Organic Syntheses, CV 8, 568
Submitted by Keiji Maruoka, Shuichi Nakai, and Hisashi Yamamoto
1.
Checked by Jeffrey Doney and Clayton H. Heathcock.
1. Procedure
Caution! Part B of this procedure should be carried out in a well-ventilated hood to prevent exposure to methanethiol, a side product.
A.
Cyclohexanone oxime methanesulfonate. A dry,
1-L, two-necked, round-bottomed flask is equipped with a
gas inlet, a
rubber septum, and a
magnetic stirring bar. The flask is charged with
17.0 g (0.15 mol) of cyclohexanone oxime (Note
1) and flushed with
argon, after which
300 mL of dichloromethane followed by
25 mL (0.18 mol) of triethylamine (Note
2) are injected through the septum into the flask. The solution is stirred and cooled to a temperature of −15 to −20°C in a
dry ice–carbon tetrachloride bath, while
12.8 mL (0.165 mol) of methanesulfonyl chloride is added over a 20-min period (Note
3) and (Note
4). The resulting mixture is stirred at this temperature for 15 min, and poured into 300 mL of ice water in a
1-L separatory funnel with the aid of three
30-mL portions of dichloromethane to rinse the flask. The lower organic layer is separated, and the aqueous layer is extracted with a
50-mL portion of dichloromethane. The combined extracts are washed successively with
250 mL of cold aqueous 10% hydrochloric acid,
250 mL of saturated sodium bicarbonate, and
250 mL of brine, and are dried over anhydrous
sodium sulfate and concentrated with a
rotary evaporator at room temperature to give
27.2–28.8 g of crude solid
cyclohexanone oxime methanesulfonate (Note
5). This material is used in Part B without purification (Note
6).
B.
2-Propyl-1-azacycloheptane. A dry,
2-L, three-necked, round-bottomed flask is equipped with a variable-speed
mechanical stirrer,
300-mL pressure-equalizing dropping funnel bearing a gas inlet at its top, and a rubber septum. The apparatus is flushed with
argon, after which
243 mL of hexane (Note
7) and
57 mL (0.3 mol) of tripropylaluminum (Note
8) are injected through the septum into the flask. The solution is stirred and cooled to a temperature of −73 to −78°C in a
dry ice–methanol bath. The crude
cyclohexanone oxime methanesulfonate prepared in Part A is dissolved in
100 mL of dichloromethane, transferred to the
dropping funnel, and added to a 1
M solution of
tripropylaluminum in
hexane over a 30-min period (Note
9). The mixture is allowed to warm to 0°C and stirred for 1 hr, and
225 mL (0.225 mol) of 1 M solution of diisobutylaluminum hydride in
hexane (Note
10) is added at 0°C and the mixture is further stirred at 0°C for 1 hr (Note
11). After addition of
100 mL of dichloromethane and
88.2 g (2.1 mol) of sodium fluoride, 28.4 mL (1.58 mol) of water is injected dropwise at 0°C (Note
12). Vigorous stirring of the resulting suspension is continued for 30 min at room temperature, and the contents of the flask are filtered with five
30-mL portions of dichloromethane (Note
13). The combined filtrates are evaporated under reduced pressure with a rotary evaporator. Distillation of the residual liquid under reduced pressure affords
11.3–12.2 g (
53–58%) of
2-propyl-1-azacycloheptane as a colorless liquid, bp
79–81°C (18 mm) (Note
14) and (Note
15).
2. Notes
1.
Reagent-grade cyclohexanone oxime, purchased from Wako Pure Chemical Industries, Ltd. (Japan), was used as received. The checkers used material obtained from the Aldrich Chemical Company, Inc. A suitable material may be prepared according to the procedures in
Organic Syntheses.2
4. The checkers found that an addition time of 40 min is required to maintain the temperature of the reaction mixture below −15°C.
5. If a crude oil was obtained at this stage, it can be solidified by cooling.
6. The reaction in Part A proceeds in almost quantitative yield.
3 Accordingly, the crude
cyclohexanone oxime methanesulfonate can be used without any purification. Prolonged standing at room temperature may cause serious decomposition. The crude material may be stored in a freezer, or as a
dichloromethane solution in a
refrigerator, and can be recrystallized from
ether-
hexane to give the white solid (mp
43–45°C).
4
9. The checkers found that an addition time of 60 min is required to maintain the temperature of the reaction mixer below −73°C.
12. To avoid excessive foaming at the beginning of the hydrolysis, water should be added carefully by syringe. The rate of addition may be increased once the initially vigorous foaming subsides.
13. The
sodium fluoride–water workup offers an excellent method for large-scale preparations and is generally applicable for product isolation in the reaction of organoaluminum compounds.
5
14. The elemental analysis and the spectral properties of the product are as follows. Anal. calcd. for C
9H
19N: C, 76.61; H, 13.47; N, 9.92. Found: C, 76.75; H, 13.74; N, 9.51; IR (liquid film) cm
−1: 3320, 2860–2970, 1460, 1165;
1H NMR (CDCl
3) δ: 0.87–0.94 (3 H, m, CH
3), 1.23–1.82 (13 H, m), 2.54–2.73 (2 H, m, CH
2N), 2.96–3.03 (1 H, m, CHN). A boiling point of
193–194°C at 750 mm has been reported for
2-propyl-1-azacycloheptane.
6
15. Gas chromatographic analysis using a 25-m PEG-HT capillary
column at 80°C indicated a purity of 97% (retention time: 8.1 min) based on
tripropylaluminum of 96% purity (Note 8). The unrearranged product,
cyclohexylpropylamine (retention time: 6.9 min), was less than 1%.
3. Discussion
This procedure illustrates a new, general method for the one-nitrogen ring expansion of cyclic ketoximes leading to α-alkylated, cyclic, secondary amines.
4,7 The key step in the sequence is the organoaluminum-promoted Beckmann rearrangement of ketoxime derivatives, in which the organoaluminum compounds are used as amphophilic reagents to induce the Beckmann rearrangement of oxime derivatives as well as to capture the intermediary imino carbocation by the alkyl group that is originally attached to aluminum. The conventional process for accomplishing this transformation consists of the following steps: (a) Beckmann rearrangement of ketoxime or its derivative to lactam; (b) conversion of the lactam to imino ether using trialkyloxonium tetrafluoroborate; (c) alkylation of the imino ether with alkyllithium or Grignard reagent to produce imine, which requires a considerably longer time for execution.
8
As oxime derivatives, oxime sulfonates can be used preferentially for the following reasons: (a) they are readily available from oximes using
p-toluenesulfonyl chloride or
methanesulfonyl chloride in the presence of base in almost quantitative yield; (b) they are easy to handle because of their fine crystalline properties; and (c) they are sufficiently reactive to initiate the rearrangement by organoaluminum reagents.
As shown in Table I, this reaction sequence has a wide generality and is readily applicable to the straightforward synthesis of various naturally occurring alkaloids such as coniine,
9 pumiliotoxin C,
10 and solenopsin A and B.
11 Oxime sulfonates of either linear or cyclic structures may be used. Obviously, the regioselectivity of the reaction follows the general rule of the Beckmann rearrangement,
12 and preferential migration of the group
anti to the oxime sulfonate is observed. Diethylaluminum alkynides can be successfully used for the selective introduction of alkynyl groups to a substrate in preference to an ethyl group. Furthermore, the present procedure reduces the intermediate imine directly without isolation by using
diisobutylaluminum hydride, thus excluding the troublesome isolation of unstable cyclic imino compound.
TABLE I
PREPARATION OF α-ALKYLATED AMINES FROM OXIME SULFONATES WITH TRIALKYLALUMINUM–DIISOBUTYLALUMINUM HYDRIDE
|
Oxime Sulfonate (mp, °C) |
Trialkylaluminum |
Amine |
Yield (%) |
|
|
Pr3Ala |
|
55-58 |
|
Me3Al |
|
70 (R = Me) |
Et2AlC CBu |
67 (R = C CBu) |
|
Me3Al |
|
67 (R = Me) |
Et2AlC CBu |
83 (R = C CBu) |
Et2AlC CPh |
67 (R = C CPh) |
|
Pr3Alb |
|
60 |
|
aTreatment with Pr3Al at 40–80°C for 15–30 min.
|
bTreatment with Pr3Al at 25°C for 30 min.
|
The organoaluminum-promoted Beckmann rearrangement–alkylation sequence represents a modern aspect of the classical Beckmann rearrangement, and has proved effective with other aluminum reagents of type R
2AlX (X = SR, SeR, CN) which would function in a similar way to trialkylaluminum compounds. Thus, a series of imino thioethers, selenoethers, and nitriles can be prepared with rigorous regioselectivity by using organoaluminum thiolates, selenolates, and cyanide, respectively.
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