4-methyl-2H-1,4-benzoxazin-3(4H)-one 1f (Table 1, entry
5) gave N-methyl benzomorpholine 3f in 75% yield.
LAB reagents can perform a reagent-controlled reduction
of amides. For example, 1-pyrrolidooctanamide can be
reduced to either 1-octanol with lithium dimethylaminoboro-
hydride 2a or 1-pyrrolidinooctane with the sterically bulky
lithium diisopropylaminoborohydride (LiH3BN(iPr)2) 2b. On
the basis of our amide reduction study with LAB reagents,14
we speculated that we could reduce lactams to either the
cyclic amine or the ring-opened amino alcohol depending
upon the steric requirement of the LAB reagent used.
However, we found that 1-phenyl-2-pyrrolidinone 4 was
the only substrate that gave any ring-opened product.
Reduction of 4 at 25 °C with both LiH3BNMe2 2a and LiH3-
BN(iPr)2 2b gave N-phenylpyrrolidine 5 and N-phenylami-
nobutanol 6 in 2:1 ratio in 95% yield (Scheme 2). It should
Scheme 1
Refluxing 1-benzyl-2-pyrrolidinone 1a in THF for 2 h with
1.5 equiv of LiH3BNMe2 2a gave N-benzylpyrrolidine 3a
(Table 1, entry 1) as the sole product. The progress of the
reactions was monitored using FTIR by the disappearance
of the lactam carbonyl at 1660-1705 cm-1. Most of the
reductions were essentially complete after 2 h.
This methodology was applied to 1-cyclohexyl-2-pyrro-
lidinone 1b (Table 1, entry 2), 1-octyl-2-pyrolidinone 1c
(Table 1, entry 3), and 1-dodecyl-2-pyrrolidinone 1d (Table
1, entry 4), and all of these substrates give the corresponding
cyclic amine products 3b-d in very good to excellent yields.
This method was also general for six-membered lactams and
may have applications in alkaloid chemistry. Reduction of
1-methyl-3,4-dihydroquinolone 1e (Table 1, entry 5) gave
N-methyl-1,2,3,4-tetrahydroquinoline 3e in 96% yield. Also,
Scheme 2
Table 1. Reduction of N-Alkyl Lactams 1 with LiH3BNMe2 2a
to the Corresponding Amine 3
be pointed out that reduction of 1-phenyl-2-pyrrolidinone
with 9-BBN gave N-phenylpyrrolidine 5 as the sole product
in 95% yield.16
A possible explanation for the ring opening of 1-phenyl-
2-pyrrolidinone 4 with LAB reagents is the stabilization of
the negatively charged nitrogen nucleofuge by delocalization
(15) General Procedure. An oven-dried 100-mL round-bottom flask
equipped with a magnetic stirring bar was sealed with a rubber septum,
cooled under nitrogen, and charged with dimethylamine-borane (0.882 g,
15 mmol) and anhydrous THF (15 mmol). At 0 °C, n-butyllithium (2.5 M,
6 mL, 15 mmol) was added dropwise via syringe, and the reaction mixture
was stirred at 0 °C for 1 h. 1-Benzyl-2-pyrrolidinone (1.75 g, 10 mmol)
was added neat via syringe. The flask was fitted with a water-cooled reflux
condenser, and the reaction mixture heated to reflux under nitrogen. The
progress of the reaction was monitored by FTIR. After 2 h, the reaction
was cooled to 0 °C under nitrogen and quenched by the slow addition of
25 mL of 3 M HCl. (Caution! Hydrogen evolution!) The aqueous layer
was then extracted with 4 × 20-mL portions of diethyl ether, and the organic
layers were separated. At 0 °C, solid NaOH was added to aqueous layer,
and the aqueous layer was extracted with 4 × 20-mL portions of diethyl
ether/THF. The ethereal fractions were combined, dried over MgSO4, and
filtered. The solvent was removed under vacuum (35 °C, 30 Torr) and then
(25 °C, 1 Torr). To give N-benzylpyrrolidine 1.39 g (86% yield) as a light
yellow oil. 1H NMR (500 MHz, CDCl3): δ 1.80-1.82 (quint, 4H), 2.52-
2.56 (quint, 4H), 3.63 (s, 2H), 7.24-7.28 (t, 2H), 7.32-7.37 (m, 3H). 13
C
NMR (125 MHz, CDCl3): δ 23.57, 54.28, 60.85, 127.0, 128.2, 128.3, 129.0,
a All reactions were carried out on 10 mmol scale unless otherwise
noted.15 b Isolated yields. c A 5 mmol scale reaction.
139.4.
(16) March, J. AdVanced Organic Chemistry, 4th ed.; Wiley and Sons:
New York, 1989; p 1208.
800
Org. Lett., Vol. 1, No. 5, 1999