Zn/ZnBr₂ Catalysed Reaction of Aldehydes with Allylbromide: Synthesis of 2,6-Disubstituted 4-Bromotetrahydropyrans

Abstract

An efficient approach for the one-pot synthesis of 4-bromotetrahydropyrans in a highly diastereoselective manner via the alkynylation followed by Prins cyclisation is described. The method employs aldehydes and allyl bromide as reactants, with a Zn/ZnBr₂ catalytic system in CH₂Cl₂. A variety of 2,6-disubstituted 4-bromotetrahydropyran derivatives were obtained in good yields.

Key words

Prins cyclisation - tetrahydropyrans - aldehydes - allylbromides - one-pot reaction

Tetrahydropyrans (THP) are prominent structural motifs in many natural products showing various biological activities. Examples include diospongin A and B, aza-diospongin A, centolobine, diarylheptanoid, catechola-I and II, the avermectins, aplysiatoxins, oscillatoxins, atrunculins, acutiphycins, kendomycin and phorboxazoles A and B (Figure [1]).[1] [2] THP rings are also key moieties in molecules demonstrating antiviral, anti-nociceptive, serotonin norepinephrine transporter inhibitory, antimicrobial and anti-proliferative activity.[3–5] Due to their wide ranging presence, there are various synthetic tactics to afford THPs.[6] Among those synthetic protocols, the Prins cyclisation has become a pre-eminent tool for the construction of THPs using acidic catalysts for coupling aldehydes and allyl alcohols.[7]

There are relatively few examples in the literature of one-pot formation of THP rings from aldehydes and allyl bromide via Barbier–Prins reactions,[8] and the reported methods suffer from extended reaction times, low yields and poor stereoselectivity.[9]

Figure 1 Bioactive compounds featuring a tetrahydropyran moiety

Zinc bromide (ZnBr₂) is known as a mild, non-toxic, moisture-tolerant, catalyst in organic transformations.[10] Herein, we demonstrate that ZnBr₂ can act as an efficient promoter for one-pot synthesis of 2,6-disubstituted 4-bromotetrahydropyrans in a highly diastereoselective manner via Babier–Prins cyclisation, using allyl bromide and aldehydes as reactants.

Initial studies were carried out with benzaldehyde (2 mmol) and allyl bromide (1 mmol) in the presence of pTSA, at room temperature in CH₂Cl₂. The reaction proceeded smoothly, but gave, 2,6-diphenyl-4-bromotetrahydropyran in low yield. Similarly, we have examined the reaction with CSA and HClO₄-SiO₂ catalysts separately and observed that conversions took place but yields were very poor. We then turned our attention to Lewis acid catalyst systems such as Zn/ZnCl₂ and Zn/ZnBr₂. While, in the case of Zn/ZnCl₂ reaction, a mixture of products, 2,6-diphenyl-4-bromotetrahydropyran and 2,6-diphenyl-4-chlorotetrahydropyran were formed, with Zn/ZnBr₂, only the desired 2,6-diphenyl-4-bromotetrahydropyran was formed in 85% yield with high diastereoselectivity for the cis-product. The predominant formation of this stereoisomer is most likely due to thermodynamic control. Assignment of the stereochemistry was based on the coupling constants of the protons at the C₂ and C₄ positions. The coupling constants of the benzylic proton 2-H_c [δ = 4.5 (J = 11.0 Hz)] and the proton on the carbon bearing the halide group 4-H_c [δ = 4.0 (J = 4.5, 11.0 Hz)] in the ¹H NMR spectrum showed a splitting consistent with two phenyl groups and the halide group being in cis-equatorial orientations, as shown in Scheme [1].

Scheme 1

To determine the role of solvent, we performed the reaction of benzaldehyde in different solvents such as dichloromethane, toluene, acetonitrile, tetrahydrofuran and found that dichloromethane provided the best results (Table [1]).

Table 1 Initial Optimization of Reaction Conditions

Entry	Catalyst	Solvent	Temp. (°C)	Time (h)	Yield (%)
1	pTSA	CH2Cl2	25	6	60
2	CSA	CH2Cl2	25	6	55
3	HClO4-SiO2	CH2Cl2	25	10	50
4	ZnCl2	CH2Cl2	25	8	50
5	ZnBr2	CH2Cl2	25	6	85
6	ZnBr2	toluene	25	12	44
7	ZnBr2	CH3CN	25	8	62
8	ZnBr2	THF	25	9	56

Figure 2 Reaction scope

Based on the results obtained with benzaldehyde, we next explored the substrate scope of various substituted aromatic as well as aliphatic aldehydes with allyl bromide to probe the generality of the reaction. Aromatic aldehydes having electron-donating or electron-withdrawing groups on the aromatic ring, reacted readily with allyl bromide to afford the corresponding 2,6-disubstituted 4-bromotetrahydropyrans in 65–85% yield (Figure [2]). However, aliphatic aldehydes and aromatic aldehydes bearing electron-withdrawing groups reacted more smoothly than those having electron-donating groups. Notably, this protocol was equally applicable to aliphatic, cyclic, and aromatic aldehydes.

On the basis of experimental results and previous reports, a reaction mechanism for the formation of 2,6-disubstituted 4-bromotetrahydropyrans from allyl bromide and aldehydes can be explained by a tandem carbonyl allylation-hemiacetal formation followed by Prins cyclisation and subsequent bromination (Scheme [2]). A rationale for the all cis-selectivity involves formation of an (E)-oxocarbenium ion via a chair-like transition state, which has increased stability relative to the open oxo-carbenium ion due to delocalization. The optimal geometry for this delocalization of hydrogen atom at C₄ in a pseudo-axial position favours equatorial attack of the activated π-bond nucleophile.[11]

Scheme 2

In conclusion, we have developed a one-pot synthesis of 2,6-disubstituted 4-bromotetrahydropyrans 3a–w from aldehydes and allyl bromide in a highly diastereoselective manner via alkenylation followed by Prins cyclisation, catalysed by Zn/ZnBr₂.

Solvents, aldehydes, allyl bromide and Zn/ZnBr₂ were purchased from a commercial source (Spectrochem) and used as received. Progress of reaction was followed by TLC on silica gel-G plates of 0.5-mm thickness, and spots were visualised by iodine vapour and UV light. Flash column chromatography was performed on silica gel (200–300 mesh). ¹H, ¹³C, and ¹⁹F NMR spectra were recorded with a Bruker AV 300/400/500 MHz instrument. Chemical shifts are reported in ppm referenced to the residual proton of CDCl₃ (7.26 ppm for ¹H NMR, 77.0 ppm for ¹³C NMR). ¹H NMR data are reported as chemical shift (ppm), multiplicity (standard abbreviations), coupling constants (Hz), and integration. ¹³C NMR data are reported as ppm. HRMS analyses were performed with a Micromass Q-TOF apparatus.

Synthesis of 2,6-Disubstituted 4-Bromotetrahydropyrans; General Procedure

To a stirred suspension of aldehyde 1a–w (2 mmol) and Zn dust (4 mmol) in CH₂Cl₂ was added allyl bromide 2 (1 mmol) and the mixture stirred at r.t. for 30 minutes. Then ZnBr₂ was added at 0 °C and the mixture was further stirred for 6–8 hours at r.t., with completion of reaction being confirmed by TLC. The reaction mixture was filtered through a bed of Celite^®, the filtrate was evaporated, and the residue was triturated with EtOAc (2 × 25 mL). The combined organic layers were washed with brine, dried over Na₂SO₄, filtered, evaporated under reduced pressure, and purified by column chromatography on silica gel (60–120 mesh), eluting with EtOAc/hexane to afford the corresponding 2,6-disubstituted 4-bromotetrahydropyrans 3a–w.

4-Bromo-2,6-diphenyltetrahydro-2H-pyran (3a)

Yield: 268 mg (85%); colourless solid; mp 86–87 °C.

IR (neat): 2928, 2850, 1665, 1590, 1376, 1288, 1166, 1090, 1051, 1011, 825, 732 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.42–7.20 (m, 10 H), 4.54 (dd, J = 11.0, 4.5 Hz, 2 H), 4.40 (tt, J = 11.0, 4.5 Hz, 1 H), 2.55 (dd, J = 12.8, 4.0 Hz, 2 H), 2.08 (q, J = 12.1 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 141.4, 128.4, 127.7, 125.7, 79.7, 46.1, 45.0, 29.6.

MS (EIMS): m/z (%) = 237 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₇O: 237.45569; found: 237.45570.

4-Bromo-2,6-bis(4-bromophenyl)tetrahydro-2H-pyran (3b)

Yield: 399 mg (84%); colourless solid; mp 129–130 °C.

IR (neat): 2958, 2928, 2858, 1901, 1686, 1590, 1486, 1407, 1378, 1290, 1115, 1082, 728 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.48 (d, J = 8.0 Hz, 4 H), 7.26 (d, J = 8.2 Hz, 4 H), 4.51 (d, J = 11.2, 4.8 Hz, 2 H), 4.39 (tt, J = 11.2, 4.8 Hz, 1 H), 2.52 (d, J = 13.0 Hz, 2 H), 2.04 (q, J = 12.1 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 139.9, 131.6, 127.4, 121.7, 78.9, 44.7, 45.2.

MS (EIMS): m/z (%) = 392 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅Br₂O: 392.94897; found: 392.94767.

4-Bromo-2,6-di-p-tolyltetrahydro-2H-pyran (3c)

Yield: 285 mg (83%); colourless solid; mp 92–93 °C.

IR (neat): 3040, 2930, 2820, 1610, 1515, 1465, 1340, 1165, 1050, 955, 777 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.32 (d, J = 7.8 Hz, 4 H), 7.22 (d, J = 7.8 Hz, 4 H), 4.34 (dd, J = 11.2, 4.0 Hz, 2 H,), 4.28 (tt, J = 11.2, 4.0 Hz, 1 H), 2.46 (s, 6 H), 2.20 (dd, J = 12.4, 3.6 Hz, 2 H), 1.94 (q, J = 11.8 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 141.2, 138.6, 134.9, 129.0, 128.2, 126.9, 78.9, 45.6, 44.2, 30.0, 21.4.

MS (EIMS): m/z (%) = 265 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₉H₂₁O: 265.26610; found: 265.26580.

4-Bromo-2,6-bis(4-chlorophenyl)tetrahydro-2H-pyran (3d)

Yield: 321 mg (84%); colourless solid; mp 111–112 °C.

IR (neat): 2958, 2928, 2858, 1901, 1686, 1590, 1486, 1407, 1378, 1290, 1115, 1052, 728 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.32–7.26 (m, 8 H), 4.50 (dd, J = 9.7, 1.2 Hz, 2 H), 4.36 (tt, J = 12.2, 4.8 Hz, 1 H), 2.54 (dd, J = 12.2, 4.8 Hz, 2 H), 2.04 (q, J = 12.2 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 139.0, 133.5, 130.8, 129.4, 128.6, 127.1, 78.9, 44.7, 45.3, 30.0.

MS (EIMS): m/z (%) = 305 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅Cl₂O: 305.05000; found: 305.04989.

4-Bromo-2,6-bis(4-isopropylphenyl)tetrahydro-2H-pyran (3e)

Yield: 324 mg (81%); colourless solid; mp 101–102 °C.

IR (neat): 2950, 2821, 2850, 1908, 1680, 1590, 1485, 1407, 1290, 1164, 1082, 728 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.30 (d, J = 8.0 Hz, 4 H), 7.18 (d, J = 7.8 Hz, 4 H), 4.50 (dd, J = 11.2, 1.2 Hz, 2 H), 4.40 (tt, J = 11.2, 1.2 Hz, 1 H), 2.96–2.85 (m, 2 H), 2.54 (dd, J = 12.2, 3.2 Hz, 2 H), 2.15 (q, J = 12.0, 2 H), 1.24 (d, J = 7 Hz, 12 H).

¹³C NMR (75 MHz, CDCl₃): δ = 146.4, 138.9, 130.8, 128.4, 127.2, 125.8, 45.2, 44.8, 34.4, 30.2, 21.9.

MS (EIMS): m/z (%) = 321 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₂₃H₂₉O: 321.40719; found: 321.40740.

4-Bromo-2,6-bis(2,4-dichlorophenyl)tetrahydro-2H-pyran (3f)

Yield: 378 mg (84%); colourless solid; mp 125–126 °C.

IR (neat): 3092, 2970, 2864, 1897, 1587, 1560, 1469, 1375, 1293, 1203, 1170, 1108, 1083, 1045, 1004, 864, 818, 784 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.58 (d, J = 8.4 Hz, 2 H), 7.36 (d, J = 2.1 Hz, 2 H), 7.31 (d, J = 8.4 Hz, 2 H), 4.91 (dd, J = 11.2, 1.2 Hz, 2 H), 4.48–4.40 (m, 1 H), 2.72–2.65 (m, 2 H), 1.94–1.84 (m, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 137.1, 134.0, 131.8, 129.1, 128.0, 127.6, 76.2, 44.4, 43.1.

MS (EIMS): m/z (%) = 373 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₃Cl₄O: 373.20410; found: 373.20412.

4-Bromo-2,6-bis(2,4-difluorophenyl)tetrahydro-2H-pyran (3g)

Yield: 310 mg (80%); colourless solid; mp 104–105 °C.

IR (neat): 3050, 2920, 2853, 1610, 1520, 1456, 1410, 1365, 1170, 835, 760 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.54 (td, J = 8.4, 6.7 Hz, 2 H), 6.94–6.88 (m, 2 H), 6.84–6.76 (m, 2 H), 4.54 (dd, J = 11.1, 1.5 Hz, 2 H), 4.42 (tt, J = 12.0, 4.3 Hz, 1 H), 2.57 (dd, J = 12.7, 3.9 Hz, 2 H), 2.06 (dd, J = 15.8, 11.9 Hz, 2 H).

¹⁹F NMR (500 MHz, CDCl₃): δ = –110.7780, –110.7930, –115.4618, –115.4768.

¹³C NMR (125 MHz, CDCl₃): δ = (d, ¹ J _CF = 248.8 Hz), 159.3 (d, ¹ J _CF = 249.0 Hz), 159.2 (d, ¹ J _CF = 249.0 Hz), 128.2 (d, ³ J _CF = 9.1 Hz), 128.1 (d, ³ J _CF = 10.0 Hz), 160.2 (d, ¹ J _CF = 246 Hz), 136.8 (d, ⁴ J _CF =2.7 Hz), 124.2 (d, ⁴ J _CF = 3.6 Hz), 124.1 (d, ⁴ J _CF = 3.6 Hz), 111.6 (d, ² J _CF = 20.8 Hz), 111.5 (d, ² J _CF = 21.7 Hz), 103.7 (d, ² J _CF = 25.4 Hz), 103.7 (d, ² J _CF = 26.3 Hz), 73.5, 44.6, 43.7.

MS (EIMS): m/z (%) = 309 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₃F₄O: 309.09025; found: 309.08858.

4-Bromo-2,6-bis(4-(trifluoromethyl)phenyl)tetrahydro-2H-pyran (3h)

Yield: 361 mg (80%); colourless solid; mp 113–114 °C.

IR (neat): 3050, 2920, 2853, 1610, 1520, 1456, 1365, 1170, 835, 760 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 7.44 (d, J = 8.0 Hz, 4 H), 7.22 (d, J = 8.0 Hz, 4 H), 4.61–4.57 (m, 2 H), 4.42 (tt, J = 12.0, 4.3 Hz, 1 H), 2.60–2.54 (m, 2 H), 2.14–2.04 (m, 2 H).

¹⁹F NMR (500 MHz, CDCl₃): δ = –57.9030.

¹³C NMR (125 MHz, CDCl₃): δ = 160.2 (d, ¹ J _CF = 246 Hz), 136.8 (d, ⁴ J _CF = 2.7 Hz), 127.5 (d, ³ J _CF = 2.7 Hz), 115.3 (d, ² J _CF = 2.7 Hz), 79.0, 45.5, 44.9.

MS (EIMS):m/zz (%) = 373 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₉H₁₅F₆O: 373.76555; found: 373.76540.

4-Bromo-2,6-bis(4-fluorophenyl)tetrahydro-2H-pyran (3i)

Yield: 281 mg (84%); colourless solid; mp 98–99 °C.

IR (neat): 3050, 2920, 2853, 1610, 1520, 1456, 1410, 1365, 1170, 835, 760 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.40–7.33 (m, 4 H), 7.08–7.01 (m, 4 H), 4.54 (dd, J = 11.2, 1.4 Hz, 2 H), 4.41 (tt, J = 11.2, 1.4 Hz, 1 H), 2.55–2.49 (m, 2 H), 2.12–2.03 (m, 2 H).

¹⁹F NMR (400 MHz, CDCl₃): δ = –118.7734, –119.5223.

¹³C NMR (100 MHz, CDCl₃): δ = 160.2 (d, ¹ J _CF = 246 Hz), 136.8 (d, ⁴ J _CF = 2.7 Hz), 127.5 (d, ³ J _CF = 2.7 Hz), 115.3 (d, ² J _CF =2.7 Hz), 79.0, 45.5, 44.9.

MS (EIMS): m/z (%) = 273 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅F₂O: 273.10910; found: 273.10974.

4-Bromo-2,6-bis(3-chlorophenyl)tetrahydro-2H-pyran (3j)

Yield: 320 mg (84%); colourless solid; mp 104–105 °C.

IR (neat): 2953, 2948, 2858, 1901, 1686, 1486, 1407, 1368, 1368, 1250, 1122, 1052, 728 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.36 (s, 2 H), 7.29–7.22 (m, 6 H), 4.52 (dd, J = 10.2, 1.8 Hz, 2 H), 4.42–4.28 (m, 1 H), 2.54 (dd, J = 12.6, 4.3 Hz, 2 H), 2.07 (q, J = 11.8 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.8, 134.4, 129.8, 128.0, 125.9, 123.9, 79.0, 45.0, 44.6.

MS (EIMS): m/z (%) = 305 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅Cl₂O: 305.05000; found: 305.04989.

4-Bromo-2,6-bis(2-chlorophenyl)tetrahydro-2H-pyran (3k)

Yield: 306 mg (85%); colourless solid; mp 103–104 °C.

IR (neat): 2924, 2866, 1685, 1536, 1448, 1363, 1325, 1274, 1127, 1047, 738 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.70 (tt, J = 7.5, 1.4 Hz, 2 H), 7.28–7.23 (m, 2 H), 7.16 (tt, J = 7.4, 1.1 Hz, 2 H), 7.05–7.00 (m, 2 H), 4.90 (dd, J = 11.1, 1.2 Hz, 2 H), 4.44 (tt, J = 12.1, 4.4 Hz, 1 H), 2.60 (dd, J = 12.6, 4.0 Hz, 2 H), 2.07 (q, J = 11.7 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 158.9 (d, ¹ J _CF = 245.7 Hz), 128.9 (d, ³ J _CF = 8.1 Hz), 128.2 (d, ³ J _CF = 13.2 Hz), 127.5 (d, ⁴ J _CF =3.7 Hz), 124.2 (d, ⁴ J _CF = 2.2 Hz), 115.9 (d, ² J _CF = 21.0 Hz), 73.4, 45.1, 43.6.

MS (EIMS): m/z (%) = 273 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅F₂O: 273.10910; found: 273.10974.

4-Bromo-2,6-bis(2-fluorophenyl)tetrahydro-2H-pyran (3l)

Yield: 298 mg (80%); colourless solid; mp 93–94 °C.

IR (neat): 2922, 2855, 1684, 1534, 1445, 1366, 1322, 1284, 1122, 1044, 733 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.70 (dd, J = 7.6, 1.4 Hz, 2 H), 7.35–7.31 (m, 4 H), 7.25–7.21 (m, 2 H), 4.99 (dd, J = 11.2, 1.5 Hz, 2 H), 4.49 (tt, J = 12.0, 4.6 Hz, 1 H, 2.72 (dd, J = 12.8, 4.4 Hz, 2 H), 1.95 (q, J = 11.8 Hz, 2 H).

¹³C NMR (75 MHz, CDCl₃): δ = 138.7, 131.1, 129.3, 128.7, 127.2, 127.1, 76.6, 45.2, 43.3.

MS (EIMS): m/z (%) = 305 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅Cl₂O: 305.05000; found: 305.04989.

4-Bromo-2,6-bis(2-bromophenyl)tetrahydro-2H-pyran (3m)

Yield: 395 mg (80%); colourless solid; mp 123–124 °C.

IR (neat): 2954, 2920, 2856, 1686, 1590, 1486, 1407, 1377, 1343, 1280, 1115, 1080, 724 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.69 (d, J = 7.8 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.52 (d, J = 8.0 Hz, 2 H), 7.38 (t, J = 7.6 Hz, 2 H), 4.95 (dd, J = 11.2, 1.5 Hz, 2 H), 4.50 (tt, J = 12.2, 4.8 Hz, 1 H), 2.76 (dd, J = 12.7, 3.2 Hz, 2 H), 1.92 (q, J = 12.1 Hz, 2 H).

¹³C NMR (100 MHz, CDCl₃): δ = 140.2, 132.6, 129.1, 127.8, 127.4, 78.8, 45.1, 43.3.

MS (EIMS): m/z (%) = 392 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₁₅Br₂O: 392.94897; found: 392.94767.

4-Bromo-2-heptyl-6-phenyltetrahydro-2H-pyran (3n)

Yield: 182 mg (70%); colourless solid; mp 86–87 °C.

IR (neat): 3028, 2924, 2852, 1648, 1451, 1364, 1140, 1081, 1053, 1010, 752 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 7.32–7.18 (m, 5 H), 4.32 (dd, J = 11.3, 2.1 Hz, 1 H), 4.22 (tt, J = 11.8., 4.5 Hz, 1 H), 3.50–3.40 (m, 1 H), 2.45 (dd, J = 12.8, 4.1 Hz, 1 H), 2.28 (dd, J = 12.2, 4.2 Hz, 1 H), 1.94 (q, J = 11.9 Hz, 1 H), 1.80 (q, J = 12 Hz, 1 H), 1.70–1.57 (m, 1 H), 1.56–1.40 (m, 2 H), 1.38–1.20 (m, 9 H), 0.87 (t, J = 6.6 Hz, 3 H).

¹³C NMR (100 MHz, CDCl₃): δ = 141.5, 128.4, 127.6, 125.7, 77.9, 47.0, 45.2, 43.2, 35.8, 29.5, 29.2, 25.3, 22.6, 14.2.

MS (EIMS): m/z (%) = 259 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₈H₂₇O: 259.20619; found: 259.20580.

4-Bromo-2-(4-chlorophenyl)-6-pentyltetrahydro-2H-pyran (3o)

Yield: 247 mg (72%); colourless solid; mp 89–90 °.

IR (neat): 2920, 2820, 1642, 1448, 1362, 1260, 1140, 1082, 1050, 974, 832, 752, 698 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 7.44 (d, J = 8.2 Hz, 2 H), 7.28 (d, J = 7.8 Hz, 2 H), 4.34 (dd, J = 11.8, 2.2 Hz, 1 H), 4.24 (tt, J = 11.8, 4.8 Hz, 1 H), 3.48–3.42 (m, 1 H), 2.40 (dd, J = 12.6, 4.1 Hz, 1 H), 2.25 (dd, J = 12.2, 3.8 Hz, 1 H), 2.02–1.82 (q, J = 11.8 Hz, 1 H), 1.84–1.68 (q, J = 11.8 Hz, 1 H), 1.68–1.22 (m, 8 H), 0.86 (t, J = 6.8 Hz, 3 H).

¹³C NMR (75 MHz, CDCl₃): δ = 142.2, 128.6, 128.2, 127.8, 126.5, 79.4, 78.2, 46.8, 45.2, 43.2, 35.1, 31.8, 30.9, 25.3, 22.6, 14.1.

MS (EIMS): m/z (%) = 266 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₆H₂₂ClO: 266.21419; found: 266.21580.

(2R,2′R)-2,2′-[(2R,4S,6S)-4-Bromotetrahydro-2H-pyran-2,6-diyl]bis(1,4-dioxaspiro[4.5]decane) (3p)

Yield: 288 mg (65%); colourless solid; mp 113–114 °C.

IR (neat): 2845, 1260, 1150, 1070, 945, 888, 750 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 4.37–4.25 (m, 1 H), 4.05 (tt, J = 10.8, 2.2 Hz, 2 H), 3.92–3.82 (m, 4 H), 3.41–3.32 (m, 2 H), 2.52 (dd, J = 12.4, 3.8 Hz, 2 H), 2.21–1.88 (m, 4 H), 1.78–1.14 (m, 18 H).

¹³C NMR (75 MHz, CDCl₃): δ = 121.6, 83.4, 79.2, 68.9, 41.4, 34.9, 33.1, 27.2, 24.6.

MS (EIMS): m/z (%) = 365 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₂₁H₃₃O₅: 365.24064; found: 365.24127.

4-Bromo-2,6-dihepyltetrahydro-2H-pyran (3q)

Yield: 282 mg (82%); colourless solid; mp 97–98 °C.

IR (neat): 2925, 2852, 1465, 1325, 1370, 1325, 1258, 1151, 1083, 1024, 961, 781, 566, 1269, 1183, 1014, 718 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 4.07 (tt, J = 11.9, 4.9 Hz, 1 H), 3.22–3.16 (m, 2 H), 2.17 (dd, J = 11.9, 4.0 Hz, 2 H), 1.64 (q, J = 11.9 Hz, 2 H), 1.56–1.16 (m, 24 H), 0.90 (t, J = 6.8 Hz, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 77.4, 47.4, 43.6, 35.6, 31.7, 30.0, 29.9, 29.6, 21.9, 14.1.

MS (EIMS): m/z (%) = 281 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₉H₃₇O: 281.28444; found: 281.28534.

4-Bromo-2,6-dinonyltetrahydro-2H-pyran (3r)

Yield: 353 mg (83%); colourless solid; mp 104–105 °C.

IR (neat): 2923, 2851, 1467, 1328, 1330, 1297, 1242, 1151, 1151, 1087, 1034, 991, 718 cm^–1.

¹H NMR (500 MHz, CDCl₃): δ = 4.08 (tt, J = 11.9, 4.9 Hz, 1 H), 3.26–3.12 (m, 2 H), 2.18 (dd, J = 12.0, 4.2 Hz, 2 H), 1.65 (q, J = 12.2 Hz, 2 H), 1.56–1.16 (m, 2 H), 1.54–1.22 (m, 30 H), 0.92–0.86 (t, J = 6.9 Hz, 6 H).

¹³C NMR (125 MHz, CDCl₃): δ = 77.6, 47.5, 43.5, 35.9, 31.8, 29.5, 29.2, 25.5, 22.6, 14.1.

MS (EIMS): m/z (%) = 337 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₂₃H₄₅O: 337.34704; found: 337.34677.

4-Bromo-2,6-dihexyltetrahydro-2H-pyran (3s)

Yield: 282 mg (82%); colourless solid; mp 91–92 °C.

IR (neat): 2925, 2854, 1466, 1365, 1370, 1269, 1225, 1152, 1183, 1014, 718 cm^–1.

¹H NMR (400 MHz, CDCl₃): δ = 4.07 (tt, J = 11.8, 4.3 Hz, 1 H), 3.30–3.15 (m, 2 H), 2.18 (dd, J = 12.4, 4.3 Hz, 2 H), 1.65 (q, J = 12.1 Hz, 2 H), 1.54–1.22 (m, 20 H), 0.88 (t, J = 6.9 Hz, 6 H).

¹³C NMR (100 MHz, CDCl₃): δ = 77.6, 47.4, 43.6, 35.9, 31.8, 29.2, 25.5, 22.6, 14.08.

MS (EIMS): m/z (%) = 253 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₇H₃₃O: 253.25314; found: 253.25214.

4-Bromo-2,6-diethyltetrahydro-2H-pyran (3t)

Yield: 183 mg (78%); colourless solid; mp 61–62 °C.

IR (neat): 2952, 2854, 1440, 1330, 1242, 1150, 1082, 1020, 718, 562 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 4.10 (tt, J = 11.7, 1.4 Hz, 1 H), 3.18–3.10 (m, 1 H), 1.24–1.16 (m, 1 H), 1.70–1.40 (m, 6 H), 0.88 (t, J = 8.0 Hz, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 78.1, 45.2, 43.8, 29.9, 26.6, 9.4.

MS (EIMS): m/z (%) = 141 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₉H₁₇O: 141.13584; found: 141.13687.

4-Bromo-2,6-dipropyltetrahydro-2H-pyran (3u)

Yield: 210 mg (79%); colourless solid; mp 68–69 °C.

IR (neat): 2950, 2840, 1365, 1278, 1180, 1070, 1025, 760 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 4.08 (tt, J = 12.0, 3.8 Hz, 1 H), 3.26–3.18 (m, 2 H), 2.16 (dd, J = 12.0, 3.8 Hz, 2 H), 1.64 (q, J = 12.0, 3.8 Hz, 2 H), 1.56–1.24 (m, 8 H), 0.88 (t, J = 6.8 Hz, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 76.8, 45.3, 44.2, 36.2, 29.8, 29.2, 21.8, 14.0.

MS (EIMS): m/z (%) = 169 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₁H₂₁O: 169.65464; found: 169.65460.

4-Bromo-2,6-diisopropyltetrahydro-2H-pyran (3v)

Yield: 202 mg (80%); colourless solid; mp 66–67 °C.

IR (neat): 2945, 2853, 2460, 1325, 1242, 1151, 1080, 1025, 716, 562 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 4.08 (tt, J = 11.5, 4.4 Hz, 1 H), 2.95–2.90 (m, 2 H), 2.19 (dd, J = 12.2, 4.5 Hz, 2 H), 1.72–1.58 (m, 4 H), 0.92 (d, J = 6.4 Hz, 6 H), 0.88 (d, J = 6.4 Hz, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 79.8, 45.4, 44.2, 30.8, 30.1, 19.2.

MS (EIMS): m/z (%) = 169 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₁H₂₁O: 169.64340; found: 169.64321.

4-Bromo-2,6-dipentyltetrahydro-2H-pyran (3w)

Yield: 258 mg (81%); colourless solid; mp 82–83 °C.

IR (neat): 2932, 2855, 1465, 1365, 1378, 1280, 1230, 1180, 1160, 1080, 1015, 730 cm^–1.

¹H NMR (300 MHz, CDCl₃): δ = 4.08 (tt, J = 12.40, 4.3 Hz, 1 H), 3.26–3.17 (m, 2 H), 2.20 (dd, J = 12.4, 3.6 Hz, 2 H), 1.65 (q, J = 12.4, Hz, 2 H), 1.57–1.23 (m, 16 H), 0.88 (t, J = 7.3 Hz, 6 H).

¹³C NMR (75 MHz, CDCl₃): δ = 77.6, 47.5, 43.5, 35.8, 30.8, 29.2, 25.5, 22.4, 14.07.

MS (EIMS): m/z (%) = 225 [M–Br]⁺.

HRMS (EI): m/z [M–Br]⁺ calcd. for C₁₅H₂₉O: 225.64632; found: 225.64644.

Conflict of Interest

The authors declare no conflict of interest.

Acknowledgment

The authors are grateful to the Directors of the Indian Institute of Chemical Technology, Hyderabad, the BSS Arts, Science & Commerce College, Makni, Latur and the Dayanand Science College, Latur for support.

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Publikationsverlauf

Eingereicht: 29. Juni 2022

Angenommen nach Revision: 20. September 2022

Artikel online veröffentlicht:
19. Oktober 2022