10.1002/ejoc.201601491
European Journal of Organic Chemistry
(1'R,2'S,3'R)-6'-formyl-2'-(pyridin-2-yl)-1',2',3',4'-tetrahydro-[1,1':3',1''-
terphenyl]-2',4,4''-tricarbonitrile (10b). Major diastereomer. Yield 42%. Dark red
solid. Column eluent: 3:1 (Hexane/EtOAc). Melting point range: 162-165 OC. IR:
2961 cm-1 (HC=C stretch), 2228 cm-1 (nitrile stretch), 1684 cm-1 (C=O aldehyde
stretch), 1607 cm-1 (aliphatic C=C stretch), 1504 cm-1, 1486 cm-1 (aromatic C=C
stretch). 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.50-8.49 (m, 1H), 7.66 - 7.64
(m, 2H), 7.47 – 7.45 (m, 4H), 7.35 - 7.28 (m, 3H), 7.21 – 7.19 (m, 1H), 6.88 – 6.86
(m, 2H), 4.68 (s, 1H), 3.65 (dd, J = 8.9, 6.1 Hz, 1H), 3.08 – 2.97 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 191.3, 154.2, 149.2, 143.9, 142.5, 140.3, 137.0, 132.3, 132.0,
130.8, 130.3, 128.5, 123.9, 123.8, 120.0, 118.6, 118.4, 112.3, 112.2, 53.5, 45.5, 44.9,
29.9. The enantiomeric excess was determined by HPLC using a Chiralpak IE
column (hexane/iPrOH = 70:30, flow rate 1.0 mL/min, λ = 265 nm): tr (S) = 38.3, tr
lower steric hindrance than the CH2CHO, which is shielding the
Si face and leading to the opposite configuration at this center
(Scheme 5).
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(R) = 41.1, 99% (R) and 99% (S) ee. [α]D = -135.4° (c = 0.4, CHCl3) (S catalyst).
HRMS m/z (ESI-) Exact mass calculated for C27H13N4O [M-H]-: 409.1095, found:
409.1093.
(1'R,2'S,3'R)-6'-formyl-4,4''-dinitro-2'-(pyridin-2-yl)-1',2',3',4'-tetrahydro-
[1,1':3',1''-terphenyl]-2'-carbonitrile (10c). Major diastereomer. Yield 69%. Red
solid. Colum chromatography eluent: 3:1 (hexane/EtOAc). Melting point range: 170-
175 OC. IR: 2962 cm-1 (HC=C stretch), 2160 cm-1 (nitrile stretch), 1686 cm-1 (C=O
aldehyde stretch), 1603 cm-1 (aliphatic C=C stretch), 1520 cm-1, 1468 cm-1 (aromatic
C=C stretch). 1H NMR (400 MHz, CDCl3) δ 9.57 (s, 1H), 8.52-8.51 (m, 1H), 8.22 (d,
J = 8.8 Hz, 2H), 8.03 (d, J = 8.8 Hz, 2H), 7.69-7.64 (m, 1H), 7.52 (d, J = 8.7 Hz, 2H),
7.41-7.37 (m, 2H), 7.33-7.29 (m, 2H), 6.93 (d, J = 6.6 Hz, 1H), 4.77 (s, 1H), 3.73 (dd,
J = 8.9, 6.0 Hz, 1H), 3.16 – 3.05 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 191.3,
154.1, 149.3, 149.0, 147.9, 147.8, 145.8, 144.5, 140.5, 137.2, 130.9, 130.5, 124.0,
123.8, 123.8, 123.4, 120.0, 53.5, 45.3, 45.0, 30.16. The enantiomeric excess was
determined by HPLC using a Chiralpak IB column (hexane/iPrOH = 70:30, flow rate
Scheme 5. Proposed reaction mechanism
Conclusion
In summary, we developed a new methodology for the
synthesis of pyridine derivatives based on a triple cascade
reaction catalyzed by chiral secondary amines. The resulting
cyclohexenes (3 C-C bond were formed) were obtained in good
19
1.0 mL/min, λ = 265 nm): tr (S) = 29.6, tr (R) = 31.8, 99% (R) and 99% (S) ee. [α]D
yields,
good
diastereoselectivities
and
excellent
= -235.8° (c = 0.5, CHCl3) (S catalyst). HRMS m/z (ESI-) Exact mass calculated for
enantioselectivities. Studies towards the development of new
methodologies for the synthesis of azaarene derivatives are
ongoing in our laboratory.
C25H17N4O5 [M-H]-: 453.1204, found: 453.1206.
(1'R,2'S,3'R)-4,4''-dichloro-6'-formyl-2'-(pyridin-3-yl)-1',2',3',4'-tetrahydro-
[1,1':3',1''-terphenyl]-2'-carbonitrile (10d). Major diastereomer. Yield 63%.
Yellow solid. Colum chromatography eluent: 3:1 (hexane/EtOAc). Melting point
range: 139-142 OC. IR: 2922 cm-1, 2852 cm-1 (HC=C stretch), 2222 cm-1 (nitrile
stretch), 1686 cm-1 (C=O aldehyde stretch), 1586 cm-1 (aliphatic C=C stretch), 1492
cm-1, 1468 cm-1 (aromatic C=C stretch). 1H NMR (400 MHz, CDCl3) δ 9.52 (s, 1H),
8.53-8.49 (m, 1H), 7.62-7.57 (m, 1H), 7.36-7.34 (m, 3H), 7.30-7.28 (m, 2H), 7.16-
7.14 (m, 4H), 6.72-6.70 (m, 2H), 4.58 (s, 1H), 3.61 (dd, J = 9.5, 6.4 Hz, 1H), 2.97 –
2.84 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 191.7, 154.9, 149.0, 148.9, 140.8,
137.3, 136.6, 135.8, 134.3, 134.2, 131.4, 131.0, 128.8, 128.4, 124.1, 123.5, 120.6,
54.1, 45.4, 43.6, 29.8. The enantiomeric excess was determined by HPLC using a
Chiralpak IB column (hexane/iPrOH = 90:10, flow rate 1.0 mL/min, λ = 265 nm): tr
(S) = 14.7, tr (R) = 18.6, 99% (R) and 99% (S) ee. [α]D19 = +97.0° (c = 0.4, CHCl3) (S
catalyst). HRMS m/z (ESI-) Exact mass calculated for C25H17Cl2N2O [M-H]-:
431.0723, found: 431.0722.
Experimental Section
General Procedure
2-(pyridin-2-yl)acetonitrile (0.2 mmol, 1 equiv), the α,β-unsaturated aldehyde (3
equiv), the Jørgensen-Hayashi catalyst (20 mol%), benzoic acid (20 mol%) and
DCM (2 ml) were added to a 6 mL vial. The crude mixture was stirred at room
temperature for 48 hours and the reaction was checked by NMR. The crude mixture
was washed with aqueous sodium bicarbonate (40 mL). The aqueous phase was
extracted with ethyl acetate (3x20 mL), the organic phases collected and dried over
MgSO4 and the solvent removed in vacuo. The reaction mixture was then purified by
flash chromatography (hexane/EtOAc).
(1'R,2'S,3'R)-3,3''-dibromo-6'-formyl-2'-(pyridin-2-yl)-1',2',3',4'-tetrahydro-
[1,1':3',1''-terphenyl]-2'-carbonitrile (10e). Major diastereomer. Yield 45%. Light
orange solid. Colum chromatography eluent: 3:1 (hexane/EtOAc). Melting point
range: 166-168 oC. IR: 3015 cm-1, 2923 cm-1 (HC=C stretch), 1687 cm-1 (C=O
aldehyde stretch), 1587 cm-1 (aliphatic C=C stretch), 1427 cm-1, 1428 cm-1 (aromatic
C=C stretch). 1H NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.54-8.52 (m, 1H), 7.64-
7.60 (m, 1H), 7.49-7.44 (m, 2H), 7.40 – 7.27 (m, 4H), 7.25-7.24 (m, 1H), 7.16 (d, J =
8.0 Hz, 1H), 7.10-7.06 (m, 1H), 6.81-6.78 (m, 2H), 4.56 (s, 1H), 3.59 (dd, J = 10.0,
6.0 Hz, 1H), 2.94-2.88 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 191.6, 154.8, 149.1,
148.9, 141.1, 140.5, 139.6, 136.5, 132.6, 131.5, 131.3, 130.1, 129.8, 129.2, 128.6,
124.2, 123.6, 122.7, 122.1, 120.3, 53.9, 45.7, 43.8, 30.0. The enantiomeric excess
was determined by HPLC using a Chiralpak IB column (hexane/iPrOH = 90:10, flow
rate 1.0 mL/min, λ = 265 nm): tr (S) = 16.1, tr (R) = 22.7, 99% (R) and 99% (S) ee.
Supporting Information
(1'R,2'S,3'R)-6'-formyl-2'-(pyridin-2-yl)-1',2',3',4'-tetrahydro-[1,1':3',1''-
terphenyl]-2'-carbonitrile (10a) major diastereomer. 1H NMR (400 MHz, CDCl3)
δ 9.56 (s, 1H), 8.35 (ddd, J = 4.7, 1.6, 0.8 Hz, 1H), 7.45 – 7.40 (m, 2H), 7.32 (t, J =
3.7 Hz, 1H), 7.22 (td, J = 7.8, 1.8 Hz, 1H), 7.18 – 7.03 (m, 6H), 6.96 (ddd, J = 7.5,
4.8, 0.9 Hz, 1H), 6.61 (dd, J = 7.4, 3.8 Hz, 3H), 4.61 (bs, 1H), 3.95 (dd, J = 9.4, 7.8
Hz, 1H), 3.22 – 3.12 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 191.6, 154.6, 149.6,
148.9, 140.9, 139.9, 136.0, 135.7, 131.1, 129.7, 129.0, 128.8, 128.7, 128.1, 127.9,
127.4, 123.3, 122.7, 122.1, 52.8, 51.2, 39.6, 35.4. The enantiomeric excess was
determined by HPLC using a Chiralpak ID column (hexane/iPrOH = 80:30, flow rate
1.0 mL/min, λ = 254 nm): tr (S) = 37.0, tr (R) = 27.2, 97% (R) ee. [α]D19 = -56.0° (c =
1.0, CHCl3) (S catalyst). HRMS m/z (ESI-) Exact mass calculated for C25H19N2O
[M-H]-: 363.1503, found: 363.1502.
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[α]D = +11.7° (c = 0.7, CHCl3) (S catalyst). HRMS m/z (ESI-) Exact mass
calculated for C25H17Br2N2O [M-H]-: 518.9713, found: 518.9713.
(1'R,2'S,3'R)-6'-formyl-4,4''-dimethyl-2'-(pyridin-2-yl)-1',2',3',4'-tetrahydro-
[1,1':3',1''-terphenyl]-2'-carbonitrile (10f). Major diastereomer. Yield 33%. Brown
oil. Colum chromatography eluent: 3:1 (hexane/EtOAc). IR: 2921 cm-1 (HC=C
stretch), 2323 cm-1 (nitrile stretch), 1690 cm-1 (C=O aldehyde stretch), 1587 cm-1,
1573 cm-1 (aliphatic C=C stretch), 1468 cm-1, 1431 cm-1 (aromatic C=C stretch). 1H
NMR (400 MHz, CDCl3) δ 9.53 (s, 1H), 8.52-8.51 (m, 1H), 7.56-7.53 (m, 1H), 7.25
– 7.19 (m, 2H), 7.12-7.10 (m, 3H), 6.99-6.97 (m, 3H), 6.69-6.67 (m, 3H), 4.55 (s,
1H), 3.70-3.66 (m, 1H), 2.88-2.85 (m, 2H), 2.36 (s, 3H), 2.29 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 191.9, 155.5, 148.7, 148.6, 141.1, 137.7, 137.6, 136.0, 135.9, 134.5,
129.9, 129.5, 129.2, 128.7, 124.2, 122.9, 120.9, 54.4, 45.9, 43.3, 30.1, 21.2, 21.0.
The enantiomeric excess was determined by HPLC using a Chiralpak IB column
(hexane/iPrOH = 90:10, flow rate 1.0 mL/min, λ = 250 nm): tr (S) = 10.7, tr (R) =
(1'R,2'R,3'R)-6'-formyl-2'-(pyridin-2-yl)-1',2',3',4'-tetrahydro-[1,1':3',1''-
terphenyl]-2'-carbonitrile (10a) minor diastereomer. 1H NMR (400 MHz, CDCl3)
δ 9.53 (s, 1H), 8.52 (ddd, J = 4.9, 1.8, 0.8 Hz, 1H), 7.55 (td, J = 7.8, 1.9 Hz, 1H),
7.39 (d, J = 3.8 Hz, 5H), 7.23 (dd, J = 7.7, 3.6 Hz, 3H), 7.18 (d, J = 7.7 Hz, 2H), 7.11
(d, J = 8.0 Hz, 2H), 6.79 (d, J = 7.4 Hz, 2H), 4.61 (s, 1H), 3.72 (t, J = 8.1 Hz, 1H),
2.92 (dd, J = 7.7, 3.2 Hz, 2H). 13C NMR (101 MHz, CDCl3) δ 192.0, 155.5, 148.9,
148.9, 141.2, 139.0, 137.6, 136.3, 131.1, 130.2, 129.8, 129.0, 128.6, 128.3, 128.2,
128.1, 124.3, 123.2, 120.9, 54.4, 46.3, 43.9, 30.2. HRMS m/z (ESI-) Exact mass
calculated for C25H19N2O [M-H]-: 363.1503, found: 363.1501.
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15.1, 99% (R) and 99% (S) ee. [α]D = +16.3° (c = 0.5, CHCl3) (R catalyst). HRMS
m/z (ESI-) Exact mass calculated for C25H23N2O [M-H]-: 391.1816, found: 391.1817.
4
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