CA1235121A - Process for the preparation of vinyl carbamates and novel vinyl carbamates - Google Patents

Abstract

NOVEL PROCESS FOR THE PREPARATION OF VINYL CARBAMATES AND NOVEL
VINYL CARBAMATES

Abstract of the Disclosure A process for the preparation of vinyl carbamates of formula I
(I) is described which comprises heating an ?-halogeno-carbamate of formula II
(II) in which X is a halogen atom at a temperature between 70°
and 250°C for a period of time between several minutes up:
to several hours.- R1, R2, R3, and R4 are the same or different.
The process is applicable to a great variety of products in which R1, R2, R3, and R4 have different meanings. The process permits to prepare in a simple and economical fashion, vinyl carbamates, which have industrial value and novel vinyl carba-mates.

Description

- 2 - ~23S~
The present invention relates to a novel process for the preparation of vinyl carbamates. This invention also relates to novel vinyl carbamates, which are valuable as agricultural pesticides, herbicides, insecticides and related materials, intermediates in the preparation of value able pharmaceuticals and which by polymerization lead to valuable substances.
Within the last 25 years, several processes of preparation of vinyl carbamates have been reported in the literature. According to French Patent No. 1,478,633 to Dow Chemical Company, some N-heterocyclic vinyl carbamates have been prepared by reaction of a vinyl haloform ate and an N-heterocyclic secondary amine. However, the vinyl halo-formats starting materials are substances very difficult to prepare. For instance, the process described in the United States Patent 2,377,085, which consists of pyrolyzing bis-glycol chloroform ate at 450C does not permit to obtain more than 11% of vinyl chloroform ate. Schaefgen in United States Patent 3,118,862 and Lee in the Journal of Organic Chemistry, Volume 30, page 3943, (1965) have improved this synthesis, but the improvements only give 30 and 44% yield respectively. One difficulty is that the tubular reactors become plugged. Another difficulty is that the by-products aye toxic and carcinogenic. A new process has been developed in the laboratories of Society National dyes Powders et Explosifs according to which phosgene is reacted with a salt of mercury. This process is described in U.S. 4,210,598.
The process permits to obtain the vinyl chloroformates in better yield and utilize them for the preparation of the carbamates on a large scale. Even this process though, presents some drawbacks, mainly in the use of the mercury salts, which are expensive and which require particular precautions.

X

~35~21 Another process of preparation of vinyl carbamates consists of dehydrohalogenatin~ ~-chloroethyl carbamates.
This process is described in Journal of Organic Chemistry, Vol. 27, p. 4331 (1962). The yields are low and several byproducts are obtained. The dehydroh~logenation only occurs it the presence of potassium tertiary but oxide, which is an expensive reagent and also difficult to handle. This process therefore, may be used on an industrial scale only with difficulty In the Journal Chemistry and Industry, in the issue of February 8, 1969, page 166, Franko-Filipasic and Patarcity reported that they obtained by reaction of a few kittens and one alluded with dialkylcarbamoyl chlorides, some vinyl carbamates with equally low yields. These investigators formulated the hypothesis that an intermediate synch as an c~,-chloroalkyl carbamate is formed and rapidly dehydrohalogenatea, but they did not detect even a trace of this intermediate and aid not succeed in increasing the rate of reaction by addition of several catalysts. Olofson and Cuomo, Tetrahedron Let. 21 819 (1980) reported the synthesis of N-(E,Z-propenyl-oxycarbonyl)~orpholine through a fluorocarbamate by- reaction with a trim ethyl sill ether W icily - S an conceive reknit.
Recently, Slang and Anderson in the Journal of Organic Chemistry, Vol. 46, p. 4585, ~1981) reported that they again attempted to prepare vinyl carbamates, but using a new route, that is using the isocyanates through the intermediate carbines. This synthesis also has drawbacks because it requires a fluoride, which is a laboratory reagent, very expensive and not suitable for large scale operations. Further, only a few milligrams of the desired product were obtained.

~3~i2:~
The foregoing summary demonstrates that there has been Audi at least within the last twenty-five years of a process of preparation of vinyl carbamates, which is simple, economical and which is utilizable on an industrial scale. There has also been a need of novel vinyl carbamates.
One object of the present invention is to prepare vinyl carbamates by a simple and economical process suitable on an industrial scale and which gives the desired products in good yields.
Another object of the present invention is to prepare novel vinyl carbamates, which have value as fragrances, pesticides and monomers and also known carbamates which after polymerization have value as moldable substances as descx;bed in French Patent 1,478,633 and Journal of Organic Chemistry, Vol. 27, p. 4331, (1962).
More specifically, the present invention covers a process for the preparation of vinyl carbamates of formula .. Al / R3 C - OH - O - C - N . (I) in which Al and R2 are the same or different and are:
- hydrogen;
- a saturated or unsaturated, substituted or unsubstituted, aliphatic, cycloaliphatic, or heterocyclic radical;
- a substituted or unsubstituted aromatic radical;
. - a group such as ROY-, ARC O-, R'NH-C-O-, O O
R'-C-I-, ROY-, WRECK-, US
b R' O O R' R' -it-, WRECK-, O .
in which R' is a hydrocarbon radical;

I ~351Z~

- a halogen atom, preferably chlorine or fluorine;
- ox Al and R2 together with the carbon atom to which they are attached form a ring, which may be saturated or unsaturated, substituted or unsubstituted;
The symbols R3 and R4 in the formula I hereinabove, may be the same or different and may vary widely since they are far from the reaction center. They may ye for instance, - hydrogen;
- a substituted or unsubstituted, saturated or unsaturated aliphatic radical, cycloaliphatic ' or heterocyclic, the unsaturation, however, being on a carbon atom which is not adjacent to the nitrogen atom;
.- - a chain which comprises carbon atoms and at least another heteroatom;
- Asian which comprises carbon atoms and at least 'another vinyl carbamate group; ;' . .
- a chain which comprises carbon atoms and at least another heteroatom and at least another vinyl carbamate group;
- a substituted or unsubstituted aromatic radical;
- or R3 and I form with the nitrogen to which they are attached, a heterocyclic ring, which may be saturated or unsaturated, substituted or unsubstituted! and which may be part of a condensed ring structure or which may contain at least another pa) heteroatom' which may be 0, S, N or N-RX, wherein Rx is a hydra-carbon radical,.and/or (b) nitrogen atom which pharisee a ~inyl~arbamate group.
.

It should be noted that R3 and R4 may include veto groups, esters of primary, secondary and tertiary alcohols and of methanol, conjugated esters, carbonate esters, ethers in-eluding aromatic ethers and aside functional groups. They may also include qua ternary ammonium salts.
According to a specific embodiment, Al and R2 are the same or elf errant and are:
- hydrogen;
- a saturated or unsaturated substituted or unsubstituted, aliph~tic radical;
- Al and R2 together with the carbon atom to which they are attached form a ring which is saturated ox unsaturated, substituted or unsubstituted;
R3 and R4 are the same or different and are:
- hydrogen;
- a substituted or unsubstituted, saturated or unsaturated, aliphatic, cycloaliphatic or heterocyclic radical, the unsaturation being on a carbon atom, which is not adjacent to the nitrogen atom;
- a radical of formula '' OR
-Z-l-fi-O-CH=C~
Y O . 2 wherein Z = a chain with 2 to 6 carton atoms, Y - alkyd, and Al and R2 are again as defined herein above;
- a substituted or unsubstit~ted aromatic radical;
- R3 and R4 form together with the nitrogen atom to which they reattached ai~h~terocylic ring;
.- R3 and R4 form together with the nitrogen atom to which they are attached, a het~!~yclic ring, which is part of a condensed ring structure;

- R3 and R4 form together with the nitrogen atom to which they are attached a heterocyclic ring which contains at least another heteroatom;
- R3 and R4 form with the nitrogen atom to which they are attached a heterocyclic ring which contains at least one oxygen atom and at least one additional nitrogen atom:
- R3 and R4 together with the nitrogen atom to which they are attached form a piperazine ring and both nitrogen atoms of the piperazine ring have attached said group of formula:

1 1l / C = OH - 0 - C -The process for the preparation of the vinyl carbamates according to formula I hereinabove according to the present invention comprises heating an a-halogeno carbamate of formula II:

Al / R3 C - OH - 0 - C - N (II) in which Al, R2, R3 and R4 have the same meaning as defined hereinabove and X is a halogen atom, at a temperature between 70 and 250C for a period of time between several minutes up to several hours whereby a halohydric acid is formed and isolating the carbamate of formula (I) from the reaction mixture. The process according to the present invention, therefore, may be represented by the equation hereinbelow:
-Al /R3 Al /R3 / C - OH - 0 - C - > / C = OH - 0 - C - N + HO

rmf~

I

As shown in the equation hereinabove, *he process according to the present invention permits to use as starting material substances which are easy to prepare and an apparatus, which is not very complex nor very expensive and permits to obtain the vinyl carbamates with a good yield and without products which would be difficult to separate and difficult to remove.
The present invention also covers novel vinyl carbamates, which are valuable industrial products, which may be represented by the formula hereinbelow:

.
i \ /R3 C = OH - O - - N (III) wherein Rip and R2 are the same or different and are:
- hydrogen;
- a saturated or unsaturated, substituted or unsubstituted, aliphatic, cycloaliphatic, or.
heterocyclic radical;
- a substituted or unsubstituted aromatic radical;
- a group such as ROY-, Rho R'NH-I-O-, O O
RUN ROY-, ROY -, R -S-, ARC WRECK-, O O
in which R' is a hydrocarbon radical;
- a halogen atom;

I I I

- or Al and R2 together with the carbon atom to which they are attached form a ring, which may be saturated or unsaturated, substituted or unsubstituted;
R4 is - hydrogen;
- a substituted or substituted saturated or unsaturated, aliphatic,. cycloaliphatic or hotter-cyclic radical, the unsaturation being on a carbon atom, which is not adjacent to the nitrogen atom;
- a chain which comprises carbon atoms and at least another heteroatom;
- a chain which comprises carbon atoms and at least another vinylcarbamate group;
- a chain which comprises carbon atoms and at least another heteroatom and at least another vinylcarbamate group;
- or a substituted or unsubstituted aromatic radical when R3 has the formula (IV) R' Z- -C -O -OH I live in which Al and R2 are identical or different and are the same as defined hereinabove, Y is the same as I and Z is:
a) a hydrocarbon chain consisting of 2-20 carbon atoms or b) a hydrocarbon chain of 2 to 20 carbon atoms additionally containing heteroatoms, W, in which W is O, S, NO", each heteroatom being separated from another heteroa.tom by at least two carbon atoms and R" is a hydrocarbon radical;
c) Z is a radical -(C~2~nOCOO(CH2~ and n is an integer number -between and lo - 1 ox 35i~
or R3 and I form tiger to the to which they arc ati~clled a ring ox formula TV) I j 'Roy -- No N -- - O OH = I IV) in which Z, Al and R2 nave the same meaning as hereinabove or R3 and R4 form together with the N to which they are attached a ring of formula (VI) - N N - R5 (VI) I . . ..

wherein Z has the same meaning as hereinabove and R5 is a hydrocarbon radical.
or R'4 is a aliphatic radical of 1 to 12 carbon atoms, preferably 1 to 4 carbon atoms, when R'3 is an aliphatic radical of 2 to 12 carbon atoms, preferably 2 to 10 carbon atoms, which radical ends with a qua ternary ammonium salt or Rip is hydrogen when R2 has a cyclic structure or is an aliphatic unsaturated radical substituted by chlorine, and when R3 is hydrogen or alkyd of 1 to 4 carbon atoms and R4 is alkyd of 1 to 4 carbon atoms.
The novel vinyl carbamates of formula III
obtained according to the process of the present application are particularly valuable when they have the formula (VII) 1 I CHOW N / \ N KOCH C / i R2 R6 7 sir' VOW) wherein Al and R2 may be the same or different and are the same as hereinabove;
- Z is an alkaline chain from 2 to 20 carbon atoms or a chain of carbon atoms and heteroatoms, W, in which W is O, S, NO" and W may be the same or different and R" is a hydrocarbon radical, each heteroatom being separated from another heteroatom by at least two carbon atoms;

35;~21 - R6 and R7 may be the same or different and haze the same meaning as R3 and R4 in formula (I) or together may be the same as Z thus forming a cyclic structure.
With reference to formula III, particularly valuable are the compounds in which a) R4 is alkyd and Z is a chain which contains :
between 2 and 10 carbon atoms, some of which may be replaced by heteroatoms, such as oxygen, provided that there-are at least two carbon atoms between each heteroatom. Preferably, the valuable vinyl carbamates are those which have a chain Z containing between 2 and 6 carbon atoms or carbon and heteroatoms and in which Al, R2, and R4 are hydrogen or alkyd or when b) R4 and R3 form a heterocyclic ring such as the piperazine ring, for example the N,N'-di-vinyloxycarbonyl-piperazine ~Di-VOC-piperazine) or such as .' ', ox '. ..
-- No J 8 .

in which n is 1, 2, or 3 and R8 is a hydrocarbon radical or another OKAY radical.
Rx, R5, R'' and R8 may be the say end are preferably hydrocarbon radicals of 1 to 10 carbon atoms.
, .

- 12 - ~3~121 One substantial advantage of the present invention is that it makes available novel compounds, which up to now have been inaccessible and which have value as agricultural pesticides, herbicide, insecticides, and related materials.
Another advantage is that they contain-a carbon-carbon double bond, which may be used to carry out additional reactions with a variety ox different compounds. Finally, in view of the presence of the double bond, they may be polymerized to prepare novel compounds, such as organic plastic materials with properties similar to glass.
The invention is described hereinbelow in more detail. With reference to formula II, which defines the carbamate starting material, X is preferably chlorine or bromide so that the compounds, which are being dodder-halogenated are preferably -chlorocarbamate or a-bromocarbamate.
For the preparation of the -halogeno-compounds, it it possible to use the process of commonly assigned, cop ending Canadian application 382,305, filed July 22, 1981, now Canadian patent 1,173,439, which permits to use readily available tertiary amine and -halochloroformates as the starting materials.
They may also be prepared by reaction of the same -halogenated chloroformates with ammonia, primary amine or secondary amine in the presence of a substance, which acts as the acceptor of the halohydric acid formed.
The -sheller chloroform ate may be prepared by photo chemical chlorination of the corresponding chloroformates or much better, by reaction of phosgene with an alluded in the presence of a catalyst as described in European Patent No. 40153.

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I

According to one embodiment of the invention, one aids to the reaction medium, at least one catalyst, which is a salt, capable of ionizing easily, the anion of which is not nucleophilic or is only weakly nucleophilic. The cation may be a metallic cation and preferably it it an alkali or alkaline earth metal cation. advantageously, the metal cation is associated in the form of a complex such as a crown-ether or a crypt and The cation may also be an organic cation. It is preferably one of the opiums such as ammonium, phosphonium, arsonium, sulfonium, and particularly the opium cations which are substituted by at least one radical and usually more than one radical having at least four carbon atoms.
The qua ternary ammonium ions are the preferred cations.
The anion is a halide, preferably chloride, bromide, or another anion which is non-nucleophilic or only weakly nucleophilic, such as for instance, C104 or NO .
It is possible to utilize as a catalyst, the sheller of lithium, sodium, potassium, magnesium, end calcium and also lithium bromide and potassium fluoride.
Potassium chloride associated with 18-crown-6 or 2,2,2-cryptand gives very good results. The qua ternary ammonium halides are among the preferred catalysts. Tao may cite bouncily tributylammonium chloride or bromide, tetrahexylammonium chloride or bromide and in particular, tetra-n-butylammonium bromide. The catalyst may be added in a quantity between 0.02 unto 0.5 equivalent and preferably 0.05 up to 0.15 equivalents with respect to each carbamate functional group to be reacted.

.

1~35121 According to a second embodiment of the invention, the reaction is carried out in the presence of an agent capable of neutralizing the halohydric acid, which is produced during the reaction. Particularly suitable for this purpose within the scope of the present invention aye the substances, which are acid acceptors and which do not exhibit a substantial nucleophilic activity, but which are sufficiently strong bases in order to form a complex with the aria formed.
the preferred substances are selected from the group, which comprises pardons substituted in the 2,4- .
or in the possession by aliphatic radicals, which may haze one carbon atom, for instance, a methyl group an up to n carton atoms, the symbol n; being sufficiently high so that the radical may be a polymeric chain; aniline substituted on the N atom by alkyds having between l an n carbon atoms, n being sufficiently high so that the radical may ye a polymeric chain and in particular, substituted aniline in which the aromatic ring is de-activated by electrophilic substituents, for instance, halogen atoms, particularly in the pane position; certain ~lkenes, such as pinion or cyclododecatriene, aromatic diisocyanates such as Tulane diisocyanate or aliphatic diisocyanates such as those of the formula O = C = N ~C~2)xN z C = O, in which is an integer number between 6 and 36; an alkali or alkaline earth carbonates. Particularly suitable are colliding, p-halo-N,N-dialkylanilines and pinion. The acid acceptor is used in a quantity equal to or greater than the statue-metric amount and preferably in slight to substantial excess.
In addition to chemical methods, it is possible to remove by physical methods, the halohydric acid, which if left in the reaction medium, could slow down the reaction and also destroy the product. Fox instance, the reaction may be performed at reduced pressure to suck out the acid as soon as formed. This may be achieved by using a system -15- I 235~LZ~L
with a high surface area such as a thin film evaporator to facilitate the escape of the acid. It is also possible to pass an inert gas for instance, nitrogen or argon through or over the reaction medium to entrap the acid in the gas and thus remove it as soon as formed, at lower pressure or atmospheric pressure or even at high pressure.
It is also possible to use molecular sieves for instance, 3~ for Huron chloride.
According to another embodiment of the invention the dehydrohalogenation may be carried out in the presence of at least one aprotic solvent, which is weakly nucleophilic or not nucleophilic and optionally also a polar solvent The solvent may be selected from the group which comprises ethers such as triglyme, (triethylene glycol dim ethyl ether),sulfones, N,N-dialkylsul*on-amides,~,NjN',N'-tetralkylsulfonylureas, aromatic hydrocarbons and preferably aromatic hydrocarbons which have a suitable boiling point and at least one electron withdrawing (electrophilic) substituent, alikeness or Alleghenies which have a suitable boiling point such as dichloroethane and in- or tetrachloroethylene and even the final product, What is the dehydrohalogenated carbamate~.
Chlorobenzene, bromobenzene, dichlorobenzenes, trichloro-bunions, tetrachlorobenzenes, and tetrachloroethylenes are among the most suitable solvents. The use of solvents simplifies frequently the recovery of the products. Preferably, one selects the conditions of temperature and pressure in a manner to lead the solvent to reflex.
period of time of a few hours is usually sufficient to obtain the vinyl carbamates. It is pie-fireball to carry out the reaction in an an hydrous medium in the absence of oxygen for instance, in a nitrogen atmosphere. The vinyl carbamates are recovered by 5~2~L

conventional methods for instance after appropriate elimination of the solvent or if more volatile may be recovered by distillation from the solvent.
According to a preferred embodiment of the process, the reaction is carried out in the presence of a catalyst as described above, in the presence of an organic acceptor of the acid as described above, and in the presence of a solvent as described above En-silent yields often are obtained by the use ox tetra-n-butyl-ammonium bromide and colliding in the presence of a solvent such as chlorobenzene or tetrachloroethylene.
An essential feature of the process according to the present invention resides in the fact that the phyla jointed carbamates of formula II are heated to a temperature between 70~ and 250C in order to achieve dehydrohalogenation.
One preferably operates at a temperature between 80 and 200C.
It is possible and sometimes convenient to form the d -halogenocarbamate and eliminate H-X to give the desired product vinyl carbamate in one step without isolating the intermediate ~-halogenocarbamate. For example, when heat is used in the synthesis of the CC-halogenocarbamate, the reaction may often be performed so that the elimination occurs almost as soon as the halogenocarbamate is generated.
Indeed, some of the halogenocarbamate may be undergoing elimination before the remainder has been completely formed.
If the elimination is not complete under these conditions, the remaining halogenocarbamate can be converted to the derived vinyl carbamate by subjecting the mixture of the two substances to any of the conditions described herein to convert essentially pure CC-halogenocarbamates of similar structure to their vinyl carbamates.

-17- ~351~1 The invention is illustrated by the examples hereinbelow.
In the examples below, ACE is often used as an abbreviation fox the CH3-CHCl-O--C(=O)-group and VOW is often used as an abbreviation for the CH2=CH-O-C~--O)-group Thus, ACE-Cl means ~-chloroethyl chloroform ate.

Example 1:
, , _ . . . ..
Preparation of N-Isobutenylox~carbonyl-N-methylcycloh~ famine . . .
, a) Synthesis of N-c~'-Chlor~isobUtylox~carbonyl-N-methyl-cyclohexylamine.

A solution of N-methylcyclohexylamine (Aldrich, dried over KOCH and distilled) (1~.9 g, 0.13 molt in 15 cc of ether was added slowly (15 minutes) to a stirred solution of ~-chloroisobutyl chloroform ate (9.91 g, 0.058 molt in 15 cc ether cooled to 0C. After the audition was complete, the mixture was warmed to room temperature and stirred for Arthur hour. The salts were filterer off and the filtrate was rotoevaporated before isolation of the product by simple vacuum distillation; 13.3 g (92~ yield) of boiling point 111-113C at 0.6 mm.

, 23~
IT I 49 (m), 5. 81 (us); CC14- .
I NOR 6.30 (d,J=4), 4.2-3.4 em), 2.80 (s), 2.4-0.8 (m with methyl d at 1.05, Jo ratio 1:1:3:17; Cal MS (m/e): 249.1319 (P137C1], I Cafe. 2~9.1310), 247~1344 ~P~35Cl~, ought Cafe. 247.1339), 206.0760 (Pi 7Cl]-CHtCH I 8%, Calm.
206.0762), 204. 0789 (P ~5Cl~-CH(CH3)2, 26%, Cafe. 204.0791), 157 (17g6), 156 (88~), 140 (69%), 114 (68~), 58 (100%~

b) DehYdrohalogenation The chlorocarbamate (4.58 g, 0.0185 molt was heated in an oil bath at 170C in a 25 cc round bottomed flask equipped with a reflex condenser and nitrogen inlet.
Vigorous evolution of Hal gas occurred during the first 30 minutes of reaction and after 1 hour the process was 94%
complete as determined by NOR analysis. After 2 hours, .
the product alkenyl carbamate was distiller directly from the reaction mixture giving 3.29 g (84~ viola, NOR pure) of boiling point 98-102C at 0.4 mm. An additional 0.46 g of residue remained in the distillation pot an this analyzed ... . .
NO as about a 1~1 mixture of N-methylcyclohexylamine hydrochloride and the product.
IRK 3.49 (m), 5.84 us CC14.
I NO 7.0-6.7 (m), 4.3-3.5 (m), 2.83 (s), 2.2-0.5 (m); ratio 1:1:3:16; CC14.
MS (m/e): 211.1573 (P, I Cafe. ~11.1573), 140.1066 (P-OCH=C(CH3)2, 45~, Cafe..
14~.1075~, 83 (100%), 72 (42~

.

' , -19~ I
c) No Isobu~ oxycarbonyl-M-met~ylcyclohex~ no A solution of N-O~-chloroisobutyloxyc~rbonyl-N-methyl-cyclohexylamine, (10.1 g, 0.041 mole), 2,4,6-collidine (6.0 g, 0.050 mow), tetrabutyl ammo~ium bromide (0.75 g, Owe mow), and tetrachloroethylene (19 cc) assay heated at 125~C for 2 hours.
After a standard extraction workup (ether and 1 N H2SO4) and rotoevaporation, the product alkenyl carbamate was isolated pure NOR by vacuum distillation; 8.50 g (99% yield) of boiling point 93-98C at 0.2 mm.

Example 2: PrcpaL-a.ion of N-Vinyloxycarbonylpiperidine (VOC-piperidine~
a) Preparation of No Chloroethoxycarbonylpiperidine (ACE-piperidine).

A solution of N-ethylpiperidine (Aldrich, distilled) (5.68 g, 0.05 molt in 20 cc of dichloroethane was dripper lo minutes) into a stirred an ice-cooled solution of ACE-Cl (9. 32 g, 0.065 mow), 1,8-bis-(dimethylamino)_ naphthalene, (0. 53 g, OUGHT molt 0. 05 equip.), and 50 cc of dichloroethane. During *he addition the solution color turned from clear to yellow and remained this color while the reaction was cold. The mixture was reflexed for 30 minutes, cooled and the solvent and excess ACE-Cl removed in vacua. Then the remaining dark red liquid was distilled at 0.2 mm to afford 9.36 g (97~ yield) of colorless title carbamate; boiling point 67-69C at 0.2 mm.

IT I 3.40 (m), 3.50 to), 5.80 us 7.01 (s);
CC14.
H NOR 6.48 I Jo 3.8-3,0 (m), 1.9-1.2 (m with methyl d at 1.75); ratio 1:4 9; CC14.

.
.
, ' MS (me): 193.0653 (I¦ (13 t I Cafe. aye), 191~ 0700 to [ Of] t I r Cluck. 191. 0700) 12~. 0712 (P 135Cl~-CIIClC~ Lowe Cluck.
128. 07123 112. 0758 (P 1 Cliche 59%, Cafe. 112. 0762), I 0808 (73%) .

b) Dehydrochlorina~ion In a glass reactor equipped with a magnetic stirrer, a thermometer, and a reflex condenser connected with a vacuum system, there was introduced 9.8 grams of N- -chloroethoxycarbonyl-piperidine of formula:

SHEA - OH - O - C -I

an 4.8 grams (0.3~ equivalent), of an hydrous tetra-n-hutyl-ammonium bromide. The-mixture was reflexed at a pressure of 0.3 mm of mercury for a period of six days, (oil bath at 105C). The reaction product was then distilled off under reduced pressure:
VOC-piperidine was obtained. Boiling Point 60-61C at 0.3 mm ~m~r~ury~ Yield: 78%. On infrared analysis, the substance gave the following banes I 5.81; 6.07; 8.57; in CC14.

Example 3 - Proration ofI~-vinyloxycarbonyl~iperiaine .

. This experiment was carried out in the same manner as Example 2 from the same reactants, but the mixture was reflexed at 0.3 mm (oil bath between 85 and 95DC) for a period of 18 hours. Then methanol was added and the mixture was reflexed for one hour and the methanol removed at reduced pressure. The remaining oil was partitioned between ether and water. The ether layer was evaporated to give pure VOC-piperidine in 54% yield.

- 21- ~2351 21 .

Example 4 - Preparation o-f--N~7inyloxycarbonylp-i In a glass reactor kept under vacuum, 0.55 grams of calcium chloride was dried for a period of one-half hour. There was then introduced N~-chloroethoxy-carbonylpiperidine in the amount of 0.75 cc.
The temperature of the oil bath was kept at 130C an the vacuum was 40 mm of mercury. after one hour and 15 minutes, the ratio of product to starting material measured by NOR was 0.2:1. After 20 hours, the ratio vinyl carbamate toci-chloxoethyl c~rbamate was 4.6 detrained by NOR.
Example 5 - Preparation of No yloxycarbonylpiperidine This experiment was carried out in the same manner as the proceeding experiment, but calcium chloride was replaced by Lithuania broomed The mixture was heated for 1 1/2 hours. The ratio of vinyl carbamate to sheller-ethyl carbamate determined by NOR was 1:1.

Examples 6-10- Preparation of N~inyloxycarbonyl~iperidine These experiments illustrate the dehyarochlorination in the presence of different catalysts and affront solvents. , In these examples, the manner of operation was as follows:
In a reactor provided with rollicks condenser and a nitrogen inlet, there were introduce the organic solvent, the N-~-chloroethoxycarbonylpiperidine and the catalyst The mixture was heated under reduced pressure under conditions to permit the solvent to reflex mildly at the temperature of operation. The experimental conditions, the materials used and the results are summarized in Table 1. The yields given were determined by WAR spectroscopy on the reaction mixture at tune end of the listed Zion time.

.

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, ~23- ~3~2~

Example Preparation of N~Jinyloxycarbonylpiperidine (VOC-Piperidine) from ACE-Piperidine in the Presence of Colliding .
A stirred solution (under No) of A OE-Piperidine-(9.6 g, 0.05 mow), 2,4,6-collidine (7.4 g,- 0.06 molt boiling point 172C), and o-dichlorobenzene (20 cc, 0.18 molt boiling point 178C) was heated to 185C in an oil bath, allowed to reflex for 3 hours and then cooled to room temperature. The mixture had darkened considerably and some colliding hydra-chloride had precipitated. Chloroform was added until the mixture was homogeneous. This solution was washed with water (3 x So cc) which removed almost all of the color and the aqueous layers were combine and extracted with chloroform (2 x 30 cc). The chloroform extracts were combined, dried (Nazi) and roto-evaporated. The product, VOC-piperidine, was isolated by means of an efficient vacuum distillation through a 35 cm vacuum-jacke~ed column with a Teflon inner coil. The column was wrapper with heating tape kept 15-20C lower than the distillation temperature. The o-dichlorobenzene fraction was followed by an intermediate fraction of boiling point 95-123C at 47 mm ~2.07 g) which contained (NORWAY analysis) 0-dichlorobenzene, colliding (3 mow I), and VOC-piperidine (31 mow %, 9% absolute yield). The final distillation traction, 6.21 g of boiling point 123-128C at 47 mm, analyzed (NOR) as pure ~OC-piperidine (80% viola; total product in both fractions 89~). Almost no residue remained in the still pot.

.

.

I

Example 12- Preparation of VOC-Piperidine In a similar experiment, bromob~nzene ~20 cc, 0.19 molt boiling point 156C~ was used as the inert solvent-diluent. The solution containing the bromobenzene~
ACE-piperidine (10.0 g, 0.052 mow), and colliding (7.70 g, 0.064 molt was heated to 170C in an oil bath an the mixture was allowed to reflex for 5.5 hours prior to cooling at room temperature. The reaction mixture was partitioned between water t20 cc) and ether ~40 cc).
The layers were separated, the organic layer was washed with water (2 x 20 cc), and the combined aqueous extracts were washed with ether I x 25 cc). The organic layers were combined, dried (Nazi), roto-evaporated, and distilled using the apparatus describe in Example 11. The bromobenzene fraction was followed by a small intermediate fraction, 0.43 g of boiling point 100-124C at 44 mm, which analyzed (NOR) as a mixture of colliding (56 mow %), bromobenzene (27 mow %), and VOC-piperidine (17 mow %). The main product fraction, ~.31 g of boiling point 124-126C at 44 mm, analyzed as VOC-piperidine contaminated by 3.5 mow % of 2,4,6-collidine (yield of VOC-piperidine 88~). The Callahan contaminant could be removed by extraction with dilute aqueous sulfuric acid.

Example 13 - Preparation of OWE Piperidine Another experiment was performed on an NOR scale in which colliding was used both as the solvent and the acid sequestering agent. In this experiment, ACE-piperiaine (1,12 g) in 3 cc of colliding (3.9 equip.) was heater for 1 hour at 170C. Based on NOR analysis, a 52% yield of ~OC-piperidine was present in the reaction medium and 33~ of the starting ACE-piperidine remained. Decomposition products accounted for the remainder of the starting material.
, .

~235~2~

Example 14 - Preparation of YOU piperidine from ACE-Piperidine using Colliding and using Additional VOC-Piperidine as the -solvent delineate A stirred solution under No) of OE-piperiaine (8.33 grams, 0.043 mow), 2,4,6-collidine ~6.43 grams, Owe mow), and VOC-piperidine (15.6 grams, 0.1 molt was heated at 185~C for 3 hours in an oil bath, then cooled, and partitioned between ether ~25 ml) and lo H2SO4 (20 ml).
The layers were separated and the organic layer was washed with additional lo H2SO4 (2 x 20 cc) and brine (20 cc). The combined aqueous acid layers were back extracted with ether (2 x 20 cc) which was then used to back extract the brine solution. The ether extracts were combined, dried (Nazi), the ether evaporated at reduced pressure, and the VOC-piperidine isolated by simple vacuum distillation; 20.6 g of material, by 60-61C at 0.3 mm (yield after subtraction of 15.6 grams included at beginning:
75~) was obtained. The product was pure NOR analysis).
Some residue remained in the still pot.

.

.
:

~26- I

Example 15 - Preparation of VOC-Pipcridine Into a glass reactor was introduced 0.932 grams of ~CE-pipericline, 0.098 grams ~0.063 equip.) of twitter-n-butylammonium bromide and 2 cc, (2.6 equip.) of N,N'-diethylaniline. The mixture was heated at 150~C
for 30 minutes. The analysis tNMR) showed that the product was VOC-piperidine in 59~ yield and that 10~
decomposition had occurred. The ratio of VOC-piperidine to ACE-piperidine was 1.9:1 (NOR).

Example 16 Preparation of VOC-Piperidine from ACE-Piperidine in the Presence of Colliding and Tetrabutylammonium bromide .
A stirred solution (under No) of ACE-piperidine (11.5 grams, 0.06 mow), tetrabutylammonium bromide ~0.97 grams, 0.003 mow), and 2,4,6-collidine (8.72 grams, 0.07 molt in chlorobenzene (25 cc, 0.25 mow), boiling point 132C) was heated to 140C in an oil bath, allowed to reflex for 21 hours, and then cooled to room temperature. Ether ~40 cc) was added to the mixture which then was extracted within R2SO4 (3 x 30 cc) and brine (30 cc). The aqueous layers were combined and back extracted with ether (Z x 40 cc). The combined ether extracts were dried Nazi), rotary evaporated, and the chlorobenzene distilled off (boiling point 55-57C at 55 mm). The YOC-piperidine was isolated by reduced pressure distillation; boiling point 130-132C at 55 mm; 8.2 grams ~88% yield); NOR pure.
In another experiment under the same conditions except that the reaction mixture was reflexed for 28 hours, the yield of distilled YOC-piperidine was 89~.

. , . . .

.. . .

-- -27- ~23~2~
In spite of the fact that the catalyst decomposed under the reaction conditions, it still significantly increases the reaction rate as demons~rat~a by the hollowing experiment.
ACE-Piperidine (10.4 grams, 0.054 mow), killed (8.00 grams, 0.066 mow), and chlorobenzene (US cc) were heater at 140C for 27 hours. Analysis by NOR indicate that the reaction was only 84~ complete. Therefore, the reaction was continued at 140~C for a total reaction time of 48 hours.
Workup as described above afforded VOW piperidine in 70%
yield.
Other salts also increase the reaction rate.
In another experiment, a mixture of ACE-piperiaine (1.78 grams, 9.3 mmol),Z,4,6-collidine (1.38 grams, 11.4 Molly), ammonium chloride (0.10 grams, lo Molly), and chlorobenzene I cc, 39.3 Molly) was heated Attica fox 25 hours an then cooled to room temperature. Ether ~20 cc) was added and the mixture was extracted with lo H2S04 I x 20 cc). The combined aqueous layers were backwashes with ether (20 cc). Toe organic layers were combined, cried ~Na2SO~J, Noah rotary evaporated. 1,1,2,2-tetrachloroethane (1.57 grams, 9.35 molt was added to the remaining oil as a quantitative interval standard for NO analysis; calculated yield 63%.

.
. .
Examplel7 - Preparation of N~Nl-Di(vinvlo~vc~r~o~vl)pi~era-in ., (Di-VOC-piperazine) a)N,N'-Di(~-chloroethoxy~arbonyl)-piperazine;(Di-AAcEE-piperazine) A solution of N,N'-dimethylpiperazine Aldrich, dried over OH and fractionally distilled) t9.50 g, 0.083 molt in 1,2-dichloroethane (40 ml) was dripped (35 mint into a stirred solution ofc~-chloroethyl chloro~ormate (32.5 g, 0.227 molt and 1,8-bis(dimethylamino)naphthalene (1.94 g, 0.009 molt 0.11 equip.) in dichloroethane (100 cc) kept at -5C. During the addition of the piperazine, a white solid precipitate which .. . .

-28- ~3~21 decreased the efficiency of mixing, but when the reaction temperature was raised to reflex, the solid dissolved. After xefluxing for 1 hour, the reddish-brown solution was cooled, charcoal was added, dry Hal was bubbled slowly through the solution for 30 seconds to complex the excess bis(dimethylamin~-naphthalene, and the solution was passed through a 3/4"x 2" plug of Silica Gel with ethylene chloride as the eluant. Vacuum evaporation of the resulting clear solution afforded an oft solution which was dried overnight in vacua at 55C; yield 97~ (24.0 g, NOR pure) of the title dicarbama~e with a mop. of 125.5-135.5C (most of the solid melted at 125.5-130C). The solid had a mop. of 131.5-138C aster recrystallization from l,2-dichloroethane, but its spectral and TLC purity was unchanged. Since the solid product is probably a mixture of a pair of diastereomers, the melting point is not a good indication of purity, but only an indication of variation in diastereomer ratio. The two choral centers, however, are trod far apart to show the presence of diastereomers in the NOR spectrum.

IT I 5.79 US 8.17 (m), 9.17 US); C~C12.
OH NOR I 6.58 (q, J = 6), 3.52 (broad d), 1.79 (d, J = 6); ratio 2:8:6; CDC13.
MS (m/e): 300 0447 (P [37C1 35C1] 2% Cafe - - -300. 0457), 298. 0471 (Pluck], 4%, Cafe. 298. 0487), 237 I 235.0476 (P 1 C1]-CHC1CH3, 19%, Cafe. 235.0485), 221 (7%), 219. 0530 (P [35C1 - - ~CHC1CH3, 12%, Cafe. 219.0536), 191 (28%), 177 (34%), 175 ~100%), ~55 (43%), 149 ~66~1, 113 (32% ) .
.

' -29- ~35~21 b) Conversion of N,N'-Di-ACE-piperazine to N,N'-ni-Voc-piperazine.

A solution of N,N'-ai-AC~-piperazine (7.61 g, 0.025 mow), 2,4,6-collidine (6.9~ g, 0.057 mow), and o-dichlorobenzene (20 cc) was heated (oil bath at 185C) for 45 minutes. color form (40 cc) was added Jo the cooled, dark-red solution which then was extracted with 1 N H2SO4 (3 x 30 cc) and brine ~20 cc).
The aqueous extracts were back-extracted with chloroform (2 x 25 cc). The combined organic layers were dried Nazi, charcoal was added, and the solvent was removed in vacua. The solid residue was passed through a silica gel plug SCHICK as eluant). The equate was evaporated at reduced pressure yielding N,NLdi-YOC-piperazine as a light tan solid; 1.88 g (33~ yield, NOR pure). The rechromatographed sample used for analysis had a melting point of 97.5-99C.
IT I 5.86 (us), 6.06 (m); SCHICK.
I NOR (S): 7.21 (d of d, J = 14, 6), 4.80 (d of d, J = 14, 1), 4.48 Ed of d, J 6, 1),

3.54 (s); ratio 2:2:2:8; CDC13~
MS Moe): 226.0947 (P, 15%, Cafe. 226.0953), 183.0762 (P-OCH=CH2, 98%, Cafe. 18~.07~0)~
139 (42%), 113 (100~), 97 ~28%).
- In a related experiment performed in bromobenzene (6.6 equip) at reflex in the presence of 2.3 eve. 2,4,6-colliding, the reaction was 42~ complete NOR analysis) after 2 hours.
I" another experiment, a solution of N,N'-di-ACE-piperazine ~5.15 g, 0.017 molt, tetra-n-butylammonium bromide (0.51 g, 0.002 mow), 2,4,6-collidine (4.91 g, 0.041 mow), an tetrachloroethylene (18 cc) was heated at reflex. After 3 hours, NOR analysis indicated that the reaction was 28~ complete-The reaction mixture was worked up as above after 24 hours and the N,N'-di-VOC-piperazine was isolated.

.

- '. Jo I

Reaction of N,N'--di-ACE-piperazine tl.71 g, 5 72 Molly) in dichloroethane ~20 cc) in the presence of benzyltri-n-butyl-ammonium chloride (1.30 q, 4.15 Molly) was performer at Rex overnight with No bubbling through the solution an allowing the solvent to evaporate the remaining brown oil solidified upon cooling. This was partitioned between C~2C12 (50 cc) and 0.01 N Hal (40 cc). The organic layer was dried tNa2so4)~
evaporated, and then heated in 5 cc of methanol at 65C.
After evaporation and attempted sublimation, the product was chromatographed through silica. The yield of chromatographed N,NI-di-~OC-piperazine was 33%.
N,N'-Di-~OC-piperazine also was produced in the absence of catalyst, solvent, or base. When N,N'-di-ACE-piperazine (0.62 g, ~.07 Molly) was heated at 185C in a 100 mm vacuum, to remove Hal as formed, for 1 hour, NOR analysis indicated 34~
conversion to VOW and 10% decomposition of the starting material.
In a final experiment -pinion was used to scavenge the Ill N,N~Di-ACE-piperazine (10.1 g, 0.034 mow), -pinion (11.1 g, 0.082 mow), and o-dichloro~enzene (25 cc) were reflexed (oil bath at 185C). After 20 hours, NOR analysis showed the reaction was 70% complete. after 41 hours, the solvent was removed at reduced pressure, charcoal was added, and the product was passed through a silica gel plug Schick as eluant). NOR analysis of the chromatographed product (4.29 go gave a VOW to ACE ratio of 86:14; absolute yield of di-VOC-piperazine: 40~.

Example 18- Preparation of N-Vinvloxycar~onyl-N-methylan; inn (N-~OC-N-methylaniline) .
a) Preparation of N-ACE-N-Methylaniline.
N,N-Dimethylaniline tl9.3 grams, 0.16 molt in dichloroethane (25 cc) was slowly added to a stirred, cooler t0C) solution of ACE-Cl (49~8 grams, 0.35 molt in dichloroethane (75 cc).
This mixture was heated to 90C toil bath) and reflexed for 3 days. The solvent and excess A OE-Cl were removed by vacuum .

~z35~21 apportion. Black oil was obtained to weakly ether, (which precipitated out a Black solid) and charcoal were added.
The solids were filtered off, thy solvent removed, and the product isolated by vacuum distillation; 29.3 grams 86%
yield, Nor pure) of boiling point 100-110~C at 0 4 mm.
IT (u): 5.78 (us), 6.~5 (my, 6.67 (m); CC14.
H NOR (;"): 7~6-6.9 (m), 6.55 (q,J=6)~ ~.21 us), 1.60 Ed, Jo ratio 5:1:3:3; CCl4 MS (m/e): 215.0562 (P[37Cl~, 389~, Cafe. 215.0527J,213.0573 (P [35C1], yo-yo, Cafe. 213.0556), 151.0646 (P-C2H3Cl, 64%, Cafe. 151.0634), 134.0594 (P-OCHClCH3, 100%, Cafe. 134.0606)~
107 ~64%), 106 (76%), 77 (6996), 63 ~80%)~

b) Colliding facilitated Conversion of NISSAN-. _ . . .
Methyl aniline to N-VOC-N=M~aniline.

A stirred mixture under No) of N-ACE-N-methyl-aniline ~10.4 grams, 0.048 molt, 2,4,6-collidine ~7.15 grams, 0.059 molt, and o-dichlorobenzene ~20 cc, 0.18 molt was heated at 185C for 3 hours in an oil bath and then cooled to room temperature. The mixture was partitioned between water and ether, the layers separated, the organic layer washed with water, dried Noah), and evaporated at reduce pressure.
The N-YOC-N-methylaniline product was isolated by rewaken distillation through a short Vigreaux column; 2.72 grams (32% yield, NORWAY pure) of boiling point 75-79C at 0.4 mm.
.
IT (p): 5.78 I 6.06 em), 6.25 (m), 6.67 my CC14.
H NOR (So I 5 6. 8 (m), 4.57 (d of d, J = 14, 1),

4.30 (d of d, J = 7, 1) j 3.20 us);
ratio 6:1:1:3; CC14.
MS (m/e): 177.0793 (P, 5896, Cafe. 177.0790), 134.0608 (P-OCH=CH2, 10096, Cafe.
134.0606~,119.0371 (P-C3H60, 12g6,CalC.
119.0371), 106.0655 (P - CO2CH~CH2, 81~, Cafe. 106.0657), 77.0391 SHEA
Cafe. 77. 0391) ,51 (28%) .

.

- 32 - ~3~2~
Example 19 - Preparation of N-Vinyloxycarbonylmorpholine a) Preparation of N-a-chloroethoxycarbonylmorpholine tACE-Morpholine A sample of N-methylmorpholine was converted to N-a-chloroethoxycarbonylmorpholine in 96~ yield by reaction in the same manner as in Example 18; boiling point 84-86C
at 0.4 mm.
IT I 5.79 (V9)~ 7.82 (m), 8.08 (s), 9.11 (s); CC14.
lo NOR I 6.50 I J = 6), 3.8-3.2 (m), 1.76 (d, J = 6); ratio 1:8:3;
CC14.
MS (m/e): 195.0462 (P[37Cl], 3%, Cafe.
195.0476), 193.0494 (P[35Cl], 8%, Cafe. 193.0506), 180.0237 (P[37Cl]-CH3, 6%, Cafe. 180.0241), 178.0269 (P[35Cl]-CH3, 19%, Cafe.
178.0271), 130.0500 (P-CHClCH3, 39~, Cafe. 130.0504), 114.0550 (P-OC~ClCH3, 71%, Cafe. 114.0555), 70 (67%), 69 (38%), 63 (100%).

b) Conversion of ACE-Morpholine to VOC-Morpholine.

A stirred mixture of ACE-morpholine (11.3 grams, 0.058 molt and 2,4,6-collidine (8.79 grams, 0.073 molt in o-dichlorobenzene (25 cc, 0.22 molt was heated at 185C
for 2 hours in an oil bath, (NOR analysis a the 1.5 hour mark showed thy reaction to be 96% complete). After the normal ethereal H2SO4 extraction workup and rotoevaporation, the product was isolated by vacuum distillation through a 35 cm vacuum jacketed column with a "Teflon" inner coil.
The solvent was removed boiling point 93-94C at 49 mm) followed by a fraction which contained 9 mow VOC-morpholine (1.90 grams, boiling point 109-126C at 49 mm, calculated yield 2%).

rum/

.
-33 ~35~

The prc~c~uct then distilled over; 7. 32 grams 5~0% yield, NOR pure) of boilirlg point 134-136C at 49 on (overall yield 829~).
IRK 5.81 (us), 6.07 (m); CC14.

H My 7.20 Ed of d, J=14, 7), 4.68 (d of d, J-- 14, I and 4.40 (d of do Jo 1), 3.9-3.2 Broadway; ratio 1:2:8, CC14.
MS (me): 157.0732 UP, 14~, Cafe. 157.0739), 114.0563 (P-OCH=CH2, 88%, Cafe. 114.0555)r 70 (100%).

xample 20 : Preparation of l-(Isobutenyloxycarbon~
benzotriazole a) l-(,~-Chloroisobutyloxycarbonyl)benzotriazole.
-Chloroisohutyl chloroform ate (7.85 grams, 0.046 molt in ether (10 cc) was added (10 mint to a stirred, cooled (0C) solution of benzotriazole (Aldrich) (11.6 grams, 0.097 mow), ether (50 cc), and ethylene chloride (10 cc).
After the addition was complete (10 mix), the mixture was stirred at room temperature for 1 hour. Excess benzotriazole was removed by bubbling Hal into the mixture and then removing all set s by filtration. The product then was passed through a silica gel plug (SCHICK as eluant). the clear oil obtained after rotary evaporation of the solvent (11.5 grams, 99%
yield) later soliaifled (melting point 42-52C).

IT I 5.65 (us), 6.19 ow), 6~23 (w), 6.71 em), 6.86 (us), 7.10 us Cal OH NOR I): 8.3-7.3 (m), 6.63 (d, Jo 2.9-2.2 (m?, 1.22 Ed, Jo ratio I 6; C~C13.

MS (m/e): 255.0582 (Pi Of], 6%, Calm.
255.0588), 253.0626 (P[35Cl], 18%, Cafe. 253.0618), 146 (85~), 135 (20%),- 119 (37%~, ~18 (43%), 91 (67%), 90 (92%), 55 (100~).

b) Conversion of l-(-Chloroisobutyloxycarbonyl)-benzotriazole to l-(Isobutenyloxycarbonyl)benzotriazole.

The chloroisobutyloxycarbonylbenzotriazole (4.72 grams, 0.019 molt and tetrabutylammonium bromide (0.29 grams, 0.001 mow), were dried overnight in vacua at 50C. Twitter-chloroethylene (10 cc) and 2,4,6-collidine (2.83 grams, 0.023 molt were added and the mixture was reflexed (125C
oil bath) for 9 hours (by MY analysis the reaction was 70~ complete after 3 hours). The dart red solution was passed through a silica gel plug SCHICK as eluant). The red oil remaining after rotary evaporation was passed through another silica plug eluded with ether:hexane (1:1). Rotary evaporation afforded the product as a yellow oil (2.48 grams, 61% crude yield). Crystallization from hexane produced a yellow solid (1.81 grams, more than 95% pure by NOR analysis, 43% yield). The filtrate also contained about 50% product (NOR analysis) (total yield 50%). the product was recrystallized again from hexane, melting point 47-49 C, Mart (Ph.D. Thesis, The Pennsylvania State University, 1982) reported a melting point of 47-49.5C for the product obtained by treating benzotriazole-l-carbonyl fluoride with isobutenyloxytrimethyl-Solon. The spectral properties listed below matched those given by Mart, (foe. cit.).

IT I 5.68 (us), 6;21 (w), 6.24 (w), 6.72 (5) 6.89 (s), 7.15 (us);
OH Of H NOR I 8.3-7.2 (m), 7.2-6.9 (m), 1.90 (s), 1.76 (s); ratio 4:1:3:3;
CDC13.
Jo rum/

I
When the reaction was performed in o-aichlorobenzene at 170C for 1 hour (no nun By present), the product yield (NOR analysis) was 30~ and much starting material and decomposition products also were present. When shellers-butylo~ycarbonylbenzotriazole was hefted at 170C under vacuum (160 mm) for 2 hours, the product was foxed in 10%
yield (NOR analysis) and the remainder of the mixture consisted almost exclusively of starting material.
Example 21 - Preparation of N(E,Z-Propenyloxycarbonyl- _ reloan a) N-(,~-ChloropropYloxycarbonyl?morpholine.

A solution of morpholine (Aldrich, dried over KOCH
and distilled) (16.1 grams, 0.18 molt in ether ~25 cc) was added (15 minutes) to a stirred! cooled (0C) solution of l-chloropropyl chloroform ate (13.0 grams, 0.083 molt in ether (25 cc). The mixture was stirred or 1 hour at room temperature, the salts filtered off, the filtrate concentrated, and the product distilled; boiling point 95-97C at 0.9 mm, 14.4 grams (84~ yield).

IRE : 5.81 (Ye); CC14.
H NOR I 6.37 (t, Jo 3.9-3.2 (broad), 2.02 (pentet, Jo 1.02 (t, Jo ratio 1:8:2:3; CDC13.

MS (me) 209.0636 (P137Cl], 6%, Cafe. 209.0633), 207.0662 (P[35Cl~, I Cafe. 207.0662), 130.0503 (P-CHClEt, 27%, Cafe, 130.0504), 114.0562 (P-OCHClEt, 81~, Cafe. 114.0555), 41 lo ' ` ' . ' . .

.

~2~5~2~ .

b) Conversion of No Chloropropyloxycar~onyl)-morpholine to N-(E,Z-Propenylo~y~ by A stirred mixture of l-chloropropylo~carbuny~
morpholine ~11.9 grams, 0.057 mow), Callahan t8.6 grams, 0.071 mow), n-tetrabutylammonium bromide, (0.9~ grams, owe mow), and tetrachloroethylene (25 cc) was heated a 125C in an oil bath for 24 hours try NOR analysis, the reaction was cay 70%
complete after 5 hours). After the standard extraction workup, ether and other volatile were distilled off and the product was isolated by vacuum distillation, boiling point 86-90C
at 0.5 mm, 8.2 grams (84% yield). The spectral properties given below match those reported by Olofson and Cuomo, Tetrahedron Let., 21, 819, (1980). Swiss on the spectral analyses and Olofson an Cuomo's data for the pure isomers, the ESSAY ratio for the new product is 1:1 8.

IT (I : 5.81 us 5.95 (w); Cal I NOR 7.2-6.8 (m), 5.19 (d of q, J=1.5,7, E-isomer), 4.73 (d of q, ~=7,7, 2-isomer), 3~9-3.2 (broad), 1.8-1.5 (m); ratio 1:0.36:~.6~:8:3; CC14.
When the dehydrochlorination was performed in bromobenzene, (oil bath at 170C, without the tetrabutyl-ammonium bromide) for 90 minutes the estimated yield of product (NOR) was 55% (ESSAY 1:2.0)s about 25~ of the starting material remained, and the remainder was accounted for by decomposition products.

.

.

_37_ I to Example I No in~lox~carbony~ N-methyl-I
a) Preparation own' ~ChloroethoxYcarbonyl-N-methylcyclo-hexylamine.
A solution of N-methylcyclohexylamine ~22.1 g, 0.2 molt in ether (10 cc) was added (20 mint to a stirred, cooled (0C) session of -chloroethyl chloro~ormate (ACE-Cl) (28.3 g, 0.2 molt in ether ~25 cc). The mixture was stirred for another hour at room temperature and then the solid was filtered off. Evaporation ox the filtrate was followed by vacuum distillation; 19.9 g I yield) of boiling point 101-103C at 0.5 mm.
IT I 5.82 (us); CC14-I NOR I 6.55 (q,JG6), 4.2-3.5 em), 2.80 is), 2.2-0.9 It with d at 1.80); ratio 1:1:3:13; CC14.
MS (m/e): 221.0995 (P[37Cl], 5%, Cafe. 221.0997), 219.1024 (P~35Cl], 16%, Cafe. 219.1026~, 156.1028 (P-CHClCH3, 93~, Cafe. 156.1024), 114 (73%), 70 (68%), 63 I 55 (74~)~
42 (100%).

b) Dehydrohalogenation to N-YOC-N-Methylcyclohexylamine.
A stirred solution of N-ACE-N-methylcyclohexylamine (5.49 g, 0.025 molt prepared in En aye, 2,4,6-collidine (4.97 g, 0.041 mow), and bromobenzene (12 cc) was heated toil bath at 170~C) for 1.5 hours (in an earlier analytical scale reaction, product was formed in 90~ yield and 10 decomposition products were present after 2 hours, NO
analysis). After the standard extraction workup, the product was isolated by vacuum distillation; by 81-85C
at 0.2 Marc Schnur,.Ph.D. thesis, the Pennsylvania State University (reported 119C at 14 mm). the product (4.09 g) was contaminated by cay 12~ starting material corrected absolute yield 78~, NOR annuluses -38- ~r~3 I 5.84 us 6.06 (m); Cal OH Nl~lR 7.19 Ed Of d, J=14,6), ~.65 (d Of d, J=14,1), 4.32 (d Of d, J=6,1), I. ~3.6 em), 20 81 I 2.1-0.8 (m);
ratio 1:1:1:1:3:10; CC14.

In another experiment, a stirred solution of Nissan methylcyclohexylamine ~10.4 g, 0.047 molt, -pinion ~8.1 g, 0.06 molt by 165-167C), and o-dichlorobenzene (25 cc) was heated (oil bath at 185~C) for 6 hours. Fractional vacuum distillation yielded 3.44 g of N-VOC-N-methylcyclohexylamine ~40~ yield;
NOR pure) of by 90-92C at 0.6 mm. The residue remaining in the distillation pot was identified (NOR) as N-methylcyclo-hexylamine hydrochloride (cay. 58% recovered).
In a test of pinion as both a solvent and acid scavenger, a solution of N-ACE-N-methylcyclohexylamine in -pinion, Katie 1:4.6 equip was heated at 170C for 1.5 hours. By NOR analysis (1,1,2,2-tetrachloroethane as quantitative internal standard), the mixture was identified as 64~ remaining starting material and 34% VOC-product.

Example 23 - Preparation of NUN- methyl O-Vinyl Carbamate tVOC^Diethylamine) a) Synthesis of NUN- methyl O- ~-Chloroethyl ~arbamate.
Triethylamine ~17.6 g, 0.17 Mullen 25 cc dichloroethane was added slowly to a stirred, cooled (0C) solution of ACE-Cl (30.3 g, 0.21 mow), in dichloroethane (75 cc).
The solution was reflexed for one hour after which the solvent was removed and the product isolated by vacuum distillation; 29.8 g, I yield, NOR pure of boiling point 83-89C at 11 mm.
IT I 5.81 (us); neat.

- ~L2~5~2~
-39- . .
I NOR I 6.58 (q, Jo 3.30 I Jo 1.80 (d, Jo 1.13 (t, J I ratio 1:4:3:6; CC14.

MS (m/e): 181.0688 (Pi clue], I Cafe. 181.0683), 179.0712 (P~35Cl], 21%, Cafe. 179.0713), 166.0436 (PI37Cl]-Me, 13~ Cafe. owe 164.0471 (Pl35Cl]-Me~ 41%, Cafe. owe 116. 0709 (P-CHClCH3, 30%, Cafe. 116.07~
102-0551 (P-C3~6Cl, 39%, Cafe. 102.0555), 100.0764 (P-OCHClCH3, 96%, Cafe. 100.0763), 72.0816 eighteen, 50%, Cafe. 72.0813), 65 (32g), 63 (100%), 58 ~82%).

b) N,N-Diethyl O- ~-Bromoethyl Carbamate.
. This broom analog of the above ~-chloroethyl carbamate had a toiling point of 63-66C at 0.7 mm and the spectral data listed below.

IT 5.78 (us); CC14, I NOR I 6.69 I Jo 3.24 (q,J=7), 1.97 Ed, Jo 1.12 it, Jo ratio 1:4:3:6; CC14.

MS lye 225.0227 (P181Br], 3%, Cafe. 225.0188), 223.0214 ~P179Br], 3%, Cafe. 223.0208), 166 lll%1, 164 (11~), 144 ~18%), 109 (40%), 107 ~39%), 101 ~19~), 100 (100%), 72, (86.~,.

.

.
,' .

--Jo--I) Dehyd~cohaloclena~ on 1235121 1. Conversion of N,N-Dicthyl Ox romoeth 1 aromatic Y
to ~OC-Diethylamine.
' on oil bath containing flask with a stirred solution ..
of CH3CHBrOC(=O)NEt2 (9.6 g, 0.043 mow), 2,4,6 colliding (6.6 g, 0.055 mow), tetrabutylammonium bromide (0.73 9, 0.002 mow), and tetrachloroethylene (18 cc, by 121C) was heated at 125C for lo hours (by NOR analysis, the reaction was actually finished after about 1 hour). After-the standard extraction workup and distillation removal of volatile, the product, YOC-NEt2 was isolated by distillation at reduced pressure; 5.6 g (92% yield, NOR pure) of by 97-98C at 62 mm. The spectral properties of the product match those reported by Shunner; ARC Shunner, Ph.D. Thesis, The Pennsylvania State University (1973). Shunner reported a boiling point Of 63C at 13 mm.
H NOR (I 7.20 (d of d, J=7,14), 4.65 Ed of d, J=14,1), 4.31 (d of d, J-7,1), 3.29 I Jo 1.12 (t, Jo ratio 4:6; CC14.

In another experiment, a solution of the same bromoethyl carbamate (12.7 g, 0.057 mow), 2,4,6-collidine t8.5 g, 0.070 mow), tetra-n-hexylammonium chlorite (1.25 g, 0.003 mow), and trichloroeth~lene (23 cc) was heated at 95C
for 5 hours reaction 90% complete after 2 hours). The product distillation fraction (NOR pure) contained 3.81 g (47% yield) of by 91-93C at 52 mm.
In an experiment performed in 1,2-dichloroethane at 95C and using colliding and Burn By as promoters, the estimated yield (NOR) of Vacant was 26~ after 2.5 hours.

.
., ' ' '' ' '' ' ,' .
... .....

, . . . . .
" . ' . , , , ; ' '- ', .

~23~
2. Conversion of N,N-Diethyl 0- -Chloroethyl Carbamate to VOC-Diethylamine~
.

The reaction of CH3C~ClOC(-O)NEt2 was slower than from the -broom compound as is evident from the following experiment. When Assent was substituted fox the broom analoc~ue in the first experiment of this series, only 15~ Vacant was foxed after 2 hours at 125C in tetrachloroethylene and 85% of the starting Assent remained (NOR analysis). With loner reaction times, however, the product yield increase!.

.

.
.
.

Example 24. Preparation of N,N-Dimethyl O-vinyl Carbamate IVY Dime thy lam no ) .
a) Preparation of ACE-Dimethylamine. The substance was prepared by N-deme~hylation of trimethylamine with ACE~Cl in dichloroethanei boiling point 82 - OKAY at 17 mm.

IT 5.81 us CC14.
OH NOR I 6.57 (q, J = 6), 2.93 us), 1.~0 Ed, = 6);
ratio 1:6:3; CC14.
MS (m/e): 153.0379 (P~37Cl], I Cafe. 153.0370), 151.0399 ~P~35Cl], 11%, Cafe. 151.0400~, 89 ~17%), 88 (20%), 72.0447 (P-OCHClCH3, 100%, Cafe. 72.0449), 65 (12%), 63 (38~).
.
b) Conversion of ACE-Dimethylamine to VOC-Dimethylami~e.

A solution of ACE-aimethylamine (7.84 g, 0.052 mow), 2,4,6-collidine (7.54 g, 0.062 mow), and 20 cc of N, N, N ', N ' - tetraethylsulfamide (Et2NSO2NEt2, dried over 4 A sieves) was heated at 155C for 30 minutes when NOR
analysis indicated that the reaction was 80~ complete.
The lower boiling point product was separated from the higher boiling solvent and salts by vacuum distillation. The fraction of boiling-point 66~71C at 30 mm contained VOC-NMe2 in 32% absolute yield contaminated by colliding and a little ACE-NMe2 and Et2NSO2NEt2. The impurities were removed by refluxing the product with 10 cc of Mesh for 30 minutes. Ether, 40 cc, was added an the organic layer washed with 1 N H2SO4, brine, the aqueous layers were backwashes with ether, dried (Nazi), rotoevaporated, and distilled to give pure VOC-NMe boiling point 57-61C at 26 mm;reported by Olofson, Sheehan and June SPY. 3,905~981; 43C at lo mm.

' , ' . ' ' ' . ' . ' '' .

'; , ' . ; ' ' , ' ' ` ' .

IT I 5.7B (us), 6.08 (1); CC14.
Al NOR (I 7.13 Ed of d, J = 14, 6), 4 65 (d of d, J = 14, I 4.30 (d of d, J - 6,1), 2~91 us);
ratio I I CC14.

In two NOR test experiments, the reaction was performed for 30 minutes at 170C and for 1 hour at 140C, respectively. In the first test, 57~ of the product was formed, but the remainder had decomposed In the second test, most of the starting material remained, but 26%
VOC-NMe2 was present and 9% decomposition was observed Example 25. Preparation of N-~inyloxycarbonyl-N-methyl-p-chloroaniline (N-VOC-N-methyl-p-chloroaniline1.

a) Preparation of N-ACE-N-Methyl-p-chloroaniline.

N-Methyl-p-chloroaniline (Aldrich, 94%), ll9.9 g, 0.13 molt and pardon (10.5 g, 0.13 molt were added to a cooled (OKAY), stirred solution of ASK (21.0 g, 0.15 molt in 25 cc of ether. The mixture was stirred at room temperature for 1 hour and then passed through a silica gel plug using ether as the eluant. The equate was evaporated in vacua and the remaining viscous yellow oil was kept under vacuum (1 mm) overnight to remove volatile. The product (32.3 g, 99%
yield) was pure by NOR analysis.
. .
IT I 5.78 (us), 6.25 ow), 6.6~ (m); Cal H NOR I 7.6-7.0 em with large spike at 7.23), 6.52 (q, = 6), 3.26 (s), 1.69 (a, J = 6);
ratio 4:1:3:3; CC14.
MS (me): 251.0104 (P~37Cl~, I Cafe. 251.0108), 249.0142 ~P~37C1 5~1~, 26~, Cafe. 249.013/), .' , ' . , .

_44_ ~2~5~2~

~47.0177 (P~35C12], 42~, Chic. 247.0166), 185 I 168 ~53%), 140 (69~), 63 ~100%).

b) Conversion of N-ACE-N-Methyl-p-chlolioaniline to N-VOC-N-Methyl-p-chloroaniline.
. .
A solution of N-~CE-N-methyl-p-chloroaniline (10.8 g, 0.044 mow), -pinion (9.4 g, 0.069 mow), and 27 cc of o-dichlorobenzene was heated toil bath at 185C) for 9 hours, (by NOR analysis, the elimination was 22% complete after 3 hours), then cooled, and vacuum distilled.
The distillation fraction of boiling point 75-95C at 0.4 mm contained N-VOC-N-Methyl-p-chloroaniline (absolute yield 40~) contaminated by much N-methyl-p-chloroaniline. The amine was removed by extraction with aqueous SUE. Analytically pure N-VOC-N-methyl-p-chloroaniline had a boiling point of ~3-95~C
at 0.3 mm.

IT I 5.76 (us), 6.05 (m), 6.67 (s); CC14.
1~1 NOR I): 7.5-7.0 (m with large spike at 7.20), 4.61 (d of d, J = 14,1), 4.36 (a of d, J = 6,1), 3.22 (s); ratio I 3; CC14.
MS (m/e): - 213.0372 (Pluckily], 9%, Cafe. ~13.0370), 211.0402 (P135ClJ, 30~, Cafe. 211.0400), 170 (31%), 168 (100%).

, : ' ' .
-45- ~z35~21 Example 26. Preparation of N-Vînyloxycarbon~l-14-AcetiylnorOxy-kidney ~N-~OC-14-acetyl-noroxycoaone) a) Preparation of N-ACE-14-Acetyln~roxycodone.

ACE-Cl (4.6 g, 32 Molly) in 5 cc of 1,2-dichloroethane was added to a cooled OKAY), stirred solution of 14-acetylOx~-condone ~2.0 g, 5.7 Molly), 1,8-bis(dimethylamino)naphthalene ~0.2 g, 1.0 Molly, and 15 cc of dichloroethane. The mixture was left at room temperature for 1 hour and then stirred over-night at 85C. An hydrous Hal was bubble into the cooler solution for 2 minutes and then the solvent and excess AcE-cl were removed in vacua. Charcoal and dichloromethane were ceded -and the mixture was passe through a silica plug (CH2C12:MeOH
95:5 as eluant). Vacuum evaporation of the solvent afforded NOR pure N-ACE-14-acetylnoroxycodone as a yellowish foam, 2.1 g, (83% yield).

IT I 5.65-5~9 (us with maxima at 5.72 and 5.83);

H NOR I 7.0-6.3 (m), S.8-5.5 (broad), 4.65 to 4.2-3.8 (m with methyl spike at 3.90), I 4-lr 3 (m with methyl s at 2.17 an methyl d at 1.84)i ratio 3 1 1 4 15; CDC13.

The product N-ACE-14-acetylnoroxycodone has- the structure hereinbelow:
' I

I`. ' - . , . ' .
.. . . .

b) Conversion of ~-ACE-14-Acetylnorox~codone to N-VOC~
Acetylnoroxycodone.

A solution of ~-~CE-14-acetylnoroxyco~one (2.1 g, 4.6 Molly) and 2,4,6-collidine (1~2 g, 10~1 Molly in 4.8 cc of bromobenzene was heated toil bottle at 170C) or 3 hours.
Methanol, S cc, was added to the cooled, red solution which then was reflexed for 30 minutes. The mixture was diluted with ethylene chloride, washed with 1 N H2SO~, and dried (Nazi). Charcoal was added and the slurry was passed through a silica gel plug using ethyl acetate as the eluant~
Vacuum evaporation afforded N-~OC-14-acetylnoroxycodone as a light yellow solid, 0.96 g (Sly yield). After recrystal-ligation from CH2C12-heptane and from methanol, the product has a melting point of 180-182C;reported by Olofson and Pope, U.S. 4,141,897: 181-182.5C, 182.5-183.5C. The IT and NOR spectral data for the product were in accord with the values reported by Olofson and Pope, foe cit.

( -47~

Example 27: Prcpaxation of N-Vlnyloyycarbon~l~q-~vacoline.
~N-~OC-Guvacoline) a PxeparatiGn of N-ACE-~uvacoline Freshly distilled ~2.08 g, 0.0139 mol)arecoline in 8 go of dichloroethane was dripped (10 minutes) into a stirred solution (-5C) of ACE-Cl (2.59 g, 0.0181 molt and 1,8-bis-~dimethyl-amino)-naphthalene (0~2S g, 0.00131 molt in 10 cc of dichloroethane. The solution first was warmed to room tempt erasure and then to reflex, during which time, a white solid precipitated. After refluxing 30 minutes, the now reddish-orange mixture was cooled, an hydrous Hal slowly was bubbled (2 minutes) through the mixture, which dissolved the solid, and the solution was passed through a silica gel plug I x 1"), ethylene chloride being used as the eluant. Rotary evaporation of the total eluant, (125 cc), afforded 3.20 g ~96~ yield) of crude N-ACE-guvacoline as a gold oil.

IT (mu): 5.81 (us), 6.10 (w); Cluck NOR (G ) 7.3-6.8 (m), 6.58 (q, Jo 4.4-3.9 I
3.8-3.2 (m with methyl spike at 3.73), 2.6-2.1 (m), 1.83 (d, Jo ratio --2:5:2:3; CDC13.

b) Conversion of N-ACE-Guvacoline to N~YOC-Guvacoline.
A solution of N-ACE-guvacoline (1.65 g, 6.66 mow), 2,4,6-collidine (1.09 g, 8.99 Molly), and 3.2 cc of bromobenzene was heated (oil bath at 170C) for 6.5 hours. Methanol was then added to the cooled solution which was subsequently relaxed for 30 minutes. Ether (20 cc) was added to the cooled solution which was extracted with 1 N H2SO4 I x 15 cc) and 10 cc of brine.
The aqueous layers were backwashes with ether (2 x 10 cc) an the combined organic phases were dried (Nazi), rotoe~aporated, and vacuum distilled to jive N-VOC-guvacoline, 0.842 g, (60~
yield of boiling point 120-122C at 0.6 mm; ROY. Olofson, ARC
Shunner, and AYE. Buses, U.S. Patent wrapper 132C
at 0.8 mm, 10~-106C at 0.2 mm).

I I
IT (mu): . 5.78 (us), 6~02 (w), 6.06 (m); CC14-H NOR t ) 7~4-6.85 (m including a of d, J = 14, 7, at 7.15), 4.71 (broad d, - 14), 4.39 (d of d, J -- 7, 17, 4. 3-4. o (m), 3.70 (s), 3.53 it, = I 2.6-2-1 (m);
ratio I 2:3:2.2; Cal N-VOC-Guvacoline is:

C~3 C- I) I I

Example 28. Preparation of N-Vinyloxycarbonyl-O-Acetylnortropine (N-VOC-O-Acetyl Nortropine) a) Preparation of N-ACE-O Acetylnortropine. ..

N-Demethylation of O-acetyltropine with suckle using the procedure already described for the similar aemethyl~
anion of arecoline afforded N-ACE-O-acetylnortropine as a yellow oil after vacuum evaporation of the chromatography equate.
IT I 5.81 (us); SCHICK.
NOR 6 . 6 0 I , J - 6 ), 5 2- 4 . 9 em), 4.5-4.1 Jo 2.5-1.6 em with methyl s at 2.03 and methyl d at 1.8D);
ratio 1:1:2:14; CDC13.
.

~Z3~
go b) Conversion of N-ACE-O-~cetylnortropine to N-VOC-O acutely-nortropine.

A solution of N-ACE-O-acetylnoxtropine t4.39 g, 0.016 molt and 2,4,6-collidine (2.36 g, 0.020 molt in 7.5 cc of bromobenzene was heated (oil bath at 170~C) or 3.5 hours.
In an earlier NOR scale experiment, 73~ of product had formed after 2 hours. The solution was cooled to cay 50C, diluted with 10 cc of methanol and stirred at this temperature for 45 minutes. The cooled solution was diluted with 40 cc of ether, washed with 1 N H2SO4 (3 x 25 cc) and brine ~15 cc). The aqueous layers were back extracted with ether (2 x 20 cc). The combined organic phases were dries (Noah), rotoevaporated, and vacuum distiller. N-VOC-O-~cetylnortropine was isolated as a colorless oil, 3.2~ g, (86~ yield, NOR pure) of boiling point 125-127C at 0.6 mm.

IT I 5.73 (us), 5.80 (us), 6.06 (m);
CC14.
I NOR (5) 7.17 (d of d, J = 14, 73, 5.2-4.~ em), 4.65 (d of a, J = 14, I 4.5-4~1 (m with d of d at 4.35), 2.4-1.5 to with methyl s at 1.98); ratio - 1:1:1:3:11; CC14.

The structure of N-VOC-O-Acetylnortropine is:
I, .

A I
I

Quick r ' .

-50- 12 3~2 En e 29. Preparation of E,Z-N-(3-Chloroprop~nyloxycarbon~
- N,N-diisopropylamine a) Preparation of N-(1,3-dichloropropyloxycarbonyl)-N,N-diisopropy~amine.

Diisopropylamine (9.4 g, 0.093 molt in 15 cc of - ¦
ether was added over 20 minutes to a cooled (15~C), stirred solution of l,3-dichloropropyl chloroform ate (boiling point 65-68C at 10 mm, 7.1 g, 0.037 molt in 40 cc of ether.
After stirring for 30 minutes a room temperature, the precipitated salts were filtered off; the solvent was evaporated and the product was isolated by vacuum distill lotion; boiling point 88-92C at 0.3 mm; 8.29 g t87% yield).
The product has the formula ClCH2CH2CHCl-OC(=~)-N(C~Me2)2.

IT I 5.79 (us); CC14.
H NriR I 6.64 it, J = 6), 4.3-3.4 (m, with t of J - 7 at 3.65), 2.46 (q with broad center peaks, J 6, 7), l.Z0 (d, J = 7); ratio 1:4:2:12i CCl4.
MS Moe): 259 (1%), 257.0751 tP~37C1 clue, 6%, Cafe. 257.0763), 255.0793 (P[35C12~, 8%, Cafe. 255.0793~, 244 I 242 (54%), 2~0 t87%), 144 ~15%), 130 (33~), 128 (45~), 43 ~100~).

b) Preparation of ~z-N-(3-chloropropenyloxycarbonyl) N,N-diisopropylamine .
A flask containing a solution of ClCH2C~32CHCl-OC~-0~-N(CHMe2)2 (8.0 g, 0.031 Mel), , .
.

, - S 1- ~L;235~
2,4,6-collidinc (4.6 y, 0.03~ mow), and terribly-a~monium bromide (0.76 g, 0.002 molt in 17 cc of tetrachloroethylene was reflexed in an oil heath maintained at SKYE. (By NOR analysis, the reaction was I complete after 3 hours). The reaction was continued for a total of 25 hours, the mixture diluted with 40 cc of ether an then extracted with 1 N ESSAY I x 30 cc) and urine ~20 cc).
The aqueous layers were back extracted with ether (2 x 20 cc3.
The combined organic layers were dried (Nazi), rotary evaporated, and vacuum distilled. The friction of boiling point 98-99C at 0.4 mm (4.67 g) contained the and Z
geometrical isomers of the product, 3-(chloropropenyloxy-carbonyl)-N,N-diisopropylamine in a yield of 56~ and an ESSAY ratio of 1:1.7. Based on NOR analysis, the product also was contaminated by 16 mow % of the starting dichloro-propel carbamate. By using longer reaction times, the product could be obtained free of this reactant. The spectral data for the pure E,Z-product are given below.
The compound has the formula ClCH2CH=CE~OC(=~N(CHMe2)2 IR(Jl): 5.81 (s), 5.99 (w); CC14.

OH NOR 7.42 (d, E-isomer, J 12), 7.20 (a, Z-isomer, J - 6),

5.7-4.7 (m), 4.3-3.4 em), 1.33-1.18 (overlapping a of - J - 6 at 1.2i and of J = 6 at 1.23); ratio 0.37:0.63 1:4:12; CC14.

MS (m/e): 221 (P~37Cl~ ), 219.1031 (Pt35Cl~, 3%, Cafe. 219.1026), 128 (61%), 86 (81%), 43 (100%).
This experiment demonstrates that the elimination of the chlorine in the l-position is surprisingly possible while the Chlorine Tom in rho 3-position is jot Autocad.

.

- ( -52- ~35~

Example 30. Preparation of CH-0-C(=O)-NH-n-Butyl (E,Z-Geometric Isomer Mixture) . . . .

a) Preparation of Cl1C]-O-C(=O)-NII-n-Butyl.

n-Butylamine (13.5 g, 0.18 molt in 10 I of ether was added over a 30 minute period to a stirrer, cooled (0C) solution of (3-cyclohexenyl)-chloromethyl chloroform ate (made by the general process described in European application 40153, boiling point 81-83~C at 1 mm) (16.6 g, 0.080 molt in 25 cc of ether. The mixture was stirred at room temperature for one hour, an hydrous Hal was bubbled through the mixture for 2 minutes, thy salts filtered off and charcoal was added to the filtrate which was then evaporated at reduced pressure. The residue was passed through a silica gel plug I x 2") using 1:1 dichloromethane-ethyl acetate as theeluant. Vacuum evaporation afforded 16.8 g (86~ yield) of the product whose structure is pictured in the title as an orange oil. The product could not be vacuum distilled without decomposition initiated by the Hal elimination process described below.

IT I 5.70 (YE); CC14.
H NOR I): 6.5-6.1 (m), 5.9-5.3 to), 3.15 (broad I, J = 6), 2.9-0.6 (m);
ratio 1:3:2:14; CC14.
MS Moe): 247.1143 (P~37Cl], I Cafe. 247.1153), 245.1181 (P~35Cl~, 3%, Cafe. 245~lls2)~
128 ~24%), 118 (100%).

. . .

A
b) Preparation of SCHICK (JO) -NH-n-Butyl (E,Z-Isomer Mixture) _ A flask containing a sample of the product chloroalkyl carbamate from Example aye ~5.0 g, 0.02 molt was stirred neat at 125C under a vacuum of 50 mm (no reflex condenser for four hours. The remaining liquid was chromatographed on a 1" x 8"
silica gel column using dichloromethane as the eluant. Vacuum evaporation of the equate afforded 0.92 g (21% yield, NOR pure, tic: single spot of Of 0.48 on silica developed with SCHICK) of the product (pair of geometrical isomers) whose structure is pictured in the title as a yellow oil.

IT I 2.90 (m, NH stretch), 5.79 (us, COO
stretch), 5.8-5.95 (m to w adsorptions, C=C stretches); SCHICK.
I NOR I 7.1 6.6 (broad so, 5.8-5.4 (broad s), 5.4-4.8 (broad s), 3.5-0.6 (m); ratio 1:2:1:13; CDC13.
MS (m/e): 209.1423 (P, 5%, Cafe. 209.1416), 128 (44%~, 110 (100%), 86 t73%~.
The Chemical Abstracts Service name given for the structure pictured in the title of Example 30b (and therefore of the product of the process described in Example 30b) it Carbamic acid, bottle-, 3-cyclohexen-1-ylidenemethyl ester.

-54~ I

Example 31. Preparation of E,Z-N-~3-Methyl-l-butenyloxycarbollyl)-N-(4-chlorobutyl)-N-ethylamine a) Preparation of N-(l-Chloro-3-methylbutyloxycarbonyl)-N-(4-chlorobutyl)-N-ethylamine.

A solution of N-ethylpyrrolidine ~7.1 g, 0.071 molt in 15 cc ox 1,2-dichloroethane was added over 15 minutes to a stirred, cooled (0C) solution of l-chloro-3-methylb~tyl sheller-format (made from isovaleraldehyde by the general process described in European application 40153, boiling point 74-76C
at 30 mm) (11.1 g, 0.06 molt in 25 cc of dichloroethane also containing 1,8-bis-(dimethylamino)-naphthalene (0.94 g, 0.004 mow). The mixture was relaxed for 30 minutes, then cooled, and an hydrous Hal was bubbled slowly through the solution for 2 minutes. Rotoevaporation of the solvent afforded a residue from which the product was isolated and purified by chromatography through a silica gel column (6" x 1") using ethyl acetate as the eluant. Vacuum evaporation of the equate gave a yellow oil, 16.4 g (96~ viola) identified as the product, (CH3)2CHCH2-CHCl-OC(-O)-N(CH2CH3)-CH2~H2C~2C~2Cl; boiling point of 119-122C at 0.4 mm.
IT I 5.82 (us); SCHICK.
H NOR I 6.47 (t, J - 6), 3.?-2.9 my 2.1-1.3 em), 1.20-0.82 (overlapping t of J
7 at 1.05 and d of J = 6 at 0.87);
ratio 1: 6:7:9; CDC13.
MS (m/e): 287.1052 (P[37C12], 0.2%, Cafe.
287.1047), 285.1106 (P[37C135Cl], 1%, Cafe. 285.1077), 283.1119 (P~35C12~, 2%, Cafe. 283.1106), 206 (51~), 102 ~51%), 69 (100~).

-55_ I 5~2~
b) Proration of EON (3-Methyl-~-butenyloxycar-bonyl)-N (4=chlorobutyl)- -ethyl amine.

A mixture of N-(l-chloro-3-methylbutyloxycarbonyl)-N-(4-chlorobutyl)-N-ethylamine (6.32 go 0.022 mow), 2,4,6-collidine (3.32 g, 0.027 mow), and tetrabutylammonium bromide (0.55 g, 0.002 molt in 10 cc of tetrachloroethylene was reflexed for I hours. (By NOR analysis, thyroxine was 43~ complete after one hour.) The cooled mixture then was poured onto a 1" x 6" silica gel chromatography column and eluded with ethyl acetate. Vacuum evaporation of the equate afforded the purified product as a yellow oil; 5~20 g ~94%
yield). Vacuum distillation of the product (boiling point of 111-114C at 0.4 mm) removed the color but did not otherwise change the purity. The ratio of is to trays isomers in the product, (CH3)2CHCH=CH-OC(=O)-N(CH2CH3)-CH2CH2CH2CH2Cl, was determined by NOR analysis (ZOO - 4:3) and was the same both before and after the distillation step.

IT I 5.81 (us), 5.95 (m); CC14.
H NOR I 7.2-6.7 (m), 5.25 (d of d, - 12, 7, E-isomer), 4.60 (d of d, J = 9,

6, Z-isomer), 3.6-3.0 em), 2.7-1.3 (m), 1 . 30-0 . 97 (overlapping t of J
= 7 at 1.15 and d of J - 7 at 1.00);
ratio 1:0.43:0.57:6:5:9; CDC13.
MS (m/e): 249.1337 (P~37Cl], 2%, Cafe. 249.1310), - 247.1338 (P[35Cl~, 5%, Cafe. 247.1339), 164 (9%), 162 ~29%), 93 (32%), 91 (100%).
This experiment demonstrates that elimination of Hal from an N-(l-chloroalkoxycarbonyl)-amine to give the derived N-(l-alkenyloxycarbonyl)-amine is surprisingly possible while another chlorine atom attached to another chloroalkyl substituent (here a 4-chlorobutyl group) on the same nitrogen is not attacked.

', .

.
, ( -56- 12~5~

Example 32. Preparation of NrN'-di-(3-Methylbutenyloxycarbonyl)-N,N~-dimethyl~ 3-~ro~anediamine .. ..

a) Propriety on of_N,N'-di-(l-Chloro-3-~eth~lbutyloxy-carbon~l)-N,N'-dimethyl-]:,3-propanedi~mine.

Reaction of N,N,N',N'-tetramethylpropanediamine (6.86 g, 0.053 molt with 1-chloro-3-methylbutyl chloroform ate (17.7 g, 0.096 Mel) in dichloroethane (total of 40 cc) in the presence of 1,8-bis(dimethylamino)-naphthalene (1.2 g, 0.006 molt as described in Example aye followed by workup of the reaction mixture and the chromatographic purification of the product also as described in Example aye afforded, after vacuum evaporation of the equate, 15.6 g (82% yield, NOR pure) of the product, (cH3)2cHcH2-cHcl-oc(=o)-N(cH3)-(cH2)3-(CH3)N-C(=o)))o-cHcl-cH2cH(cH3) as a yellow oil.

IT I 5-82 (us); SCHICK.
H NOR I 6.47 (broad t, J = 6), 3.29 broad t, J =

7), 2.92 (s), 2.2-1.5 (m), 0.93 (d, J =
6); ratio 2:4:6:8:12; CDC13.
MS (m/e): 400.1744 (P[37C135C1], I Calm.
40p.1709), 398.1762 (Pt35C12], 1%, Alec " 398.1739), 277 I 154 (14~, 128 (100%).
.

b) Preparation of N,N'-di-(3-Methylbutenyloxycarbonyl~?-N,N'-dimethyl-1,3-pxopanediamine.
.
A solution of N,N'-di-(i-chloro-3-methylbutyloxycarbonyl)--N,N'-dimethyl-1,-3-propanediamine (6.19 g, 0.016 mow), 2,4,6-collidine (4.4 g, 0.036 mow), and'tetrabutylammonium bromide (0.65 g, 0.002 molt in 13 cc of tetrachloroethylene was reflexed for 12 hours. (A smaller scale reaction was 44~ complete after one hour; NOR analysis.) The mixture was cooled, poured onto a silica get column I x 1"), and chromatographed with ethyl acetate as the eluant. 'Vacuum evaporation of the equate afforded a tan oil, 4.70 g (93% yield, NOR pure), identified as the product, (SHEA ) 2CHCH=CH-OC two) -N Shea SHEA ) 3- ITCH ) N-C (JO) okay ( SHEA 1 2 Based on NOR analysis, the geometries at the two carbon to carbon . .
.

I ~23~1Z~ .

- double bonds were 43% trays and 57~ is. Thus, the calculated geometric isomer mixture is 18~ HE, 49~ I and 32~ ZZ assuming no long distance interactions. Based on the isomer ratio found in Example 31 b, such a long distance interaction would be extremely unlikely Slight product decomposition lNMR analysis) occurred on vacuum distillation; howling point of 163-171C at 0.4 mm.

IT I 5.81 (us), 5.96 (m); CC14.
lo NOR I 7.2-6.7 (m), 5.2~ (a of a, J = 12, 7, - geometry), 4.58 (d of d, J = 9, 6, Z-geometry), 3.32 (broad t, J = I
2.96 and 2.93 overlapping singlets for different N-Me conformations), 2.7-1.5 (m), 1.00 (d, J = 6); ratio 2:0..86:1.14:4:6:4:12; CDC13.
MS (m/e)- 326.2210 (P, I Cafe. 326.2206), 241 - . (35%), 184 (44%), 1 9 (100~). .
. . .
. , ' , , .

" .

.

-58- ~35~21 xample 33. Preparation of N,N'-Di-(3-Methylbutenyloxy carbonyl)-l,10-diaza-18-crown-6.

a) separation of N,N'-Di-(l-Chloro-3-methylbutyloxycarbo~yl)-lrlo-diaza-l8 crown-6 A solution of l-chloro-3-methylbutyl chloroform ate (1.58 g, 8.54 Molly) in dichloromethane (10 cc) was added to a cooled (0C), stirred solution of 1,10-diaza-18-erown-6 (Owe g, 3.75 Molly) and pardon (0.68 g, 8.60 Molly) in dichloromethane (10 go). The reaction mixture was warmed to room temperature, stirred for 1 hour, and poured onto a silica gel plug (eluded with ethyl acetate). Upon vacuum evaporation of the equate and drying the residue in vacua overnight, a clear oil remained; 1 78 g (85% yield, OH NOR pure).
IT I 5.82 (us); SCHICK.
H NOR I 6.50 (broad t, J = 6), 3.60 (broad s), 2.2-1.6 (m), 0.95 (broad d, J = 6);
ratio 2:24:6:12; CD513.
MS (me): 562 tP~37C12], 0.2%), 560.2402 ~P~37C135Cl], 0.8~, gala. 560.2444), 558.2452 (Pluck], 1.2%, Cafe.
558.2475), 351 (19~), 289 (11%), 158 I 114 (100%).

b) Preparation of N,N'-Di-(3-Methylbutenyloxy-carbonyl)-l,10-diaza-18-erown-6.

Lo A mixture of N,N'-di(1 sheller-3-Methylbutyloxycarbonyl)-l,10-diaza-18-crown-6 (0.64 g, 1.14 Molly), colliding (0.40 g, 3.30 Molly), and twitter-butylammonium bromide (0.055 g, 0.17 Molly) was reflexed in tetrachloroethylene (1.3 cc) for 8.5 hours. After pouring onto a silica gel plug and elusion with ethyl acetate, 0.40 g of a yellow oil remained after drying the residue in vacua at 80C
overnight (71% yield, lo NOR pure with an ESSAY ratio of 0.68:1).
IT I 5.81 (us), 5.98 (m); CC14.
H NOR I 7.2-6.8 (m), 5.26 (d of d, J = 12, 7, E-geometry), 4.63 (d of d, J = 9, 6, Z-geometry), 3.60 (broad s), 2~8-2.0 (m), 1.02 (d, J = 6); ratio 2:0.81:1.19:24:2:12; CDC13.
MS (m/e): 486.2907 (P, I Cafe. 486.2941), 401 (48%), 357 (95%), 114 (100~).
The structure of the product in b) is:

I / SHEA SHEA OUCH 2 2 2 \
(CH3)2CHCH=CH~C-N \ / N-C-O-CH=CHCH(CH3)2 In a similar manner, 1,10-diaza-18-crown-6 is reacted with c~-chloroethyl chloroform ate (ACE-Cl) to give the inter-mediate N~N~-di-occhloroethyl compound which is dihedral-jointed similarly to Example 21b to give N,N'-di-(vinyloxy-carbonyl)-l,10-diaza-18-crown-6.

-60- 123~21 xample 34. Preparation of N-(Isobutenyloxycarbonyl)-N'-Methylpiperazine.
a) Preparation of N-(CC-Chloroisohutyloxy-carbonyl)-N'-Methylpiperazine.
Cc-Chloroisobutyl chloroform ate (9.51 g, 0.056 molt in 15 cc of dichloroethane was added (20 minutes) to a cooled (-5C), stirred solution of N,N'-dimethylpiperazine (11.7 g, 0.102 molt in 25 cc of dichloroethane. The reaction mixture was stirred at room temperature (1 hour) and thenrefluxed (30 minutes. After removal of the solvent, the product was purified by passage through a silica gel plug (ethyl acetate as eluant). upon evaporation of the equate, a yellow oil remained (later solidified on standing); 11.2 g (85% yield, OH NOR pure).
IT I 3.56 (w), 5.78 (us); CC14.
H NOR (or): 6.31 (d, J = 5), 3.51 (t, J = 5), 2.6-1.8 (m with t of J 5 at 2.36 and methyl s at 2.28), 1.05 (d, J = 6);
ratio 1:4:8:6; CDC13.
MS (m/e): 236.1113 (P~37Cl], 6%, Cafe. 236.1106), 234.1140 (Pickle], 20%, Cafe.
234.1135), 127 (73%), 70 (100%).

b) Preparation of N-(Isobutenyloxycarbonyl)-N'-methylpiperazine.
A mixture of No ~-Chloroisobutyloxycarbonyl)-N'-methylpiperazine l10.6 g, 0.0452 molt and tetrabutyl-ammonium bromide (0.90 g, 0.003 molt was heated neat for 3 hours at 125C and 1 mm. The mixture reflexed for cay 15 minutes and then solidified. Water (15 ml) and 10 cc of dichloromethane were added to the cooled reaction vessel. Excess solid K2CO3 then was added slowly to the stirred mixture (to phi he organic phase was separated and washed with 10% K2CO3 solution (50 cc). The combined aqueous extracts were washed with dichloromethane (2 x 20 cc) and the dichloromethane layers were combined, dried (Nazi), rotoevaporated, and vacuum distilled;
5.67 g (63% yield, lo NOR pure) of by 94-99C at 0.7 mm.

IT (jut: 3.55 (w), 5.81 (us); CC14.
H NOR (I ): 6.9-6.6 (m), 3.53 (t, J = 5), 2.45-2.28 (overlapping t of J = 5 at 2.34 and methyl s at 2.28), 1.63 (broad so; ratio 1:4:7:6; CDC13.
Mime 198.1364 (P, 26%, Cafe. 198.1368), 127 (100%), 98 (9%), 70 (13%).
In another smaller scale reaction performed in the same manner, the product was purified by passing the residue (after aqueous K2CO3 workup and evaporation of solvent) through a silica gel plug (ethyl acetate as eluant). A yellow oil, with some white solid present, was isolated after rotoevaporation of the equate (85% crude yield). The solid was triturated with hexane and a white solid remained imp 149-151C). Analysis of spectral data showed the by-product to be N,N'-di-(isobutenyloxycarbonyl) piperazine.
IT (p): 5.85 (vs2; SCHICK.
H NOR I 6.78 (broad s), 3.53 (s), 1.63 (broad s); ratio 2:8:12; CDC13.
MS (m/e): 282.1567 (P, 18~, Cafe. 282.1580~, 211 (100%~, 139 (26%), 55 (65%).
In a similar manner, N,N'-di-methylpiperazine is reacted with C~-chloroethyl chloroform ate (ACE-Cl) to give the intermediate N- -chloroethoxycarbonyl Methyl piperazine, which is then dehydrohalogenated as in Example 21b to give N-(vinyloxycarbonyl)N'-methylpiperazine.

example 35. Preparatioll of N-3-[N'-(Iso~utellyloxycarbollyl)-N'-Metllylamino]propyltril~ethylammollium Chloride.
a) Preparation of (3-Dilnethyla]ninopropyl)tri-methyl.alnmonium Chloride.
(3-Dimethylamirlopropyl)trimethylammoniwll iodide was made as described by Seaman and sass field in J. Cry.
Chum., I 2337 (1977); my 171.5-172.5C (limp 173.5-174.5C) 3.76 g (13.8 Molly) : was dissolved in 95~ ethanol and passed through a column of ion exchange resin("Amberlite IRK. P., R~Me3 Of , 35 g, 150.5 Molly) with 95%
ethanol as the eluant. The equate was rotoevaporated and the product (3-dimethylaminopropyl)trimethylammonium chloride was dried in vacua at 80C; 2.48 g (99% yield) of a white powder imp 146-148C).

H NOR (I ): 3.9-3.4 (m with spike at 3.47), 2.6-1.7 (m with spike at 2.20);
ratio 11:10; CDC13.

b) Preparation of N-3-~N'-(oc-Cllloroisobutyloxy . carbonyl)-N'-methylamino]prOpyltrilnetllY
ammonium Chloride.
A solution of CC-c]lloroisobutyl chloroform ate (2.40 g, 14.0 Molly) in 10 cc of dichloroethane was added (10 minutes) to a cooled (0C), stirred mixture of the 3-dimethylaminopropyltr~nethylammoniwn chloride (2.48 g, 13.~ Noel) -63- ~3~2~

in 10 cc of dichloroethane. The reaction mixture was heated to 75C for 30 minutes, cooled, and filtered.
The filtrate was concentrated and a light brown oil no-mined ~3.94 g). Analysis (lo NOR) showed that the product mixture contained N-3-[N'-(~-chloroisobutyloxycarbonyl)-N'-methylamino]propyltrimethylammonium chloride and some isobutenyl carbamate (2:1, respectively). The combined yield of the two carbamates was 95~. The spectra for the pure chloroisobutyl carbamate are given below.
IT (Jut); 5.82 (ye); SCHICK.
H NOR (I ): 6.3-6.1 (m), 3.9-2.8 (m with Moe spike at 3.47 and N-Me spike at 3.02), 2.5-1.8 (m), 1.09 (broad d, J = 6); ratio 1:16:3:6; CDC13.
c) Preparation of N-3-~N'-(Isobutenyloxy-carbonyl)-N'-methylamino]propyltrimethyl-ammonium Chloride.
The mixture from b) above (3.81 g, 13.3 Molly was-refluxed in 20 cc of dichloroethane. A piece of pi paper held over the Cook drying tube indicated that Hal gas was evolving from the heated mixture. After 4.5 hours, the reaction mixture was cooled and littered.
The gum remaining after the filtrate was concentrated was identified as the e~pected-product (lo NOR pure, 3.42 g, 97% yield) of structure:
O OH

~CH3)2C=CH-O-C-N-CH2-CH2-CH2-N(CH3)3 C1 IT I 5 84 (us); SCHICK
H NOR I 6.65 (broad s), 4.2-2.8 (m with Moe spike 3.45 and N-Me spike at 3.01), 2.6-1.9 (m), 1.65 broad I ratio 1:16:2:6; CDC13.

-64- 1~3512~

MS (m/e) 214.1680 (P-MeCl, 1.2~, Cafe. 214.1681), 143 ~23%1, 84 I 58 (100~).
In another experiment, the chloroisobutyl carbamate intermediate was not isolated. After demethylation of the 3-dimethylaminopropyltrimethylammonium chloride (4.17 g, 23.1 Molly) with chloroisobutyl chloroform ate t5.50 g, 32.2 molt in dichloroethane, followed by filtration and concentration of the filtrate (as before), the residue was heated to 70C at cay 1 mm for 2 days. Analysis (lo NOR) of the product mixture (5.62 g) showed a ratio of 4.4:1 of isobutenyl to chloroisobutyl carbamates, respectively (75% corrected yield).
Similarly,(3-dimethylaminopropyl)irimethylam~oniummm chloride is reacted with ~-chloroethyl chloroform ate (ACE-Cl) to give the intermediate ~-chloroethyl compound which is then dodder-halogenated as in Example 21B to give N-3-(N'-(vinyloxy-carhDnyl)-N'-methylamino]propyltrimethyl ammonium chloride.
xample 36. Propriety _ of N,N'-Di-VOC-N!N'-di-(2-methyl-amin~ethyl) Carbonate.
a) Preparation of N,N'-Di-ACE-N,N'-di-(2-methylaminoethyl) Carbonate A solution of ACE-Cl (12.6 g, 0.088 molt in 15 cc of dichloroethane was added over 15 minutes to a cooled (0C) stirred solutioncf2-dimethylaminoethyl carbonate (prepared as described by Angler et at, in J. Med. Chum., 11, 720 (1968~), (8.65 g, 0.042 molt and Proton Sponge (0.35 g, 0.002 molt in dichloroeth2ne (25 cc). The reaction mixture was stirred at room temperature for 1 hour and then reflexed for 30 minutes. An hydrous Hal was bubbled into the cooled mixture for 2 minutes and the solvent and excess ACE-Cl were removed in vacua. A light yellow oil was obtained after thy: residue was passed through a silica -65- ~23~2~

gel plug (ethyl acetate as eluant) and the equate was vacuum evaporated; 9.70 g (59% yield, lo NOR pure).
IT I 5~70 (so, 5.78 (us); CC14.
H NOR (I lo 6.43 (q, J = 6), 4.19 (broad t, J = 5), 3.49 (broad t, J = 5), 2.95 (s), 1. 77 (d, J = 6); relic 2 : 4 4 : 6 : 6 ; CDC 1 3 .

b) Preparation of N,N'-Di-VOC-N,N'-di-(2-methylaminoethyl) Carbonate.
A mixture of N,N'-di-ACE-N,N'-di- (2-methylaminoethyl) carbonate (8.51 g, 0.022 molt and killed (5.91 g, 0.049 molt in 15 cc of o-dichlorobenzene was reflexed for 75 minutes.
The solvent and excess colliding were removed in vacua and the dark red residue was passed through a silica gel plug methyl acetate as eluantl. Evaporation of the equate followed by vacuum distillation of the remaining oil afforded a fraction of by cay 170-180~C at 0.6 mm (1.59 g, 23% yield) identified as the title divot product.
IT I 5.70 (s), 5.78 (YE), 6.06 (m); CC14 H NOR I 7,00 (d of d, j = 14, 6), 4.9-3.8 (m with t of j = 5 at 4.14), 3.4Ç
(broad t, j = 5), 2.95 (broad s);
ratio 2:8:4:6; CC14.
MS (m/e): 316 (P, 0.1%), 273.1081 (P-OCH=CH2, 6%, Cafe. 273~1087), 172 (4%), 128 (100%), 102 (60%).

~23S12~
--foe--xample 37. Preparation of N,N'-Di-(Isobutenyloxycarbonyl)-dibenzo-l, Dixie ,12_diaza_cyclopentadeca-5,1~-dine.

a) Preparation of N,N'-di-~-ch]oroisobutyloxycarbonyl)-dibenzo-1,4-dioxa-8,12-diaza cyclopentadeca-5,14-dine.
A solution of a-chloroisobutyl chloroform ate (0.68 g, 3.98 Molly) in 7 cc ox dichlorome~hane was added over 10 minutes to a cooled 10C), stirred solution of dibenzo-1,4-dioxa-8,12 diaza-cyclopentadeca-5,14-diene (from Fluke, 0.48 g, 1.54 Molly) and pardon (0.26 g, 3.29 Molly) in 7 cc of dichloromethane.
After stirring overnight at room temperature, the yellow reaction mixture was poured onto a silica gel plug and eluded with ethyl acetate. Toe Lotte was rotoevaporated and the residue was dried in vacua giving the product as a white powder; 0.84 g (94% yield) which liquefied at 54-58C.
IT I 5.85 (us), 6.29 (w), 7.07 us SCHICK.
OH NOR I 7.6-6.7 (m), 6.5-6.2 (m), 4.56 (s), 4.40 (s), 3.5-2.9 (m), 2.5-007 (m with d of J = 6 at 1.05); ratio

8:2:4:4:4:16; CDC13.

b) Preparation of N,N'-Di-(isobutenyloxycarbonYl)-dibenzo-lj4-dioxa 8,12-diaza-cycloperltadeca-Dunn.
A mixture Of the product from example aye (0.75 g, 1.29 Molly), tetrabutylammonium bromide (0.057 g, 0.18 Molly), and colliding (0.52 g, 4.29 Mullen 1.1 cc of tetrachloro-ethylene was reflexed for 4 hours. The solvent and excess colliding were removed under vacuum from the reaction mixture at 100C and the residue which remained was diluted with dichloromethane and passed through a silica gel plug using ethyl acetate as the elite. Rotoevaporation of the equate followed by drying in vacua afforded the title product as a light yellow gum; 0.64 g, 98% yield.
IT I 5.88 (us), 6.92 (s); SCHICK
OH NOR I 7.5-6.5 (m), 4.51 (s), 4.32 (s), 3.4-2.9 (m), 2.5-1.4 em with broad s at 1.58); ratio 10:4:4:4:14; CDC13.
The final product from Example 37b has the structure drawn below:

Me C~C R No I OCH=C Me ox In a similar manner, dibenzo-1,4-dioxa-8,12-diaza-cyclopentadeca-5,14-diene was reacted with -chloroethyl chloroform ate (ACE-Cl) to give the intermediate NUN'-dip -chloroethyl compound which was dodder-halogenated as in Example 21b to give di-vinyloxycarbonyl dibenzo-1,4-dioxa-8,12-diaza-cy~lopentadeca-5,14-diene.

Claims (28)

THE EMBODIMENTS OF THE INVENTION IN WHICH AN EXCLUSIVE PROPERTY
OR PRIVILEGE IS CLAIMED ARE DEFINED AS FOLLOWS;

1. A process for the preparation of vinyl carbamates of formula I

(I) in which R1 and R2 are the same or different and are:
1) - hydrogen;
2) - alkyl of 1 to 6 carbon atoms which is unsubstituted or substituted by halogen atoms;
3) - or R1 and R2 together with the carbon atom to which they are attached form a saturated or un-saturated, 6-carbon atom ring;
R3 and R4 are the same or different and are:
a) - hydrogen;
b) - a C1 - C4 alkyl which is unsubstituted or sub-stituted by halogen or cyclohexyl;
c) - one of R3 or R4 is - (CH2)3N+(CH3)3C1-d) - a radical of formula Claim 1 cont'd (2) wherein z = a chain with 2 to 6 carbon atoms, Y = C1 - C2 alkyl, and R1 and R2 are as defined hereinabove, or Z is -(CH2)20COO(cH2)2-.
e) - phenyl which is unsubstituted or substituted by chlorine:
f) R3 and R4 form together with the nitrogen atom to which they are attached a 5 or 6 member heterocylic ring which is a piperidine, piperazine, benzotriazole, morpholine or guvacoline ring;
g) - R3 and R4 together with the N atom to which they are attached form a lower N'-alkyl piperazine;
h) - R3 and R4 together with the N atom to which they are attached form the noroxycodone or nortropine radical; or i) - R3 and R4 form with the nitrogen atom to which they are attached a 1,10-diaza, 18-crown-6 ring;
or j) - when R3 and R4 together with the N atom to which they are attached form the piperazine or the 1,10-diaza, 18-crown-6 ring, both nitrogen atoms of the ring have attached said group of formula which consists of heating an n-halogenocarbamate of formula II:
1. Claim 1 cont'd (3) ( II ) in which R1, R2, R3 and R4 have the same meaning as defined hereinabove and X is chlorine or bromine, and when in said compound of formula I, R3 and R4 are a radical which contains a vinyl carbamate group, the latter is present in said compound of formula II in the form of a saturated carbamate containing a hydrogen atom in the 3 position and X in the .alpha. position, at a temperature between 80°C and 200°C for a period of time between several minutes up to several hours whereby a halohydric acid is formed and isolating said carbamate of formula (I) from the reaction mixture.
2. 2. The process according to claim 1 which is carried out in the presence of a catalyst, which is an easily ionizable salt, the anion of which is non-nucleophilic or weakly nucleophilic.
3. 3. The process according to claim 2 wherein the cation of said salt is a member selected from the group consisting of a) a metallic cation, b) a metallic cation complexed with a crown ether, c) a metallic cation complexed with a cryptand d) an unsubstituted onium cation and e) an onium cation substituted by at least one organic radical of 1 to 7 carbon atoms.
4. 4. The process according to claim 3 wherein the cation is an alkali metal or alkaline earth metal cation.
5. 5. The process according to claim 3 wherein said onium cation is an ammonium, phosphonium, arsonium or sulfonium cation.
6. 6. The process according to claim 3 wherein the onium cation is tetra-n-butylammonium cation.
7. 7. The process according to claim 2 wherein the anion is a member selected from the group consisting of halides, C10?, and N0?.
8. 8. The process according to claim 7 wherein the halide is a chloride or bromide.
9. 9. The process according to claim 2 wherein the catalyst is added in an amount between 0.02 and 0.5 equivalents with respect to each carbamate group in said compound of formula II.
10. 10. The process according to claim 9 wherein the catalyst is in an amount between 0.05 and 0.15 equivalents with respect to said carbamate group.
11. 11. The process according to claim 1 wherein an acid acceptor is used which has little or no nucleophilic activity and which is a sufficiently strong base to form a complex with said halohydric acid.
12. 12. The process according to claim 11 wherein the acid acceptor is a member selected from the group consisting of 1) 2,4-dialkylpyridines and 2,4,6-trialkylpyridines, said alkyl group containing between one and n carbon atoms, n being an integer number sufficiently high so that the alkyl group includes a polymeric carbon chain, 2) N,N-dialkylanilines, which are unsubstituted or substituted in the ring by at least one electrophilic group, 3) alkenes, 4) diisocyanates which are aliphatic diisocyanates of formula O=C=N-(CH2)x-N=C=O, wherein x is between 6 and 36, or aromatic diisocyanates, 5) alkali carbonates and alkaline earth carbonates.
13. 13. The process according to claim 12 wherein said electrophilic group in said dialkylanilines is a halogen atom, said diisocyanate is hexamethylene diisocyanate or toluene diisocyanate and said alkene is pinene or cyclo-dodecatriene.
14. 14. The process according to claim 1 wherein said halohydric acid is eliminated by physical means, said means being a) removal under vacuo:
    b) removal under vacuo using a system with a high surface area;
    c) passing an inert gas over or through the reaction mixture;
    d) molecular sieves.
15. 15. The process according to claims 1, 2 or 11 wherein the reaction is carried out in an aprotic solvent, which is not nucleophilic or only weakly nucleophilic.
16. 16. The process according to claim 1 wherein the solvent is a member selected from the group consisting of ethers, sulfones, N,N-dialkylsulfonamides, N,N,N',N'-tetraalkylsulfonylureas, aromatic hydrocarbons, aromatic hydrocarbons having a suitable boiling point and at least one electrophilic substituent, alkanes or alkenes having a suitable boiling point and the dehydrohalogenated carbamate final products of formula I.
17. 17. The process according to claim 16 wherein the solvent is chlorobenzene, bromobenzene, a dichlorobenzene, a trichlorobenzene, a tetrachlorobenzene, or tetrachloroethylene.
18. 18. The process according to claim 16 wherein said .alpha.-halogenocarbamate of formula II is reacted in the presence of a catalyst, which is an easily ionizable salt, the anion of which is weakly nucleophilic or not nucleophilic and an organic acceptor of said halohydric acid, said acceptor having little or no nucleophilic power, said acceptor being a sufficiently strong base capable of complexing said halohydric acid formed and in the presence of at least one solvent, which is an aromatic hydrocarbon, substituted by at least one electrophilic group, an alkane, an alkene or said dehydro-halogenated carbamate final products of formula I.
19. 19. A vinyl carbamate of formula (III) (III) wherein R'1 and R'2 are the same or different and are:
    1) hydrogen;
    2) a saturated C1-C6 aliphatic radical, unsubstituted or substituted with halogen atoms;
    R'3 and R'4 form together with the nitrogen atom to which they are attached a) a ring wherein Z
    is an hydrocarbon chain of 2 to 6 carbon atoms or a hydrocarbon chain additionally containing at least two oxygen atoms, each oxygen atom being separated from another oxygen atom by at least two carbon atoms;
    and R5 - is a group wherein R'1 and R'2 are as defined hereinabove or R5 is C1-C4 alkyl; or b) R'3 and R'4 form together with the nitrogen atom to which they are attached a ring which is condensed with two phenyl radicals, and R5 is as defined hereinabove.
20. 20. The compound according to claim 19 which is N,N'-di-(vinyloxycarbonyl) piperazine of formula
21. 21. The compound according to claim 19 which is N,N'-di-(3-Methylbutenyloxycarbonyl)-1,10-diaza-18-crown-6.
22. 22. The compound according to claim 19 which is N-(Isobutenyloxycarbonyl)-N'-Methylpiperazine.
23. 23. The compound according to claim 19 which is N,N'-di-(Isobutenyloxycarbonyl)-dibenzo-1,4-dioxa,8,12-diaza-cyclopentadeca-5,14-diene.
24. 24. The compound according to claim 19 which is di-vinyloxycarbonyl dibenzo-1,4-dioxa-8,12-diazacyclo-pentadeca-5,14-diene.
25. 25. The compound E,Z-n-(3-Chloropropenyloxycarbonyl) N,N-diisopropylamine.
26. 26. The compound CH-O-C(=O)-NH-n-Butyl in the form of the E,Z-geometric isomer mixture.
27. 27. The compound N-3-[N'-(Isobutenyloxycarbonyl)-N'-Methylamino] propyltrimethyl ammonium Chloride.
28. 28. The compound N-N'-di-vinyloxycarbonyl-N,N'-di-(2-methylaminoethyl) carbonate.