Single vessel synthesis of aminoacetonitriles

This invention relates to two processes for preparing aminoacetonitriles in one vessel under anhydrous conditions. Process I involves the steps of: (A) reacting trimethylsilyl cyanide and an aldehyde in a water miscible amide solvent to obtain a silyl blocked cyanohydrin solution; (B) adding a catalytic amount of water to the silyl blocked cyanohydrin solution from Step (A); and (C) passing ammonia through the solution to obtain an aminoacetonitrile. Process II involves the steps of: (A') reacting trimethylsilyl cyanide with an aldehyde in the absence of solvent to form a silyl blocked cyanohydrin; (B') adding a water miscible amide solvent to the silyl blocked cyanohydrin from Step (A') to obtain a solution; and (C') passing ammonia through the solution to obtain an aminoacetonitrile. Aminoacetonitriles are important intermediates in the preparation of amino acids, thiadiazoles, acylaminoacetonitriles, and imidazole derivatives.

FIELD OF THE INVENTION 
This invention relates to two processes for preparing aminoacetonitriles in 
one vessel under anhydrous conditions. Process I involves the steps of: 
(A) reacting trimethylsilyl cyanide and an aldehyde in a water miscible 
amide solvent to obtain a silyl blocked cyanohydrin solution; (B) adding a 
catalytic amount of water to the silyl blocked cyanohydrin solution from 
Step (A); and (C) passing ammonia through the solution to obtain an 
aminoacetonitrile. Process II involves the steps of: (A') reacting 
trimethylsilyl cyanide with an aldehyde in the absence of solvent to form 
a silyl blocked cyanohydrin; (B') adding a water miscible amide solvent to 
the silyl blocked cyanohydrin from Step (A') to obtain a solution; and 
(C') passing ammonia through the solution to obtain an aminoacetonitrile. 
Aminoacetonitriles are important intermediates in the preparation of amino 
acids, thiadiazoles, acylaminoacetonitriles, and imidazole derivatives. 
BACKGROUND OF THE INVENTION 
Aminoacetonitriles have been prepared by reacting aldehydes with alkali 
metal cyanides followed by isolation of the cyanohydrin and subsequent 
reaction with ammonia in a suitable solvent. Isolation of the cyanohydrin 
can be difficult due to the solubility of cyanohydrin in aqueous medium. 
Moreover, isolation of the cyanohydrin is inconvenient and increases the 
risk of exposure to hydrogen cyanide. 
Aminoacetonitriles have also been prepared without isolation of the 
cyanohydrin by the Strecker synthesis using an alkali metal cyanide and an 
ammonium salt under aqueous conditions. The Strecker synthesis, however, 
is not practical in cases where the aminoacetonitriles are subsequently 
used under nonaqueous conditions because it is difficult to isolate the 
aminoacetonitriles which are unstable and often water soluble. 
In addition, aminoacetonitriles have been prepared by reacting aldehydes 
with trimethylsilyl cyanide in the presence of a catalytic amount of zinc 
iodide to obtain silyl blocked cyanohydrins which have been reacted with 
ammonia using protic solvents such as methanol to obtain 
aminoacetonitriles. Mai and Patil in an article entitled, "Facile 
Synthesis of alpha-Aminonitriles" which appeared in TETRAHEDRON LETTERS, 
Vol. 25, No. 41, pp. 4583-4586, 1984, disclose the preparation of 
aminonitriles by reacting trimethylsilyloxynitriles with various amines in 
methanol. On page 4583 of the article, Mai and Patil state that the 
amination step requires alcohol as a solvent. Moreover, they explicitly 
state that the amination did not proceed in an aprotic medium. 
Mai and Patil in another article entitled, "A Fast N-Substituted 
alpha-Aminonitrile Synthesis" which appeared in SYNTHETIC COMMUNICATIONS, 
Vol. 15, No. 2, pp. 157-163, 1985, disclose the preparation of 
aminonitriles by reacting an aldehyde, an amine and trimethylsilyl cyanide 
at 100.degree. C. for one minute. On page 158 of the article, Mai and 
Patil explicitly state that the silyloxynitrile does not react with an 
amine in an aprotic solvent even at elevated temperatures. In contrast to 
the articles by Mai and Patil, the present invention uses a water miscible 
amide solvent which is an aprotic solvent. 
Mai and Patil also state in their article entitled, "A Fast N-Substituted 
alpha-Aminonitrile Synthesis" that the reaction is not applicable to the 
preparation of primary aminonitriles since gaseous ammonia does not react 
with the carbonyl compounds in the presence of aprotic solvents. In 
contrast, the present inventor has determined that gaseous ammonia reacts 
with silyl blocked cyanohydrin compounds in the presence of a water 
miscible amide solvent. Amide solvents are relatively involatile, thus, 
allowing passage of ammonia to occur over several hours without incurring 
significant solvent loss. Futhermore, clean conversion to the 
aminoacetonitriles occurs when amide solvents are used. The use of amide 
solvents allows the aminoacetonitriles to be converted to important 
intermediates such as thiadiazoles and acylamino derivatives. Other 
solvents are not as useful in these respects. For example, use of pyridine 
or acetonitrile as solvents in the amination step leads to the formation 
of by-products. 
The processes of the present invention for preparing aminoacetonitriles and 
thereafter thiadiazole derivatives are represented as follows. The numbers 
appearing under each compound will be referred to throughout this 
document. 
##STR1## 
SUMMARY OF THE INVENTION 
Accordingly, it is one object of the present invention to provide a process 
for preparing aminoacetonitriles. 
Accordingly, it is another object of the invention to provide a process for 
preparing aminoacetonitriles in one vessel. 
These and other objects are accomplished herein by a process, Process I, 
for preparing aminoacetonitriles in one vessel under anhydrous conditions, 
said process comprising: 
(A) reacting trimethylsilyl cyanide and an aldehyde in water miscible amide 
solvent to obtain a silyl blocked cyanohydrin solution; 
(B) adding a catalytic amount of water to the silyl blocked cyanohydrin 
solution from Step (A); and 
(C) passing ammonia through the solution to obtain an aminoacetonitrile. 
The present invention is also directed to a process, Process II, for 
preparing aminoacetonitriles in one vessel under anhydrous conditions, 
said process comprising: 
(A') reacting trimethylsilyl cyanide with an aldehyde the absence of 
solvent to form a silyl blocked cyanohydrin; 
(B') adding a water miscible amide solvent to the silyl blocked cyanohydrin 
from Step (A') to obtain a solution; and 
(C') passing ammonia through the solution to obtain an aminoacetonitrile. 
DESCRIPTION OF THE INVENTION 
Process I for preparing aminoacetonitriles in one vessel under anhydrous 
conditions involves three steps. In the first step, Step (A), 
trimethylsilyl cyanide and an aldehyde are reacted in a water miscible 
amide solvent to obtain a silyl blocked cyanohydrin solution. The aldehyde 
has the general formula RCHO and is characterized by an unsaturated 
carbonyl group (C.dbd.O). The R group is selected from hydrogen, 
unsubstituted or substituted straight chain or branched C.sub.1 -C.sub.20 
alkyl, unsubstituted or substituted C.sub.3 -C.sub.8 cycloalkyl, C.sub.3 
-C.sub.8 alkenyl, C.sub.3 -C.sub.8 alkynyl, and C.sub.6 -C.sub.14 aryl. 
The unsubstituted and substituted C.sub.3 -C.sub.8 cycloalkyl groups refer 
to cycloaliphatic hydrocarbon groups which contain 3 to 8 carbons in the 
ring, preferably 5 or 6 carbons, and these cycloalkyl groups substituted 
with one or two of C.sub.1 -C.sub.4 alkyl, C.sub.1 -C.sub.4 alkoxy, 
hydroxy or C.sub.1 -C.sub.4 alkanoyloxy. 
The C.sub.3 -C.sub.8 alkenyl and C.sub.3 -C.sub.8 alkynyl groups represent 
straight or branched chain hydrocarbon radicals containing 3 to 8 carbons 
in the chain and which contain a carbon-carbon double bond or a 
carbon-carbon triple bond, respectively. 
The term "aryl" is used to include carbocyclic aryl groups containing up to 
fourteen carbons, e.g., phenyl and naphthyl, and those substituted with 
one or two groups selected from C.sub.1 -C.sub.4 -alkyl, C.sub.1 -C.sub.4 
alkoxy, C.sub.1 -C.sub.4 -alkoxycarbonyl, C.sub.1 -C.sub.4 -alkanoyloxy, 
C.sub.1 -C.sub.4 -alkanoylamino, halogen, cyano, C.sub.1 -C.sub.4 
-alkylsulfonyl, C.sub.1 -C.sub.4 -alkylene-(OH).sub.n, O--C.sub.1 -C.sub.4 
-alkylene-(OH).sub.n, --S--C.sub.1 -C.sub.4 -alkylene-(OH)hd n, --SO.sub.2 
--C.sub.1 -C.sub.4 -alkylene-(OH).sub.n, --CO.sub.2 --C.sub.1 -C.sub.4 
-alkylene-(OH).sub.n, SO.sub.2 N (R.sub.17)C.sub.1 -C.sub.4 
-alkylene-(OH).sub.n, --SO.sub.2 N (C.sub.1 -C.sub.4 -alkylene-OH).sub.2, 
--CON(R.sub.17)C.sub.1 -C.sub.4 -alkylene-(OH).sub.n, --CON(C.sub.1 
-C.sub.4 -alkylene-OH).sub.2, --N(SO.sub.2 C.sub.1 -C.sub.4 
-alkyl)-alkylene-(OH).sub.n or --N(SO.sub.2 phenyl)-C.sub.1 -C.sub.4 
-alkylene-(OH).sub.n ; wherein n is one or two. 
The term "aryl" is also used to include heterocyclic aryl groups such as a 
5 or 6-membered heterocyclic aromatic ring containing one oxygen atom, 
and/or one sulfur atom, and/or up to three nitrogen atoms, said 
heterocyclic aryl ring optionally fused to one or two phenyl rings or 
another 5 or 6-membered heteroaryl ring. Examples of such ring systems 
include thienyl, furyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, 
isothiazolyl, oxazolyl, isoxazolyl, triazolyl, thiadiazolyl, oxadiazolyl, 
tetrazolyl, thiatriazolyl, oxatriazolyl, pyridyl, pyrimidyl, pyrazinyl, 
pyridazinyl, thiazinyl, oxazinyl, triazinyl, thiadiazinyl, oxadiazinyl, 
dithiazinyl, dioxazinyl, oxathiazinyl, tetrazinyl, thiatriazinyl, 
oxatriazinyl, dithiadiazinyl, imidazolinyl, dihydropyrimidyl, 
tetrahydropyrimidyl, tetrazolo-[1,5-b]pyridazinyl and purinyl, 
benzoxazolyl, benzothiazolyl, benzimidazolyl, indolyl, and the like and 
those rings substituted with one or more substituents listed above in the 
definition of the term "aryl". 
In addition, the term "aryl" includes arylene groups. The term "arylene" is 
used to represent a divalent carbocylic aryl hydrocarbon moiety containing 
up to fourteen carbons, e.g., o-, m- and p-phenylene, and those 
substituted with one or two groups selected from C.sub.1 -C.sub.4 -alkyl, 
C.sub.1 -C.sub.4 -alkoxy or halogen. Examples of suitable aldehydes for 
use in the process of this invention are: p-anisaldehyde, 
thiophene-2-carboxaldehyde, furan-2-carboxaldehyde, benzaldehyde, 
crotonaldehyde, trimethylacetaldehyde, acetaldehyde, 4-methylbenzaldehyde, 
4-N,N-dimethylaminobenzaldehyde, 3-pyridinecarboxaldehyde, valeraldehyde, 
and 2-chlorobenzaldehyde. It is important to note that the use of 
3-nitrobenzaldehyde as the aldehyde in the processes of the present 
invention does not result in the desired aminoacetonitrile. 
In the second step, Step (B), a catalytic amount water is added to the 
silyl blocked cyanohydrin solution from Step (A). In the third step, Step 
(C), ammonia is passed through the solution to obtain an 
aminoacetonitrile. A catalytic amount of water must be added to the silyl 
blocked cyanohydrin before gaseous ammonia is applied otherwise no 
reaction occurs. Catalytic amount is a term which is understood by those 
skilled in the art. Preferably, 0.5 milligrams to 10 milligrams of water 
per gram of water miscible amide solvent, is added. There is no advantage 
to using more than a catalytic amount of water since Process I and Process 
II are conducted under anhydrous conditions and removal of water is 
difficult. 
Process II for preparing aminoacetonitriles in one vessel under anhydrous 
conditions involves three steps. In the first step, Step (A'), 
trimethylsilyl cyanide is reacted with an aldehyde in the absence of 
solvent to form a silyl blocked cyanohydrin. In the second step, Step 
(B'), a water miscible amide solvent is added to the silyl blocked 
cyanohydrin from Step (A') to obtain a solution. In the third step, Step 
(C'), ammonia is passed through the solution to obtain an 
aminoacetonitrile. Unlike in Process I, no addition of water is required 
in Process II to facilitate the reaction between the silyl blocked 
cyanohydrin and ammonia. 
Suitable water miscible amide solvents for use in the processes of the 
present invention are: N,N-dimethylformamide, N,N-diethylformamide, 
N,N-dimethylacetamide, N,N-diethylacetamide, N,N-dimethylpropionamide, 
N,N-diethylpropionamide and formamide. The water miscible amide solvent 
may also include a combination of such solvents. The use of pyridine or 
acetonitrile as solvents in the amination step leads to the formation of 
by-products. 
Steps (A), (A'), (B), (B'), (C) and (C') in the processes of the present 
invention are conducted at a temperature from 20.degree. C. to 50.degree. 
C. A preferred temperature range is 30.degree. C. to 40.degree. C. 
Although higher temperatures may be employed, there is no advantage to 
conducting these reactions at higher temperatures. Moreover, at 
temperatures above 50.degree. C., the aminolysis reaction requires the use 
of pressurized equipment. 
The aminoacetonitriles are important intermediates in the preparation of 
amino acids, thiadiazoles, acylaminoacetonitriles, and imidazole 
derivatives. It is important to note, however, that aminoacetonitriles 
containing primary and secondary alkyl groups are not useful when the 
desired product is a thiadiazole. For example, where the aminoacetonitrile 
contains an n-butyl group, reaction with sulfur monochloride results in a 
complex mixture which does not contain any thiadiazole. Sulfur 
monochloride may be reacted with the aminoacetonitriles to obtain 
3-chloro-4-substituted-1,2,5-thiadiazoles which are useful as 
intermediates in the synthesis of M1 selective muscarinic agonists, 
analgesics, antiglaucoma drugs and for treating Alzheimer's disease. 
Alternatively, the aminoacetonitriles may be reacted with heterocyclic 
acid chlorides to obtain carboxamide derivatives which are useful as 
intermediates for agrochemical fungicides and microbicides. 
Examples of agrochemical carboxamide intermediates derived from 
aminoacetonitriles include: 
##STR2## 
The process of the present invention will be further illustrated by a 
consideration of the following examples, which are intended to be 
exemplary of the invention. All parts and percentages in the examples are 
on a weight basis unless otherwise stated.

EXAMPLE 1 
Preparation of 2-trimethylsilyloxy-2(3-pyridinyl)acetonitrile (3a, 
R=3-pyridyl) 
##STR3## 
Trimethylsilyl cyanide, 25 grams, (0.2525 moles) was added in one portion 
to 150 grams (159 ml) N,N-dimethylformamide in a 500 ml three necked flask 
equipped with a nitrogen inlet, overhead stirrer and thermometer. No 
exotherm or endotherm occurred on mixing of the cyanide and 
N,N-dimethylformamide. 3-Pyridinecarboxaldehyde, 24.61 grams, (0.23 moles) 
was added dropwise to the stirred mixture over 40 minutes. The temperature 
rose gradually from 26.degree. C. to 42.degree. C. 
No catalyst was used in the reaction. Mixing of the reactants in the 
absence of solvent is very exothermic but does not appear to result in 
decomposition up to 100.degree. C., of either the starting materials or 
product. The temperature of the yellow solution was allowed to fall to 
26.degree. C. over 1 hour and the mixture analyzed by NMR spectroscopy. 
The NMR spectrum was consistent with the desired product (CH at delta=5.4) 
and showed that no aldehyde starting material was present. Thus, the yield 
of the product was quantitative. 
EXAMPLE 2 
Preparation of 2-Amino-2-(3-pyridyl)acetonitrile (4a, R=3-pyridyl) 
Ammonia was passed through the solution of 
2-trimethylsilyloxy-2-(3-pyridinyl)acetonitrile (0.23 moles) prepared in 
Example 1, in N,N-dimethylformamide for 1 hour at room temperature, until 
the mixture became saturated. During this time, 5 grams (0.29 moles) of 
ammonia was absorbed and the temperature rose to 29.degree. C., and the 
mixture became slightly more yellow. CDCl.sub.3 was added to the reaction 
mixture in order to obtain NMR spectra of the N,N-dimethylformamide 
solutions. An NMR spectrum indicated that no reaction had taken place. 
The temperature was increased to 33.degree. C. and maintained for one hour. 
During this time, the rate of passage of ammonia was reduced so that 
excess gas was just able to escape through a nitrogen bubbler. No reaction 
took place. A catalytic amount of water, 150 mg, (0.008 mole) was added. 
The mixture changed color from yellow to reddish orange. Passage of 
ammonia was continued for one hour at 33.degree. C. and the solution again 
analyzed by NMR spectroscopy. The spectrum indicated that conversion to an 
intermediate and product had begun (new methylene signals at 5.3 and 4.7 
respectively). This suggested that the presence of water is necessary to 
catalyze the reaction. Any water in the N,N-dimethylformamide, would have 
been removed by initial reaction with trimethylsilyl cyanide. Subsequent 
passage of ammonia resulted in substantial reaction within 4 hours. The 
volatile by-product hexamethyldisiloxane was removed by the ammonia. 
Passage of ammonia was stopped and the mixture was stirred for 17 hours at 
a temperature of 30.degree. C. to 33.degree. C. The ratio of silyloxy 
starting material and cyanohydrin to aminonitrile product was 
approximately 5:1.5 indicating a 23% conversion. Ammonia was again passed 
through the solution and the temperature was maintained at 35.degree. to 
39.degree. C. for 7 hours. Passage of ammonia was stopped and the mixture 
was stirred at 35.degree. C. to 39.degree. C. for 21 hours, after which 
time the reaction was complete. 
The amount of conversion to product during the 7 hour period, based on the 
integrals for the methene signals due to starting material, intermediate 
and product, was found to be 23% (at t=0 hr), 38% (at t=2 hr) and 65% (at 
t=7 hr). A plot of this data suggested that had water been added at t=0 hr 
and ammonia gas passed throughout, the reaction would have been complete 
in approximately 11 hours. Excess ammonia was removed by application of 
water pump pressure for one hour. The solution was treated with S.sub.2 
Cl.sub.2. 
EXAMPLE 3 
Preparation of 3-(4-chloro-1,2,5-thiadiazol-3-yl) pyridine (5a, 
R=3-pyridyl) 
Sulfur monochloride, 62.1 grams, (0.46 mole, 38 ml) was added dropwise with 
stirring over 1.5 hours, to the 2-Amino-2-(3-pyridyl)acetonitrile solution 
prepared in Example 2 which had been cooled to -5.degree. C. (approx. 0.23 
mole) in N,N-dimethylformamide. The mixture was stirred at 0.degree. C. 
for one hour and then allowed to reach room temperature over 15 hours. The 
mixture was cooled to 0.degree. C. and ethyl acetate, 150 ml, (135 grams) 
was added followed by addition of 70 grams of water over 15 minutes. A 
mixture of sodium hydroxide, 32.9 grams (0.82 mole) and 44.5 grams of 
water was added over one hour, while temperature was maintained at 
5.degree. to 10.degree. C., to bring the pH of the mixture to 7. 
The mixture was stirred for 15 minutes and then filtered through 40 grams 
of supercell to remove sulfur and salts. The residue was washed with 100 
mt of ethyl acetate. A 20% sodium chloride solution, 200 grams, and 400 ml 
of toluene were added and the layers separated. It was necessary to add 
more solvents, because the solution was a dark orange brown making it 
impossible to see the liquid/liquid interface. The lower aqueous layer was 
discarded. The upper toluene/ethyl acetate layer was evaporated at 
45.degree. C. under reduced pressure to obtain 32 grams of crude product 
(70% overall yield from the aidehyde) as a brownish orange oil which 
solidified on standing overnight. 
The NMR spectrum (CDCl.sub.3) of the oil indicated that it contained 
approximately 87 weight percent of the desired product, the remainder 
being largely N,N-dimethylformamide. Heptanes, 180 ml, was added to 18 
grams of the crude product and the mixture stirred and heated to 
60.degree. C. After 5 minutes, the clear yellow supernatant was removed 
from a small amount of dark insoluble liquid residue. The heptanes 
solution was cooled to 10.degree. C. and the solid collected and dried to 
give 15.5 grams of 98% pure 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridine 
(60% yield) as a yellow solid. Elemental analysis determined: C,42.78; H, 
2.19; N, 20.85; S, 15.99. C.sub.7 H.sub.4 N.sub.3 S req. C, 42.54; H, 
2.04; N, 21.26; S, 16.22%. The aqueous phase was extracted for a second 
time with 400 ml of toluene and gave only one gram of product. Thus, this 
second extraction was unnecessary. 
One gram of the 3-(4-chloro-1,2,5-thiadiazol-3-yl)pyridinethiadiazole was 
dissolved in 5 grams of N,N-dimethylformamide and a solution of sodium 
chloride. 1.7 grams, and water, 6 grams, was added followed by 10 grams of 
toluene. After thorough mixing, the layers were allowed to separate and 
the bottom aqueous layer was removed. 11.5 grams of solution was recovered 
indicating that approximately 1.2 grams of N,N-dimethylformamide was 
extracted into the top toluene layer. The top layer was washed with 5 
grams of 20% sodium chloride solution. The bottom layer was removed and 
found to weigh 5.8 grams indicating that most of the N,N-dimethylformamide 
had been removed. The top toluene layer was dried with 500 mg of sodium 
sulfate and evaporated to give the product as a cream solid (1 gram). 
Clearly, toluene is a very effective solvent for extracting the product 
from N,N-dimethylformamide/sodium chloride/water mixtures. However, the 
toluene extract must be washed to ensure removal of N,N-dimethylformamide. 
EXAMPLES 4-6 
Trimethylsilyl blocked cyanohydrins (3b, R=3-nitrophenyl), (3c, R=n-butyl) 
and (3d, R=2-chlorophenyl) 
Trimethylsilyl cyanide (1), 4.95 grams, (0.05 mole) was added in one 
portion to 30 ml of N,N-dimethylformamide in a 100 ml three necked flask 
equipped with a nitrogen inlet, stirrer bar and thermometer. No exotherm 
or endotherm occurred on mixing of the cyanide and N,N-dimethylformamide. 
The aldehyde (2), 0.05 moles, was added dropwise to the stirred mixture 
over 5 minutes. After reaction was complete as evidenced by I.R. and NMR 
spectroscopy, the product was treated with ammonia. After 2 hours I.R. 
analysis (nitrile region) of the mixtures showed the absence of 
trimethylsilyl cyanide (2188 cm.sup.-1), indicating that reaction was 
complete. The NMR spectra (CDCl.sub.3) were consistent with formation of 
the desired products. No aldehyde starting material was present, which 
implies that the yield of the product was quantitative for these examples. 
______________________________________ 
ALDEHYDES USED TO PREE CYANOHYDRINS 
CHEMICAL NAME M.W. GRAMS 
______________________________________ 
3 NITROBENZALDEHYDE (2b)* 
151 7.55 
VALERALDEHYDE (2c) 86 4.3 
2-CHLOROBENZALDEHYDE (2d) 
140.5 7.0 
______________________________________ 
*Dissolved in N,Ndimethylformamide (5 ml) and added to trimethylsilyl 
cyanide in N,Ndimethylformamide (25 ml) 
EXAMPLES 7-14 
Preparation of Trimethylsilyl Blocked Cyanohydrins (3e, R=4-methoxyphenyl), 
(3f, R=2-thienyl), (3g, R=2-furanyl), (3h, R=phenyl), (3i, 
R=MeCH.dbd.CH--), (3j, R=t-Bu), (3k, R=4-methylphenyl) , (31, 
R=4-N,N-dimethylaminophenyl) 
Trimethylsilyl cyanide, 4.95 grams, (0.05 mole) was added to a 100 ml three 
neck flask equipped with a nitrogen inlet, stirrer bar and thermometer, 
followed by the 0.05 moles of the aldehyde as set forth in Table II. 
N,N,-dimethylaminobenzaldehyde (21), a solid, and trimethylsilyl cyanide 
were warmed to produce a solution. No reaction occurred. Zinc iodide, 0.1 
gram was added at which point all the mixtures became hot and required 
cooling in order to keep the temperature below 70.degree. C. The mixtures 
were then allowed to cool to room temperature and kept for two additional 
hours before analysis. Reaction was complete as evidenced by I.R. and NMR 
spectroscopy. Anisaldehyde required 0.25 grams of trimethylsilyl cyanide 
and heat at 100.degree. C. for 30 minutes to complete the reaction. 
I.R. analysis (0.025 mm solution cell) was used to monitor disappearance of 
the aldehyde carbonyl band. The NMR spectra 
(N,N-dimethylformamide/CDCl.sub.3,) were consistent with formation of the 
desired products. No aldehyde starting material was present, which implies 
that the yield of the product was quantitative for these examples. 
N,N-Dimethylformamide was added and the product was treated with ammonia. 
______________________________________ 
ALDEHYDES USED TO PREE 
BLOCKED CYANOHYDRINS(3) 
CHEMICAL NAME M.W. GRAMS 
______________________________________ 
p-ANISALDEHYDE (2e) 136 6.8 
THIOPHENE-2-CARBOXALDEHYDE (2f) 
112 5.6 
FURAN-2-CARBOXALDEHYDE (2g) 
96 4.8 
BENZALDEHYDE (2h) 86 5.3 
CROTONALDEHYDE (2i) 70 3.5 
TRIMETHYLACETALDEHYDE (2j) 
86 4.3 
4-METHYLBENZALDEHYDE (2k) 
120 6.0 
4-N,N-DIMETHYLAMINO- 149 7.45 
BENZALDEHYDE (21) 
______________________________________ 
Spectroscopic data for compounds (3a): R=3-pyridyl, (3b): R=3-nitrophenyl, 
(3c): R=n-butyl, (3d): R=2-chlorophenyl, (3e): R=4-methoxyphenyl, (3f): 
R=2-thienyl, (3g): R=2-furanyl, (3h): R=phenyl, (3i): R=4-MeCH.dbd.CH--, 
(3j): R=t-Bu, (3k): R=4-methylphenyl, (31) R=4-N,N-dimethylaminophenyl, 
was as follows: 
______________________________________ 
.sup.1 H NMR SPECTRAL DATA FOR SILYL 
BLOCKED CYANOHYDRINS 
COMPOUND CHEMICAL SHIFT (ppm)* 
______________________________________ 
3a 0.0(s, 9H), 5.4(s, H), 7.1(m, 1H), 7.6(m, 1H), 
8.4(m, 1H), 8.5(d, 1H) 
3b 0.0(s, 9H), 5.5(s, 1H), 7.3(t, 1H), 7.5(t, 1H), 
7.8(d, 1H), 8.0(s, 1H) 
3c -0.1(s, 9H), 0.6(t, 3H), 1.1(m, 4H), 1.4(m, 2H), 
4.1(t, 1H) 
3d -0.3(s, 9H), 5.3(s, 1H), 6.9(m, 3H), 7.2(m, 2H) 
3e 0.2(s, 9H), 3.8(s, 3H), 5.4(s, 1H), 6.9(d, 2H), 
7.4(d, 2H) 
3f 0.3(s, 9H), 5.7(s, 1H), 7.0(dd, 1H), 7.2(d, 1H), 
7.4(d, 1H) 
3g 0.2(s, 9H), 5.5(s, 1H) 6.4(t, 1H), 6.5(d, 1H), 
7.5(d, 1H) 
3h 0.2(s, 9H), 5.5(s, 1H), 7.4 to 7.5 (m, 5H) 
3i 0.2(s, 9H), 1.8(m, 1H), 5.6(m, 1H), 6.0(m, 1H) 
3j 0.3(s, 9H), 1.1(s, 9H), 4.0(s, 1H) 
3k 0.3(s, 9H), 2.4(s, 3H), 5.5(s, 1H), 7.2(d, 1H), 
7.4(d, 1H) 
0.3(s, 9H), 3.0(s, 6H), 5.4(s, 1H), 6.7(d, 2H), 
7.3(d, 2H) 
______________________________________ 
*Compounds 3a to 3d used 1:1 N,Ndimethylformamide/CDCl.sub.3 as the 
solvent and Compounds 3e to 3g used CDCl.sub.3 as the solvent. 
EXAMPLES 15-24 
Preparation of Aminoacetonitriles (4c, R=n-butyl), (4d, R=2-chlorophenyl), 
(4e, R=4-methoxyphenyl), (4f, R=2-thienyl), (4g, R=2-furanyl), (4h, 
R=phenyl), (3i, R=MeCH.dbd.CH--), (3j, R=t-Bu), (3k, R=4-methylphenyl), 
(31, R=4-N,N-dimethylaminophenyl). 
A catalytic amount of water, 0.1 grams, (0.0056 mole) was added to a 
solution of the silyl blocked cyanohydrin (assume 0.05 mole) in 30 ml of 
N,N-dimethylformamide. (It is necessary to add water in order to ensure 
subsequent reaction with ammonia.) Ammonia was passed through the solution 
for 24 to 48 hours at room temperature so that excess gas was just able to 
escape through a nitrogen bubbler. The mixture was analyzed by NMR 
spectroscopy to determine that the reaction was complete. CDCl.sub.3 was 
added to the reaction mixture in order to obtain NMR spectra of the 
N,N-dimethylformamide solutions. The spectra indicated that clean 
conversion to the product was complete in 24 to 48 hours, except for the 
nitro-substituted material (3b). Excess ammonia was removed by application 
of water pump pressure for 1 hour. The resulting solution of 
aminoacetonitrile was treated with sulfur monochloride or a carboxylic 
acid chloride. 
Spectroscopic data for compounds (4a): 3-pyridyl, (4b): 3-nitrophenyl, 
(4c): n-butyl, (4d): 2-chlorophenyl, (4e): 4-methoxyphenyl, (4f): 
2-thienyl, (4g): 2-furanyl, (4h): phenyl, (3i): MeCH.dbd.CH--, (3j): t-Bu, 
(3k): 4-methylphenyl, (31): 4-N,N-dimethylaminophenyl, were as follows: 
______________________________________ 
.sup.1 H N.M.R. SPECTRAL DATA 
FOR AMINOACETONITRILES 
COMPOUND CHEMICAL SHIFT (ppm)** 
______________________________________ 
4a 4.8(s, 1H), 7.1(m, 1H), 7.7(m, 1H), 8.4(m, 1H), 
8.6(d, 1H) 
4b Spectrum inconsistent with desired product 
4c 0.3(t, 3H), 0.8(m, 4H), 1.1(m, 2H), 1.4 (br.s, 
NH2/NH3), 3.1(t, 1H) 
4d 2.0(br.s, NH2/NH3), 4.7(s, 1H), 6.8(m, 3H), 
7.2(m, 2H) 
4e 2.1(br.s, NH2), 3.4(s, 3H), 4.6(s, 1H), 
6.8(d, 2H), 7.1(d, 2H) 
4f 2.1(br.s, NH2/NH3), 4.8(s, 1H), 6.6(dd, 1H), 
6.8(d, 1H), 7.0(d, 1H) 
4g 2.2(br.s, NH2/NH3), 4.7(s, 1H), 6.1(t, 1H), 
6.2(d, 1H), 7.2(d, 1H) 
4h 1.9(br.s, NH2/NH3), 4.5(s, 1H), 7.0(m, 3H), 
7.1(m, 2H) 
4i 1.5(m, 3H), 2.0(br.s, NH2/NH3), 
4.0(m, 1H), 5.3(m, 1H), 5.7(m, 1H) 
4j 0.6(s, 9H), 1.3(br.s, NH2/NH3), 3.0(s, 1H) 
4k 2.1(br.s. CH3/NH2/NH3), 4.7(s, 1H), 7.0(d, 2H), 
7.2(d, 2H) 
4l 1.9(br.s, NH2/NH3), 4.6(s), 6.4(d), 7.1(d) 
______________________________________ 
**Solvent 1:1 N,NdimethylformamideCDCl.sub.3 
EXAMPLES 25-29 
3-Chloro-4-substituted-1,2,5-thiadiazoles (5d, R=2-chlorophenyl), (5e, 
R=4-methoxyphenyl), (5f, R=2-thienyl), (5h, R=phenyl), (5j, R=t-Bu-). 
Sulfur monochloride, 20.25 grams, (0.15 mole, 12 ml) was added dropwise 
over 30 minutes with stirring, to previously cooled (-10.degree. C.) 
solutions of the aminonitriles (approx. 0.05 mole) in 30 ml of 
N,N-dimethylformamide so that the temperature was maintained at 
-10.degree. to 0.degree. C. The mixture was stirred at 0.degree. C. to 
5.degree. C. for 1 hour and then allowed to stir at room temperature for 
24 hours. Toluene (30 ml, 26 grams) was added followed by addition of 25 
grams of ice cold water. The mixture was stirred for a further 15 minutes 
and then filtered through 2 grams of supercell to remove sulfur. The 
residue was washed with 10 ml, 8.7 grams of toluene. The layers were 
separated and the lower aqueous layer was discarded. The upper toluene 
layer was washed with a 12.5% sodium chloride solution in water and the 
bottom aqueous layer discarded. The washing was repeated. The upper 
toluene layer was dried over 8 grams of sodium sulfate and the solvent 
evaporated at 40.degree. C. under reduced pressure (water pump) to obtain 
the crude product (5) as a brownish orange oil which was analyzed by NMR 
spectroscopy and gas chromatography. The .sup. 1 H and .sup.13 C NMR 
spectra (CDCl.sub.3) of the oils were consistent with the structure of the 
desired products. G.C. analysis indicated that the products were 77 to 98% 
pure. 
Spectroscopic data for compounds (5a) :- 3-pyridyl, (5d) :- 2-chlorophenyl, 
(5e) :- 4-methoxyphenyl, (5f) :- 2-thienyl, (5h) :- phenyl and (5j) :- R 
=t-Bu- were as follows: 
______________________________________ 
.sup.13 C NMR SPECTRAL DATA FOR 
3-CHLOROTHIADIAZOLES (5) 
COMPOUND CHEMICAL SHIFT (ppm)*** 
______________________________________ 
5a 123, 127, 136, 149, 144 (C.dbd.N), 151, 155(ClC.dbd.N) 
5d 127, 130, 130, 131, 131, 134, 146(C.dbd.N), 
157(ClC.dbd.N) 
5e 56(CH.sub.3 O), 114, 124, 130, 143(C.dbd.N), 
158(ClC.dbd.N), 161 
5f 129, 129, 130, 133, 142(C.dbd.N), 152(ClC.dbd.N) 
5h 128, 129, 130, 131, 144(C.dbd.N), 158(ClC.dbd.N) 
5j 28, 36, 143(C.dbd.N), 167(ClC.dbd.N) 
.sup.1 H NMR SPECTRAL DATA FOR 
3-CHLOROTHIADIAZOLES (5) 
COMPOUND CHEMICAL SHIFT (ppm)*** 
______________________________________ 
5a 7.5(q, 1H), 8.3(dt, 1H), 8.7(br.d, 1H), 
9.2(br.s, 1H) 
5d 7.3 to 7.5(m) 
5e 3.9(s, 3H), 7.0(d, 2H), 8.0(d, 2H) 
5f 7.2(dd, 3H), 7.5(dd, 1H), 8.0(dd, 1H) 
5h 7.5(m, 3H), 8.0(d, 2H) 
5j 1.5(s) 
YIELD AND PURITY (G.C) OF 
3-CHLOROTHIADIAZOLES (5) 
COM- 
POUND MOL. FORM. MW YIELD (%) 
PURITY(G.C.) 
______________________________________ 
5d C.sub.8 H.sub.4 Cl.sub.2 N.sub.2 S 
231 96 98 
5e C.sub.9 H.sub.7 ClN.sub.2 OS 
226.5 71 79 
5f C.sub.6 H.sub.3 ClN.sub.2 S.sub.2 
202.5 37 79 
5h C.sub.8 H.sub.5 ClN.sub.2 S 
196.5 76 9 
5j C.sub.6 H.sub.9 ClN.sub.2 S 
176.5 50 77 
______________________________________ 
***Solvent CDCl.sub.3 
EXAMPLE 30 
##STR4## 
Triethylamine, 10.1 grams, (0.1 mole) was added to a solution of 
amino-2-thienylacetonitrile (0.05 mole) in 15 ml of N,N-dimethylformamide. 
The mixture was cooled to 0.degree. C. and 8.9 grams of nicotinyl chloride 
hydrochloride (0.05 mole) was added. After stirring at 0.degree. C. for 1 
hour, the mixture was stirred at room temperature for an additional 24 
hours. Water, 100 ml, was added and the solid was collected. The solid was 
boiled with water and the supernatant was decanted. Cooling of this 
solution gave a yellow solid whose NMR spectrum was consistent with the 
desired product, m.p. 136.degree. to 137.degree. C. 
.sup.1 H NMR data (solvent d6-DMOS); ppm: 6.7(d, 1H, H.sup.a), 7.1(dd, 1H, 
H.sup.b), 7.3 (m, 1H, H.sup.c), 7.55(dd, 1H, H.sup.d), 7.65(dd, 1H, 
H.sup.3), 8.3(dt, 1H, H.sup.f), 8.8(dd, 1H, H.sup.g), 9.1(d, 1H, H.sup.h), 
10.1(d, 1H, H.sup.i). 
##STR5## 
Many variations will suggest themselves to those skilled in this art in 
light of the above detailed description. All such obvious modifications 
are within the full intended scope of the appended claims.