Reduction of steroidal ketones with amine - Boranes

Article abstract of DOI:10.1023/B:RUCB.0000035660.32775.ab

Complexes of secondary amines with borane, R₂NH·BH ₃, surpass sodium borohydride as reducing agents for saturated and unsaturated steroidal 3-, 12-, 17-, and 20-ketones as regards chemo- and regioselectivity and mildness of the reaction conditions. In the case of 12-ketones, stereoselectivity is also improved.

Full text of DOI:10.1023/B:RUCB.0000035660.32775.ab

Russian Chemical Bulletin, International Edition, Vol. 53, No. 3, pp. 703—708, March, 2004
703
Reduction of steroidal ketones with amine—boranes
A. E. Leontjev, L. L. Vasiljeva, and K. K. Pivnitskyꢀ
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences,
47 Leninsky prosp., 119991 Moscow, Russian Federation.
Fax: +7 (095) 135 5328. Eꢀmail: kpiv@mail.ru
Complexes of secondary amines with borane, R2NH•BH3, surpass sodium borohydride as
reducing agents for saturated and unsaturated steroidal 3ꢀ, 12ꢀ, 17ꢀ, and 20ꢀketones as regards
chemoꢀ and regioselectivity and mildness of the reaction conditions. In the case of 12ꢀketones,
stereoselectivity is also improved.
Key words: amine—boranes, reduction, hecogenin acetate, dihydroprogesterone, dimethylꢀ
amine—borane, dicyclohexylamine—borane, diethylamine—borane, ketones, keto steroids,
methyltestosterone, morpholine—borane, prednisolone 21ꢀacetate.
Amine—boranes have not yet found extensive use as
reducing agents in organic chemistry, despite their stabilꢀ
ity, ready availability including commercial one, and the
possibility to control the reactivity by varying the amine
(see reviews, Ref. 1). In recent years, the interest in
amine—boranes as reducing or hydroborating reagents
has markedly increased. They have been proposed as reꢀ
agents of choice for reductive amination of carbonyl comꢀ
pounds,2 reduction of oximes to hydroxylamines,3 synꢀ
thesis of higher dialkylboranes (they are used instead of
diborane),4 reductive dehalogenation of aryl halides,5 and
other reductive processes.6,7 Against this background, the
use of amine—boranes for the reduction of carbonyl comꢀ
pounds into alcohols appears inadequately studied. Alꢀ
though this reduction has long been investigated for simple
aldehydes and ketones,8 cases of application of this reacꢀ
tion in the syntheses are few. These include the reduction
of several steroidal ketones9,10 and effective use in the
synthesis of the antiviral drug Cyclaradine where steꢀ
reospecific reduction of the carbonyl group was attained
only using the tertꢀbutylamine—borane complex.11
The purpose of the present study is to evaluate the
synthetic potential of these complexes using the reduction
of several types of steroidal ketones as examples. The reꢀ
agents chosen were amine—boranes R2NH•BH3 derived
from dialkylamines, viz., dimethylamine and diethylamine
(R = Me and Et, DMAB and DEAB, respectively),
morpholine (R2 = O(CH2CH2)2, MorB) and dicycloꢀ
hexylamine (R = cycloꢀC6H11, DCyAB). The complexes
of dialkylamines, unlike derivatives of trialkylamines, are
sufficiently reactive to react with carbonyl compounds
without activators, and they give no byꢀproducts resulting
from reductive amination of reactive carbonyl compounds,
which was noted in the case of using even more reactive
complexes with monoalkylamines.12 The most imporꢀ
tant types of steroidal ketones used included saturated
3ꢀ (1, 13), 12ꢀ (3), 17ꢀ (5), and 20ꢀketo steroids (15) and
unsaturated 3ꢀketo steroids (6β, 7, 11) (Scheme 1).
The workup of reaction mixtures after reduction with
amine—boranes deserves special mention. The ketone reꢀ
duction products, viz., the corresponding alcohols, are
formed in organic solvents as alkyl borates, which, in
addition, bind more or less strongly the amine present in
the mixture. If the alcohols formed are acidꢀstable, they
can be easily liberated from the borates by acidification
with a mineral acid (method A, see Experimental). Howꢀ
ever, most of allylic alcohols are partially or completely
dehydrated under these conditions. Transesterification
with methanol and distillation of trimethyl borate, norꢀ
mally used to destroy borates, proved to be inefficient for
amine—boranes, and the removal of boronꢀcontaining
components was unacceptably slow. This is apparently
due to the presence of amine and to the low rate of the
reaction of the B—H bonds with methanol. The use of
carbonꢀsupported palladium to catalyze the reaction with
methanol, which has been recommended for similar
cases,13 did accelerate the process but brought about side
hydrogenation of double bonds in the products. This can
be suppressed by adding excess allyl alcohol, which is
easily hydrogenated. Therefore, we have used for some
period the following workup procedure: Pd/C + MeOH +
+ CH2=CHCH2OH, stirring for 2 h, concentration, and
extraction. This gave the target reduction products with
only minor amounts of boronꢀcontaining impurities. Nevꢀ
ertheless, this procedure is not given in the Experimental,
because a simpler and a more efficient method has been
found. The method is based on the report that the reacꢀ
tion of an aqueous solution of an amine—borane with
excess acetone is accompanied by evolution of hydrogen,
because the intermediate product of acetone reduction,
namely, unstable amine•BH(PriO)2 complex, reacts comꢀ
petitively with water due to the easy dissociation into
Published in Russian in Izvestiya Akademii Nauk. Seriya Khimicheskaya, No. 3, pp. 670—675, March, 2004.
1066ꢀ5285/04/5303ꢀ0703 © 2004 Plenum Publishing Corporation

704
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Leontjev et al.
Scheme 1
components.14 The same can be expected in the case of
the methanolic medium. Therefore, a novel, nonacidic
workup of the reaction mixtures formed after the reducꢀ
tion with amine—boranes (method B) consists of decomꢀ
position of excess hydride and intermediate borates with
an acetone—methanol mixture followed by washing of
the extract with an aqueous solution of a weak base. The
products obtained with a quantitative balance are free
from boronꢀcontaining impurities (Table 1). This nonꢀ
acidic workup of the reaction mixtures can also be recomꢀ
mended for other reactions with amine—boranes.
ing either the alcohols themselves and/or their acetates.
The reporter signals used for this purpose and characterisꢀ
tics of the alcohols are listed in Tables 2 and 3.
The influence of the conditions and structures of
amine—boranes on the results of reduction were studied
taking 12ꢀketone 3 as an example. Strange as it may seem,
the effect of the amine structure on the reduction rate and
stereochemistry was insignificant (runs 5—7, 9), nor was
the effect of the solvent (run 8). Therefore, all the subꢀ
sequent reduction experiments were carried out with
morpholine—borane (MorB) in toluene (with addition of
ethanol if this was required by the solubility of the starting
ketone). The fact that the amine structure does not influꢀ
ence the reaction selectivity, even in the case of sterically
most hindered amine—borane complex (DCyAB), is conꢀ
sistent with the mechanism of reduction, which includes
displacement of the amine from the complex during the
The results of reduction of the ketones are summaꢀ
rized in Table 1; for comparison, the Table also gives the
results of reduction of the same ketones with sodium boroꢀ
hydride carried out in parallel. The ratio of the αꢀ to
βꢀepimers of the alcohols 2, 4, 6, 8—10, 12, 14, and 16
1
was determined using H NMR spectroscopy by analyzꢀ

Reduction of steroidal ketones with amineboranes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
705
Table 1. Reduction of steroidal ketones with amine—boranes
Entry Keꢀ
tone
Hydride
(mol.ꢀequiv.)
Reaction conditions
Yield of
alcohols (%)
Ratio of
α : β epimers*
Solvent
Т/°C
τ/h Method
1
1
NaBH4 (3.6)
CH2Cl2—EtOH—H2O
(32 : 62 : 6)
PhMe
20
1.5
С
2 (96)
29 : 71
2
3
4
MorB (2.9—3.4)
DCyAB (2.9)
NaBH4 (2.0)
20
20
25
1.5
1.5
72
А
А
С
2 (100)
2 (100)
4 (95)
25 : 75
27 : 73
25 : 75
PhMe
3
CH2Cl2—EtOH—H2O
(32 : 62 : 6)
PhMe
PhMe
PhMe
EtOH
PhMe
EtOH—H2O (81 : 19)
PhMe—EtOH (93 : 7)
EtOH—H2O (94 : 6)
5
6
7
8
DMAB (3.3)
DEAB (2.9)
MorB (2.4)
MorB (2.5)
DCyAB (1.6)
NaBH4 (0.4)
MorB (3.0)
NaBH4 (1.9)
19
17
26
26
27
22
20
25
2
3
2
1
1
0.25
20
3
А
А
А
А
А
С
А
D
4 (94)
4 (98)
4 (98)
4 (∼100)
4 (97)
6 (100)
6 (96)
8 (43)
6.5 : 93.5
4.5 : 95.5
5 : 95
9
7 : 93
2 : 98
8 : 92
5 : 95
10
11
12
5
6b
9 (47)
8 (44)
50 : 50
6 : 94
13
MorB (3.0)
PhMe—EtOH (93 : 7)
70—110
3
B
9 (44)
55 : 45
4.5 : 95.5
12 : 88
23 : 77
31 : 69
10 : 90
14
15
16
17
18
7
NaBH4 (3.6)
MorB (3.5)
NaBH4 (10.8)
MorB (3.1)
EtOH
20
65—75
22
65—70
21
2
D
B
D
B
C
10 (97)
10 (95)
12 (99)
12 (92)
14 (100)
PhMe—MeOH (96 : 4)
EtOH—H2O (94 : 6)
PhMe—EtOH (96 : 4)
EtOH—PhMe—H2O
(73 : 26 : 1)
70
0.5
12
0.5
11
13
NaBH4 (0.34)
19
20
MorB (1.3)
NaBH4 (0.65)
PhMe
EtOH—PhMe—H2O
(83 : 14 : 3)
23
19
1.5
1.0
A
D
14 (100)
16 + 17 (85)
6.5 : 93.5
22 : 78
15
21
MorB (3.6)
PhMe—EtOH (87 : 13)
18
20
B
16 (90)
28 : 72
1
* Epimer ratio in the crude product was determined from the reporter signals in the H NMR spectrum (see Table 2).
process.15 This hypothesis accounts for the parallel variaꢀ
tion of the reactivity and the ease of dissociation of the
amine complexes with borane (primary > secondary >
> tertiary), but it is at variance with the known substantial
difference between the stereoselectivities of reduction with
diborane and amine—boranes.16
with its excess, the 3ꢀketo group is also rapidly reduced
(entry 12).
It should be noted that neither double bond hydroꢀ
boration nor reductive amination was observed even unꢀ
der drastic conditions used for the reduction of unsaturꢀ
ated keto groups. Yet another positive feature of the reꢀ
duction with amine—boranes is that lowꢀpolar aprotic solꢀ
vents (toluene, dichloromethane) can be employed. The
reaction media are weakly basic, which is due to the amine,
this, in addition, being complexed with boronꢀcontaining
compounds. Therefore, the acetoxy groups in hecogenin
acetate 3 and prednisolone acetate 15 are completely stable
during the reduction with amineꢀboranes, even in the presꢀ
ence of ethanol (entries 8, 21), whereas in the reducꢀ
tion with sodium borohydride, which produces a highly
basic medium, partial deacetylation always takes place
(entries 4, 20).
Chemoselectivity of reduction
Morpholine—borane (MorB) reduces saturated keꢀ
tones 1, 3, and 13 (entries 2, 7, and 19) and nonconjugated
keto groups in steroids 5 and 15 (entries 11 and 21) an
order of magnitude faster than conjugated enones and
dienones 6β, 7, and 11 (entries 13, 15, and 17). Whereas
the reduction of saturated ketones occurs rapidly at room
temperature, the reduction of unsaturated ketones starts
only at 65 °C and requires many hours for completion.
This chemoselectivity allows one to carry out totally seꢀ
lective reduction of saturated ketones (the 17ꢀketo group
in diketone 5 (entry 11) and the 20ꢀketo group in predꢀ
nisolone acetate 15 (entry 21)) in the presence of unsatꢀ
urated ketones (the 3ꢀketo group) using an excess of
MorB, whereas similar reduction with NaBH4 requires
dosage of the reducing agent (entries 10 and 20), while
The selectivity of reduction of saturated
carbonyl compounds
Even in an early publication,12 considerable (up to a
25ꢀfold) difference was noted between the rates of reducꢀ
tion of different saturated ketones with ButNH2•BH3,

706
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Leontjev et al.
Table 2. Characteristics of the reduction products of steroidal
ketones with amine—boranes
prone to conjugate addition, only the carbonyl groups are
reduced (entries 15 and 17), whereas in the case of crossꢀ
conjugated dienone 6β, highly susceptible to 1,4ꢀaddiꢀ
tion, both reducing agents produced equal amounts of
1,2ꢀ and 1,4ꢀaddition products. In the latter, it is the less
substituted double bond that is involved (entries 12 and 13).
Entrya Alcoꢀ Yieldb Epimer
M.p./°C
(solvent)
[lit. data]c
TLC,
Rf,
α/β
hol (its (%)
acetate)
ratio
α : β
b
2
7
2
80
25 : 75d
201—202 (EtOH)
[208—209]17
0.22e
Stereochemistry of reduction
3,17ꢀOꢀAc2ꢀ2 f
25 : 75
0.73e
d
4
83
β (100) 225—226 (MeOH) 0.28g
This aspect shows some ambiguity of the results. The
stereoselectivities of reduction of the 3ꢀketo groups of
ketones 1, 6β, 7, 11, and 13, the 17ꢀketo group in
diketone 5, and the 20ꢀketo group in diketone 15 with
MorB were somewhat higher (entries 2 and 19), or apꢀ
proximately the same (entries 13 and 21), or markedly
lower (entries 11, 15, and 17) than those for the reduction
with NaBH4, and the use of much more bulky DCyAB did
not enhance the stereoselectivity (entry 3). However, the
reduction of the 12ꢀketo group in ketone 3 with the
amine—borane studied was much more stereoselective
(4α : 4β = (5—7) : (93—95)) than the reduction with
NaBH4 (25 : 75) (entries 4—7 and 9). The reduction of
other 12ꢀketo steroids with ButNH2•BH3 has been studꢀ
ied previously, and the stereoselectivity was found to vary
from 17 : 83 to 40 : 60, depending on the substrate.10
Thus, the reduction with secondary amine—boranes, at
least, for hecogenin acetate 3, is the most stereoselective
method for the synthesis of rockogenin acetate 4β.
[218—220]18
212—213 (MeOH) 0.56g
[204—206]18
170—171 (EtOH)
[168—169]19
12ꢀОꢀАсꢀ4 f
β (100)
11
13
6
74
4 : 96
0.28e
h
8
9
—
—
6 : 94
55 : 45
h
see Ref. 20
0.44/
–0.30e
0.19i
15
17
10
12
90
82
β (100)
172—173 (MeOH)
[166—170]21
182—192
22 : 78
0.30/
(PhMe—MeOH) –0.24 j
[125—127.5 (12α),
156—158 (12β)]22;
[183—184 (12α+12β)]23
19
21
14
91
58
β (100)
194
0.38/
(EtOH—hexane) –0.34k
[194]24
16
20,21ꢀOꢀ
ꢀAc2ꢀ16
<5 : >95d
<5 : >95
211—213 (H2O)
243—244 (H2O)
[241.5—243]25
0.27l
0.40l
To summarize, we can conclude that the reduction
with commercially available amine—boranes can serve as
a convenient alternative to the reduction with sodium
borohydride, being superior as regards the chemoꢀ and
regioselectivity, mildness of the reaction conditions, and,
in some cases, stereoselectivity.
a The numbering of the entries is the same as in Table 1.
b After recrystallization.
c The best published data for the individual major epimers.
d Analyzed as the acetate.
e Silufol, EtOAc—hexane (3 : 2, two runs).
f Prepared by standard acetylation (Ac2O—Py).
g Silufol, EtOAc—PhMe (1 : 9).
h Recrystallization was not carried out due to instability of the
compounds.
i Alufol, EtOAc—hexane (2 : 3, two runs).
j Silufol, EtOAc—hexane (4 : 1, three runs).
k Silufol, EtOAc—hexane (2 : 3, two runs).
l Silufol, EtOAc (two runs).
Experimental
1
H NMR spectra were recorded in CDCl3 on Bruker
WMꢀ250 (250.13 МHz) and Bruker AMꢀ300 (300.13 МHz)
spectrometers, the chemical shifts being referred to internal
Me4Si (δ 0.00). The melting points were determined on a Koefler
(Boetius) hot stage and were not corrected. Analytical TLC was
performed on Silufol and Alufol plates (Czechia) in the indiꢀ
cated solvent systems, the spots being visualized with a 5% soluꢀ
tion of phosphomolybdic acid in ethanol or a solution of
Ce(SO4)2 in 10% H2SO4 with subsequent heating. The extracts
were concentrated in vacuo (waterꢀjet pump) at 30 °C, and the
residues were dried to a constant weight in vacuo (2 Torr).
All steroids with >98% purity were taken from the laboraꢀ
tory collection. Amine—boranes, DMAB (m.p. 37 °C, b.p. 63 °C
(1 Torr)),26 DEAB (b.p. 98—100 °C (12 Torr)),27 MorB (m.p.
95 °C),28 and DCyAB were synthesized according to a general
procedure,26,29 i.e., by the reaction of the corresponding amine
hydrochlorides with sodium borohydride in DME. The comꢀ
plexes were >95% pure (according to NMR).
which was the highest for cyclohexanone and the lowest
for heptanꢀ4ꢀone. A similar selectivity is also observed in
the reduction of steroidal ketones with MorB. Competiꢀ
tive reduction experiments have revealed the following
sequence for the ease of reduction of saturated steroidal
ketones: 12ꢀketo ≈ 3ꢀketo > 17ꢀketo >> 20ꢀketo (for the
ketones used in this study). This allowed us to conduct
highly regioselective reduction of the 3ꢀketo group in
3,20ꢀdiketone 13 (entry 19).
The 1,2 and 1,4 (or 1,6) addition to unsaturated ketones
In this respect, MorB proved to be analogous to
NaBH4. In particular, in ketones 7 and 11, which are not
Dicyclohexylamine—borane complex (DCyAB). A 12% soluꢀ
tion of HCl (18 mL, 60 mmol) was added with shaking to

Reduction of steroidal ketones with amineboranes
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
707
1
Table 3. H NMR spectra of the reduction products of steroid ketones with amine—borane complexes
Alcohol
(its acetate)
1H NMR (CDCl3, δ, J/Hz)
Major epimer
Mixture of α/β epimersa
2
4.07/3.85
5.06/4.86
0.83/0.81
3.69/3.33
2β: 0.80 (s, 3 H, C(18)H3); 3.70 (t, 1 H, H(17), J = 8.2); 3.85 (m, 1 H, H(3))
3,17ꢀOꢀAc2ꢀ2β: 0.81 (s, 3 H, C(18)H3); 2.04 (s, 6 H, 2 ОАс); 4.63 (dd, 1 H,
H(17), J = 7.8, J = 8.9); 4.86 (s, 1H, H(3))
4β: 0.76 (s, 3 H, C(18)H3); 0.80 (d, 3 H, C(27)H3, J = 6.2); 0.86 (s, 3 H, C(19)H3);
1.04 (d, 3 H, C(21)H3, J = 7.0); 2.03 (s, 3 H, ОАс); 3.33 (dd, 1 H, H(12), J = 4.6,
J = 11.2); 3.37 (t, 1 H, H(26α), J = 10.8); 3.46 (dd, 1 H, H(26β), J = 4.2, J = 10.8);
4.41 (q, 1 H, H(16), J = 7.1); 4.68 (tt, 1 H, H(3), J = 5.3, J = 10.6)
3,17ꢀOꢀAc2ꢀ2
4
12ꢀОꢀАсꢀ4
4.92/4.55
2.06/2.03
12ꢀОꢀАсꢀ4β: 0.86 (s, 3 H, C(18)H3); 0.79 (d, 3 H, C(27)H3, J = 6.0); 0.85 (s, 3 H, C(19)H3);
0.91 (d, 3 H, C(21)H3, J = 6.5); 2.01 (s, 3 H, 3ꢀОАс); 2.03 (s, 3 H, 12ꢀОАс); 3.36 (t, 1 H,
H(26α), J = 10.8); 3.45 (dd, 1 H, H(26β), J = 4.2, J = 10.8); 4.40 (q, 1 H, H(16), J = 7.4);
4.55 (dd, 1 H, H(12), J = 4.8, J = 11.4); 4.68 (tt, 1 H, H(3), J = 5.3, J = 10.6)
6β: 0.83 (s, 3 H, C(18)H3); 1.25 (s, 3 H, C(19)H3); 3.65 (t, 1 H, H(17), J = 8.2);
6.08 (br.s, 1 H, H(4)); 6.24 (dd, 1 H, H(2), J = 1.7, J = 10.3); 7.05 (d, 1 H, H(1), J = 10.3)
8β: 0.76 (s, 3 H, C(18)H3); 1.06 (s, 3 H, C(19)H3); 3.62 (t, 1 H, H(17), J = 8.3);
4.14 (m, 1 H, H(3)); 5.28 (d, 1 H, H(4), J = 1.5)
6
3.77b/3.65;
0.74/0.83
5.46/5.28
8
9
5.53/5.50
5.47c/5.29
9α: 0.78 (s, 3 H, C(18)H3); 1.12 (s, 3 H, C(19)H3); 3.62 (t, 1 H, H(17), J = 8.3); 4.48 (m,
1 H, H(3)); 5.53 (m, 1 H, H(4)); 5.77 (d, 1 H, H(2), J = 10.7); 5.96 (d, 1 H, H(1), J = 10.7)
10β: 0.88 (s, 3 H, C(18)H3); 1.07 (s, 3 H, C(17)H3); 1.19 (s, 3 H, C(19)H3); 4.14 (m, 1 H,
H(3)); 5.28 (q, 1 H, H(4), J = 1.7)
12β: 0.86 (s, 3 H, C(18)H3); 3.63 (t, 1 H, H(17), J = 8.2); 4.32 (m, 1 H, H(3));
5.36 (br.s, 1 H, H(4))
10
12
14
16
5.42b/5.36
4.22/4.32
4.04d/3.59
14β: 0.60 (s, 3 H, C(18)H3); 0.81 (s, 3 H, C(19)H3); 2.10 (s, 3H, C(20)H3); 2.52 (t, 1 H,
H(17), J = 8.5); 3.59 (tt, 1 H, H(3), J = 5.0, J = 11.0)
16β: 1.11 (s, 3 H, C(18)H3); 1.46 (s, 3 H, C(19)H3); 2.10 (s, 3 H, 21ꢀOAc); 4.02 (dd, 1 H,
H(20), J = 3.0, J = 7.7); 4.08—4.28 (m, 2 H, H2(21)); 4.41 (q, 1 H, Н(11), J = 2.8);
6.01 (br.s, 1 H, Н(4)); 6.26 (dd, 1 H, Н(2), J = 1.8, J = 10.1); 7.28 (d, 1 H, Н(1), J = 10.1)
20,21ꢀOꢀAc2ꢀ16β: 1.04 (s, 3 H, C(18)H3); 1.45 (s, 3 H, C(19)H3); 2.02 (s, 3 H, 20ꢀOAc);
2.12 (s, 3 H, 21ꢀOAc); 4.14 (dd, 1 H, H(21A), J = 8.2, J = 12.3); 4.40—4.48 (m, 2 H,
H(11) + H(21B)); 5.38 (dd, 1 H, H(20), J = 2.3, J = 8.2); 6.01 (br.s, 1 H, Н(4));
6.26 (dd, 1 H, Н(2), J = 1.3, J = 10.3); 7.23 (d, 1 H, Н(1), J = 10.3)
20,21ꢀOꢀAc2ꢀ16
5.35/5.38
a The reporter signals in the epimer mixture.
b Unlike the corresponding triplet signal of the epimer, this signal is a doublet with J = 4.4 Hz.
c Unlike the corresponding signal of the epimer, this signal is a doublet with J = 5.0 Hz.
d Unlike the corresponding signal of the epimer, this signal is a quintet with J = 2.5 Hz.
dicyclohexylamine (5.0 g, 27.6 mmol). After cooling, the white
crystalline precipitate was filtered off and dried in a vacuum
desiccator to give 6.0 g (100%) of the corresponding hydrochloꢀ
ride. Sodium borohydride (400 mg, 10.6 mmol) was added in
portions with stirring at 20 °C to a suspension of this hydrochloꢀ
ride (4.3 g, 19.7 mmol) in 30 mL of DME. The suspension was
stirred for 1 h and the precipitate was filtered off and washed
with hexane. The filtrate was concentrated in vacuo to dryness,
and the residue was recrystallized from hexane to give 2.41 g
(63%) of DCyAB as a white crystalline solid stable in air and
during storage, m.p. 121—122 °C. Found (%): C, 73.73, 73.87;
H, 13.62, 13.62; B, 5.66, 5.62; N, 7.01, 7.15. C12H26BN. Calcuꢀ
the steroid solubility, 15—30 mL per mmol of the steroid) was
stirred at the temperature indicated in Table 1 to complete transꢀ
formation of the starting compound (TLC). The reaction mixꢀ
ture was diluted with EtOAc, and 7% aqueous HCl was added
until the mixture became acidic and hydrogen evolution ceased.
The organic layer was separated and washed with a saturated
aqueous solution of NaHCO3 and water to a neutral pH. The
solution was dried by filtering through a microcolumn with
MgSO4 and concentrated. The crystalline precipitate was anaꢀ
lyzed (NMR) before and after recrystallization. When indicated
in Table 2, the sample was acetylated before analysis (excess
Ac2O—Py, 15 h, concentration to dryness).
Method B. The reduction was carried out as described in
method A, but the workup was performed in the following way:
the reaction mixture was diluted with a mixture of acetone with
methanol (10 mol.ꢀequiv. each per mole of the amine—borane)
and kept until hydrogen evolution ceased (2 h), CH2Cl2 (up to
35% of the total volume) and a saturated aqueous solution of
NaHCO3 were added, and the organic layer was washed to a
lated (%): C, 73.86; H, 13.43; B, 5.54; N, 7.18. IR, ν/cm–1
:
1280 (B—N); 2288, 2328, 2344, 2368, 2396 (B—H); 3224
(N—H). 1H NMR, δ: 0.70—1.45 (m, 7 H, 3 BH + 2 CH2);
1.45—2.00 (m, 16 H, 8 CH2); 2.85 (m, 3 H, NH + 2 HCN).
Reduction of ketones with amine—boranes (general proceꢀ
dures). Method A. A solution of a steroidal ketone and an
amine—borane in toluene or in another solvent (depending on

708
Russ.Chem.Bull., Int.Ed., Vol. 53, No. 3, March, 2004
Leontjev et al.
neutral pH, dried by filtering through a microcolumn with Al2O3,
and concentrated. Subsequent analysis of the residue was carꢀ
ried out as in procedure A.
5. B. H. Lipshutz, T. Tomioka, and K. Sato, Synlett, 2001, 970.
6. (a) J. H. Billman and J. W. McDowell, J. Org. Chem., 1961,
26, 1437; (b) A. M. Salunkhe and E. R. Burkhardt, Tetraꢀ
hedron Lett., 1997, 38, 1519.
7. (a) M. Couturier, J. L. Tucker, B. M. Andresen, P. Dube,
S. J. Brenek, and J. T. Negri, Tetrahedron Lett., 2001, 42,
2285; (b) M. Couturier, B. M. Andresen, J. L. Tucker,
P. Dube, S. J. Brenek, and J. T. Negri, Tetrahedron Lett.,
2001, 42, 2763.
The reduction of ketones with sodium borohydride (general
procedures). Method C. An aqueous solution of NaBH4 (1—2 mL
per mmol of the steroid) was added to a solution of the steroidal
ketone in the mixture of organic solvents indicated in Table 1
(determined by the steroid solubility, 15—30 mL per mmol of
the steroid) and the solution was stirred at 19—25 °C to comꢀ
plete transformation of the starting compound (TLC). The
workup of the reaction mixture and analysis were carried out as
described in method A.
8. (a) H. Noth and H. Beyer, Chem. Ber., 1960, 93, 1078;
(b) S. S. White and H. C. Kelly, J. Am. Chem. Soc., 1970,
93, 1078.
Method D. The reduction and analysis were carried out as
described in method C but the phosphate buffer (рH 5) was used
instead of hydrochloric acid.
9. F. K. V. Yorka, W. L. Truett, and W. S. Johnson, J. Org.
Chem., 1962, 27, 4580.
10. F. C. Chang, Synthetic Commun., 1981, 11, 875.
11. Eur. Pat. EP 0246605, 1986; Chem. Abstr., 1988, 109, 38192.
12. G. C. Andrews, Tetrahedron Lett., 1980, 21, 697.
13. C. M. Couturier, J. L. Tucker, B. M. Andresen, P. Dubu,
and J. T. Negri, Organic Letters, 2001, 3, 465.
14. S. S. White and H. C. Kelly, J. Am. Chem. Soc., 1968,
90, 2009.
15. S. S. White and H. C. Kelly, J. Am. Chem. Soc., 1970,
92, 4203.
16. G. C. Andrews and T. C. Crawford, Tetrahedron Lett., 1980,
21, 693.
Competitive reduction of ketones with amine—boranes. A mixꢀ
ture of equal amounts of 12ꢀketo steroid 3 and keto steroid 5, 13,
or 15 was reduced at ∼20 °C according to methods A or B
(depending on the structure) using 1.2 mol of MorB per mole of
both ketones. During the period from 3 to 120 min, aliquots of
the reaction mixtures were withdrawn and the product ratio was
determined by TLC after the appropriate workup. In aliquots
with ≥95% reduction of ketone 3, the degree of reduction of the
second ketone was 90, 70, and 20% for ketones 13, 5, and 15,
respectively.
The conditions and results of preparative reduction are sumꢀ
marized in Table 1, while characteristics of the products are
given in Table 2. All the obtained steroidal alcohols (except
for 16) had been described in the literature and were identified,
in addition to other methods, by direct comparison with authenꢀ
tic samples either from the laboratory collection of steroids or
specially prepared by reported procedures. Alcohols 16 obtained
by reduction with MorB were identified by comparison with the
sample prepared by reduction with NaBH4, for which the
20βꢀconfiguration for the major isomer was accepted on the
basis of the wellꢀknown stereochemistry of the reduction of the
20ꢀketo group in the dihydroxyacetone side chain of steroids.30
17. G. A. Hartman, J. Am. Chem. Soc., 1955, 77, 5151.
18. (a) R. E. Marker, R. B. Wagner, P. R. Ulshafer, E. L.
Wittbecker, D. P. G. Goldsmith, and C. H. Ruof, J. Am.
Chem. Soc., 1947, 69, 2167; (b) R. B. Wagner, R. F. Folker,
and P. F. Spitzer, J. Am. Chem. Soc., 1951, 73, 2494.
19. H. H. Inhoffen, G. Zuhlsdorff, and H. Minlon, Ber., 1940,
73, 451.
20. L. L. Vasiljeva, P. M. Demin, D. M. Kochev, M. A.
Lapitskaya, and K. K. Pivnitsky, Izv. Akad. Nauk. Ser. Khim.,
1999, 599 [Russ. Chem. Bull., 1999, 48, 593 (Engl. Transl.)].
21. S. Bernstein, S. M. Stolar, and M. Heller, J. Org. Chem.,
1957, 22, 472.
22. Pat. US 3423404; Chem. Abstr., 1969, 70, 106759; Pat. US
3424768.
23. A. A. Shishkina, Ph.D. Thesis, Moscow, 1975, p. 118 (in
Russian).
24. L. F. Fieser and M. Fieser, Steroids, Reinhold Publishing
Corporation, New York.
25. E. G. Balashova, K. N. Gabinskaya, L. M. Alekseeva, V. F.
Shner, O. V. Messinova, and N. N. Suvorov, Khimiya
Prirodn. Soedinen., 1975, 11, 360 [Chem. Nat. Compd., 1975,
11 (Engl. Transl.)].
This work was supported by the Russian Academy of
Sciences (fundamental research program of the Presidium
of the RAS for 2003ꢀ2005.) and President of the Russian
Federation (program for the support of young Rusꢀ
sian Scientists and Leading Scientific Schools, Project
NShꢀ1802.2003.3).
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Received December 30, 2003