Organic Syntheses, CV 6, 893
Submitted by Albert Padwa
1, Thomas Blacklock, and Alan Tremper.
Checked by W. F. Oettle, E. R. Holler, and William A. Sheppard.
1. Procedure
Caution! Although the organic azide intermediates used in this procedure have not shown any explosive hazard under the experimental conditions, they should always be handled with adequate shielding and normal protective equipment such as face shield and leather gloves.
A.
(1-Azido-2-iodo-3,3-dimethoxypropyl)benzene. A
dry, 1-l., three-necked, round-bottomed flask fitted with an efficient magnetic stirrer and two 250-ml. pressure-equalizing dropping funnels charged with
75 g. (1.l moles) of sodium azide and
450 ml. of dry acetonitrile (Note
1). The mixture is stirred and cooled in an
ice–salt bath (−5° to 0°), and
83 g. (0.51 mole) of iodine monochloride (Note
2) is added dropwise from one of the addition funnels over 10–20 minutes. The solution is stirred for an additional 5–10 minutes before
81 g. (0.45 mole) of cinnamaldehyde dimethyl acetal (Note
3) is added from the other dropping funnel over a 15–20 minute period, while the cooling bath temperature is maintained at 0–5°. The resulting red-brown mixture is stirred for 12 hours at room temperature, poured into 500 ml. of water, and extracted with three
500-ml. portions of diethyl ether. The combined organic extracts are washed successively with
700 ml. of 5% aqueous sodium thiosulfate (Note
4) and 1 l. of water. The ether solution in dried over
magnesium sulfate. The solvent is removed with a
rotary evaporator, giving the azide product as a orange oil (Note
5),
150–156 g. (
97–98%), of sufficient purity to be used for the next step.
B.
(1-Azido-3,3-dimethoxy-1-propenyl)benzene. A
2-l., one-necked, round-bottomed flask equipped with a magnetic stirrer and powder funnel is charged with
156 g. (0.450 mole) of the iodoazide from Part A and
1500 ml. of anhydrous ether. The solution is stirred and cooled in an ice-salt bath (−5° to 0°), and
62 g. (0.55 mole) of potassium tert-butoxide (Note
6) is added. The powder funnel is replaced with a
calcium chloride drying tube and the mixture is stirred for 4–5 hours at 0° , at which time 350 ml. of water is added while the mixture is still cold. The ethereal layer is separated, washed with three 350-ml. portions of water, and dried over
magnesium sulfate. The solvent is removed with a rotary evaporator without heating, leaving
67–75 g. (
68–76%) of
(1-azido-3,3-dimethoxy-1-propenyl)-benzene as a dark oily liquid (Note
7), which can be used without further purification for Part C (Note
8).
D.
3-Phenyl-2H-azirine-2-carboxaldehyde. The product from
Part C (59.0 g., 0.31 mole) is placed in a
3-l., three-necked, round-bottomed flask fitted with a mechanical stirrer, a reflux condenser, and a thermometer of sufficient length to extend into the liquid contents of the flask. After addition of
600 ml. of 1,4-dioxane (Note
11) and
800 ml. of 20% acetic acid, the mixture is stirred and heated sufficiently to bring the temperature of the reaction mixture up to 90° over a period of one hour (Note
12). The temperature of the reaction mixture is held at 90° for an additional 5 minutes, then the flask is rapidly cooled in an ice-salt bath (−5° to 0°). The product is extracted with four
1-l. portions of ether, and the combined organic extracts are washed successively with
1 l. of 5% aqueous sodium hydrogen carbonate and
1-l. of saturated aqueous sodium chloride. After the
ether layer has been dried over
anhydrous magnesium sulfate, the solvent is removed with a rotary evaporator, and a mixture of
5 ml. of ether and 10 ml. of pentane is added. The residual oil is allowed to stand in a refrigerator (0–3°) for 12 hours, completing the crystallization of the crude product. The crystalline solid is collected on a
cold filter and sublimed at 35° (0.01 mm.), giving
13.3 g. (
30%) (Note
13) of
3-phenyl-2H-azirine-2-carboxaldehyde, m.p.
49–51° (Note
14).
2. Notes
1.
Reagent grade acetonitrile (J. T. Baker Chemical Company) was used without further purification.
2.
Iodine monochloride, purchased from J. T. Baker Chemical Company, was used without further purification.
4. The orange color of the ethereal solution is completely discharged after washing with
5% aqueous sodium thiosulfate.
5. The product has the following spectral properties: IR (neat) cm.
−1: 2120 (strong N
3 absorption);
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons, assignment): 3.38 (s, 3H, OC
H3), 3.46 (s, 3H, OC
H3), 3.93 (d,
J = 4, 1H, 1- or 3-C
H), 4.38 (d of d,
J = 9 and 4, 1H, C
HI) 4.78 (d,
J = 9, 1H, 1- or 3-C
H), 7.33 (s, 5H, C
6H5).
6.
Potassium tert-butoxide, purchased from Columbia Organic Chemicals Company, Inc., was sublimed at 150° (0.02 mm.) before use and was added in one portion.
7. The submitters reported a yield of
94–96 g. (
97–98%). The spectral properties of the product are: IR (neat) cm.
−1: 2151 and 1642;
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons, assignment): 3.26 (s, 6H, 2 OC
H3), 4.78 [d,
J = 8, 1H, C
H(OCH
3)
2], 5.60 (d,
J = 8, 1H, C
H), 7.45 (s, 5H, C
6H5).
8. The intermediate vinyl azide should either be used immediately or stored cold in a
vented container, since it slowly evolves
nitrogen on standing at room temperature.
9. The reaction can be conveniently monitored by IR spectroscopy by observing the intensity of the band at 2150 cm.
−1 (N
3).
10. The spectral properties are: IR (neat) cm.
−1: 1754 (azirine);
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons, assignment): 2.38 (d,
J = 3, 1H, C
H), 3.35 (s, 3H, OC
H3), 3.47 (s, 3H, OC
H3), 4.39 [d,
J = 3, 1H, C
H(OCH
3)
2], 7.3–8.0 (m, 5H, C
6H5).
11.
1,4-Dioxane available from Fisher Scientific Company was used without further purification.
12. The mixture is brought to 90° by heating at a rate of 1° per minute. The mixture
must not be overheated, or else the final product will be very difficult to crystallize.
13. Starting with
45.3 g. (0.237 mole) of the dimethyl acetal from p.htmart C, the checkers obtained
10.2 g. (
30%) of the product.
14. The submitters reported a yield of
35–38 g. (
55–60%) based on 78–84 g. of starting material and using appropriate proportions of reagents. Their product had m.p.
45–47°. The spectral properties of the azirine product are: IR (KBr) cm.
−1 1786 and 1709;
1H NMR (CDCl
3), δ (multiplicity, coupling constant
J in Hz., number of protons, assignment): 2.89 (d,
J = 7, 1H, C
H), 7.5–8.0 (m, 5H, C
6H5), 9.04 (d,
J = 7, 1H, C
HO).
3. Discussion
The formation of substituted azirines by the thermal decomposition of vinyl azides is a general reaction.
3 Iodine azide offers an excellent route to vinyl azides;
4,5 it adds to many olefinic compounds, giving α iodoazides which can easily eliminate
hydrogen iodide upon treatment with base. The direction of
iodine azide addition is consistent with electrophilic attack of I

, giving a cyclic iodonium ion which is opened by azide ion. The presence of the dimethyl acetal moiety in the system above does not not interfere with the iodine azide reaction. This procedure does not work with
trans-cinnamaldehyde, owing to a competing aldol condensation in the elimination step.
The aldehyde functionality present in
3-phenyl-2H-azirine-2-carboxaldehyde reacts selectively with amines, and Grignard and Wittig reagents, yielding a variety of substituted azirines,
6 which have been used, in turn, to prepare a wide assortment of heterocyclic rings such as oxazoles, imidazoles, pyrazoles, pyrroles, and benzazepins.
6,7
In addition to the present method, 2
H-azirines can be prepared by a modified Neber reaction,
8,9,10 or by heating 4,5-dihydro-1,2,5-oxazaphospholes.
11,12,13,14
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