Org. Synth. 1989, 67, 170
DOI: 10.15227/orgsyn.067.0170
ETHYL α-(HEXAHYDROAZEPINYLIDENE-2)ACETATE FROM O-METHYLCAPROLACTIM AND MELDRUM'S ACID
[Acetic acid, (hexahydro-2H-azepin-2-ylidene)-, ethyl ester, (Z)-]
Submitted by J. P. Celerier, E. Deloisy-Marchalant, G. Lhommet, and P. Maitte
1.
Checked by Ting-Zhong Wang and Leo A. Paquette.
1. Procedure
A. Isopropylidene α-(hexahydroazepinylidene-2)malonate. In a 1-L, round-bottomed flask fitted with an efficient reflux condenser and equipped with a magnetic stirrer are placed 50.8 g (0.40 mol) of O-methylcaprolactim (Note 1), 57.6 g (0.40 mol) of Meldrum's acid (Note 2), and 0.25 g of nickel acetylacetonate monohydrate (Note 3) in 500 mL of anhydrous chloroform. The reaction mixture is refluxed for 12 hr. The solvent is removed with a rotary evaporator and the bright-yellow precipitate is recrystallized from absolute ethanol to give 77–78 g (81–82%) of pale-yellow crystals, mp 147–149°C (Note 4).
B. Ethyl α-(hexahydroazepinylidene-2)acetate. A solution of sodium ethoxide is prepared from 8.3 g (0.36 mol) of freshly cut sodium and 600 mL of freshly distilled absolute ethanol (Note 5) in a 1-L, round-bottomed flask equipped with a magnetic stirrer and fitted with a reflux condenser. To the stirred solution is added in one portion 71.7 g (0.30 mol) of freshly recrystallized isopropylidene α-(hexahydroazepinylidene-2)malonate. The mixture is refluxed and a white precipitate begins to appear. Refluxing is continued for 12 hr. The solvent is removed with a rotary evaporator and the white precipitate is placed in a 2-L beaker. Water (300 mL) is added and a 1 N hydrochloric solution is added dropwise to pH 6. The reaction mixture is extracted with four 100-mL portions of chloroform. The extracts are dried over anhydrous sodium sulfate and the solvent is removed with a rotary evaporator. The yellow solid residue is recrystallized from methanol to give 43–44 g (78–80%) of white powder, mp 55–56°C (Note 6).
2. Notes
1.
O-Methylcaprolactim (
1-aza-2-methoxy-1-cycloheptene) is available from the Janssen Chimica Society (France) and from the Aldrich Chemical Company, Inc. It may be also prepared from
ε-caprolactam and
dimethyl sulfate.
22.
Meldrum's acid (
2,2-dimethyl-1,3-dioxane-4,6-dione) is available from the Janssen Chimica Society (France) or can be prepared from
malonic acid and
acetone.
3 The checkers purchased Meldrum's acid from the Aldrich Chemical Company, Inc.
3.
Nickel acetylacetonate monohydrate is a better basic catalyst than
triethylamine for the condensation of Meldrum's acid and the lactim ether. The yields are higher and the product is easier to purify.
4.
The submitters report mp
145–147°C.
5.
Absolute
ethanol must be freshly distilled to obtain good yields in the transesterification.
6.
The submitters report mp
48–50°C. The product,
ethyl α-(hexahydroazepinylidene-2)acetate, shows a
Z geometry. The
1H NMR (300 MHz) spectrum of this compound is as follows: δ: 1.22 (t, 3 H,
J = 7.1), 1.65 (m, 6 H), 2.25 (m, 2 H), 3.25 (m, 2 H), 4.06 (q, 2 H,
J = 7.1), 4.42 (s, 1 H), 8.83 (br s, 1 H).
3. Discussion
This procedure is representative of a general and versatile method for the preparation of cyclic β-enamino esters that are known to be precursors of many alkaloids such as camptothecin,
4 (±)-lamprolobine,
5 (±)-lupinine,
6 or isoretronecanol.
7Common synthetic methods for the preparation of cyclic β-enamino esters are the condensation between a lactim ether and
benzyl cyanoacetate followed by hydrogenolytic decarboxylation,
8 or the imino ester carbon–carbon condensation with
tert-butyl cyanoacetate followed by a
trifluoroacetic acid treatment.
9 The use of a thiolactam condensed with
ethyl bromoacetate gives, after
sulfur extrusion by
triphenylphosphine,
10 cyclic β-enamino esters. Compared with these methods, the
Meldrum's acid condensation followed by the monodecarboxylating transesterification described here is more convenient and practical. An extension of this procedure permits preparation of smaller cyclic β-enamino esters in comparable yields.
11 The results are reported in Table I.
TABLE I
PREPARATION OF SMALL-RING β-ENAMINO ESTERS
|
|
|
|
Product
|
n Yield (%)
|
mp (solvent) (°C) or bp (mm)
|
Ref.
|
|
|
A
|
3
|
92–94
|
170–172°C (ethanol)
|
11
|
|
B
|
3
|
85–87
|
61–63°C (hexane)
|
2,7,11
|
|
A
|
4
|
90–92
|
118–120°C (ethanol)
|
11
|
|
B
|
4
|
80–84
|
90–94°C / 0.1 mm
|
2,5,6,11
|
|
Only ethyl or methyl esters can be prepared by this procedure. However, pyrolysis of the cyclic β-enamino diesters at 225°C in the presence of different alcohols, thiols, or amines is a versatile and rapid method for preparing cyclic β-enamino esters, thioesters. or amides.
2
Appendix
Chemical Abstracts Nomenclature (Collective Index Number);
(Registry Number)
nickel acetylacetonate monohydrate
ethanol (64-17-5)
methanol (67-56-1)
chloroform (67-66-3)
sodium sulfate (7757-82-6)
sulfur (7704-34-9)
dimethyl sulfate (77-78-1)
acetone (67-64-1)
sodium (13966-32-0)
sodium ethoxide (141-52-6)
Malonic acid (141-82-2)
ε-caprolactam (105-60-2)
Ethyl bromoacetate (105-36-2)
hexane (110-54-3)
triethylamine (121-44-8)
trifluoroacetic acid (76-05-1)
O-Methylcaprolactim (2525-16-8)
triphenylphosphine (603-35-0)
2,2-dimethyl-1,3-dioxane-4,6-dione,
MELDRUM'S ACID (2033-24-1)
tert-Butyl cyanoacetate (1116-98-9)
1-aza-2-methoxy-1-cycloheptene
benzyl cyanoacetate (14447-18-8)
Ethyl α-(hexahydroazepinylidene-2)acetate
Acetic acid, (hexahydro-2H-azepin-2-ylidene)-, ethyl ester, (Z)- (70912-51-5)
Isopropylidene α-(hexahydroazepinylidene-2)malonate (70912-54-8)
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