Organic Syntheses, CV 6, 293
Submitted by George W. Kabalka
1, Robert Hutchins
2, Nicholas R. Natale
2, Dominic T. C. Yang
3, and Vicky Broach
3.
Checked by Steven J. Brickner and Martin F. Semmelhack.
1. Procedure
B.
5β-Cholest-3-ene. A dry,
100-ml., two-necked, round-bottomed flask equipped with a magnetic stirring bar, a
rubber septum, and a reflux condenser connected to a
mercury bubbler (Note
3) is charged with
4.98 g. (0.00950 mole) of cholest-4-en-3-one p-toluenesulfonylhydrazone and
20 ml. of chloroform, and the apparatus is evacuated with an aspirator and filled with
nitrogen three times. The solution is stirred and cooled at 0° as
1.29 g. (1.21 ml., 0.0108 mole) of catecholborane (Note
4) is injected through the septum into the flask. Stirring and cooling are continued for 2 hours, after which
2.5 g. (0.018 mole) of sodium acetate trihydrate and
20 ml. of chloroform are added. The mixture is allowed to warm to room temperature over
ca. 30 minutes, heated under reflux for 1 hour, cooled to room temperature, and filtered. The solid material is washed with
50 ml. of chloroform, and the combined filtrates are evaporated under reduced pressure. The remaining oil is purified by chromatography on a
5 × 50 cm. column packed with
200 g. of alumina (Note
5). The column is eluted with
hexane and 200-ml. fractions are collected. Evaporation of the second 200-ml. fraction affords
2.76–2.95 g. (
83–88%) of
5β-cholest-3-ene as a colorless oil which eventually crystallizes on standing, m.p.
48–50°, [α]
24D = 19.6° (
c = 63,
chloroform) (Note
6).
2. Notes
2. The reported
4 melting point is
139–142°.
3.
Nitrogen is introduced
via a syringe needle that pierces the septum. A positive pressure of
nitrogen is maintained in the apparatus during the following operations.
4.
Catecholborane with a purity of 95% was purchased from Aldrich Chemical Company, Inc.
5. Activity grade I, neutral alumina was supplied by Brinckmann Instruments, Inc., Westbury, New York. The checkers used a
3 × 30 cm. column.
6. A TLC analysis was carried out by the submitters on a precoated silica gel plate (type Q6) purchased from Quantum Industries, 341 Kaplan Drive, Fairfield, New Jersey 07006. The chromatogram was developed with
cyclohexane and showed a single spot for the product after visualization by charring with concentrated
sulfuric acid.
5β-Cholest-3-ene is reported
5 to melt at 48–49°. The spectral properties of the product are as follows: IR (CHCl
3) cm.
−1: 2926, 1658, 1465, 831, 758, 678;
1H NMR (CDCl
3), δ (multiplicity, number of protons, assignment): 0.66 (s, 3H, C-18 C
H3), 0.82 (s, 3H, C
H3), 0.92 (s, 3H, C
H3), 0.94 (s, 3H, C-19 C
H3), 5.2–5.7 (m, 2H, vinyl
H); mass spectrum
m/e: 370 (M+).
The submitters prepared the dibromide derivative,
3α,4β-dibromo-5β-cholestane, m.p.
98–99°. The melting point of the dibromide is reported as
98–100°.
6 The mass spectrum of the dibromide exhibits three molecular ions at
m/e (relative intensity, assignment): 532 (25%,C
27H
4681Br
81Br), 530 (50%, C
27H
4679Br
81Br), 528 (25%, C
27H
4679Br
79Br).
3. Discussion
The reduction of
p-toluenesulfonylhydrazone derivatives of α,β-unsaturated ketones and aldehydes with
aluminum7 or
boron hydride reagents
8,9,10,11 effects a formal "conjugate" hydride transfer and produces alkenes in which the double bond has migrated to the position between the α-carbon and the carbonyl carbon. The mechanism of the reaction is presumed to involve initial reduction of the C=N double bond, elimination of
p-toluenesufinate, forming an
allyl diazene, and concerted fragmentation of the
diazene with 1,5-hydrogen transfer. One or both of the last two steps may take place during a subsequent hydrolysis. The reductions have been carried out with excess
lithium aluminum hydride in
tetrahydrofuran,
7 with
catecholborane in
chloroform at 0° followed by hydrolysis at
ca. 60° (Procedure A),
8 with
sodium cyanoborohydride in 1:1 (v/v)
N,N-dimethylformamide–
sulfolane acidified with concentrated
hydrochloric acid at 100–105° (Procedure B),
9,10 and with
sodium borohydride in
acetic acid at 70° (Procedure C).
11 A selection of examples of these reductions is given in Table I.
TABLE I
CONJUGATE REDUCTION OF α,β-UNSATURATED p-TOLUENESULFONYLHYDRAZONES TO ALKENES
|
p-Toluenesulfonylhydrazonea,b |
Alkeneb |
Procedurec |
Yield (%) |
|
|
C6H5CH2CH=CHCH3 |
A |
72d |
B |
54 |
C |
54 |
|
C6H5CH2CH=CH2 |
A |
53d |
B |
98d |
C |
42–56 |
|
(CH3)2CH-CH=CHCH3 |
A |
65d |
|
|
A |
77d |
B |
79 |
C |
61–72 |
|
|
A |
66e |
B |
4d,f |
C |
18 |
|
|
B |
70 |
C |
51 |
|
CH3(CH2)3-CH=C=CH-CH3 |
A |
64 |
|
CH3-CH=C=CH-C6H5 |
A |
75 |
|
|
b The p-toluenesulfonylhydrazones and alkenes with acyclic disubstituted double bonds are the E isomers.
|
c See text for descriptions of the procedures.
|
d Yield determined by GC.
|
e Yield determined by 1H NMR spectroscopy.
|
f The cycloalkane was also formed in 32% yield.
|
This method provides a convenient synthesis of alkenes with the double bond in a relatively unstable position. Thus, reduction of the
p-toluenesulfonylhydrazones of α,β-unsaturated aryl ketones and conjugated dienones gives rise to nonconjugated olefins. Unsaturated ketones with endocyclic double bonds produce olefins with double bonds in the exocyclic position. The reduction of
p-toluenesulfonylhydrazones of conjugated alkynones furnishes a simple synthesis of 1,3-disubstituted allenes.
12,13
The present procedure illustrates this method with the preparation of
5β-cholest-3-ene by reduction of
cholest-4-en-3-one p-toluenesulfonylhydrazone, using
catecholborane as the reducing agent.
8,14 The advantages of
catecholborane include its high solubility in common aprotic and nonpolar solvents, the low temperatures required for the reduction (0–25°), and the generally mild conditions used. Although the
sodium cyanoborohydride and
sodium borohydride procedures require higher temperatures, the use of polar solvents and protic conditions offers a valuable complement to the nonpolar, aprotic medium employed in the
catecholborane procedure. However, the reduction of
cholest-4-en-3-one p-toluenesulfonylhydrazone with
sodium cyanoborohydride (Procedure B) gave a 71% yield of a mixture consisting of
5β-cholest-3-ene (
32.5%),
5β-cholestane (
30.5%),
5α-cholestane (
30.5%), and
5α-cholest-3-ene (
6.5%).
15
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