS ((+)-ESI): m/z = 199.1245 (calcd. 199.1235 for C13H15N2, [M]+).

4.6.1 Stevens rearrangement of compound 4

Compound 4 (248 mg, 0.71 mmol, 1 eq) was dissolved in dry THF (13 mL) and KHMDS (187 mg, 0.93 mmol, 1.3 eq) was added portionwise at −78°C. The mixture was allowed to slowly warm to ambient temperature and was stirred for a further 2 h, after which the solvent was evaporated under reduced pressure. The residue was taken up in sat. aq. NaHCO3 (20 mL) and extracted with EtOAc. The combined organic layers were washed three times with brine, dried over sodium sulfate and the solvent evaporated under reduced pressure. The crude product mixture was purified by column chromatography (SiO2, Cy-EtOAc 30:1–1:1) to yield the following products:

4.7 1-Methyl-2-phenyl-1,2,3,6-tetrahydropyridine-2-carbonitrile (13)

Isolated as a yellow oil (9 mg, 0.045 mmol, 7%). – Rf = 0.13 (Cy-EtOAc 30:1). C13H14N2 (198.3). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 7.65–7.62 (m, 2H, Ph-2,6-H), 7.45–7.36 (m, 3H, Ph-3,4,5-H), 5.90–5.75 (m, 2H, 4,5-H), 3.56 (d, J = 17.7 Hz, 1H, 6-Ha), 3.16 (d, J = 17.7 Hz, 1H, 6-Hb), 2.75 (d, J = 18.1 Hz, 1H, 3-Ha), 2.54–2.46 (m, 1H, 3-Hb), 2.09 (s, 3H, NCH3). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 129.1 (Ph-C-3,5), 129.0 (Ph-C-6), 126.5 (Ph-C-2,4), 125.3 (C-5), 122.2 (C-4), 116.5 (CN), 65.7 (C-2), 53.0 (C-6), 41.2 (C-3), 40.5 (NCH3). – IR (ATR): v (cm−1) = 3041, 2915, 2794, 2220, 1493, 1449, 1252, 1053, 757, 701. – MS (ESI): m/z (%) = 199.1 (100) [M+H]+, 172.1 (53) [M–CN]+. – HRMS ((+)-ESI): m/z = 199.1245 (calcd. 199.1235 for C13H15N2, [M+H]+).

4.8 (1Z,2Z)-N-methyl-1-phenylpenta-2,4-dien-1-imine (16)

Isolated as a colorless oil (6 mg, 0.035 mmol, 6%). – Rf = 0.64 (Cy-EtOAc 30:1). – C12H13N (171.2). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 7.54–7.49 (m, 2H, Ph-2,6-H), 7.42–7.33 (m, 3H, Ph-3,4,5-H), 6.61 (dddd, J = 16.8, 11.2, 10.2, 1.1 Hz, 1H, 4-H), 6.19–6.10 (m, 1H, 2-H), 5.56–5.50 (m, 1H, 3-H), 5.26–5.16 (m, 2H, CH2), 3.34 (s, 3H, NCH3). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 171.1 (C-1), 135.8 (Ph-C-1), 130.9 (C-2), 130.7 (C-4), 130.5 (Ph-C-4), 128.5 (Ph-C-2,6), 128.2 (Ph-C-3,5), 120.4 (C-3), 119.3 (C-5), 36.9 (br, CH3). – IR (ATR): v (cm−1) = 3065, 2937, 2251, 1630, 1578, 1060, 906, 727. – MS (ESI): m/z (%) = 172.2 (100) [M+H]+. – HRMS ((+)-ESI): m/z = 172.1122 (calcd. 172.1126 for C12H14N, [M+H]+).

4.9 3-Ethenyl-1-methyl-2-phenylazetidine-2-carbonitrile (17)

Isolated as a colorless oil (3 mg, 0.015 mmol, 2%). – Rf = 0.27 (Cy-EtOAc 30:1). – C13H14N2 (198.3). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 7.51–7.47 (m, 2H, Ph-2,6-H), 7.43–7.31 (m, 3H, Ph-3,4,5-H), 5.70–5.58 (m, 1H, CH=CH2), 5.08–4.98 (m, 2H, CH=CH2), 3.62–3.57 (m, 1H, 4-Ha), 3.49–3.41 (m, 2H, 4-Hb, 3-H), 2.52 (s, 3H, CH3). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 134.4 (2C, Ph-C-1, CH=CH2), 129.0 (Ph-C-4), 128.8 (Ph-C-3,5), 126.6 (Ph-C-2,6), 119.5 (CH=CH2), 118.8 (CN), 72.3 (C-2), 56.3 (NCH2), 47.46 (C-3), 39.13 (CH3). – IR (ATR): v (cm−1) = 2941, 2842, 2789, 2254, 2221, 1733, 1449, 987, 905. – MS (ESI): m/z (%) = 199.4 (38) [M+H]+, 172.2 (100) [M–CN]+. – HRMS ((+)-ESI): m/z = 199.1259 (calcd. 199.1235 for C13H15N2, [M+H]+), 172.1140 (calcd. 172.1126 for C12H14N, [M–CN]+).

4.10 Phenyl(prop-2-en-1-ylamino)acetonitrile (19)

A solution of benzaldehyde (2.53 mL, 25.0 mmol, 1.0 eq) and allylamine (1.88 mL, 25.0 mmol, 1.0 eq) in methanol (60 mL) was stirred at ambient temperature for 150 min. Potassium cyanide (2.44 g, 37.5 mmol, 1.5 eq) and acetic acid (2.15 mL, 37.5 mmol, 1.5 eq) were added and stirring was continued for a further 3 h. Water (40 mL) was added and a constant stream of nitrogen was passed through, in order to remove excess hydrogen cyanide formed during the reaction (CAUTION!). The resulting solution was extracted with CH2Cl2 (3 × 20 mL) under an argon atmosphere, the combined organic extracts were washed with brine (2 × 20 mL), dried over sodium sulfate and the solvent was removed under reduced pressure to yield 19 as a red oil (4.16 g, 24.1 mmol, 96%). – Rf = 0.43 (Cy-EtOAc 4:1). C11H12N2 (172.2). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 7.56–7.50 (m, 2H, Ph-2,6-H), 7.44–7.37 (m, 3H, Ph-3,4,5-H), 5.90 (dddd, J = 17.0, 10.2, 6.5, 5.5 Hz, 1H, CH=CH2), 5.37–5.16 (m, 2H, CH=CH2), 4.79 (s, 1H, 2-H), 3.54–3.35 (m, 2H, NCH2), 1.66 (br s, 1H, NH). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 134.8 (2C, CH=CH2, Ph-C-1), 129.0 (Ph-C-4), 129.0 (Ph-C-3,5), 127.3 (Ph-C-2,6), 118.8 (CN), 117.8 (CH=CH2), 53.5 (C-2), 49.8 (NCH2). The spectroscopic data are in accordance with the literature [22].

4.11 2-Phenyl-2-(allylamino)pent-4-enenitrile (20)

Compound 19 (1.61 g, 9.33 mmol, 1.0 eq) was dissolved in dry THF (93 mL) under an argon atmosphere and the resulting solution was cooled to −78°C. KHMDS (2.42 g, 12.13 mmol, 1.3 eq) was added portionwise and the red mixture was stirred for 10 min. Allyl bromide (0.81 mL, 9.33 mmol, 1.0 eq) was added dropwise and stirring was continued for another hour. The mixture was allowed to warm to ambient temperature slowly over a period of 30 min, after which the solvent was removed under reduced pressure at ambient temperature. The residue was taken up in 1 m aq. HCl (50 mL) and extracted with CH2Cl2 (4 × 20 mL). The combined organic extracts were washed with brine (2 × 20 mL), dried over sodium sulfate and the solvent was removed under reduced pressure at ambient temperature. The crude product was filtered over a short plug of silica gel, eluting with Cy-EtOAc (4:1) to yield 20 as a yellow oil (1.91 g, 9.00 mmol, 97%). – Rf = 0.67 (Cy-EtOAc 4:1). C14H16N2 (212.3). – 1H NMR, COSY (400 MHz, CDCl3): δ (ppm) = 7.62–7.59 (m, 2H, Ph-2,6-H), 7.43–7.32 (m, 3H, Ph-3,4,5-H), 5.93–5.76 (m, 2H, 4-H, NCH2CH=CH2), 5.28–5.21 (m, 3H, 2 × 5-H, NCH2CH=CH2a), 5.12–5.08 (m, 1H, NCH2CH=CH2b), 3.36–3.29 (m, 1H, NCH2a), 3.03–2.98 (m, 1H, NCH2b), 2.72–2.56 (m, 2H, 3-H). – 13C NMR, HSQC, HMBC (100.6 MHz, CDCl3): δ (ppm) = 138.4 (Ph-C-1), 135.4 (NCH2CH=CH2), 131.1 (C-4), 128.9 (Ph-C-3,5), 128.7 (Ph-C-4), 126.1 (Ph-C-2,6), 121.7 (C-5), 120.3 (CN), 116.5 (NCH2CH=CH2), 64.0 (C-2). 48.3 (C-3), 47.5 (NCH2). – IR (ATR): v (cm−1) = 3324, 3081, 2983, 2917, 2843, 1643, 1447, 1117, 993, 922, 762, 699. – MS (ESI): m/z (%) = 186.3 (100) [M–CN]+. – HRMS ((+)-ESI): m/z = 186.1283 (calcd. 186.1283 for C13H16N, [M–CN]+).

4.12 Phenyl[(1-phenylprop-2-en-1-yl)amino]acetonitrile (27)

This compound was prepared as described for 19 using benzaldehyde (3.25 mL, 32.1 mmol, 1.0 eq) and 1-phenylprop-2-en-1-amine (4.28 g, 32.1 mmol, 1.0 eq) in methanol (70 mL), potassium cyanide (3.13 g, 48.1 mmol, 1.5 eq) and acetic acid (2.75 mL, 48.1 mmol, 1.5 eq) to yield 27 as a red oil (7.50 g, 30.2 mmol, 94%). The compound was isolated as 1:1 mixture of two diastereomers A and B. – Rf = 0.46 (hexanes-EtOAc 10:1). C17H16N2 (248.3). – 1H NMR, COSY (300 MHz, CDCl3), characteristic signals of diastereomer A: δ (ppm) = 7.61–7.44 (m, 4H, 2-Ph-2,6-H, 1′-Ph-2,6-H), 7.48–7.26 (m, 6H, 2-Ph-3,4,5-H, 1′-Ph-3,4,5-H), 5.98–5.86 (m, 1H, 2′-H), 5.32 (dt, J = 17.1, 1.2 Hz, 1H, 3′-H), 5.15 (dt, J = 10.2, 1.1 Hz, 1H, 3′-H), 4.86 (d, J = 9.9 Hz, 1H, 2-H), 4.59 (d, J = 8.0 Hz, 1H, 1′-H), 2.02–1.77 (m, 1H, NH). Characteristic signals of diastereomer B: δ (ppm) = 7.61–7.44 (m, 2H, 2-Ph-2,6-H), 7.48–7.26 (m, 8H, 2-Ph-3,4,5-H, 1′-Ph-3,4,5-H, 1′-Ph-2,6-H), 6.01 (ddd, J = 17.1, 10.1, 7.0 Hz, 1H, 2′-H), 5.54 (dt, J = 17.1, 1.2 Hz, 1H, 3′-H), 5.29 (ddd, J = 10.1, 1.3, 0.5 Hz, 1H, 3′-H), 4.64 (d, J = 7.0 Hz, 1H, 1′-H), 4.46 (d, J = 9.9 Hz, 1H, 2-H), 2.02–1.77 (m, 1H, NH). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 141.5 (1′-Ph-C-1 A), 140.3 (1′-Ph-C-1 B), 139.9 (C-2′ B), 138.8 (C-2′ A), 135.1 (2C, 2-Ph-C-1 A+B), 129.1 (4C, CAR), 128.9 (CAR), 128.2 (CAR), 128.1 (CAR), 127.8 (CAR), 127.5 (CAR), 127.4 (CAR), 127.3 (CAR), 119.0 (CN, A), 118.9 (CN, B), 117.9 (C-3′, B), 116.1 (C-3′, A), 64.8 (C-1′, B), 64.6 (C-1′, A), 52.3 (C-2, A), 51.9 (C-2, B). – As a mixture of two diastereomers A and B. – IR (ATR): v (cm−1) = – 3314, 3063, 3031, 1602, 1494, 1452, 1275, 992, 697, 650. – MS (ESI): m/z (%) = 222.0 (100) [M–CN]+. – HRMS ((+)-ESI): m/z = 222.1290 (calcd. 222.1283 for C16H16N, [M–CN]+).

4.13 2-Phenyl-2-[(1-phenylprop-2-en-1-yl)amino]pent-4-enenitrile (28)

This compound was prepared as described for 20 using Compound 27 (585 mg, 2.36 mmol, 1.0 eq), KHMDS (593 mg, 3.06 mmol, 1.3 eq) and allyl bromide (0.21 mL, 2.43 mmol, 1.0 eq) to yield 28 as a yellow oil (543 mg, 1.80 mmol, 76%). – Rf = 0.54 (hexanes-EtOAc 10:1). C20H20N2 (288.4). – 1H NMR, COSY (300 MHz, CDCl3), characteristic signals of diastereomer A: δ (ppm) = 7.71–7.64 (m, 2H, 2-Ph-2,6-H), 7.44–7.12 (m, 8H, 2-Ph-3,4,5-H, 1′-Ph), 5.89–5.66 (m, 1H, 4-H), 5.64 (ddd, J = 17.1, 10.1, 7.1 Hz, 1H, 2′-H), 5.28–5.13 (m, 2H, 5-H), 5.05 (dt, J = 17.1, 1.2 Hz, 1H, 3′-H), 4.80 (dt, J = 10.1, 1.2 Hz, 1H, 3′-H), 4.47 (dt, J = 7.1, 1.2 Hz, 1H, 1′-H), 2.67–2.54 (m, 2H, 3-H), 2.23 (s br, 1H, NH). Characteristic signals of diastereomer B: δ (ppm) = 7.55–7.47 (m, 2H, 2-Ph-2,6-H), 7.44–7.12 (m, 8H, 2-Ph-3,4,5-H, 1′-Ph), 6.08 (ddd, J = 17.2, 10.2, 7.2 Hz, 1H, 2′-H), 5.89–5.66 (m, 1H, 4-H), 5.28–5.13 (m, 3H, 5-H, 3′-Ha), 5.14 (dt, J = 17.2, 1.2 Hz, 1H, 3′-Hb), 4.33 (dt, J = 7.2, 1.2 Hz, 1H, 1′-H), 2.72 (dt, J = 7.1, 1.1 Hz, 2H, 3-H), 2.23 (s br, 1H, NH). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 142.5 (1′-Ph-C-1 A), 142.3 (1′-Ph-C-1 B), 140.4 (C-2′ A), 139.9 (C-2′ B), 139.4 (2-Ph-C-1 A), 138.0 (2-Ph-C-1 B), 131.2 (C-4 A), 131.2 (C-4 B), 128.8 (CAr), 128.7 (CAr), 128.6 (CAr), 128.5 (2C, CAr), 128.3 (CAr), 127.7 (CAr), 127.4 (2C, CAr), 127.1 (CAr), 126.6 (2C, 2-Ph-C-2,6 A+B), 121.7 (2C, C-5 A+B), 120.9 (CN, B), 119.9 (CN, A), 116.6 (C-3′ B), 115.1 (C-3′ B), 63.8 (C-2 B), 63.5 (C-2 A), 63.3 (C-1′ A), 62.1 (C-1′ B), 48.8, 48.7 (C-3 A+B). – As a mixture of two diastereomers A and B. – IR (ATR): v (cm−1) = 3322, 3062, 2981, 2225, 1639, 1491, 1449, 1106, 924, 761, 701. – MS (ESI): m/z (%) = 289.1 (8) [M+H]+, 262.1 (100) [M–CN]+. – HRMS ((+)-ESI): m/z = 262.1589 (calcd. 262.1596 for C19H20N, [M–CN]+).

4.14 2-Phenylpyridine (22)

A solution of compound 21 (45 mg, 0.21 mmol, 1.0 eq) in degassed dry CH2Cl2 (36 mL) was added to a solution of Grubbs’ second generation metathesis catalyst (76; 18 mg, 0.021 mmol, 10 mol–%) in degassed dry CH2Cl2 (0.91 mL) under an argon atmosphere. The mixture was stirred at ambient temperature for 18 h before the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography (SiO2, Cy-EtOAc 20:1) to obtain 22 as a colorless oil (16 mg, 0.10 mmol, 48%). – Rf = 0.42 (Cy-EtOAc 4:1). C11H9N (155.0). – 1H NMR, COSY (400 MHz, CDCl3): δ (ppm) = 8.72–8.70 (m, 1H, 6-H), 8.02–7.97 (m, 2H, Ph-2,6-H), 7.79–7.73 (m, 2H, 3,4-H), 7.51–7.46 (m, 2H, Ph-3,5-H), 7.45–7.40 (m, 1H, Ph-4-H), 7.26–7.23 (m, 1H, 5-H). The spectroscopic data are in accordance with the literature [23].

4.15 2,6-Diphenylpyridine (29)

The title compound was prepared as described for 22 using compound 28 (67 mg, 0.23 mmol, 1.0 eq) and Grubbs’ second generation metathesis catalyst (76; 15.3 mg, 0.018 mmol, 8 mol–%). The crude product was purified by column chromatography (SiO2, hexanes-EtOAc 50:1) to yield 29 as a colorless oil (13 mg, 0,056 mmol, 24%). – Rf = 0.22 (hexanes-EtOAc 50:1). – C17H13N (231.3). – 1H NMR, COSY (300 MHz, CDCl3): δ (ppm) = 8.23–8.09 (m, 4H, 2′,6′-H), 7.86–7.77 (m, 1H, 4-H), 7.75–7.61 (m, 2H, 3,5-H), 7.56–7.48 (m, 4H, 3′,5′-H), 7.48–7.39 (m, 2H, 4′-H). – 13C NMR, HSQC, HMBC (75.5 MHz, CDCl3): δ (ppm) = 156.9 (C-2), 139.6 (C-1′), 137.6 (C-4), 129.1 (C-4′), 128.8 (C-3′,5′), 127.1 (C-2′,6′), 118.8 (C-3). – The spectroscopic data are in accordance with the literature [24].

Acknowledgments:

The authors thank Dr. J. C. Liermann and Lars Andernach (both Mainz) for NMR-spectroscopic analysis and Dr. N. Hanold (Mainz) for mass spectrometry.

References

  • [1]

    T. Opatz, Synthesis2009, 2009, 1941.

  • [2]

    N. Otto, T. Opatz, Chem. Eur. J.2014, 20, 13064.

  • [3]

    C. Kison, T. Opatz, Chem. Eur. J.2009, 15, 843.

  • [4]

    T. Opatz, D. Ferenc, Org. Lett.2006, 8, 4473.

  • [5]

    I. Bergner, T. Opatz, J. Org. Chem.2007, 72, 7083.

  • [6]

    N. Meyer, T. Opatz, Synlett2003, 2003, 1427.

  • [7]

    N. Meyer, T. Opatz, Synlett2004, 2004, 787.

  • [8]

    N. Meyer, F. Werner, T. Opatz, Synthesis2005, 2005, 945.

  • [9]

    W. A. L. van Otterlo, C. B. de Koning, Chem. Rev.2009, 109, 3743.

  • [10]

    M. D. Hill, Chem. Eur. J.2010, 16, 12052.

  • [11]

    J. C. Orejarena Pacheco, G. Lahm, T. Opatz, J. Org. Chem.2013, 78, 4985.

  • [12]

    G. Lahm, J. C. Orejarena Pacheco, T. Opatz, Synthesis2014, 46, 2413.

    • Crossref
    • Export Citation
  • [13]

    J. C. Orejarena Pacheco, T. Opatz, J. Org. Chem.2014, 79, 5182.

  • [14]

    A. A. Fleming, US Patent US5268498A, 1993.

  • [15]

    C. S. Adjiman, A. J. Clarke, G. Cooper, P. C. Taylor, Chem. Commun.2008, 2008, 2806.

  • [16]

    J. B. Binder, J. J. Blank, R. T. Raines, Org. Lett.2007, 9, 4885.

  • [17]

    C. Deraedt, M. d’Halluin, D. Astruc, Eur. J. Inorg. Chem.2013, 2013, 4881.

  • [18]

    L. E. Overman, J. Am. Chem. Soc.1976, 98, 2901.

  • [19]

    A. M. Schmidt, P. Eilbracht, J. Org. Chem.2005, 70, 5528.

  • [20]

    H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem.1997, 62, 7512.

  • [21]

    R. Stürmer, B. Schäfer, V. Wolfart, H. Stahr, U. Kazmaier, G. Helmchen, Synthesis2001, 2001, 46.

    • Crossref
    • Export Citation
  • [22]

    J. H. Atherton, J. Blacker, M. R. Crampton, C. Grosjean, Org. Biomol. Chem.2004, 2, 2567.

    • Crossref
    • PubMed
    • Export Citation
  • [23]

    H.-J. Cho, S. Jung, S. Kong, S.-J. Park, S.-M. Lee, Y.-S. Lee, Adv. Synth. Catal.2014, 356, 1056.

    • Crossref
    • Export Citation
  • [24]

    M.-N. Zhao, R.-R. Hui, Z.-H. Ren, Y.-Y. Wang, Z.-H. Guan, Org. Lett.2014, 16, 3082.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • [1]

    T. Opatz, Synthesis2009, 2009, 1941.

  • [2]

    N. Otto, T. Opatz, Chem. Eur. J.2014, 20, 13064.

  • [3]

    C. Kison, T. Opatz, Chem. Eur. J.2009, 15, 843.

  • [4]

    T. Opatz, D. Ferenc, Org. Lett.2006, 8, 4473.

  • [5]

    I. Bergner, T. Opatz, J. Org. Chem.2007, 72, 7083.

  • [6]

    N. Meyer, T. Opatz, Synlett2003, 2003, 1427.

  • [7]

    N. Meyer, T. Opatz, Synlett2004, 2004, 787.

  • [8]

    N. Meyer, F. Werner, T. Opatz, Synthesis2005, 2005, 945.

  • [9]

    W. A. L. van Otterlo, C. B. de Koning, Chem. Rev.2009, 109, 3743.

  • [10]

    M. D. Hill, Chem. Eur. J.2010, 16, 12052.

  • [11]

    J. C. Orejarena Pacheco, G. Lahm, T. Opatz, J. Org. Chem.2013, 78, 4985.

  • [12]

    G. Lahm, J. C. Orejarena Pacheco, T. Opatz, Synthesis2014, 46, 2413.

    • Crossref
    • Export Citation
  • [13]

    J. C. Orejarena Pacheco, T. Opatz, J. Org. Chem.2014, 79, 5182.

  • [14]

    A. A. Fleming, US Patent US5268498A, 1993.

  • [15]

    C. S. Adjiman, A. J. Clarke, G. Cooper, P. C. Taylor, Chem. Commun.2008, 2008, 2806.

  • [16]

    J. B. Binder, J. J. Blank, R. T. Raines, Org. Lett.2007, 9, 4885.

  • [17]

    C. Deraedt, M. d’Halluin, D. Astruc, Eur. J. Inorg. Chem.2013, 2013, 4881.

  • [18]

    L. E. Overman, J. Am. Chem. Soc.1976, 98, 2901.

  • [19]

    A. M. Schmidt, P. Eilbracht, J. Org. Chem.2005, 70, 5528.

  • [20]

    H. E. Gottlieb, V. Kotlyar, A. Nudelman, J. Org. Chem.1997, 62, 7512.

  • [21]

    R. Stürmer, B. Schäfer, V. Wolfart, H. Stahr, U. Kazmaier, G. Helmchen, Synthesis2001, 2001, 46.

    • Crossref
    • Export Citation
  • [22]

    J. H. Atherton, J. Blacker, M. R. Crampton, C. Grosjean, Org. Biomol. Chem.2004, 2, 2567.

    • Crossref
    • PubMed
    • Export Citation
  • [23]

    H.-J. Cho, S. Jung, S. Kong, S.-J. Park, S.-M. Lee, Y.-S. Lee, Adv. Synth. Catal.2014, 356, 1056.

    • Crossref
    • Export Citation
  • [24]

    M.-N. Zhao, R.-R. Hui, Z.-H. Ren, Y.-Y. Wang, Z.-H. Guan, Org. Lett.2014, 16, 3082.

FREE ACCESS

Journal + Issues

Search

  • View in gallery

    Synthetic approaches towards precursor 4 for the [1,2]-Stevens rearrangement.

  • View in gallery

    Ruthenium catalysts used for ring-closing metathesis experiments.

  • View in gallery

    Attempted [1,2]-Stevens rearrangement of 4.

  • View in gallery

    Alternative approach towards 2-phenylpyridine including RCM of α-aminonitrile 20.

  • View in gallery

    Preparation of 2,6-diphenylpyridine from α-aminonitrile 28via the alkylation/RCM sequence.