The preparation and use of aryl and vinyl nitriles are well known in the field of synthetic organic chemistry. The nitrile moiety may serve as a synthetic equivalent for a number of other substituents such as a primary amine or aldehyde. Alternatively, nitriles may be converted into ketones, carboxylic acids, esters or amides. Compounds bearing the nitrile moiety also serve as useful intermediates for the preparation of heterocyclic ring systems.

Aryl nitriles may be prepared by a number of methods well known in the art. One strategy is the transformation of a carboxylic acid, amide or ester into the corresponding nitrile when appropriate substrates are readily available and if no other sensitive functionality in the molecule precludes subjecting the substrate to the necessary reaction conditions. The electrophilic aromatic addition of chlorosulfonylisocyanate to an appropriate substrate may be employed for the preparation of aryl nitriles, but positional isomers are frequently possible and other functionality in the molecule many times complicates these reactions. The Sandmeyer reaction provides nitriles by diazotization of an appropriate aniline followed by displacement of the diazonium salt with cuprous cyanide. This methodology is limited by the requirement that the diazotization step be performed in strong acid, the potential for explosive decomposition of the intermediate diazonium salt, and disposal issues associated with stoichiometric or excess copper. Direct displacements of aryl halides by cuprous cyanide at high temperature are well known in the art but yields are compromised by chelation of the product by the waste copper salts (Ellis, G.P., et al . , Chem. Rev. , 87, 779 (1987)) and disposal and environmental issues associated with the use of copper.

The preparation of vinyl nitriles is typically accomplished by reaction of a vinyl organometallic reagent, such as the corresponding organolithium or organocuprate, with an electrophilic cyanide source such as cyanogen

chloride. These reactions must typically be performed at very low temperatures and the reaction conditions limit the diversity of functionality allowed in the substrate.

Palladium catalyzed cyanation reactions for the preparation of aryl and vinyl nitriles have been reported in the literature. Depending on the substrate, these reactions often proceed slowly and commonly do not go to completion in a reasonable period of time, even when performed at elevated temperatures. A variety of palladium catalysts and additional reagents, such as zinc cyanide, cyanotrimethylsilane, alumina, crown ethers, and excess copper(I) iodide, have been suggested to accelerate these reactions. Many of the reaction conditions which have been disclosed for palladium catalyzed cyanations are substrate specific, and a general method has not yet been reported.

This invention provides an improved process for the preparation of aryl and vinyl nitriles comprising reacting the corresponding aryl and vinyl halide or triflate substrates with a source of cyanide ion, a palladium catalyst, and a catalytic amount of a source of metal ion, selected from the group consisting of copper(I), copper(II), or zinc(II) ion, in a suitable reaction medium. The process of the invention provides aryl and vinyl nitriles in superior yields, at higher reaction rates and generates significantly less waste copper or zinc than comparable methods.

This invention is useful for the transformation generically represented by the following equation:

R-X ^ R-CN

where R represents a radical characterized by an arrangement of atoms comprising a first sp2-hybridized carbon atom double-bonded to a second sp^-hybridized atom which may be either carbon or nitrogen, said first sp2-hybridized carbon atom bearing a substituent, X, which is selected from iodo, bromo or trifluoromethanesulfonyloxy as illustrated by the formulae:

C N

II or II

^x ^ x

( i ) ( « ) .

The arrangement of atoms may be part of a chain or ring. The nature of the other groups attached to either the first sp2-hybridized carbon or second sp^-hybridized atom are not critical to the use of the process of the invention so long as the compound is stable under the conditions employed.

The process of the invention is performed by combining an aryl or vinyl halide or triflate substrate with a source of cyanide ion, a palladium catalyst, and a catalytic amount of a source of copper(I), copper(II), or zinc(II) ion in an appropriate reaction medium. Once the reaction is complete as measured by total consumption of the substrate, the resultant nitrile is isolated by standard extractions and filtrations. If desired, the nitrile product may be further purified by chromatography, crystallization or distillation as appropriate.

The order and manner of combining the reactants are not important and may be varied as a matter of convenience. The substrate, source of cyanide ion, palladium catalyst, and a catalytic amount of a source of copper(I), copper(II), or zinc(II) ion may first be combined and then the reaction medium added. Alternatively, the substrate may first be dissolved in an appropriate reaction medium and this solution added to a mixture of the source of cyanide ion, palladium catalyst, and catalytic amount of a source of copper(I), copper(II), or zinc(II) ion. Also, a solution of the substrate in an appropriate reaction medium may be added to a slurry of the source of cyanide ion, palladium catalyst and copper(I), copper(II), or zinc(II) catalyst in the same reaction medium. Furthermore, a first slurry containing part of the reactants in an appropriate reaction medium may be added to a second slurry of the remaining reactants in an

appropriate reaction medium as is desired or convenient. All of these methods are useful for the process of the present invention.

Reactions employing the process of the invention are preferably performed at the reflux temperature of the chosen reaction medium. The reactions may be performed at temperatures below reflux if convenient or desired. The skilled artisan will appreciate that reaction rates typically decrease as temperature is lowered. The overall reaction rate enhancement due to the process of the invention, however, renders lower temperature reactions synthetically useful in many cases.

As discussed previously, compounds useful as substrates for the present invention are aryl and vinyl compounds generically characterized by the arrangement of atoms comprising a first sp ² -hybridized carbon atom double-bonded to a second sp ² -hybridized atom which may be either carbon or nitrogen as illustrated by the formulae:

C N

II or II

^x ^ x

(i) (H) .

An sp ² -hybridized carbon atom is one that uses sp ² -hybridized orbitals to form bonds with the three atoms to which it is connected. Likewise, an sp ² -hybridized nitrogen atom is one that uses sp ² -hybridized orbitals to form bonds with the two atoms to which it is connected. These sp ² -hybridized orbitals arise from hybridization of one 2s and two 2p electrons (March, Advanced Organic Chemistry, Third Edition (1985), pages 6-9, John Wiley and Sons, New York, NY). The first sp ² -hybridized carbon atom bears a substitutent which is selected from iodo, bromo or trifluoromethanesulfonyloxy. It is this substituent which is displaced to give the corresponding aryl and vinyl nitrile products afforded by the process of the invention.

The skilled artisan will appreciate that several types of organic molecules contain the requisite sp -hybridized atoms in the configuration required to be useful as substrates for the process of the invention. The class of organic molecules known as alkenes, for example, is distinguished by the carbon-carbon double bond. This carbon- carbon double bond is constructed from two sp -hybridized carbon atoms bonded to each other (Morrison and Boyd, Organic Chemistry, Sixth Edition (1992), Section 8.2, pages 273-275, Prentice Hall, Englewood Cliffs, NJ) . Alkenes in which at least one of the sp ² -hybridized carbons bears a substituent X as defined supra, correspond to the arrangement of atoms of formula (i) and are therefore useful substrates for the preparation of vinyl nitriles by the process of the invention. The alkene double bond may be part of a chain or ring. When part of a chain, the double bond may be terminal or within the chain. When part of a ring, the double bond may be exocyclic or incorporated into the ring system. The chain or ring system of which the double bond is part may be further substituted so long as the requirements described supra are met.

Another class of compounds which correspond to the arrangement of atoms of formula (i) are those compounds which contain at least one benzene ring. Benzene rings are characterized by six sp ² -hybridized carbon atoms bonded together into a ring (Morrison and Boyd, ibid. , Section 14.8, pages 501-503). Compounds which incorporate at least one benzene ring into their structure, where at least one of the sp ² -hybridized carbons bears a substituent X as defined supra, correspond to the arrangement of atoms of formula (i) and are therefore useful substrates for the preparation of aryl nitriles by the process of the invention.

Compounds containing the pyridine ring system are illustrative of the arrangement of atoms of formula (ii) . The pyridine ring system is characterized by five sp ² - hybridized carbon atoms and one sp ² -hybridized nitrogen atom bonded together into a ring (Morrison and Boyd, ibid. ,

Section 30.6, pages 1066-1067) . Those pyridine ring compounds where an X substituent is attached to the carbon atom adjacent to the nitrogen atom satisfy the requirements of formula (ii) . The skilled artisan will also appreciate that pyridine ring compounds where an X substituent is attached to a carbon not adjacent to the nitrogen atom satisfy the requirements of formula (i) . As such, compounds which incorporate at least one pyridine ring into their structure, where at least one of the sp ² -hybridized carbons bears a substituent X as defined supra , are therefore useful substrates for the preparation of aryl nitriles by the process of the invention.

Aryl compounds which are useful substrates for the process of the invention include compounds containing an aromatic ring. These rings may be isolated or fused in the molecule and may be optionally substituted so long as the requirements described supra are satisfied. Examples of aromatic rings which may be incorporated into compounds useful as substrates for the process of the invention include benzene, naphthalene, pentalene, indene, azulene, heptalene, biphenylene, indacene, acenaphthylene, fluorene, phenalene, anthracene, fluoranthene, acephenanthrylene, aceanthrylene, triphenylene, biphenyl, pyrene, chrysene, naphthacene, pleiadene, picene, perylene, pentaphene, pentacene, tetraphenylene, hexaphene, hexacene, rubicene, coronene, trinaphthylene, heptaphene, heptacene, pyranthrene, ovalene, indan, tetralin, acenaphthene, cholanthrene, aceanthrene, acephenanthrene, violanthrene, isoviolanthrene, naphthoperylene, indenoindene, benzocyclooctene and the like.

Aryl compounds which are useful substrates for the process of the invention also include compounds containing a heterocyclic ring. These rings may be isolated or fused in the molecule and may be optionally substituted so long as the requirements described supra are satisfied. Examples of heterocyclic rings which may be incorporated into compounds useful as substrates for the process of the invention include furan, thiophene, pyrrole, isopyrroles, pyrazole, imidazole,

isoimidazole, triazoles, dithioles, oxathiole, isoxazole, oxazole, thiazole, isothiazole, oxadiazoles, oxatriazoles, dioxazoles, oxathiazole, oxathiole, pyrans, pyrones, dioxins, pyridine, pyridizine, pyrimidine, pyrazine, triazines, oxazines, isoxazines, oxathiazines, oxadiazines, azepine, benzazepines, oxepin, benzoxepins, thiepin, benzthiepins, diazepin, benzdiazepins, benzofuran, isobenzofuran, thionaphthene, isothionaphthene, indole, isoindole, indolenine, pyrindines, pyranopyrazoles, benzpyrazole, benzisoxazole, benzoxazole, anthranil, benzopyrans, benzopyrones, quinoline, isoquinoline, cinnoline, quinazoline, naphthyridine, pyridopyridines, benzoxazines, benzisoxazine, carbazole, xanthene, acridine, purine, and the like.

The skilled artisan will appreciate that if more than one iodo, bromo or trifluoromethanesulfonyloxy substituent is present on an aryl or vinylic position in the substrate, mixtures of mono- and polycyanation products are possible. The exact nature of the product mixture will be dependent upon the reaction conditions and the specific substrate employed.

The source of cyanide ion for the process of this invention is preferably sparingly soluble in the reaction medium. Cyanide ion sources which are completely soluble in the reaction medium, such as tetrabutylammonium cyanide, fail to provide the advantages of the process of the invention. An alkali metal cyanide, such as potassium or sodium cyanide, is especially preferred. The cyanide ion source may be present in from the stoichiometric amount to about 10 equivalents based on the amount of substrate. Preferably from one to two molar equivalents of the cyanide ion source will be present. It is most preferred that about 2 molar equivalents of the cyanide ion source be present. When a solid, it is preferred that the cyanide ion source be ground to a powder for the process of the present invention.

The palladium catalyst for the process of the present invention must be a palladium(O) catalyst such as

tris (dibenzylideneacetone)dipalladium(O) , tetrakis(tri¬ phenylphosphine)palladium(O) , and tetrakis (methyldiphenyl- phosphine)palladium(O) . Where the palladium(O) catalyst is complexed to ligands, at least one of the ligands may be bound to an insoluble solid support if desired. Preferably, the palladium catalyst is tetrakis(triphenyl¬ phosphine)palladium(0) . The palladium catalyst may be present in from about 2 to about 25 mole percent based on the amount of substrate. The amount of palladium catalyst ranging from about 5 to about 10 mole percent is preferred, and about 5 mole percent is most preferred for the process of the present invention. It is also preferred that the palladium(O) catalyst be freshly prepared prior to use. When the palladium(O) catalyst is tetrakis(triphenylphos¬ phine)palladium(0) , it is preferred that it be freshly prepared using triphenylphosphine which has been recrystallized from ethanol. The palladium^0) catalyst may alternatively be generated in si tu from an appropriate source of palladium (II). This alternative is a further embodiment of the present invention.

The metal catalyst for the process of the present invention must be a source of copper(I) ion, such as copper(I) cyanide, a copper(I) halide such as copper(I) iodide or bromide, or potassium dicyanocopper(I) ; a source of copper(II) ion, such as copper (II) acetate, acetylacetonate, bromide, carbonate, fluoride, hexafluoroacetylacetonate, methoxide, nitrate, perchlorate, sulfate, tetrafluoroborate, trifluoroacetate, trifluoroacetylacetonate, or trifluoromethanesulfonate; or a source of zinc(II) ion, such as zinc(II) cyanide or acetate, or a zinc(II) halide such as zinc(II) fluoride, chloride, bromide, or iodide. When the metal catalyst is copper, the copper catalyst is preferably a source of copper(I) ion. When the metal catalyst is zinc(II), it is preferred that it is zinc(II) iodide. It is especially preferred that the metal catalyst is copper(I) and it is most preferred that the copper catalyst is copper(I) iodide. The metal catalyst may be present in from about 4

mole percent to about 50 mole percent based on the amount of substrate. The amount of metal catalyst ranging from about 5 to about 25 mole percent is preferred, and about 5 to about 10 mole percent is most preferred for the process of the present invention.

Reaction media useful for the process of the invention must be capable of dissolving a sufficient amount of the substrate for the reaction to proceed. Organic solvents useful as reaction media for the process of this invention include ethers such as tetrahydrofuran, tetrahydropyran, dioxane, diethyl ether and diisopropyl ether, alkyl nitriles such as acetonitrile and propionitrile, and alkyl acetates such as methyl acetate and ethyl acetate. While all of these organic solvents are useful, certain solvents are preferred. Preferred organic solvents include the ethers, especially tetrahydrofuran, and the alkyl nitriles, especially acetonitrile and propionitrile. It is preferred that the reaction media used for the process of the reaction are anhydrous. While it is not necessary to rigorously exclude water for the process of the present invention, excess water will decrease the rate of the reaction. It is also preferred that the reaction medium be deoxygenated by bubbling nitrogen through it prior to use in the process of the invention. Failure to deoxygenate the reaction medium comprises the efficiency of the reaction.

The process may be carried out over a large range of concentrations, from about 0.05 molar to about 1 molar of the substrate, dependent upon the solubility of the particular substrate in the chosen reaction medium. The reaction may also be performed on slurries of the substrate so long as a sufficient amount of the substrate is soluble in the reaction medium for the reaction to proceed. Preferably the process is performed at a concentration from about 0.4 molar to about 1 molar. A concentration of about 0.4 molar to about 0.8 molar is most preferred.

The advantage of the process of the invention is achieved by the addition of a catalytic amount of a source of

copper(I), copper(II), or zinc(II) ion to a palladium(O) catalyzed cyanation reaction. This advantage is best demonstrated by comparing cyanation reactions with and without the addition of catalytic metal ion. Typical reaction conditions are described in the following paragraph.

The substrate, 2.0 equivalents of the source of cyanide ion, and 0.05 equivalents of the palladium(O) catalyst are combined in a flask. Parallel reactions are performed with and without 0.1 equivalents of the metal catalyst to demonstrate the advantage obtained by the process of the invention. After the reagents are combined, the reaction flask is placed under vacuum and then refilled with nitrogen. This evacuation/fill cycle is repeated twice, leaving the flask under nitrogen. Nitrogen is bubbled into the desired reaction medium for 5 minutes and then the reaction medium (5.0 mL reaction medium/gm of substrate) is added to the reaction flask. The reaction mixture is then heated to reflux under nitrogen and the reaction monitored by HPLC until complete.

Comparative reactions as described supra, using tetrakis(triphenylphosphine)palladium^0) as the palladium(O) catalyst and potassium cyanide as the cyanide ion source were performed on the following series of naphthalene derivatives

I II III

The results obtained from these reactions are summarized in

Table I.

TAI3LE I

W Cuj ADDED Cul ADDED

Reaction Time i Time 1

S bstrate Medi m (hr) Nitrile^ ⁽ ∑± Nitrilea

I THF 1 2 2 100

I CH3CN 8.0 12 0.25 100

II CH3CN 23.0 37 7.0 97

III CH3CN 22.8 41 0.63 100 ^a % product relative to remaining starting material

The data presented in Table I clearly demonstrate the advantage to be gained through the use of the method of the present invention. In all cases, rates of reaction were dramatically increased by addition of a catalytic amount of the copper(I) catalyst to the reaction mixtures. Addition¬ ally, in most cases conversions of starting material to product were also dramatically increased.

Comparative reactions as described supra, using tetra¬ hydrofuran as the solvent, tetrakis(triphenylphosphine) - palladium(O) as the palladium(O) catalyst and potassium cyanide as the cyanide ion source were performed on 1- iodonaphthalene (I), varying the metal catalyst. The results of these experiments are summarized in Table II.

TABLE II

CATALYST AMOUNT TIME (HR) % NITRILE none none 1 2

Cul 5 mole % 2 100

Cul 10 mole % 1 99

CuCN 10 mole % 3 100

CuOTf 10 mole % 4 94

Cu ⁽ OTf ⁾ 2 10 mole % 3 57

Cu ⁽ OTf)2 10 mole % 19 100

CuBr 10 mole % 3 100

CuBr2 10 mole % 6 100

Znl2 10 mole % 2.7 94

The scope of the present invention can be illustrated further by comparing the results of experiments varying the source of cyanide ion and solvent on the same substrate. (+) -l-Benzoyl-4-dipropylamino-l,2,2a,3,4,5-hexahydrobenz[cd] indole-6-carbonitrile (IV) is a key intermediate in the preparation of (-)-4-dipropylamino-l,3,4,5-tetrahydrobenz- [cd]indole-6-carboxamide (V).

The 6-carboxamide (V) is a potent 5-HTχ _a agonist with therapeutic indications for refractory depression patients and emesis. This intermediate has been prepared from the corresponding 6-bromo-4-dipropylamino-l,2,2a,3,4,5- hexahydrobenz[cd]indole in 76% yield using stoichiometric copper cyanide in N-methyl-2-pyrrolidinone (Martinelli, M.J., et al . , Tetrahedron Let ters , 31, 7579 (1990)). The 6-bromo and 6-iodo-4-dipropylamino-l,2,2a,3,4,5-hexahydro- benz[cd]indoles were each subjected to the process of the present invention. The results of these experiments are summarized in Table III.

TABLE III

Y M mol % Cul SOLVENT TIME (hr) % IV

I K 0 THF ¹ 18 8

I K 10 THF ¹ 2.4 100

I Na 10 THF ¹ 0.5 100

I K 10 ACN ² 0.5 99

I Na 10 ACN ² 0.5 99

I K 10 EtOAc ³ 4.7 96

I Na 10 EtOAc ³ 0.6 98

Br Na 10 EtCN ⁴ 3.1 97

¹ tetrahydrofuran, ² acetonitrile, ³ ethyl acetate, propionitrile

The higher yields and reduction in the amount of copper waste generated in these reactions further demonstrate the advantages of the process of the present invention. The results of these experiments also serve to demonstrate the diversity of substrate functionality tolerated by the process of the invention.

Cinoxacin, 1-ethyl-1,4-dihydro-4-oxo[1,2]dioxolo[4,5- g]cinnoline-3-carboxylic acid (VI), is an antibacterial used for urinary tract infections. An intermediate in its synthesis, 1-ethyl-1,4-dihydro-4-oxo[1,2]dioxolo[4,5- g]cinnoline-3-carbonitrile (VII) is prepared by prior art

methods from the corresponding 3-bromo compound by reacting it with stoichiometric amounts of copper cyanide. To

VI VII reduce the amount of copper in the final product to acceptable levels, a quantity of the cinoxacin is sacrificed during the prior art synthesis. Subjecting 3-bromo-l-ethyl- 1,4-dihydro-4-oxo[l,2]dioxolo[4, 5-g]cinnoline to the conditions of the process of the invention using 0.25 equivalents of tetrakis(triphenylphosphine)palladium(0) and 0.50 equivalents of cuprous iodide, 92% of VII was formed after 5 hours in refluxing propionitrile. The process of the invention significantly reduced the amount of copper required for this step in the synthesis of cinoxacin. This reaction further demonstrates the structural diversity tolerated by the process of the present invention.

While a wide variety of structural diversity in the substrate is tolerated by the process of the invention, not all substrates are suitable. The electronic nature of the substrate, for example, can moderate or inhibit the catalytic effect of the present invention. This phenomenon is illustrated by comparing the conversions of substituted iodobenzenes under standard conditions. The results of these experiments are summarized in the following table.

TABLE IV

Y Cul (mole %) TIME (hr) % NITRILE*

H 0 4 11

H 10 1.5 100

OCH ₃ 0 4 14

OCH ₃ 10 4 97

C(0)CH ₃ 0 4 47

C(0)CH ₃ 10 1 100

N0 ₂ 0 1 98

N0 ₂ 10 5 48 ^a As determined by gas chromatography The beneficial effects of the process of the present invention are lost on the nitro-substituted iodobenzene. This result suggests that nitro-substituted substrates may not be suitable substrates for the process of the present invention. Assay Svstem

The reactions were assayed by gas chromatography on an HP5890 gas chromatograph with a flame ionization detector and using a 30 m DB-1 (0.25 μm) column (Fisher Scientific). The injection and detection temperatures were both 300°C. The temperature routine began at 50°C for 2 minutes and then the oven temperature increased at a rate of 25°C/minute until it reached a final temperature of 300°C, and was maintained at that temperature for 20 minutes.

EXAMPLE 1 Reaction of 1-iodonaphthalene A flask containing 1.00 gm (3.94 mMol) 1-iodo- naphthalene, 0.23 gm (0.20 mMol) tetrakis(triphenyl¬ phosphine)palladium(0) , 0.51 gm (7.87 mMol) powdered

potassium cyanide, and 0.075 gm (0.39 mMol) copper(I) iodide was placed under vacuum and then charged with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into tetrahydrofuran for 5 minutes and then 5.0 mL were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC. The time course of the reaction is summarized in the following table.

Time (hr) % nitrile

0.85 74

2.1 96

3.1 99

Assay Svstem

The reactions were assayed by HPLC using a Zorbax SB-C8 column (4.6 mm x 25 cm) . Peaks were detected with a UV detector at 230 nm. The assays were performed at a flow rate of 1 mL/min with a gradient program. The solvent systems were 1:1 acetonitrile:methanol and 25 mM NaH2Pθ4 in water adjusted to pH 2.5 with H3PO4. The gradient uses 50% of the 1:1 acetonitrile:methanol for 0 to 5 minutes, rises to 60% at 10 minutes, holds steady for 15 minutes, then lowers back to 50% at 20 minutes. Samples for analysis were prepared by adding one drop of the reaction mixture in 6 mL 1:1 methanol:aqueous buffer solution.

EXAMPLE 2 Reaction of 1-bromonaphthaiene A flask containing 1.00 gm (4.83 mMol) 1-bromo- naphthalene, 0.28 gm (0.24 mMol) tetrakis (triphenyl- phosphine)palladium(O) , 0.63 gm (9.66 mMol) powdered potassium cyanide, and 0.092 gm (0.48 mMol) copper(I) iodide was placed under vacuum and then charged with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into acetonitrile for 5 minutes and then 5.0 mL were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen

with stirring and the reaction monitored by HPLC. The time course of the reaction is summarized in the following table.

Time (hr) % nitrile

0 , . 6 27

3 . .5 87

4 . .4 92

5 . 55 95

7 . . 1 97

23 . 2 100

EXAMPLE 3 Reaction of 1-trifluoromethanesulfonyloxynaphthalene A flask containing 0.50 gm (1.81 mMol) 1-trifluoro¬ methanesulfonyloxynaphthalene, 0.10 gm (0.09 mMol) tetra¬ kis (triphenylphosphine)palladium(0) , 0.24 gm (3.62 mMol) powdered potassium cyanide, and 0.34 gm (0.18 Mol) copper(I) iodide was placed under vacuum and then charged with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into acetonitrile for 5 minutes and then 2.5 mL were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC. The reaction was complete within 0.63 hour.

EXAMPLE 4 Reaction of 6-bromo-4-dipropylamino-l,2,2a,3, 4,5- hexahydrobenz[cd]indole A flask containing 0.50 gm (1.13 mMol) 6-bromo-4- dipropylamino-1,2,2a,3,4, 5-hexahydrobenz[cd]indole, 0.065 gm (0.057 mMol) tetrakis(triphenylphosphine)palladium(O) , 0.11 gm (2.27 mMol) powdered sodium cyanide, and 0.022 gm (0.116 mMol) copper(I) iodide was placed under vacuum and then charged with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into propionitrile for 5 minutes and then 2.5 mL

were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC. The time course of the reaction is summarized in the following table.

Time (hr) % nitrile

1.0 85 1.6 95

3.1 97 4.0 99

5.2 99 6.4 100

EXAMPLE 5 Reaction of 6-iodo-4-dipropylamino-l,2,2a, 3, 4, 5- hexahydrobenz [cd] indole in acetonitrile A flask containing 1.00 gm (2.05 mMol) 6-iodo-4- dipropylamino-1,2,2a,3,4, 5-hexahydrobenz[cd]indole, 0.12 gm (0.10 mMol) tetrakis (triphenylphosphine)palladium(0) , 0.20 gm (4.10 mMol) powdered sodium cyanide, and 0.039 gm (0.21 mMol) copper(I) iodide was placed under vacuum and then charged with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into acetonitrile for 5 minutes and then 5.0 mL were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC. The reaction was complete within 0.50 hour.

EXAMPLE 6 Reaction of 6-iodo-4-dipropylamino-l,2, 2a, 3, 4, 5- hexahydrobenz [cd] indole in ethyl acetate A flask containing 1.00 gm (2.05 mMol) 6-iodo-4- dipropylamino-1, 2,2a, 3, 4, 5-hexahydrobenz [cd] indole, 0.12 gm (0.10 mMol) tetrakis(triphenylphosphine)palladium(0) , 0.20 gm (4.10 mMol) powdered sodium cyanide, and 0.039 gm (0.21 mMol) copper(I) iodide was placed under vacuum and then charged

with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into ethyl acetate for 5 minutes and then 5.0 mL were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC. The reaction was 98% complete within 0.55 hour and 100% complete at 1.07 hr.

EXAMPLE 7 Reaction of 3-bromo-l-ethyl-l,4-dihydro-4- oxo[l,2]dioxolo[4, 5-g]cinnoline A flask containing 0.20 gm (0.67 mMol) 3-bromo-1-ethyl- l,4-dihydro-4-oxo[l,2]dioxolo[4, 5-g]cinnoline, 0.19 gm (0.17 mMol) tetrakis (triphenylphosphine)palladium(O) , 0.33 gm (6.73 mMol) powdered sodium cyanide, and 0.064 gm (0.34 mMol) copper(I) iodide was placed under vacuum and then charged with nitrogen. This evacuation/fill cycle was repeated twice and the flask left under nitrogen. Nitrogen was bubbled into propionitrile for 5 minutes and then 10 mL were added to the reaction flask. The reaction mixture was then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC. The time course of the reaction is summarized in the following table.

Time (hr) %, ni r l

0.67 76

1.93 88

3.12 92

5.0 92

EXAMPLE 8 Preparation of benzonitrile A flask containing 1.00 gm (6.4 mMol) bromobenzene, 0.38 gm (0.32 mMol) tetrakis (triphenylphosphine)palladium(O) , 0.64 gm (13.12 mMol) powdered sodium cyanide, and 0.12 gm (0.67 mMol) copper(I) iodide is placed under vacuum and then charged with nitrogen. This evacuation/fill cycle is repeated twice and the flask left under nitrogen. Nitrogen

is bubbled into tetrahydrofuran for 5 minutes and then 5.0 mL are added to the reaction flask. The reaction mixture is then heated to reflux under nitrogen with stirring and the reaction monitored by HPLC until complete. The reaction mixture is then cooled to room temperature, filtered and the title compound isolated by fractional distillation of the filtrate.