Application of the Nicholas reaction to the synthesis of dicobalt hexacarbonyl complexed diyne ethers

Journal of Organometallic Chemistry 776 (2015) 43e50

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Application of the Nicholas reaction to the synthesis of dicobalt hexacarbonyl complexed diyne ethers Jahangir Amin a, Majid Motevalli b, Christopher J. Richards a, * a b

School of Chemistry, University of East Anglia, Norwich Research Park, Norwich NR4 7TJ, UK School of Biological and Chemical Sciences, Queen Mary University of London, Mile End Road, London E1 4NS, UK

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 September 2014 Accepted 23 October 2014 Available online 31 October 2014

Addition of propargylic or homopropargylic ynols to dicobalt hexacarbonyl propargylium cations gave the expected ether products of the Nicholas reaction, with the exception of 4-phenyl-3-butyn-1-ol which gave a dihydrofuran due to propargylium cation promoted 5-endo ring-closure. Use of chiral dicobalt hexacarbonyl complexed propargylic ynols as both propargylium cation precursor and nucleophile gave racemic doubly complexed disymmetric diyne ethers, each as a single diastereoisomer. Addition of dicobalt hexacarbonyl complexed 1-phenyl-1-butyne-3-ene to the propargylium cation derived from dicobalt hexacarbonyl complexed 1-phenyl-1-butyn-3-ol, followed by the addition of a nucleophile (NuH), gave double complexed 1,7-diphenyl-3-Nu-5-methylhepta-1,6-diynes (d.r. > 10:1). © 2014 Elsevier B.V. All rights reserved.

Keywords: Alkynes Cobalt Ethers Cations Diastereoselective

Introduction Transition metal catalysed [2 þ 2 þ 2] cyclotrimerisation is a valuable procedure for the synthesis of arenes [1], including bicyclic compounds generated from linked diyne precursors (Scheme 1 e [a]) [2]. In a related process, that also proceeds via an intermediate metallocyclopentadiene [3], we have reacted ether and ester linked chiral diynes with (h5-cyclopentadienyl)cobaltdicarbonyl to give planar chiral cyclopentadienone metallocenes with moderate diastereoselectivity (Scheme 1 e [b]) [4]. In an extension of this chemistry we chose to explore the possibility of employing cobalt for the synthesis of ether linked diynes by utilisation of the Nicholas reaction starting from a dicobalt hexacarbonyl complexed propargylic alcohol (Scheme 1 e [c]) [5]. Subsequent generation of an intermediate metal-stabilised propargylium cation followed by addition of a nucleophile has been demonstrated repeatedly [6], but the use of ynols in this reaction is limited [7]. In this paper we describe our studies in this area, including the use of dicobalt hexacarbonyl complexed propargylic alcohols as nucleophilic components in a highly diastereoselective synthesis of C2-symmetric doubly-complexed diyne ethers. A series of propargylic alcohols 1aed were complexed by stirring with dicobalt octacarbonyl in dichloromethane at room temperature to give 2aed in high yield (Scheme 2). Treatment of 2a

* Corresponding author. Tel.: þ44 (0)1603 593890; fax: þ44 (0)1603 592003. E-mail address: [email protected] (C.J. Richards). http://dx.doi.org/10.1016/j.jorganchem.2014.10.030 0022-328X/© 2014 Elsevier B.V. All rights reserved.

with boron trifluoride etherate in dichloromethane at 0  C gave the corresponding propargylium cation in situ. Addition of 2-propyn-1ol or 3-phenyl-2-propyn-1-ol followed by aqueous sodium hydrogencarbonate work-up and chromatography resulted in the isolation of mono-complexed diyne ethers 3 and 4 respectively (Scheme 3). Further application of this procedure, with the objective of generating the homologue of 4, had a different outcome (Scheme 4). Addition of 4-phenyl-3-butyn-1-ol to the in-situ generated propargylium cation from 2a resulted in dihydrofuran 5 as the sole isolable product identified, in-part, by the absence of signals for uncomplexed alkyne carbons in the 13C NMR spectrum. Instead signals at 112.7 and 127.6 ppm were assigned to the alkene functionality resulting from electrophile promoted nucleophilic closure via 6 to give the 5-endo cyclisation product [8]. In the absence of the 4-phenyl substituent on the alkyne, the expected Nicholas-type reaction proceeded as expected with 3-butyn-1-ol giving adducts 7 and 8 from complexes 2a and 2b respectively (Scheme 5). Subsequent Sonogashira cross-coupling with iodobenzene introduced the 4-phenyl substituent and enabled the isolation of 9, the target of the reaction that resulted in dihydrofuran 5. The same sequence of reactions starting with 2b resulted in the isolation of complex 10. In addition to using the dicobalt hexacarbonylealkyne complexes as precursors to intermediate propargylium cations, we also wished to explore the use of these as nucleophilic components in these ether formation reactions. Although the reaction of a propargylic alcohol with the cation generated from it to give a

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J. Amin et al. / Journal of Organometallic Chemistry 776 (2015) 43e50

Scheme 1. Linked Diynes. Uses [a,b] and proposed method of synthesis [c].

symmetrical ether has been observed [7], the stereochemistry of this reaction does not appear to have been reported. To this end, and to ensure compete conversion to the intermediate carbocation, fluoroboric acid was added to complex 2a in ether at 35  C. After isolation of the resulting propargylium salt by filtration, dissolution in dichloromethane followed by the addition of a further equivalent of 2a gave the doubly-complexed diyne ether adduct 11 in good yield, and as a single isomer as determined by 1H NMR spectroscopy (Scheme 6). An X-ray crystal structure analysis revealed the relative configuration as R*, R* (Fig. 1). The formation of a single isomer from racemic starting materials is a consequence of the stereochemical lability of the intermediate dicobalt hexacarbonyl propargylium cation due to the antarafacial migration of an alkylidene moiety from one cobalt tricarbonyl unit to the other [9]. Rapid racemisation and minimisation of steric interaction as represented in Scheme 7 explains the observed selectivity for the C2isomer. When this protocol was repeated with 2b, the doubly complexed diyne ether 12 was also obtained as a single isomer, and the same relative stereochemistry confirmed by X-ray crystallography (Fig. 2, S*, S*-isomer shown). Boron trifluoride etherate may also be used to generate the intermediate propargylium cation, as demonstrated with the butyl-substituted starting material 2c which gave only doubly complexed diyne ether 13, with the stereochemistry assigned by analogy to 11 and 12 (Scheme 8). In contrast, a quite different outcome was observed with diphenyl congener 2d where THF was employed as the solvent to aid solubility in the propargylium cation generation step with

Scheme 4. Generation of dihydrofuran 5.

Scheme 5. Mono-complexed diyne ether synthesis and subsequent Sonogashira coupling.

fluoroboric acid. Following the addition of a further equivalent of 2d, an adduct was generated containing a new carbonecarbon bond in a diastereomeric ratio of 12:1 (Scheme 9). Following recrystallisation, the relative stereochemistry of the major isomer was revealed as R*, R* by X-ray crystallography (Fig. 3). Related coupling reactions of radicals generated in situ in THF from dicobalt hexacarbonyl propargylium cations containing an a-aryl substituent have been reported previously [10,11], the reactions proceeding with high diastereoselectivity to give predominantly racemic C2symmetric dimers, as observed in this example [12]. During the course of the synthesis of mono-complexed diyne ether 3, a further complex was isolated in 15% yield identified as doubly-complexed triyne 15 (Fig. 4), apparently as essentially a single diastereoisomer as determined by NMR spectroscopy. A

Scheme 2. Synthesis of dicobalt hexacarbonyl complexes 2aed.

Scheme 3. Synthesis of mono-complexed diyne ethers 3 and 4.

Scheme 6. Diastereoselective synthesis of doubly-complexed C2-symmetric diyne ethers 11 and 12.

J. Amin et al. / Journal of Organometallic Chemistry 776 (2015) 43e50

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Fig. 1. A representation of (R*, R*)-11 from the X-ray analysis. Principal bond lengths [Å] include: Co(1)eCo(2) 2.4685(7), Co(3)eCo(4) 2.4653(7), C(3)eC(4) 1.349(5), C(19)eC(20) 1.350(5). Principal bond angles [ ] include: C(4)eC(3)eC(1) 142.8(3), C(3)eC(4)eC(5) 142.4(3), C(20)eC(19)eC(17) 140.6(3), C(19)eC(20)eC(21) 142.6(3). Principal torsion angles [ ] include: C(3)eC(1)eO(1)eC(17) 139.4(3), C(19)eC(17)eO(1)eC(1) 156.1(3).

related by-product 16 was isolated in 3% yield from the reaction resulting in the generation of dihydrofuran 5. These can be rationalised by the addition to an intermediate dicobalt hexacarbonyl propargylium cation of the corresponding dicobalt

Scheme 7. Suggested basis of diastereoselectivity in the synthesis of 11, 12 and 13.

hexacarbonyl alkene elimination product 17, followed by trapping of the new propargylium cation by the ynol nucleophile (Scheme 10). This outcome is related to intramolecular alkene trapping of a dicobalt hexacarbonyl propargylium cation followed by intermolecular addition of a nucleophile [13]. To examine this further, complexed enyne 17 was generated in 82% yield from 2a by initial generation of the corresponding dicobalt hexacarbonyl propargylium cation followed by addition of two equivalents of DBU (Scheme 11). Complex 17 was also generated from 2a following addition of one equivalent of trifluoroacetic acid, albeit in a lower yield of 45%. Addition to 2a at 35  C of fluoroboric acid in ether, salt isolation and dissolution in dichloromethane, followed by addition of 17 and then 2-propyn-1-ol, gave 15 in 47% yield as a >10:1 ratio of diastereoisomers (Scheme 12, Table 1, entry 1). Repetition of this protocol employing methanol as a nucleophile gave 18, also as a >10:1 ratio of diastereoisomers (entry 2). When methanol was added after warming of the reaction mixture to room

Fig. 2. A representation of (S*, S*)-12 from the X-ray analysis. Principal bond lengths [Å] include: Co(1)eCo(2) 2.4770(4), Co(3)eCo(4) 2.4776(3), C(13)eC(14) 1.339(3), C(17)eC(18) 1.337(3). Principal bond angles [ ] include: C(13)eC(14)eC(15) 143.42(18), C(17)eC(18)eC(19) 143.26(18). Principal torsion angles [ ] include: C(14)eC(15)eO(13)eC(19) 62.7(2), C(18)eC(19)eO(13)eC(15) 59.0(2).

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Scheme 8. Lewis acid promoted diastereoselective synthesis of 13. Fig. 4. Doubly-complexed hepta-1,6-diyne by-products isolated from the synthesis of 3 and 5.

Scheme 9. Diastereoselective CeC coupling to give doubly-complexed C2-symmetric diyne 14. Scheme 10. Mechanism to account for the synthesis of doubly-complexed hepta-1,6diyne derivatives.

temperature there was a reduction in yield and an almost complete loss of diastereoselectivity (entry 3). These results were mirrored when diethylamine was used as the nucleophile to give 19 selectively at 35  C (entry 4), but with reduced yield and loss of selectivity at room temperature (entry 5). The reduced yield observed at room temperature is, in part, accounted for by the formation of by-products 20 and 21. The determination of the relative stereochemistry of the predominant diastereoisomer formed at lower temperature was thwarted by our inability to grow suitable crystals of 15, 18 or 19 for X-ray analysis. The release of an alkyne from the corresponding dicobalt hexacarbonyl complex is a well established protocol, typically by reaction with ceric ammonium nitrate [7,9,13]. As an alternative, we performed a preliminary experiment to determine if a dicobalt hexacarbonyl complexed diyne ether could be used for the synthesis of cobalt-based metallocenes. Thus heating 4 with cyclopentadiene, followed by isolation of the coloured organometallic reaction products, gave a 3:2 ratio of cyclopentadienone metallocenes 22 and 23 (Scheme 13) as determined by comparison to the NMR data reported previously for these complexes (d.r. ¼ 4:1) [4].

In conclusion, we have demonstrated the addition of ynols and dicobalt hexacarbonyl complexed ynols to dicobalt hexacarbonyl propargylium cations, the latter proceeding with excellent diastereoselectivity. Examination of the by-products of ynol addition led to a new protocol for the synthesis of complexes of 1,6-diynes, and the main product of ynol addition may be used for the synthesis of a cyclopentadieone metallocene.

Scheme 11. Synthesis of complexed enyne 17.

Fig. 3. A representation of (R*, R*)-14 from the X-ray analysis. Principal bond lengths [Å] include: Co(1)eCo(2) 2.4654(7), Co(3)eCo(4) 2.4656(8), C(1)eC(2) 1.353(5), C(29)eC(30) 1.357(6). Principal bond angles [ ] include: C(2)eC(1)eC(15) 151.4(4), C(1)eC(2)eC(3) 148.1(3), C(30)eC(29)eC(22) 150.4(4), C(29)eC(30)eC(31) 145.4(4). Principal torsion angles [ ] include: C(2)eC(1)eC(15)eC(22) 52.9(8), C(15)eC(22)eC(29)eC(30) 71.2(8), C(1)eC(15)eC(22)eC(29) 146.7(3).

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stirred for ca. 1.5e3.0 h until CO evolution was no longer observed. The solvent was removed in vacuo and the residue subjected to silica gel column chromatography. Initial elution with hexane to remove cobalt derived impurities followed by 20:1 hexane/EtOAc gave the complexed propargylic alcohol. Alternatively the crude solution was passed through a plug of neutral alumina using dichloromethane (10 mL/mmol) and used in a subsequent reaction without further purification.

Scheme 12. Synthesis of doubly-complexed hepta-1,6-diynes 15, 18 and 19 and byproducts 20 and 21. Table 1 Synthesis of doubly-complexed hepta-1,6-diynes 15, 18 and 19. Entry

Diyne product

NuH

Temp.

Diastereoselectivitya

Yield (%)

1 2 3 4 5

15 18 18b 19 19c

HCCCH2OH MeOH MeOH HNEt2 HNEt2

35  C 35  C R.T. 35  C R.T.

>10:1 >10:1 2:3 >10:1 4:3

47 40 19 37 20

a b c

As determined by 1H NMR. Also 20 (47%). Also 21 (31% d.r. ¼ 4:1).

Experimental section General procedures All reactions were carried out in an atmosphere of dry nitrogen. Dichloromethane was freshly distilled from CaH2 prior to use. Diethyl ether and THF were dried over and distilled from sodium/ benzophenone. Column chromatography was performed using silica gel (Kieselgel Merck 9385 40e63 mm). Thin layer chromatography was performed with Kieselgel 60 F254 aluminium sheets. All reagents, solvents and starting materials were used without purification unless otherwise stated. Cobalt complexes were stored below 20  C under an inert atmosphere to minimise decomposition. 4-Phenyl-3-butyn-2-ol (1a), 3-butyn-2-ol (1b) and 1,3diphenyl-2-propyn-1-ol (1d) are available commercially. 3-Octyn2-ol (1c) was prepared as reported previously [14].

General procedure for the complexation of propargyl alcohols To a flask containing Co2(CO)8 (1 eq.) was added anhydrous CH2Cl2 (5 mL/mmol) followed by an anhydrous CH2Cl2 (0.33 mL/ mmol) solution of the propargyl alcohol (1 eq.). The solution was

Scheme 13. Synthesis of (ƞ5-cyclopentadienone)(ƞ5-cyclopentadienyl)cobalt metallocenes 22 and 23.

Synthesis of 2a. [15] Prepared from 1a (1.000 g, 6.83 mmol) using the general procedure to give 2a in 95% yield. 2a. 1H NMR (d, 270 MHz, CDCl3) 1.61 (3H, d, J 5.4, CH3), 1.94 (1H, d, J 2.7, OH), 5.24e5.30 (1H, m, CH), 7.33e7.35 (3H, m, ArCH), 7.52e7.54 (2H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 25.3 (CH3), 68.8 (CH), 90.8 (CC), 102.4 (CC), 128.1 (ArC), 129.1 (ArC), 129.6 (ArC), 137.2 (ArC), 199.5 (CO). Synthesis of 2b. [9] Prepared from 1b (0.500 g, 7.14 mmol) using the general procedure to give 2b in 99% yield. 2b. 1H NMR (d, 270 MHz, CDCl3) 1.49 (3H, d, J 6.2, CH3), 1.80 (1H, d, J 4.9, OH), 4.92e5.00 (1H, m, CH), 6.03 (1H, s, CH); 13C NMR (d, 100 MHz, CDCl3) 25.7 (CH3), 68.4 (CH), 71.4 (CC), 101.1 (CC), 199.6 (CO). Synthesis of 2c Prepared from 1c (1.000 g, 7.95 mmol) using the general procedure to give 2c in 94% yield. 2c. 1H NMR (d, 270 MHz, CDCl3) 0.97 (3H, t, J 7.4, CH3), 1.39e1.47 (2H, m, CH2), 1.49 (3H, d, J 6.2, CH3), 1.58e1.66 (2H, m, CH2), 1.75 (1H, d, J 4.9, OH), 2.82 (2H, t, J 7.4, CH2), 4.95e5.03 (1H, m, CH); 13C NMR (d, 67 MHz, CDCl3) 13.9 (CH3), 22.8 (CH3), 25.1 (CH2), 33.5 (CH2), 34.1 (CH2), 68.5 (CH), 98.8 (CC), 102.5 (CC), 200.0 (CO). Synthesis of 2d. [15] Prepared from 1d (1.000 g, 4.80 mmol) using the general procedure to give 2d in 80% yield. 2d. 1H NMR (d, 270 MHz, CDCl3) 2.45 (1H, brs, OH), 6.14 (1H, brs, CH) 7.26e7.39 (6H, m, ArCH), 7.46e7.56 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 74.7 (CH), 91.6 (CC), 102.1 (CC), 126.0 (ArC), 127.9 (ArC), 128.4 (ArC), 128.7 (ArC), 128.9 (ArC), 129.6 (ArC), 137.9 (ArC), 144.1 (ArC), 199.1 (CO). General procedure for the synthesis of mono-complexed diyne ethers A flask was charged with dicobalt hexacarbonyl propargyl alcohol (1 eq.) and anhydrous CH2Cl2 (10 mL/mmol) and cooled to 0  C. To this was added BF3$OEt2 (4 eq.) and the resulting mixture left to stir at 0  C for ca. 20 mins before the appropriate nucleophile (2.5 eq.) was added by syringe. The reaction mixture was allowed to warm gradually to room temperature and then quenched by the addition of saturated NaHCO3 (10 mL/mmol). A further 8 mL/mmol of CH2Cl2 was added and the organic solution washed with deionised water (10 mL/mmol) and saturated brine (10 mL/mmol), dried (MgSO4), filtered and the solvent removed in vacuo. The products were purified using silica gel column chromatography. Synthesis of 3 Using the general procedure, 2a (0.400 g, 0.93 mmol) and 2propyn-1-ol (0.13 mL, 2.23 mmol) gave 3 (0.30 g, 68%) as a burgundy oil and 15 (0.062 g, 15%) as a burgundy solid after purification using silica gel column chromatography (3:7 EtOAc/CH2Cl2 to obtain 3, 1:19 CH2Cl2/petroleum ether 40e60  C to obtain 15).

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3. IR (thin film) nmax/cm1 1612; 1H NMR (d, 270 MHz, CDCl3) 1.59 (3H, d, J 6.2, CH3), 2.46 (1H, t, J 2.7, CH), 4.28e4.40 (2H, m, CH2), 5.15 (1H, q, J 6.2, CH), 7.31e7.39 (3H, m, ArCH), 7.54e7.60 (2H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 22.1 (CH3), 56.4 (CH2), 74.5 (CH), 74.6 (CC), 79.9 (CC), 90.7 (CC), 99.2 (CC), 127.9 (ArC), 128.9 (ArC), 129.7 (ArC), 137.9 (ArC), 199.5 (CO); m/z (FAB e NOBA) 415.0 (100) [MeOCH2C^CH]þ. 15: m.p. 198e200  C; Anal. Calc. for C35H20Co4O13: C, 47.54; H, 2.28. Found; C, 47.53; H, 2.36; IR (thin film) nmax/cm1 1575; 1H NMR (d, 270 MHz, CDCl3) 1.52 (3H, d, J 6.7, CH3), 1.86 (1H, dd, J 13.6, 1.7, CH2), 2.29 (1H, dd, J 13.6, 1.7, CH2), 2.50 (1H, t, J 2.5, CH), 3.71 (1H, m, CH), 4.30 (1H, dd, J 16.3, 2.5, CH2), 4.36 (1H, dd, J 16.3, 2.5, CH2), 5.12e5.22 (1H, m, CH), 7.25e7.36 (6H, m, ArCH), 7.40e7.55 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 21.6 (CH3), 33.7 (CH2), 47.0 (CH), 57.5 (CH2), 75.2 (CH), 75.5 (CC), 79.8 (CC), 91.6 (CC), 92.1 (CC), 96.9 (CC), 106.9 (CC), 127.7 (ArC), 128.0 (ArC), 128.8 (ArC), 129.0 (ArC), 129.4 (ArC), 129.5 (ArC), 137.7 (ArC), 138.2 (ArC), 199.2 (CO), 199.8 (CO); m/z (FAB e NOBA) 889.9 (30) [M þ Li]þ. Synthesis of 4 Using the general procedure, 2a (0.500 g, 1.12 mmol) and 3phenyl-2-propyn-1-ol (0.37 g, 2.80 mmol) gave 4 (0.45 g, 71%) as a burgundy oil after purification using silica gel column chromatography (3:7 EtOAc/hexanes). 4: IR (thin film) nmax/cm1 3078, 1612; 1H NMR (d, 270 MHz, CDCl3) 1.62 (3H, d, J 5.9, CH3) 4.51, (1H, d, J 16.0, CH2), 4.54 (1H, d, J 16.0, CH2), 5.21 (1H, q, J 5.9, CH), 7.25e7.38 (6H, m, ArCH), 7.40e7.49 (2H, m, ArCH), 7.53e7.63 (2H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 22.2 (CH3), 57.2 (CH2), 74.4 (CH), 85.3 (CC), 86.5 (CC), 90.9 (CC), 99.4 (CC), 122.7 (ArC), 127.9 (ArC), 128.4 (ArC), 128.6 (ArC), 128.9 (ArC), 129.7 (ArC), 131.8 (ArC), 138.0 (ArC), 199.4 (CO); m/z (CI e NH3) 546.4 (40) [M]þ. Synthesis of 5 Using the general procedure, 2a (1.000 g, 2.31 mmol) and 4phenyl-3-butyn-1-ol (0.84 mL, 5.77 mmol) gave 5 as a burgundy solid (1.03 g, 79%) and 16 (0.03 g, 3%) as a burgundy solid after purification using silica gel column chromatography with a 3:7 EtOAc/hexanes. 5: IR (thin film) nmax/cm1 2974, 1601, 1481, 1447, 1242; 1H NMR (d, 270 MHz, CDCl3) 1.62 (3H, d, J 8.1, CH3), 2.59e2.67 (1H, m, CH2), 2.91 (1H, dt, J 10.8, 2.7, CH2), 4.25 (1H, app q, J 10.8, CH2), 4.31e4.39 (1H, m, CH2), 4.51 (1H, q, J 8.1, CH), 7.24e7.35 (6H, m, ArCH), 7.40e7.46 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 22.4 (CH3), 31.0 (CH2), 36.8 (CH), 68.1 (CH2), 92.3 (C^C), 104.2 (C^C), 112.7 (C]C), 127.6 (C]C), 127.7 (ArC), 128.5 (ArC), 128.7 (ArC), 128.8 (ArC), 129.5 (ArC), 131.6 (ArC), 138.2 (ArC), 150.7 (ArC), 199.7 (CO); m/z (FAB e NOBA) 476.1 (100) [Me3CO]þ. 16: m.p. 212e214  C; Anal. Calc. for C42H26Co4O13: C, 51.77; H, 2.69. Found: C, 51.72; H, 2.75; IR (thin film) nmax/cm1 2928, 1605, 1481, 1443; 1H NMR (d, 270 MHz, CDCl3) 1.50 (3H, d, J 6.4, CH3), 1.85 (1H, dd, J 12.1, 1.2, CH2), 2.34 (1H, dd, J 12.1, 1.2, CH2), 2.69e2.75 (2H, m, CH2), 3.72e3.78 (2H, m, CH2), 3.97e4.03 (1H, m, CH), 4.91e5.01 (1H, m, CH), 7.25e7.55 (15H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 21.6 (CH3), 31.0 (CH2), 34.0 (CH2), 47.3 (CH), 69.7 (CH), 78.1 (CH2), 81.6 (CC), 86.7 (CC), 91.6 (CC), 92.1 (CC), 97.9 (CC), 106.8 (CC), 123.6 (ArC), 127.7 (ArC), 127.9 (ArC), 128.3 (ArC), 128.9 (ArC), 129.4 (ArC), 131.6 (ArC), 137.8 (ArC), 138.1 (ArC), 199.3 (CO), 199.7 (CO). Synthesis of 7 Using the general procedure, 2a (1.220 g, 2.83 mmol) and 3butyn-1-ol (0.5 mL, 6.61 mmol) gave 7 as a burgundy oil (0.61 g, 44%) after purification using silica gel column chromatography with a 3:7 EtOAc/hexanes.

7: IR (thin film) nmax/cm1 1705; 1H NMR (d, 270 MHz, CDCl3) 1.55 (3H, d, J 6.2, CH3), 1.96 (1H, t, J 3.4, CH), 2.49 (2H, td, J 7.2, 2.7, CH2), 3.67e3.73 (2H, m, CH2), 4.86 (1H, q, J 6.2, CH), 7.28e7.36 (3H, m, ArCH), 7.50e7.54 (2H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 20.1 (CH3), 21.5 (CH2), 67.6 (CH2), 69.3 (CH), 76.2 (CC), 81.2 (CC), 90.5 (CC), 99.6 (CC), 127.7 (ArC), 128.8 (ArC), 129.5 (ArC), 137.9 (ArC), 199.5 (CO); m/z (FAB e NOBA) 428.0 (100) [Me2CO]þ. Synthesis of 8 Using the general procedure, 2b (0.200 g, 0.56 mmol) and 3butyn-1-ol (0.10 mL, 1.32 mmol) gave 8 (0.210 g, 92%) as a burgundy oil after purification using silica gel column chromatography with a 3:7 EtOAc/hexanes. 8. IR (thin film) nmax/cm1 1558; 1H NMR (d, 270 MHz, CDCl3) 1.51 (3H, d, J 6.2, CH3), 1.98 (1H, t, J 2.7, CCH), 2.48 (2H, td, J 7.2, 2.7, CH2), 3.67e3.77 (2H, m, CH2), 4.62 (1H, q, J 6.2, CH), 6.09 (1H, s, CH); 13 C NMR (d, 67 MHz, CDCl3) 20.0 (CH3), 23.3 (CH2), 67.6 (CH), 69.4 (CH2), 72.4 (CC), 75.8 (CC), 81.2 (CC), 97.2 (CC), 199.8 (CO); m/z (FAB e NOBA) 338.0 (70) [MeC4H5O]þ. General procedure for Sonogashira cross-coupling To a flask covered with aluminium foil was added the alkyne complex (1 eq.) dissolved in anhydrous triethylamine (10 mL/ mmol). To this solution was added CuI (10 mol%), PdCl2(PPh3)2 (3 mol%) and the mixture warmed to 60  C before the addition of ArI. The reaction mixture was stirred overnight under nitrogen at 60  C before being cooled, quenched with aqueous NH4Cl (10 mL/ mmol) and extracted using CH2Cl2 (3  10 mL/mmol). The combined organic layers were washed with sat. brine (10 mL/ mmol), dried with MgSO4, filtered and solvent removed in vacuo. The products were purified using silica gel column chromatography. Synthesis of 9 Using the general procedure 7 (0.450 g, 0.93 mmol) and iodobenzene (0.11 mL, 1.0 mmol) gave 9 as a burgundy oil (0.29 g, 56%) after purification using silica gel column chromatography with a 1:20 EtOAc/CH2Cl2. 9: IR (thin film) nmax/cm1 1599; 1H NMR (d, 270 MHz, CDCl3) 1.57 (3H, d, J 6.2, CH3), 2.71 (2H, t, J 6.9, CH2), 3.75e3.85 (2H, m, CH2), 4.90 (1H, q, J 6.2, CH), 7.26e7.31 (6H, m, ArCH), 7.32e7.38 (2H, m, ArCH), 7.51e7.55 (2H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 15.4 (CH3), 21.2 (CH2), 67.4 (CH2), 68.0 (CH), 81.6 (CC), 86.8 (CC), 90.7 (CC), 99.8 (CC), 123.8 (ArC), 127.8 (ArC), 128.3 (ArC), 128.9 (ArC), 129.7 (ArC), 131.7 (ArC), 138.0 (ArC), 199.6 (CO). Synthesis of 10 Using the general procedure, 8 (0.240 g, 0.60 mmol) and iodobenzene (0.07 mL, 0.63 mmol) gave 10 (0.08 g, 28%) as a burgundy oil after purification using silica gel column chromatography with a 3:7 EtOAc/hexane. 10: IR (thin film) nmax/cm1 1600; 1H NMR (d, 270 MHz, CDCl3) 1.52 (3H, d, J 6.2, CH3), 2.70 (2H, t, J 7.2, CH2), 3.69e3.89 (2H, m, CH2), 4.63 (1H, q, J 6.2, CH), 6.09 (1H, s, CH), 7.25e7.28 (2H, m, ArCH), 7.36e7.40 (3H, m, ArCH). General procedure for diastereoselective synthesis of di-complexed diyne ethers via salt isolation Tetrafluoroborate salts derived from 2a and 2b were synthesised by the drop wise addition of tetrafluoroboric acid diethyl ether complex (2 eq.) at 35  C to a solution of 2a or 2b dissolved in the minimum quantity of Et2O, followed by removal of the supernatant from the resulting precipitate. A solution of the tetrafluoroborate

J. Amin et al. / Journal of Organometallic Chemistry 776 (2015) 43e50

salt (1 eq.) and anhydrous CH2Cl2 (10 mL/mmol) was cooled to 35  C. To this was added propargyl alcohol dicobalt hexacarbonyl (1 eq.) and the mixture stirred at 35  C for 15 min. The reaction mixture was allowed to warm gradually to room temperature. The reaction was quenched by the addition of saturated NaHCO3 (10 mL/mmol). A further 8 mL/mmol of CH2Cl2 was added, the organic solution washed with deionised water (10 mL/mmol) and saturated brine (10 mL/mmol), dried (MgSO4), filtered and the solvent removed in vacuo. The products were purified using silica gel column chromatography. Synthesis of 11 Using the general procedure, 2a (0.750 g, 1.73 mmol) and the tetrafluoroborate salt generated from 2a (0.860 g, 1.73 mmol) gave 11 (1.26 g, 86%) as a burgundy coloured solid after purification using silica gel column chromatography with a 3:7 EtOAc/ hexane. 11. m.p. 108e110  C; Anal. Calc. for C32H18Co4O13: C, 45.42; H, 2.14. Found: C, 45.40; H, 2.51; IR (thin film) nmax/cm1 1608; 1H NMR (d, 270 MHz, CDCl3) 1.58 (6H, d, J 6.7, CH3), 5.13 (2H, q, J 6.7, CH), 7.26e7.31 (6H, m, ArCH), 7.49e7.54 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 22.8 (CH3), 75.9 (CH), 91.7 (CC), 99.5 (CC), 127.8 (ArC), 128.8 (ArC), 129.8 (ArC), 138.0 (ArC), 199.5 (CO); m/z (FAB e NOBA) 677.9 (100) [Me6CO]þ. Synthesis of 12 Using the general procedure, 2b (0.500 g, 1.40 mmol) and the tetrafluoroborate salt generated from 2b (0.600 g, 1.40 mmol) gave 12 as a burgundy coloured solid (0.78 g, 80%) after purification using silica gel column chromatography with a 3:7 EtOAc/hexane. 12: m.p. 66e68  C; Anal. Calc. for C20H10Co4O13: C, 34.61; H, 1.45. Found: C, 34.51; H, 1.41; IR (thin film) nmax/cm1 1530; 1H NMR (d, 270 MHz, CDCl3) 1.51 (6H, d, J 6.2, CH3), 4.96 (2H, q, J 6.2, CH), 6.06 (2H, s, CH); 13C NMR (d, 67 MHz, CDCl3) 23.6 (CH3), 72.9 (CH), 73.2 (CC), 96.8 (CC), 199.6 (CO); m/z (FAB e NOBA) 609.7 (100) [Me3CO]þ. Synthesis of 13 To a solution of 2c (0.50 g, 1.22 mmol) in CH2Cl2 (12 mL) at 0  C was added BF3$OEt2 (0.60 mL, 4.9 mmol) and the resulting mixture stirred at 0  C for ca. 20 mins. The reaction mixture was then cooled to 35  C followed by the addition of 2c (0.50 g, 1.22 mmol). After stirring at 35  C for 15 min the reaction mixture was allowed to warm gradually to room temperature and then quenched by the addition of saturated NaHCO3 (12 m). A further 10 mL of CH2Cl2 was added, the organic solution washed with deionised water (12 mL) and saturated brine (12 mL), dried (MgSO4), filtered and the solvent removed in vacuo. Silica gel column chromatography with a 3:7 EtOAc/hexane gave 13 as a burgundy coloured oil (0.59 g, 60%). 13. IR (thin film) nmax/cm1 1602; 1H NMR (d, 270 MHz, CDCl3) 0.97 (6H, t, J 7.4, CH3), 1.43e1.53 (10H, m, CH3 and CH2), 1.58e167 (4H, m, CH2), 2.82 (4H, t, J 7.4, CH2), 4.81e4.89 (2H, m, CH); 13C NMR (d, 67 MHz, CDCl3) 13.9 (CH3), 22.6 (CH2), 22.8 (CH3), 33.5 (CH2), 34.2 (CH2), 75.0 (CH), 99.2 (CC), 99.7 (CC), 200.1 (CO); m/z (FAB e NOBA) 721.9 (100) [Me3CO]þ. Synthesis of 14 Using the same method as for the synthesis of 11 and 12, except that THF instead of diethyl ether was used in the tetrafluoroborate salt generation step, 2d (2  0.500 g, 1.01 mmol each) gave 14 as a red solid (0.65 g, 67%, d.r. ¼ 12:1) that was subsequently recrystallised to diastereomeric purity using 3:7 EtOAc/hexane. 14: m.p. 148e150  C; Anal. Calc. for C42H22 Co4O12: C, 52.86; H, 2.32. Found: C, 52.83; H, 2.35; IR (thin film) nmax/cm1 1601; 1H

49

NMR (d, 270 MHz, CDCl3) 5.15 (2H, s, CH), 6.93e7.07 (12H, m, ArCH), 7.13e7.22 (8H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3); 60.5 (CH), 93.0 (CC), 103.2 (CC), 127.6 (ArC), 128.0 (ArC), 128.6 (ArC), 130.0 (ArC), 131.5 (ArC), 138.2 (ArC), 140.8 (ArC), 198.9 (CO), 199.9 (CO); m/ z (EI) 869.9 (100) [Me3CO]þ. Synthesis of 17 To the tetrafluoroborate salt (0.590 g, 1.18 mmol) generated from 2a and HBF4 (as described above) in CH2Cl2 (12 mL) was added 1,8ediazabicyclo[5.4.0]undec-7-ene (0.370 g, 2.43 mmol) and the resulting mixture stirred for 72 h at room temperature. The reaction was poured into aqueous NH4Cl (2  20 mL), extracted CH2Cl2 (20 mL) and the organic extract washed with deionised water (20 mL) before being dried (MgSO4), filtered, and the solvent removed in vacuo. Silica gel column chromatography using 1:9 EtOAc/hexane gave 2a as a burgundy oil (0.41 g, 84%). 17: 1H NMR (d, 270 MHz, CDCl3) 5.57 (1H, d, J 10.1, CH), 5.71 (1H, d, J 16.6, CH), 7.07 (1H, dd, J 16.6, 10.1, CH), 7.28e7.36 (3H, m, ArCH), 7.51e7.53 (2H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 91.3 (C^C), 92.4 (C^C), 120.4 (C]C), 128.0 (C]C), 129.0 (ArC),129.3 (ArC), 134.1 (ArC), 138.3 (ArC), 199.1 (CO). Alternative procedure for the synthesis of 17 A round bottom flask (100 mL) was charged with 2a (0.500 g, 1.16 mmol), CH2Cl2 (15 mL) and trifluoroacetic acid (0.09 mL, 1.16 mmol) and the reaction mixture stirred overnight. To this was added water (20 mL) and the organic layer extracted, dried (MgSO4), filtered and the solvent removed in vacuo. Silica gel column chromatography using 1:9 EtOAc/hexane gave 17 as a burgundy oil (0.22 g, 45%). Synthesis of 18 To a solution of the tetrafluoroborate salt (0.590 g, 1.18 mmol) generated from 2a and HBF4 (as described above) and 17 (0.500 g, 1.21 mmol) in CH2Cl2 (12 mL) at 35  C was added MeOH (0.19 mL, 4.7 mmol) and the solution allowed to warm slowly to room temperature. Work up and purification, as described for the synthesis of 2aed, gave 18 as a burgundy coloured oil (0.40 g, 40%, d.r. > 10:1). 18: IR (thin film) nmax/cm1 1605; 1H NMR (d, 270 MHz, CDCl3) 1.49, (3H, d, J 6.7, CH3), 1.84 (1H, ddd, J 13.6, 10.8, 2.0, CH2), 2.32 (1H, ddd, J 13.6, 10.8, 2.0, CH2), 3.55 (3H, brs, OCH3), 3.59e3.67 (1H, m, CH), 4.75 (1H, dd, J 10.8, 2.0, CH), 7.25e7.34 (6H, m, ArCH), 7.41e7.54 (4H, m, ArCH); 13C NMR (d, 67.0 MHz, CDCl3) 21.5 (CH3), 34.0 (CH2), 47.1 (CH), 59.4 (CH), 79.4 (OCH3), 91.7 (CC), 92.0 (CC), 97.8 (CC), 106.8 (CC), 127.7 (ArC), 127.8 (ArC), 128.9 (ArC), 129.4 (ArC), 137.9 (ArC), 138.2 (ArC), 199.4 (CO), 199.8 (CO); m/z (FAB e NOBA) 776.0 (100) [Me3CO]þ. Repetition, with addition of MeOH at room temperature, resulted in the isolation of 18 as a 2:3 mixture of diastereoisomers (0.19 g, 19%) in addition to the isolation of 20 (0.46 g, 47%), both as burgundy coloured oils. Selected 1H NMR (d, 270 MHz, CDCl3) data for the major diastereoisomer of 18:1.54 (3H, d, J 6.2, CH3), 3.48 (3H, brs, CH3), 3.67e3.75 (1H, m, CH), 4.73e4.81 (1H, m, CH). 20: IR (thin film) nmax/cm1 1605, 1481, 1443, 949; 1H NMR (d, 270 MHz, CDCl3) 1.57 (3H, d, J 5.4, CH3), 4.10 (1H, dq, J 8.1, 5.4, CH), 6.31 (1H, dd, J 14.8, 8.1, CH), 6.97 (1H, d, J 14.8, CH), 7.30e7.32 (6H, m, ArCH), 7.45e7.54 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 23.0 (CH3), 41.7 (CH), 89.5 (C^C), 91.7 (C^C), 92.6 (C^C), 103.2 (C^C), 127.3 (ArC), 127.8 (C]C), 127.9 (C]C), 128.9 (ArC), 129.2 (ArC), 129.4 (ArC), 138.0 (ArC), 138.3 (ArC), 140.4 (ArC), 199.2 (CO), 199.7 (CO); m/ z (FAB e NOBA) 743.8 (100) [Me3CO]þ.

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Synthesis of 19 To a solution of the tetrafluoroborate salt (0.580 g, 1.16 mmol) generated from 2a and HBF4 (as described above) and 17 (0.500 g, 1.21 mmol) in CH2Cl2 (12 mL) at 35  C was added NHEt2 (0.48 mL, 4.6 mmol) and the solution allowed to warm slowly to room temperature. Work up and purification, as described for the synthesis of 2aed, gave 19 as a burgundy coloured oil (0.39 g, 37%, d.r. > 10:1). 19: IR (thin film) nmax/cm1 1606; 1H NMR (d, 270 MHz, CDCl3) 1.07 (6H, t, J 6.9, CH3), 1.41 (3H, d, J 6.4 Hz, CH3), 1.80 (1H, app t, J 11.9, CH2), 2.40 (1H, app t, J 11.9, CH2), 2.56 (2H, q, J 6.9, CH2), 2.74 (2H, q, J 6.9, CH2), 3.59e3.67 (1H, m, CH), 4.51 (1H, dd, J 11.9, 2.0, CH), 7.25e7.33 (6H, m, ArCH), 7.41e7.47 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 15.6 (CH3), 21.2 (CH3), 34.7 (CH2), 44.5 (CH2), 60.7 (CH), 92.5 (CC), 95.3 (CC), 97.7 (CC), 107.8 (CC), 127.5 (ArC), 127.6 (ArC), 128.8 (ArC), 128.9 (ArC), 129.2 (ArC), 129.3 (ArC), 138.4 (ArC), 138.5 (ArC), 199.9 (CO); 845.0 (FAB e NOBA) 845.0 (100) [Me2CO]þ, 816.9 (100) [Me3CO]þ. Repetition, with addition of NHEt2 at room temperature, resulted in the isolation of 19 as a 4:3 mixture of diastereoisomers (0.21 g, 20%), in addition to the isolation of 21 as a 4:1 mixture of isomers (0.30 g, 31%), both as burgundy coloured oils. Selected 1H NMR (d, 270 MHz, CDCl3) data for the minor diastereoisomer of 19: 1.53 (3H, d, J 6.4, CH3), 3.61e3.69 (1H, m, CH), 4.76e4.84 (1H, m, CH). 21: IR (thin film) nmax/cm1 1706; 1H NMR (d, 270 MHz, CDCl3) 1.51, (3H, d, J 6.7, CH3*), 1.52, (3H, d, J 6.7, CH# 3 ), 1.92 (1H, ddd, J 16.1, 13.6, 2.0, CH2), 1.98 (1H, d, J 5.0, OH), 2.20 (1H, ddd, J 16.1, 13.6, 2.0, CH2), 3.66e3.74 (1H, m, CH#), 3.71e3.79 (1H, m, CH*), 5.01e5.09 (1H, m, CH#), 5.23 (1H, ddd, J 7.2, 5.0, 2.0, CH*), 7.25e7.34 (6H, m, ArCH), 7.41e7.54 (4H, m, ArCH); 13C NMR (d, 67 MHz, CDCl3) 21.3 # # (CH3*), 23.8 (CH# 3 ), 34.0 (CH2*), 35.6 (CH2 ), 47.6 (CH ), 47.9 (CH*), # 69.9 (CH*), 70.1 (CH ), 90.7 (CC), 91.2 (CC), 101.2 (CC), 106.7 (CC), 127.8 (ArC), 128.1 (ArC), 128.9 (ArC), 129.1 (ArC), 129.3 (ArC), 129.5 (ArC), 137.4 (ArC), 138.2 (ArC), 199.2 (CO), 199.8 (CO). (* ¼ major isomer, # ¼ minor isomer). Synthesis of 22 and 23 A solution of 4 (0.250 g, 0.46 mmol) and cyclopentadiene (0.07 mL, 0.8 mmol) in toluene (2 mL) was heated at 110  C for 2 h. After cooling the reaction mixture was column chromatographed (SiO2, petroleum ether followed by 1:1 MeOH/EtOAc) to give 22 and 23 (0.046 g, 24%) as a 3:2 mixture of diastereoisomers assigned by comparison to literature data [4].

Acknowledgements The authors would like to thank the EPSRC (Grant No. EP/ C511034/01) for financial support (J.A.) and the EPSRC Mass Spectrometry Unit (University of Swansea).

Appendix A. Supplementary material CCDC 1023662 (11), 1023663 (12) and 1023664 (14) contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.

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