PAPER
One-Carbon Homologation of Aldehydes to Nitriles
1053
product was extracted with EtOAc (2 × 10 mL). The combined or-
ganic extracts were washed with brine (10 mL) and dried (MgSO4).
The solvent was evaporated and the residue was chromatographed
on silica gel (15 mL, hexanes–EtOAc, 9:1) to give cyanide 3c (112
mg, 68%). 1H and 13C NMR spectra were in accord with those re-
ported.23
spectra were in accord with those reported24), and unchanged start-
ing material 4 (20 mg, 10%) in that order.
6 -Cyano-3 ,5 -cyclo-24-nor-5 -cholanenitrile (8)
Reaction of 4 with Bu3SnCN/Sc(OTf)3 in CH2Cl2 afforded a com-
plex mixture of products. The nitrile 8 was isolated from the product
mixture by column chromatography on silica gel (eluent: hexane–
EtOAc, 9:1 6:1).
6 -methoxy-22 -[2-(p-toluenesulfonyl)hydrazino]-23-nor-
3 ,5 -cyclo-5 -cholanenitrile (5)
IR (film): 2941 m, 2233 m, 1461 m, 1383 m cm–1.
To a stirred solution of tosylhydrazone 46 (205 mg, 0.4 mmol) in
THF (5 mL) at –30 °C was added dropwise Et2AlCN (1 M in tolu-
ene, 1.2 mL, 1.2 mmol). The mixture was allowed to warm to r.t.,
and was set aside. After 15 h, aq HCl (1 M, 15 mL) was added and
the product was extracted with EtOAc (2 × 10 mL). The combined
organic extracts were washed with brine (10 mL) and dried
(MgSO4). The solvent was evaporated and the residue was chro-
matographed on silica gel (15 mL, hexanes–EtOAc, 9:1) to give ad-
duct 5 (diastereomer A, 41 mg), a mixed fraction (50 mg), and
adduct 5 (diastereomer B, 82 mg) in that order.
1H NMR (200 MHz): δ = 0.36 (dd, J = 8.5 Hz, 1 H), 0.76 (s, 3 H),
1.13 (s, 3 H), 1.16 (d, J = 6.6 Hz, 3 H), 0.60–2.04 (m, 21 H), 2.18–
2.42 (m, 3 H).
13C NMR (50 MHz): δ = 12.32, 12.67 (2), 18.59 (3), 19.34 (3),
22.57 (2), 24.03 (2), 24.66 (2), 24.85 (2), 26.23 (1), (3), 28.07 (2),
32.60 (1), 32.89 (2), 33.22 (2), 33.42 (1), 34.00 (0), 39.57 (2), 42.86
(0), 43.19 (0), 47.31 (1), 54.68 (1), 55.61 (3), 118.73 (0), 122.25 (0).
HRMS (ESI/APCI): m/z calcd for C24H34N2Na: 373.2614; found:
373.2612.
5; Diasteromer A
3-Oxo-23-norchol-4-enenitrile (11)
1H NMR (500 MHz): δ = 0.46 (dd, J = 8.0, 5.1 Hz, 1 H), 0.67 (s, 3
H), 1.02 (s, 3 H), 1.07 (d, J = 7.1 Hz, 3 H), 0.64–2.0 (m, 21 H), 2.45
(s, 3 H), 2.79 (t, J = 2.6 Hz, 1 H), 3.33 (s, 3 H), 3.73 (dd, J = 10.2,
2.7 Hz, 1 H), 3.82 (dd, J = 10.2, 3.0 Hz, 1 H), 6.43 (d, J = 2.9 Hz 1
H), 7.34 (d, J = 8.0 Hz, 2 H), 7.82 (d, J = 8.3 Hz, 2 H).
A solution of aldehyde 9 (165 mg, 0.5 mmol) and tosylhydrazine
(95 mg, 0.5 mmol) in CH2Cl2 (4 mL) was stirred at r.t. for 1 h. To
the solution of tosylhydrazone 10 thus formed, were added TMSCN
(150 mg, 1.5 mmol), and Sc(OTf)3 (75 mg, 0.15 mmol, 30 mol%).
The mixture was allowed to warm to r.t. (3 h) and then refluxed for
3 h. After cooling, aq HCl (1 M, 5 mL) was added and the product
was extracted with EtOAc (2 × 10 mL). The combined organic ex-
tracts were washed with brine (10 mL) and dried (MgSO4). The sol-
vent was evaporated and the residue was chromatographed on silica
gel (15 mL, hexane–EtOAc, 2:1 1:1) to give nitrile21 11 (107 mg,
63%).
1H NMR (200 MHz): δ = 0.72 (s, 3 H), 1.15 (d, J = 6.8 Hz), 1.16 (s,
3 H), 0.80–2.54 (m, 23 H), 5.70 (s, 1 H).
13C NMR (50 MHz): δ = 12.01,17.33, 19.23, 20.89, 24.01, 24.71,
27. 96, 31.83, 32.77, 33.49, 33.89, 35.50, 35.60, 38.49, 39.17,
42.45, 53.51, 54.66, 55.58, 118.79, 123.73, 171.15, 199.39.
13C NMR (125 MHz): δ = 11.98 (3), 13.09 (2), 14.48 (3), 19.22 (3),
21.45 (1), 21.63 (3), 22.62 (1), 23.99 (2), 24.94 (2), 27.34 (2), 30.51
(1), 33.34 (2), 35.05 (2), 35.22 (0), 38.87 (1), 39.90 (2), 42.69 (0),
43.35 (0), 47.88 (1), 51.41 (1), 56.36 (1), 56.56 (3), 57.56 (1), 82.23
(1), 119.45 (0), 128.50 (1), 129.60 (1), 134.65 (0), 144.44 (0).
5; Diasteromer B
1H NMR (500 MHz): δ = 0.44 (dd, J = 8.0, 5.1 Hz, 1 H), 0.65 (app.
t, J = 4.5 Hz, 1 H), 0.69 (s, 3 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.01 (s,
3 H), 0.75–2.0 (m, 20 H), 2.44 (s, 3 H). 2,77 (t, J = 2.6 Hz, 1 H),
3.32 (s, 3 H), 3.68 (dd J = 8.1, 3.2 Hz, 1 H), 4.02 (dd, J = 8.1, 2.7
Hz, 1 H), 6.52 (d, J = 2.6 Hz 1 H), 7.34 (d, J = 8.0 Hz, 2 H), 7.81 (d,
J = 8.3 Hz, 2 H).
13C NMR (125 MHz): δ = 12.33 (3), 13.06 (2), 14.22 (3), 19.17 (3),
21.35 (1), 21.55 (3), 22.62 (2), 23.97 (2), 24.86 (2), 24.92 (0), 27.42
(2), 30.47 (1), 33.29 (2), 35.07 (2), 37.74 (1), 39.91 (2), 42.95 (0),
43.28 (0), 47.77 (1), 52.63 (1), 56.04 (1), 56.53 (3), 57.76 (1), 82.21
(1), 117.70 (0), 128.23 (1), 129.73 (1), 134.71 (0), 144.53 (0).
References
(1) Bamford, W. R.; Stevens, T. S. J. Chem. Soc. 1952, 4735.
(2) Eschenmoser, A.; Felix, D.; Ohloff, G. Helv. Chim. Acta
1967, 50, 708.
(3) Shapiro, R. H. Org. React. 1976, 23, 405.
(4) Addlington, R. M.; Barrett, A. G. M. Acc. Chem. Res. 1983,
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(5) Vedejs, E.; Stolle, W. T. Tetrahedron Lett. 1977, 135.
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In total 173 mg (80%) of adduct 5 was obtained. Analysis of the 1H
NMR spectra of the crude product indicated that diastereomers A
and B are present in a ratio of ca. 1:1.
5; Diasteromers A/B
IR (film): 3303 m, 2938 s, 2212 w, 1598 m, 1457 m, 1385 m, 1164
s, 1092 s, 814 m, 702 s, 554 s cm–1.
HRMS (ESI/APCI): m/z Calcd for C31H45N3O2NaS: 562.3074.
Found: 562,3074.
6 -Methoxy-23-nor-3 ,5 -cyclo-5 -cholanenitrile (6)
To a stirred solution of tosylhydrazone 4 (205 mg, 0.4 mmol) in
THF (5 ml) at –30 °C was added dropwise Et2AlCN (1 M in toluene,
0.8 mL, 0.8 mmol). The mixture was allowed to warm to r.t. in 1 h
and then refluxed for 2 h. After cooling, aq HCl (1 M, 5 mL) was
added and the product was extracted with EtOAc (2 × 10 mL). The
combined organic layers were washed with brine and dried
(MgSO4). The solvent was evaporated and the residue was chro-
matographed on silica gel (15 mL, hexanes–EtOAc, 9:1, 6:1 and
4:1) to afford 6β-methoxy-3α,5α-cyclo-23,24-bisnor-5α-chol-
20(22)-ene (26 mg, 20%), nitrile 6 (90 mg, 63%, 1H and 13C NMR
(10) Myers, A. G.; Kukkola, P. J. J. Am. Chem. Soc. 1990, 112,
8208.
(11) Vedejs, E.; Dolphin, J. M.; Stolle, W. T. J. Am. Chem. Soc.
1979, 101, 249.
(12) Katritzky, A. R.; Tymoshenko, D. O.; Belyakov, S. A. J.
Org. Chem. 1999, 64, 3332.
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42, 4759.
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Synthesis 2003, No. 7, 1049–1054 ISSN 0039-7881 © Thieme Stuttgart · New York