Organic Syntheses, Vol. 79, pp. 165-175
Checked by Patrick Foyle, Peter Belica, and Steven Wolff.
1. Procedure
A.
1-Triisopropylsilyloxy-1-azidocyclohexane: A
2-L, two-necked, round-bottomed
flask is equipped with a
magnetic stirrer,
argon
inlet, and a
rubber septum (Note
1).
The flask is charged with freshly-distilled
1-triisopropylsilyloxycyclohexene (25.47 g, 100
mmol, Note 2) and
anhydrous dichloromethane (1.0 L,
Note 3).
Azidotrimethylsilane
(68.5 mL,
500 mmol, Note 4)
is added via syringe, immediately followed by anhydrous Dowex
® 50 × 8-100
(24.98 g, Note
5) in a single portion from
a dry flask. The suspension is stirred vigorously at ambient temperature for ca. 48
hr (Note
6). The reaction mixture is filtered to recover the
Dowex
® resin and solvent is removed under reduced pressure to afford a
clear, colorless oil. The crude oil is applied to a
5 × 13-cm
column of silica gel (120 g, 230-400 mesh packed with hexanes).
The column is quickly eluted with
hexanes (750 mL)
and fractions are collected in
25-mL test tubes (Note
7).
The fractions containing the desired product are identified by thin layer chromatography,
combined, and concentrated under reduced pressure to afford the
1-triisopropylsilyloxy-1-azidocyclohexane
(
26.75 g,
90%) as a colorless oil
(Note
8).
B.
ε-Caprolactam:
The reaction apparatus (see Fig. 1, Note
9)
is charged with
1-triisopropylsilyloxy-1-azidocyclohexane
(25.9 g, 87.1 mmol) and
cyclohexane
(435 mL, Note 10).
The clear, colorless solution is purged with
nitrogen for a 15
min period to exclude
oxygen. The solution is cooled to ca. 0°C
and irradiated (≥200 nm) for 3.5 hr (Note
11). The solvent
is removed under reduced pressure to afford a pale yellow oil. The crude oil is dissolved
in
dichloromethane (ca. 10 mL)
and applied to a
6 × 6-cm column of silica gel (88
g,
230-400 mesh packed with 1 : 1 ethyl acetate/hexanes).
An additional 1 cm of silica gel is added to the top of the column and the mixture
is stirred with a
glass rod to homogenize the layer, rinsed
with eluent, and the column is repacked. The column is eluted with
1
: 1 ethyl acetate/hexanes (200 mL, Note 12), then with
1
: 9 methanol/ethyl acetate (500
mL), and fractions are collected in
25-mL test tubes.
The fractions containing the desired product are identified by thin layer chromatography
(Note
13), combined, and concentrated under reduced pressure
to afford
ε-caprolactam
(
8.20 g,
83%, Note
14)
as an off-white solid.
2. Notes
1. The assembled glassware was flame-dried under high vacuum, then
cooled to ambient temperature under a positive pressure of dry
argon.
2. The following procedure was used to prepare
1-triisopropylsilyloxycyclohexene.
A
500-mL, three-necked, round-bottomed flask was charged with
9.81 g (0.10 mol) of cyclohexanone,
180 mL of dry dichloromethane
(anhydrous grade from Aldrich Chemical Company, Inc.),
and
20.9 mL (0.15 mol) of
triethylamine.
The mixture was cooled to −20° and a solution of
32.25
mL of triisopropylsilyl trifluoromethanesulfonate2 in
20
mL of
dichloromethane was added dropwise, while maintaining
the temperature of the reaction below 5°C. After completion of the addition, the reaction
mixture was stirred at 0-5°C for 1 hr, then at ambient temperature for 2 hr. The reaction
mixture was washed with
80 mL of brine,
then dried with
magnesium sulfate.
After filtration to remove the drying agent, the filtrate was concentrated under vacuum
to yield a residue consisting of two phases. The residue was diluted with
200 mL of hexanes, washed with
50 mL of brine, dried with
magnesium
sulfate, and filtered. The filtrate was concentrated under vacuum
to give
28.37 g of a pale yellow
oil. Distillation afforded
24.97 g
of a colorless oil,
bp 75-85°C (0.2-0.3 torr,
0.15-0.23 mm). The NMR spectrum of this material indicated the possible
presence of
cyclohexanone.
Redistillation gave
20.25 g (
78%) of
1-triisopropylsilyloxycyclohexene
as a colorless oil,
bp 85-90°C (0.3 torr, 0.23
mm).
4. The
azidotrimethylsilane
was purchased from Acros Organics and used without
further purification.
5. Dowex
® 50X8-100 was purchased from Acros Organics and
dried in the following manner. Approximately 50 g of the commercially available resin
is washed with
anhydrous methanol (3
× 50 mL), then with
anhydrous
ethyl ether (2 × 50 mL) in a
Buchner
funnel. The granular solid is dried under high vacuum for
ca. 24
hr.
6. The progress of the reaction is monitored by thin layer chromatography,
eluting with
hexanes, then dried quickly with
a stream of
nitrogen and eluted a second time with
hexanes (product R
f = 0.75, visualized and developed
using UV light and KMnO
4, respectively). The checkers found that the reaction
was not complete after 72 hr. Stirring was continued until TLC analysis indicated
the absence of the enol ether (5-6 days).
7. Discoloration of the column is often observed, which may be due
to hydrazoic acid formation upon hydrolysis of the
azidotrimethylsilane.
8. The product exhibits the following spectroscopic and analytical
properties: IR (neat) cm
−1:
2948, 2892, 2865, 2104;
1H NMR (250 MHz,
C
6D
6) δ: 1.04-1.18 (m, 21 H), 1.26-1.57
(m, 8 H), 1.66-1.76 (m, 2 H);
13C NMR (62.5 MHz, C
6D
6)
δ: 13.56, 18.45, 23.4, 25.16,
38.50, 91.57; HRMS
(EI) calcd for C
11H
24N
3OSi 254.1689
found 254.1674. Anal. calcd. for C
15H
31N
3OSi:
C, 60.56; H, 10.50; N, 14.12 Found: C, 60.51; H, 10.76; N, 14.04.
9. The reaction apparatus (Figure 1) requires a
tubular
quartz flask with two side arms and a large ground-glass joint at the
top to accommodate the
water-cooled UV lamp. One of the side
arms is fitted with a Teflon
® tube, the second side arm is fitted with
a
rubber septum and
wide-bore needle,
which has a Teflon
® tube leading to a
nitrogen bubbler.
A vigorous stream of
nitrogen is allowed to flow into the flask
through the Teflon
® tube to agitate the solution during irradiation. The
entire apparatus is placed inside a
vacuum-jacketed Dewar flask
filled with ice to maintain the reaction temperature at
ca. 0°C.
10.
Cyclohexane was
purchased from Acros Organics and used without further
purification.
11. The
UV lamp generates a great deal of
heat, and thus it is necessary to interrupt the reaction
ca. every hour to
remove water from the Dewar and replenish it with ice.
12. The
triisopropylsilanol
side-product is eluted first through the column. Alternatively, the bulk of this material
may be removed via distillation under reduced pressure (50-60°C at 2-3 mmg).
13. The progress of the reaction is monitored by thin layer chromatography,
eluting with
ethyl acetate
(product R
f = 0.06, visualized and developed using UV light and KMnO
4, respectively).
14. The product exhibits the following spectroscopic and analytical
properties:
mp 68-69°C; lit.
3 68-70°C;
IR (CHCl
3) cm
−1:
3420, 3293, 3224, 3019, 2937,
2859, 1660;
1H NMR (250 MHz, C
6D
6) δ: 1.14-1.33
(m, 6 H), 2.21-2.25 (m, 2 H), 2.68-2.74 (m, 2 H),
8.33 (bs, 1 H); HRMS
(EI) calcd for C
6H
11NO: 113.0841; found: 113.0833.
All toxic materials were disposed of in accordance with "Prudent Practices in the
Laboratory"; National Academy Press; Washington, DC, 1995.
3. Discussion
The synthesis of lactams has attracted considerable attention in recent years.
This is presumably because they represent versatile synthetic intermediates that are
present in many biologically important molecules.
4
Despite the wide range of methodologies that have been examined for the synthesis
of lactams,
5
6 the Beckmann
7 and Schmidt
8
rearrangements still remain by far the most convenient and general methods. The strongly
acidic conditions required for the Schmidt rearrangement often lead to undesired by-products.
This is a major limitation particularly with acid-labile substrates.
The method outlined here
9 represents
a convenient and environmentally benign Schmidt rearrangement, in which the azidohydrin
is prepared using a recyclable acid catalyst and
trimethylsilyl
azide, a non-explosive source of azide.
10
Photolysis of the azidocyclohexane results in the ring expansion, probably through
the formation of a reactive nitrene. The by-products from this reaction are gases
or innocuous silanes. The main limitation with the method is that at present the ring
expansion is not regioselective, as exemplified by entries 1 and 2 in the Table, in
which a mixture of regioisomers is obtained.
A further advantage of this protocol is that it allows the azidohydrin intermediate
to be isolated. This will facilitate important mechanistic work to clarify the nature
of the reactive species responsible for the ring expansion. Although only the preparation
of azepin-2-ones have been reported, other ring sizes have also been successfully
examined. Hence, this method provides a general method for the preparation of lactams.
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