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-Hc [δ = 4.5 (J = 11.0 Hz)] and the proton on the carbon bearing the halide group 4-Hc [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
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
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)
(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)
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)
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)
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)
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)
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)
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)
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.
