Notes
Ta ble 1. Red u ction of Ad a m a n ta n on e Der iva tives
J . Org. Chem., Vol. 63, No. 8, 1998 2759
49:51. Similarly, the ratio of the keto ester 1-COOMe
(57:43) is inverted to 45:55 if the acid itself (1-COOH) is
reduced in the presence of sodium hydroxide in methanol.
No such inversion occurred if D2O was used, and inter-
mediate compositions resulted if mixtures of these sol-
vents were employed.
In conclusion, it appears in principle possible to raise
the selectivity in addition reactions by introducing or
augmenting positive charge at either the trigonal atom
being added to or at the remote substituent, and to
diminish it by means of negative charge in the substitu-
ent. The failure to observe such an effect in the boro-
hydride reduction of imine 4-Ph may well be an indication
that the nitrogen atom in this species is bound to or
paired with a cation prior to reaction.
E/ Z
product
ratio ref
substrate reducing agent
solvent
THF
Me2CHOH
Me2CHOH
additive
3-F
1-F
NaBH4
NaBH4
NaBH4
-
83:17 5a
62:38 1a
58:42 1a
49:51 1a
42:58 1a
50:50 1a
67:33
68:32
65:35
66:34
68:32
43:57
64:36
-
1-Ph
1-Ph
1-t-Bu
1-t-Bu
4-Ph
5-Ph
4-Ph
4-Ph
4-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-Ph
1-NMe2
1-NMe3
1-OMe
1-OH
1-OH
-
LiAl(O-t-Bu)3H Et2O
LiAl(O-t-Bu)3H Et2O
-
-
LiAlH4
NaBH4
NaBH4
NaBH4
NaBH4
n-Bu4NBH4
n-Bu4NBH4
LiBH4
LiBH4
LiBH4
LiBH4
LiBH4
LiBH4
LiBH4
LiBH4
LiBH4
NaBH4
NaBH4
NaBH4
NaBH4
NaBH4
Et2O
-
MeOH
MeOH
MeOH
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
D2O
-
-
-
-
-
-
-
-
-
-
3M MeO-
-
-
-
SbCl5
TiCl4 (1M) 62:38
TiCl3
MgCl2
NiBr2
SnCl4
BF3‚Et2O
AlCl3
Et2AlCl
-
64:36
61:39
61:39
62:38
64:36
62:38
62:38
65:35 13
86:14
64:36 13
58:42 1a
-
-
-
-
-
-
Exp er im en ta l Section
2-(N-Meth ylim in o)a d a m a n ta n e (4-H). This compound was
prepared as a pale yellow oil in 98% yield by stirring a solution
of adamantanone (100 mg, 0.67 mmol) in a mixture of dry THF
(1.5 mL) and methylamine (2.0 M in THF, 1 mL) and 4A
molecular sieves (1.0 g) at room temperature under nitrogen
overnight. After centrifugation, the solvent was evaporated; a
GC of the residue showed only a single peak. 1H NMR (C6D6),
δ 3.08 (s, 3H), 2.88 (bs, 1H), 2.76 (bs, 1H), 1.80-1.56 (m, 12H);
13C NMR, δ 177.92 (CN), 43.91 (CH3), 39.25 (2C, CH2), 38.13
(2C, CH2), 36.95 (CH), 36.81 (CH2), 32.15 (CH), 28.29 (2C, CH).
Imine 4-H is very sensitive to hydrolysis and is best kept in ether
solution if it must be stored.
I
D2O
-
-
D2O or MeOH
MeOH
THF
MeOH
MeOH
MeOH
-
-
NaH
-
49:51
57:43
45:55
-
-
-
1-COOMe NaBH4
1-COOH
1-COOH
NaBH4
NaBH4
NaOH
-
52:48 14
in excess by a margin of 65:35, compared with that of
57:43 for the free ketone.1a However, the Lewis-acid
enhanced reaction also led to side products: a mixture
of 2-chloro-5-phenyladamantanes is present as well as
two other components that were not identified. Similar
results were obtained by adding titanium tri- or tetra-
chloride; stannic, magnesium, aluminum, or diethylalu-
minum chloride; nickel bromide; or boron trifluoride
etherate; the quantities of side products (but not the E/ Z
ratio) varied from negligible to serious depending on the
counterion, medium, reaction time, and so on, but we did
not undertake a systematic investigation (see Table 1).
We assume that the similarity of the ratios regardless
of the strength of the Lewis acid is due to the more rapid
reaction of the complexed ketone, so that the proportion
of this species is not important.
Finally, we were interested in modifying 5-substituent
X itself as a way to influence selectivity. We showed
earlier that replacing C-5 by positive nitrogen greatly
increased E/Z ratios,9 and that replacing it by negative
boron inverted the ratio of deuterium atom capture by
2-adamantyl radicals.10 The question considered here is
how this effect diminishes as the charged atom resides
at a greater distance. To that end, we compared the
reduction ratio of 5-(dimethylamino)adamantan-2-one
1-NMe2 with that of its methyl iodide salt, and indeed
we found a still sizable increase in the E/Z ratio, from
65:35 to 86:14. Conversely, while the reduction of
5-methoxyadamantan-2-one 1-OMe with sodium boro-
hydride in either methanol or D2O gives an E/Z ratio of
64:36, and that of alcohol 1-OH gives a ratio of 58:42
(with or without added base), the reaction of 1-OH in
THF in the presence of sodium hydride gave a ratio of
2-(N,N-Dim eth ylim in iu m a d a m a n ta n e iod id e (5-H io-
d id e). Freshly prepared imine 4-H (50 mg, 0.31 mmol) in dry
THF (1.5 mL) is treated with 4A molecular sieves (0.5 g), and
methyl iodide (0.10 mL, 1.6 mmol) is added in portions over 30
min. After 6 h, the drying agent is removed and the solvent
evaporated; the salt is dissolved in acetonitrile, reprecipitated
by adding ether, and washed with ether to give an off-white solid
(87 mg, 93%); mp 144-5 °C. 1H NMR (CD3OD), δ 3.57 (s, 6H),
3.38 (bs, 2H), 2.21-1.94 (m, 12H); 13C NMR, δ 166.45 (CdN),
45.61 (2C, CH3), 39.32 (4C, CH2), 38.14 (2C, CH), 35.53 (CH2),
26.98 (2C, CH). This compound is also sensitive to hydrolysis.
2-(N-Meth yla m in o)a d a m a n ta n e. This known amine11 was
obtained by reducing the imine 4-H (50 mg, 0.31 mmol) with
sodium borohydride (0.46 mg, 1.2 mmol, in four portions) in
methanol (2.0 mL) during 20 min. Stirring was continued for 6
h. The pH was adjusted to 1 with concentrated hydrochloric
acid to decompose unreacted borohydride and then to 12 with
concentrated sodium hydroxide to liberate the amine. After
evaporation to dryness, the amine was isolated by extraction of
the residue with ether and evaporation of solvent to give a white
solid (46 mg, 91%); mp 86 °C, lit.11 87 °C. 1H NMR (C6D6), δ
2.46 (s, 1H), 2.34 (s, 3H), 2.16 (s, 1H), 2.11 (s, 1H), 1.80-1.61
(m, 11 H), 1.44 (s, 1H), 1.39 (s, 1H); 13C NMR, δ 64.24 (CH),
38.40 (CH2), 37.69 (2C, CH2), 33.99 (CH3), 32.26 (2C, CH), 31.56
(2C, CH2), 28.41 (CH), 28.30 (CH).
2-(N,N-Dim eth yla m in oa d a m a n ta n e. This known amine11
was obtained by reducing the iminium salt (50 mg, 0.16 mmol)
exactly as described for the monomethylamine. Mp 30-31 °C,
lit.11 30-31 °C. 1H NMR (C6D6), δ 2.30 (bs, 1H), 2.25 (bs, 1H),
2.10 (s, 6H), 1.96 (bs, 2H), 1.82-1.55 (m, 9H), 1.43 (bs, 1H), 1.38
(bs, 1H); 13C NMR, δ 70.02 (CH), 43.05 (2C, CH3), 38.19 (CH2),
37.54 (2C, CH2), 31.64 (2C, CH2), 30.20 (2C, CH), 28.05 (CH),
27.67 (CH).
2-(N-Meth ylim in o-5-ph en yladam an tan e (4-P h ). This com-
pound was prepared from the ketone12 in 97% yield in exactly
the same way as the parent imine (see above). Mp 45-8 °C. 1H
NMR (C6D6), δ 7.37-7.10 (m, 5H), 3.11 (s, 3H), 2.95 (bs, 1H),
(11) Lavrova, L. N.; Klimova, N. V.; Shmar’yan, M. I.; Ul’yanova,
O. V.; Vikhlyaev, Y. I.; Skoldinov, A. P. J . Org. Chem. USSR 1974,
10, 761. (b) Pekh, T. I.; Lippma, E. T.; Lavrova, L. N.; Vinogradova,
N. N.; Klimova, N. V.; Shmar’yan, M. I.; Skoldinov. A. P. J . Org. Chem.
USSR, 1978, 14, 1526.
(9) Hahn, J . M.; le Noble, W. J . J . Am. Chem. Soc. 1992, 114, 1916.
(b) Lau, J .; Gonikberg, E. M.; Hung, J . t.; le Noble, W. J . J . Am. Chem.
Soc. 1995, 117, 11421.
(10) Gonikberg, E. M.; Picart, F.; le Noble, W. J . J . Org. Chem. 1996,
61, 9588 and 1997, 62, 4885.
(12) Geluk, H. W. Synthesis 1972, 374.