Chapter-II

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)

catalyzed, three-component, one-pot synthesis of

partially hydrogenated triazolopyrimidines and

benzimidazolopyrimidines

This work is communicated to Catalysis Communications

73

CHAPTER - II

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) catalyzed, three-

component, one-pot synthesis of partially hydrogenated

triazolopyrimidines and benzimidazolopyrimidines

2.1 Pharmaceutical applications of azolopyrimidines

Among the nitrogen containing heterocycles, triazolopyrimidines and

benzimidazolopyrimidines represent a pharmaceutically important class of

compounds because of their diverse range of biological activities, such as

antitumor[1]

,cytotoxicity[2]

, therapeutic potentiality[3]

, potent and selective ATP

site directed inhibition of the EGF-receptor protein tyrosine kinase[4]

and

cardiovascular[5]

activities. In addition, they havebeen found in DNA-interactive

drugs[6]

and as useful building blocks in the synthesis of herbicidaldrugs like

Metosulam, Flumetsulam, Azafenidim, Diclosulam, Penoxsulam,

Floransulam,Cloransulam, etc.

2.2 Literature survey of method of synthesis

Hassan Sheibaniet. al,described chemoselectivesynthesis of 4-oxo-2-

aryl-4,10-dihydropyrimido[1,2-a][1,3]benzimidazol-3-yl cyanides from three-

componentreactions of 2-aminobenzimidazole, aldehydes, and

ethylcyanoacetate or malononitrile by usingacetonitrile as a solvent and in the

presence of base catalysts such astriethylamine, sodium acetate, and

magnesium oxide.[7]

These processes are highly regioselective, and

chemoselective synthesis of these compounds depends on the reactivity of

binucleophiles(Scheme 2.1).

Scheme 2.1

N

NH

NH2 ArCHOCatalyst

CH3CN

CN

COOEt

CN

CN

+

N

N NH

CN

Ar

O

N

N NH

CN

O

Ar

or

not formed

N

NH

N

CN

Ar

NH2

N

N NH

Ar

CN

NH2

or

not formed

74

Nosrat O. Mahmoodiet. al,havereported one-pot, three component

protocol under ultrasoundirradiation which provides a regioselective, fast, and

practical method for the preparationof fused pyrazolo[3,4-b]pyridine

carbonitriles from 5-amino-3-methylpyrazole, malononitrile and various aryl

aldehydes in short reaction times and in an excellent yields,which pave the way

for assessment of pharmacological activities of these novelpyrazolopyridine

derivatives.[8]

The simplicity, high atom economy, easy execution,best workup

and productivity, together with the use of an inexpensive material

andenvironmentally friendly procedure, are the remarkable features of this

procedure (Scheme 2.2).

Scheme 2.2

Karimiet. al,have reported the efficient and regioselective one-pot

synthesis of thebenzimidazolo[3,4-b]pyridine carbonitrilesuses an inexpensive,

water-soluble, non-toxic, and commerciallyavailable catalyst.[9]

2-

Aminobenzothiazole instead of 2-Aminobenzimidazole does not react (Scheme

2.3).

Scheme 2.3

AnshuDandiaet. al,havereported a rapid, efficient, clean and

environmentally benign exclusive synthesis of 1,2,4-triazolo[4,3-a]pyrimidines

from the reaction of amino triazole, carbonyl compounds and alkene-

nitrilederivatives has been developed in an aqueous medium in an excellent

75

yields using microwaves orultrasonic waves.[11]

The results are compared with

conventional heating. Further the product structure isconfirmed by the single-

crystal X-ray molecular structure of 7′-amino-8′H-spiro [cyclohexane-1,5′-

[1,2,4] triazolo [4,3-a] pyrimidine]-6′-carbonitrile (Scheme 2.4).

.

Scheme 2.4

Yahya S. Beheshtihaet. al,have reported in several noteworthy features

of a newcatalyst for the synthesis of 4-amino-5-pyrimidinecarbonitriles through

thethreecomponent reaction of malononitrile, aldehydes, and N-

unsubstitutedamidinesusing ZnOnano-particles.[12]

This protocol offers many

attractive features suchas reduced reaction times, greater yields, and economic

viability of the catalyst.The reaction proceeds under aqueous conditions.

Isolation of the catalyst is easilyachieved, and the catalyst is recoverable and

can be used in several runs without lossof catalytic activity (Scheme 2.5).

Scheme 2.5

Ershovet. al, have reported2-(4-amino-2,5-dihydro-1H-imidazol-4-

ylidene)malononitriles were synthesized by three componentreaction of

tetracyanoethylene, carbonyl compound, and ammonium acetate.[13]

The

synthesis can beperformed in two steps with an intermediate isolation of 2-

aminoethene-1,1,2-tricarbonitrile, as well as usingpreliminarily prepared 2-

aminoethene-1,1,2-tricarbonitrile and 1,3,5-trisubstituted 2,4-diazapentadienes

(Scheme 2.6).

76

Scheme 2.6

Chao Guo Yan et. al, have reported polysubstitutedpyrido[1,2-

a]benzimidazole derivatives efficiently produced in moderate yields through

anovel one-pot, four-component reaction from pyridine or 3-picoline,

chloroacetonitrile, malononitrile and aromatic aldehyde in refluxing

acetonitrile.[14]

The mechanism of this novel reaction was believedinvolving the

formation of polysubstituted benzenes with subsequent substitution and

annulation reactionof pyridine. All pyrido[1,2-a]benzimidazoles,

polysubstituted benzenes, polysubstitutedindoles, and somekey reaction

intermediates are characterized by 1H NMR,

13CNMR, MS, IR spectra,

elemental analysis and X-ray crystallography (Scheme 2.7).

Scheme 2.7

KeyumeAblajanet. al, have reported asynthesis of series of novel 5-

amino-7-aryl-7,8-dihydro-[1,2,4] triazolo[4,3-a]-pyrimidine-6-carbonitriles by

a one-pot reaction of 3-amino-1,2,4-triazole,malononitrile and aryl aldehydes

in the presence of 20 mol% of sodium hydroxide in ethanol underheating or

ultrasonic irradiation.[15]

The advantages of this methods are short reaction

times, good yields, high selectivity and operational simplicity (Scheme 2.8).

2ArCHO + 2CN

CN+ ClCH 2CN +

N

R

MeCN

Heat

N

N

Ar

Ar

NC

CN

R

R = H, CH 3

77

Scheme 2.8

2.3 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)

1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)[16]

is a clear, light yellow

liquid readily soluble in water, ethanol, benzene, acetone, acetonitrile,

ethylacetate, carbon tetrachloride, diethyl ether, 1,4-dioxane, 1,4-

butanediol,dimethyl sulfoxide.It is hardly soluble in petroleum ether.It’s

boiling point is 259–260°C and density is 1.0192g/cm3.It is stable at an ambient

temperaturebut is hygroscopic. Over-exposureto atmosphere resultsin water

absorption which can lead to hydrolysis.Contact with undiluted productmay

cause skin irritation or burns.

DBU is anorganic soluble amidine base which has been used effectively,

andunder relatively mild conditions, for variety of base-mediatedorganic

transformations including eliminations, isomerizations, esterifications,

amidations, etherifications, condensations, carboxylations, carbonylations, and

halogenations. A related reagent1,5-diazabicyclo[4.3.0]non-5-ene (DBN) is

also used for similar reactions.

2.3.1 Elimination reactions

DBU has been used widely for dehydrohalogenations as well as for the

introduction of unsaturation by elimination of sulfonic acids. Reactions

generally proceed under mild conditions and without side reactions. Typical

procedures use equimolar base and elevated reaction temperatures (generally

80–100°C). Reaction solvents such as DMF, benzene, and DMSO have been

used with reaction times varying from several hours to several days. Products

may be distilled directly from the reaction mixture or separated from the DBU

salt byproduct by extraction with a nonpolar solvent. Terminal as well as

internal doublebonds can be introduced with a high degree of

regioselectivity.Additionally, this method has been used to prepare

78

functionalizedalkenes such as vinyl halides and vinyl ethers. Alkynes are

nottypically prepared using DBU-mediated eliminations,propargylethers,

however, are an exceptions.

Oediger and Möller introduced DBU in 1967 for the

dehydrohalogenationof bromoalkanes. DBN was found to beless

effective.[17]

DBU was used in the following one-pot procedure for convertingβ-

disubstituted primary alkyl iodides to the terminal alkenes.[18]

DBN was also

used effectively for this procedure. The THPprotectedtosylate was converted to

the corresponding iodidewith NaI in DMF and subsequent addition of 1.5 equiv

of DBU andheating at 80°C for 3–4 hr afforded terminal alkene in 82%overall

yield(Scheme 2.9).

Scheme 2.9

DBU was found to be an effective base for converting piperidine into

3,4-dehydropiperidinewithout formation of the undesired2,3-dehydro-

piperidine in the synthesis of the alkaloid sedinine[19]

(Scheme 2.10).

Scheme 2.10

DBU has also been used to prepare (E)-1-iodo-1-alkenes from1,1-

diiodoalkanes.In a representative procedure (Scheme 2.11), diiodobutane was

combined with equimolar DBU and heated at 100°Cuntil appearance of a

brown solid (15–20 min). The product (E)-1-iodo-1-butene was isolated in 80%

yield by distilling directlyfrom the reaction mixture. Higher-boiling vinyl

iodidesrequired DMSO as reaction solvent and product extraction withpentane.

Scheme 2.11

79

Otter used DBU to effect the elimination of methanesulfonicacid in the

final step of his preparation of 1,3-dimethyl-6-propyluracil,a synthetic

pyrimidine nucleoside (Scheme 2.12).

Scheme 2.12

2.3.2 Isomerization

1,8-Diazabicyclo[5.4.0]undec-7-ene is usedfor base-mediated double

bond migrations and epimerizations.Isomerizations generally require proton

abstraction at a carbonα to a carbonyl group (or related functionality) and are

thermodynamicallycontrolled.DBUwas used to equilibrate a mixture of

substituted pyrrolidin-2-ones in the final step of a herbicide synthesis.[20]

The

mixture ofisomerswas allowed to stand for 1 hr at room temperature with

DBUin tolueneto give the pure 3,4-trans isomer in 96% yield (Scheme 2.13).

Scheme 2.13

DBU has been employed to convert esters with β,γ-unsaturationinto the

corresponding α,β-unsaturated isomers.[21]

Thus 3-pentenoate underwent up to

60% isomerization to 2-pentenoate in the presence of DBU at 100°C (Scheme

2.14). Corresponding exposureof pure cis-2-pentenoate to DBU at 130°C for 4

h afforded a similar product mixture (53% trans-2-pentenoate, 40% of 3-

pentenoate and 7% recovered starting material), suggesting thermodynamic

equilibrium.[22]

For comparison, in acontinuous process using 4-

Dimethylaminopyridine at reflux, upto 78% of the thermodynamically

favoredwas converted to over the course of 30 hr.

80

Scheme 2.14

β,γ-Unsaturated nitrileshave been isomerized to thethermodynamically

favored α,β-unsaturated nitriles inthe presence of catalytic DBU or

DBN[23]

(Scheme 2.15).

Scheme 2.15

Several biomimetic methods for the conversion of amines tocarbonyl

compounds have used amidine bases to effect equilibrationof the intermediate

imine.[24–26]

Rapoport used DBU in theoxidation of amines with 4-formyl-1-

methylpyridinium benzenesulfonates(FMPBS).[26]

Phenylacetaldehyde was

obtained in 83% yield from β-phenylethylamine aftertreatment with FMPBS

and DBU in CH2Cl2/DMF (Scheme2.16).

Scheme 2.16

2.3.3 Esterifications, Amidations, and Etherifications

DBU hasbeen used to prepare esters[27]

and amides[28]

from carboxylic

acidsas well as ethers[29]

, esters[30]

and carbamates[31]

from alcohols.These

procedures involve proton abstraction followed by reactionof the carboxylate

or alkoxide with an alkyl halide, acylatingagent, or other suitable electrophile.

Esterifications and amidationsare generally conducted at or near room

temperature, whereas etherificationsrequire elevated temperatures (60–80°C).In

1978, Ono reported a convenient procedure for the esterificationsof carboxylic

acids using DBU.[27]

Esters were producedin high yield from acids, alkyl

halides, and DBU. The advantageof this procedure is that it provides mild

conditions for esterification,it is not necessary to prepare the carboxylate anion

81

in aseparate step, and side reactions, especially dehydrohalogenation,are

avoided. Amino acids have been esterified without racemizationusing this

procedure. As a representative example, benzoicacid reacted with ethyl iodide

in the presence of DBU for 1hrto give ethyl benzoate in 95% yield. The same

reaction usingtriethylamine instead of DBU afforded essentially no ethyl

benzoate.With benzyl bromide, benzoic acid, and DBU in DMSO,benzyl

benzoate was formed quantitatively at 30°C in 10 min.[32]

Triethylamine, when

substituted for DBU, afforded benzyl benzoatein 81% after 1 hr at 30°C;

Pyridine afforded a 15% yield ofbenzyl benzoate after 6 hr.The high yields of

ester afforded by this method make it attractivefor polyester synthesis.[33]

Thus

isophthalic acid reacted withm-xylenedibromide in the presence of 2 molar

equivalent of DBUin DMSO at 30°C for 3 hr to afford polyester in high

yieldand viscosity (Scheme 2.17). Other organic bases such as

triethylamine,pyridine, N,N-dimethylaminopyridine or a DBU–pyridine

mixturedid not afford any polymer.

Scheme 2.17

Polyimides containing pendant carboxylic acids have also beenesterified

using 1-phenethyl bromide and DBU.[34,35]

In an alternative approach to

esterification, DBU was used toaccelerate the reaction of N-acylimidazoles

with t-butanol in aone-pot conversion of carboxylic acids into their t-butyl

esters.The general reaction is outlined in (Scheme 2.18). Acids were treated

with1 molar equiv of N,N-Carbonyldiimidazole in DMF under a

nitrogenatmosphere at temperatures from 40 to 80 ◦C and reactiontimes of 5 to

24 hr. Products were extracted from the reaction mixtureswith diethyl ether.

82

Tert-butyl benzoate, t-butylcinnamate, and t-butyl heptanoate were prepared in

91%, 64%and 68% yield respectively. With sodium t-butoxide rather

thanDBU, there was competitive formation of 3-oxoalkanoic esterswith acids

having one or two protons at C-2.[36]

A similar limitationwas noted for the

conversion of N-acylimidazoles to t-butylesters using t-butanol and NBS.[37]

Scheme 2.18

Enolizable acyl cyanides have been converted into 1-cyano-1-alkenyl

esters upon treatment with tertiary amines (e.g. DBU,pyridine, dimethylamine,

and 1,4-Diazabicyclo[2.2.2]octane) andcarboxylic acid chlorides or

anhydrides.[38]

With acid chlorides,equimolar base was required. Propionyl

cyanide was treated with a stoichiometricamount of DBU and acetyl chloride in

methylene chloride at room temperature toafford 1-cyanovinyl acetate in 61%

yield.DBUhas also been used for certain de-esterification’s. In the caseof

acetates, deacetylation with DBU occurs under relatively mildconditions (rt to

80°C; 5–45 hr).[39]

The method only works foresters derived from acetic acid.

Methanol is the solvent of choice,although dichloromethane or benzene may be

added to improvereactant solubility. It was speculated, though not confirmed,

thatthe mechanism involves formation of the desired alcohol by eliminationof

ketene. Acetate was deacetylated in93% yield to alcohol with DBU in methanol

at room temperature for 24 hr(Scheme 2.19). The same reaction using DBU in

xylene afforded onlystarting material.[40]

Scheme 2.19

83

Methyl esters are cleaved with DBU. High reaction temperaturesand

extended reaction times are required. However, the correspondingacid is

generally obtained in high yield (>90%) withoutthe use of ionic nucleophiles

such as lithium iodide, lithium thiolate,or potassium t-butoxide.[40]

Thus a

solution of methyl mesitoate,10 equivalent of DBU and 10 equivalentof o-

xylene was heated to165°C for 48 hr affording mesitoic acid which was

isolated in95% yield after ether extraction (Scheme 2.20).

Scheme 2.20

DBU was one of several effective bases used in an amidessynthesis from

N,N-bis(2-oxo-3-oxazolidinyl)phosphorodiamidicchloride, primary or

secondary amines, and carboxylic acids.[41]

Reactions were conducted at room

temperature for 1–2 hr, avoidingracemization of optically pure substrates. Thus

3,3-dimethylacrylicacid and the acid salt of (S)-(−)-α-methylbenzylaminein

DMA were treated with 2 equiv of DBU at room temperature over 30 min,then

allowed to react at room temperature for 75 min to afford amide in75% yield

(Scheme 2.21). Other methods require higher reaction temperatures, longer

reactiontimes (1,3-Dicyclohexylcarbodiimide[42]

and Diphenylphosphinic

chloride[43]

procedures require up to 12 hr and result in only modestyields for

similar conversions), or excess reagents or reactants(the cyanuric chloride

method[44]

requires excess acid and theo-

nitrophenylthiocyanate/Tributylphosphine method[45]

uses excessreagent and

amine).

Scheme 2.21

84

2.3.4 Condensations

DBUhas been used to effect condensations ofactive methylene

compounds and other substrates containing activehydrogen. Reactions

generally use equimolar DBU and aproticsolvents such as THF or benzene.

Reaction times and temperaturesvary.DBUwas shown to be an effective base

for the Michael reactionof diethylacetamidomalonate with methyl acrylate in a

synthesisof glutamic acid[45]

(Scheme 2.22). 1,1,3,3-Tetramethylguanidineand

DBN were found to be equally effective. All resulted in theformation of

glutamic acid derivative quantitatively.

Scheme 2.22

In the Knoevenagel condensation of malonicacid with hexanal,the β,γ-

unsaturated isomer was obtained with 94%selectivity and 56% yield after 10 hr

at 90°C in the presence ofequimolar DBU[47]

(Scheme 2.23). Other bases

selective for includedtriethanolamine, triethylamine, ethylpiperidine, N,N-

dimethylanilineand 2,6-Lutidine. Pyridine, 3-methylpyridineand 4-

methylpyridine showed approximately 90% selectivity for the α,β-unsaturated

isomer. A β,γ-unsaturated carbonyl compound wasalso obtained from the

condensation of formaldehyde with pentenonein the presence of catalytic DBU

or DBN.[48]

Scheme 2.23

Diesters of homophthalic acid condensed with aromatic aldehydesin the

presence of equimolar DBU in refluxing benzene for6–10 hr to give excellent

yields of cinnamic esters. The reaction ofdimethyl homophthalate with 3-

benzyloxy-4-methoxybenzaldehydeto afford cinnamic esteris

representative[49]

(Scheme 2.24). Sodium hydride, sodium alkoxides and

potassium acetate wereall found to be ineffective for this reaction.

85

Scheme 2.24

DBU catalyzed the asymmetric synthesis of δ-oxocarboxylicacids from

(2R,3S)-3,4-dimethyl-5,7-dioxo-2-phenylperhydro-1,4-oxazepine.[50]

The

michael reaction of δ-oxocarboxylicacid with 2-cyclopenten-1-one afforded the

(+)-3-cyclopentanoneacetic acid inmoderate yield (43%) and high optical

purity (96%) after hydrolysisand decarboxylation (Scheme 2.25). Trityllithium

(triphenylmethyllithium)or potassium t-butoxide afforded in similaryields (30–

50%) but poorer optical purity (7–76%).

Scheme 2.25

2.3.5 Carbonylation and Carboxylations

DBU has been usedto prepare amides or imides.[51–53]

and esters[54]

via

the sequentialcarbonylation/alkylation of amines and alcohols,

respectively.Similarly, the carboxylation of amines and alcohols

affordsurethanes and carbonates.[55]

Reactions use stoichiometricbase and are

catalyzed by palladium or nickel complexes.Product yields are generally high

(80–100%). Carbonylationshave been conducted in DMA at elevated

temperatures(115–150°C), whereas carboxylations have been performed at

room temperaturein a variety of solvents including methylene chloride,

DMSO,THF and glyme. Scheme 2.26 and Scheme 2.27 shows the preparation

ofN-phenylbenzamide and allylbenzylethylcarbamate by these procedures.The

efficacy of various bases was compared in thecarboxylation/alkylation of

benzylethylamine using a catalyticamount of

tris(dibenzylideneacetone)dipalladium [Pd2(dba)3].DBU, N-cyclohexyl-

86

N,N,N,N-tetramethylguanidine and 7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-

ene were preferred. DBNafforded a modest 49% yield of urethane and

essentially no urethanewas formed using Diisopropylethylamine.

Scheme 2.26

Scheme 2.27

Methods for the preparation of thiocarbamates from alcohols,carbon

disulfide, and alkylating agents[56]

or via the sulfur-assistedcarbonylation of

alcohols[57]

are related. These do not require ametal catalyst. Thus S-benzyl-O-

n-butylcarbonothionate was isolatedin 86% yield after the carbonylation of n-

butanol in THF at80°C for 4 hr in the presence of 3 equivalentof powdered

sulfur and 5equivalent of DBU followed by esterification with 1.2 equivalentof

benzylbromide (Scheme 2.28).

Scheme 2.28

DBU has also been used in the nickel- or palladium-catalyzedcoupling

of alkenes with Carbon Dioxide.[58,59]

Isoprene was treated with Pd(Ac)2, a

phosphine ligand,DBU and tributyltinethoxide for 84 hr at 80°C under CO2

toafford an isomeric mixture of C10-carboxylic acids(Scheme 2.29). It was

found that DBU and tributyltinethoxide independently promote the reaction but

not aseffectively as when used as a combination.

87

Scheme 2.29

2.3.6 Halogenations

DBU-based brominating agents such asDBU/bromine[59]

,

DBU/hydrobromideperbromide[61]

, andDBU/bromotrichloromethane[62-63]

, have

been used to brominates enolizable substrates and aromatic compounds. 3-

halomethylcephems, convenient intermediates forthe synthesis of 3-substituted

cephalosporins, were prepared bytreatment of exo-methylene cephems with

DBU/brominein THF over the temperature range (−80) to 0°C (Scheme 2.30).

Scheme 2.30

2.3.7 Nucleophilic Reactions

DBU is normally a non-nucleophilicbase. However, in recent years, it

has been observedthat DBU can also act as a nucleophile leading to, in some

cases,unforeseen products. Agarwal and Mereu used DBU as a

Nucleophiliccatalyst for the Baylis-Hillman reaction.[64]

Thus, the reactionof

benzaldehyde and methyl acrylate proceededquite cleanly and at an

exceedingly faster rate in the presenceof 1 equivalent of DBU, providing the

corresponding Baylis-Hillmanproduct in 89% yield after just 6 hr(Scheme

2.31). In contrast,decomposition occurred when other amidine bases such as

DBNand N-methyl-4,5-dihydroimidazole were employed. DBU wasalso

superior to 3-hydroxyquinuclidine and DABCO.

88

Scheme 2.31

Shi et al, have shown that Baylis-Hillman reaction ofp-

nitrobenzaldehyde and methyl vinyl ketone in the presenceof 1.4 equivalentof

TiCl4 and 20 mol% of DBU at −78°C givesthe abnormal chlorinated product in

82% yield (Scheme 2.32).[65]

Scheme 2.32

It is noteworthy that these 1,4-addition reactions catalyzed byDBU are

slower than phosphine-promoted processes. However,reaction features such as

air atmosphere, non-degassed solvent,and easy removal of DBU by mild acidic

workup, make the DBUprotocol extremely attractive.DBU has been

successfully employed as a nucleophilicpromoter for the methylation of

phenols, indoles, benzimidazolesand carboxylic acids with dimethyl carbonate

(DMC) asthe methylating reagent. Methylationof 1-naphthol with DMC in the

presence of 1 equivalentof DBU at 90°C gives 99% conversion in 16

hr(Scheme 2.33), whereasthe use of Na2CO3 as the base requires 7 days at

120°C for 91%conversion.[66]

Scheme 2.33

The reaction is believed to proceed via the formation of

unstablecarbamate, which serves as a highly activated methylatingagent.

89

2.3.8 Protecting Group Removal

3-Phenylsulfonyl 1,2-propanediolis an efficient acetal class of protective

groups for both aldehydesand ketones. This is readily obtained as a white solid

upondihydroxylation of allylphenylsulfone. Acid-catalyzed protectionof

aldehydes (or ketones) gives the 1,3-dioxolane derivative. Asshown in Scheme

2.34, DBU efficiently facilitates the deprotection of1,3-dioxolane derivative

providing the parent aldehyde ingood yield.[67]

Avariety of functional groups

including silyl ethers,tosyl esters, THP-ethers, and carboxylic esters were

compatible with the DBU protocol. The reaction proceeds via DBU-initiated

deprotonation followed by β-elimination.

Scheme 2.34

DBU was also used in the deprotection of pyrrolecarbonylamine to the

aldehyde(Scheme 2.35). The reaction was catalyticin DBU (5 mol %).[68]

Smoother deprotection resulted fromaromatic aldehyde pyrrole adducts as

compared with carbonylamines derived from enolizable aldehydes.

Scheme 2.35

2.3.9 Oxidations

Allylic oxidation of olefins with tert-butylperbenzoate produces allylic

esters. This reaction is usuallyperformed in the presence of Cu(I) at elevated

temperatures(80–120°C). In seeking milder conditions, Singh and co-

workersreported that oxidation can be performed in the presence of

catalyticamounts of Cu(OTf)2 and DBU or DBN.[69]

Control

experimentsshowed that in the absence of DBU (or DBN) the oxidationwas

90

very sluggish. These reactions used acetone as the solvent andproceeded either

at room temperature or under reflux condition. Olefin was converted to the

corresponding allylicester by dropwise addition of tert-butyl perbenzoate to a

stirredsolution of DBU and Cu(OTf)2 in acetone (Scheme 2.36).

Scheme 2.36

The (o-Tol)3BiCl2/DBU binary system was introduced byMatano and

Nomura[70]

as a highly effective and chemoselectiveoxidizing agent for

converting primary and secondaryalcohols to aldehydes and ketones,

respectively. The reaction proceededsmoothly in toluene and resulted in the

precipitation of[o-Tol2BiCl2][DBU-H+], a Bi(III) by-product. This proved tobe

advantageous compared with the (o-Tol)3BiCl2/KO-t-Bu/H2Osystem as the by-

product could be removed by filtration and thedesired product obtained using a

short pad of silica gel and asmall amount of eluent. Oxidation of benzylic,

secondary, allylicand non-conjugated aliphatic alcohols occurred in excellent

yields(Scheme 2.37). No over-oxidation of aldehydes to carboxylicacids was

observed.

Scheme 2.37

Oxidation of 1-phenyl-1,4-butanediol by using (o-Tol)3BiCl2/-DBUgave

chemospecifically4-hydroxy-1-phenybutane-1-one in 98% yield(Scheme

2.38).[71]

91

Scheme 2.38

2.3.10 Miscellaneous

DBU was used as the catalyst in the reactionof phosphate esters with

aldehydes to form phosphates via thephospha-brookrearrangement.[72]

Electron-

poor aldehydes andketones worked best, and moderate to good yields of

correspondingphosphates were obtained. Thus, naphthaldehyde reactedwith

dimethylphosphite at 80°C in DMF in the presence of10 mol% of DBU to

afford phosphate in 70% yield (Scheme 2.39).

Scheme 2.39

In 1997, Rodriguez reported an unprecedented reaction ofβ-ketoesters

with α,β-unsaturated aldehydes promoted by DBU-MeOH,leading to

diastereoselective formation of densely functionalized1,3-cis

cycloheptenes.[73,74]

This reaction can be explained mechanistically by

invokingfive different reactions, namely a Michael addition, an

intramolecularaldol condensation, a retro-Dieckman reaction followed

bydehydration, and a chemoselective ester saponification. Otherbases such as

KOH and K2CO3 were less effective. Simple acidicworkup gave the

cycloheptenes with high chemical purity. Esterreacts with 2-methylpropenalin

92

the presence of 1 equivalent ofDBU in MeOH at room temperature for 18 hr to

give the cycloheptenein 90% yield (Scheme 2.40).

Scheme 2.40

However, when β-ketoamides were reacted with α,β-

unsaturatedaldehydes using 1 equivalentof DBU, the reaction

proceededthrough a γ-aldol dehydration sequence leading to syntheticallyuseful

γ-allylideneketoamides[75]

(Scheme 2.41). Notably, the productwas formed

stereoselectively with E,E-configuration.

Scheme 2.41

The coupling reaction of thiolactams with α-bromocarbonylcompounds

providing β-enaminocarbonyl derivatives is knownas the Eschenmoser

coupling. This coupling is usually carried outin the presence of triethylamine

and a phosphine, which serves as thesulfur scavenger. Russowskyet. al, have

discovered that Eschenmosercoupling of piperidin-2-thione with bromoestersin

the presence of 2 equiv of DBU (and in absence of phosphine)gave either β-

enaminoesters or thiazolidinones as the reactionproduct depending on the

93

nature of the R1 substituent of thebromoester.

[76] Thus, when R

1 is phenyl, β-

enaminoester wasthe only product observed, whereas when R1 is Me, n-Pr or n-

Bu,thiazolidinone was the sole product (Scheme 2.42).

Scheme 2.42

They also observed that reactions of pyrrolidin-2-thionewith

bromoesters using 2 equiv of DBU gave, in contrastthioimines in high yields

independent of the nature of the R1group

[76](Scheme 2.43).

Scheme 2.43

Wróbel reported the combination of DBU and an appropriateadditive for

the condensation of nitroarenes withcinnamyl-type sulfones to produce 2-aryl-

4-arylsulfonylquinolinederivatives[77-78]

(Scheme 2.44).Silylating agents such as

TMSCl,TBSCl, bis(trimethylsilyl)acetamide (BTMSA) or lewis acidslike

Ti(OEt)4 and MgCl2 were the most effective additives.

94

Scheme 2.44

In the case of allyl aryl sulfones, modified conditions of combinationof

DBU, BTMSA, and MgCl2 in HMPA as solvent provedsuccessful.[79]

Schreiner

and co-workers have reported an efficient methodfor the synthesis of

substituted 2- and 3-azachalcones.[80]

Usingthe optimized conditions of 1

equivalentof acetophenone, 2 equiv of2- or 3-pyridine carboxaldehyde and 1

equivalentof DBU, substituted2- and 3-azachalcones were obtained in

moderate to high yields(Scheme 2.45).

Scheme 2.45

DBU has also been successfully employed in the [5+1]annulation

reaction of α-alkenoyl ketene-(S,S)-acetals withnitroalkanes providing highly

functionalized phenols and cyclohexenones. The identity of which can be

controlled by the amountof base and reaction temperature used.[81]

The

reactionof 2-[bis(ethylthio)methylene]-N-(4-chlorophenyl)-3-oxo-5-p-

95

tolylpent-4-enamide with nitroethane using 1 equiv. of DBU in DMF as solvent

at room temperature yielded 88% ofcyclohexenone(Scheme 2.46).

Scheme 2.46

By increasing the amount of DBU to 1.5 equiv and elevating the

temperature to 70°C, the phenol was obtained exclusively in 67% yield

(Scheme 2.47).

Scheme 2.47

Wang and co-workers have demonstrated that acyldiazomethanescan be

readily deprotonated with catalytic DBU at roomtemperature and the

deprotonated species then reacted with aldehydesand imines to give the

corresponding β-hydroxy-α-diazocarbonyl compounds in high

yields[82]

(Scheme 2.48). LDA, the morecommonly used base for the

96

aforementioned reaction requireslow temperature and absolutely anhydrous

conditions.

Scheme 2.48

Trauner and co-workers used DBU in benzene atreflux condition for the

cyclization of diketoester to γ–hydroxy-α-pyrone in good yield (Scheme 2.49)

while working on the synthesisof the placidene family of natural products.[83]

Scheme 3.49

Zard and Moutrille have developed an interesting reaction

ofdihydrobenzoisothiazole dioxide derivatives with DBU leadingto the

formation of indolines in good yields[84]

(Scheme 2.50). The

dihydrobenzoisothiazoledioxide derivative is readily prepared byintermolecular

radical addition of a xanthate to a vinyl sulfanilidefollowed by lauroyl

peroxide-induced ring closure to the aromaticring. The formation of indolines

could be explained by retro-cheletropicloss of sulfur dioxide followed by a 1,5-

sigmatropicshift of a hydrogen to give the 2-substituted aniline as the

initialproduct, which then undergoes DBU-induced migration of thedouble

bond followed by intramolecular Michael addition.

97

Scheme 2.50

2.4 Present work

The widespread interest in heterocyclic azole containing systems has

promoted extensive studies of their syntheses. Substituted azoles are useful

intermediates for the syntheses of fused heterocyclic ring systems.

In this chapter, we have reported the multi-component condensation of

3-amino-1, 2, 4-triazole (1), malononitrile (2) and aldehyde (3)in ethanol to

form product triazolopyrimidines (4) by using DBU as a novel catalyst

(Scheme 2.51).

Scheme 2.51

Nucleophilic reactions of binucleophilicazoles takes place through either

of the exocyclic or the endocyclic nitrogen centre, depending on the nature of

the electrophile and the reaction conditions.These azoles and α-

cyanocinnamonitrile have several electron rich and electron deficient sites,

respectively. Thus these reactions are highly regioselective, leading to only one

of the possible isomers (Isomer 1 and Isomer 2) that can be formed under

different conditions (Table 2.1).

NN

NH NH2

+

Ar

N

NN

NH

CN

NH2

EthanolH O

Ar

CN

CN+

DBU

NH2

N

NN

NH

CN

Ar

4 [Isomer 2 (Not formed)]

4 [Isomer 1 (Formed)]

1 23

98

NH

NCN

NH2

N

N

NH

N

NH2

CNN

N

Regioisomer-1 Regioisomer-2

Table 2.1: Effect of catalysts and reaction conditions on the formation of

regioisomers 1 and 2.

Sr.

No. Condition Solvent

Base

Catalyst Isomer 1 Isomer 2

1. Neat[87]

--- --- Not

Formed

Not

Formed

2. Microwave[87]

--- --- Formed Not

Formed

3. Conventional[87]

Ethanol --- Not

Formed

Not

Formed

4. Microwave[87]

Ethanol --- Not

Formed Formed

5. Ultrasonic

Bath[87]

Ethanol ---

Not

Formed Formed

6. Conventional[87]

Water --- Formed Not

Formed

7. Microwave[87]

Water --- Formed Not

Formed

8. Ultrasonic

Bath[87]

Water --- Formed

Not

Formed

9. Conventional[85,86]

Water NaOH Not

Formed Formed

10. Microwave[87]

Water PTC* Formed Not

99

Formed

11. Ultrasonic

Bath[87]

Water PTC* Formed

Not

Formed

12. Conventional[85,86]

Ethanol NaOH Not

Formed Formed

13. Conventional[85,86]

Acetonitrile NaOH Not

Formed Formed

14. Conventional[85,86]

Ethanol TEA Formed Not

Formed

15. Conventional[85,86]

Ethanol L-proline Formed Not

Formed

16. Microwave[85,86]

Ethanol L-proline Formed Not

Formed

17. Conventional[85,86]

Ethanol Acetic acid Formed Not

Formed

18. Microwave[85,86]

Ethanol Acetic acid Formed Not

Formed

In these protocols as mentioned in Scheme2.51, we have investigated

the reactions of α-cyanocinnamonitrile which have three electron deficient

centers two at carbons of nitrile and another at carbon of Cβ with 1,3-

dinucleophile. In these reactions 1, 3-dinucleophiles act via regioselective on

Cβ and carbon of cyano group of α-cyanocinnamonitrile which have three

electron deficient centers. We have reported regioselectivity of the reaction by

using DBU as a novel catalyst (Scheme 2.51).

2.5 Results and Discussion

To optimize the method, the reaction was studied under different

reaction conditions to find the best results. Initially, we examined the reaction

in ethanol with triethylamine as a catalyst as reported under the conventional

method and observed that the desired product was formed in a low yield

(68%).[87]

Interestingly, no product was formed when the reaction was carried

out in ethanol in the absence of catalyst under the conventional method. Further

100

all our attempts to improve the yields at elevated temperature and longer

reaction times were unsuccessful. Accidently, to increase the efficiency and test

the impact of catalyst on regioselectivity we decided to perform the reaction by

using DBU which is a novel catalyst for this type of reaction. We observed that

the reaction proceeded uneventfully in reduced time, forming the desired

product (Isomer 1) in good to an excellent yield(Table2.2). Which shows

thatDBU was found to be superior to other tertiary amines as the catalyst, base

orpromoter.

Table2.2: Effect of Base on % yield of the azolopyrimidines

Entry Ar

Base Catalyst

Triethylamine[87]

DBU

Time (h) Yield (%) Time

(mins) Yield (%)

a

2. 4-ClC6H4 600 68 70 89%

8. 4-OCH3C6H4 720 68 95 84%

Reaction conditions: Aminoazole: 2 mmol, aldehyde: 2mmol, Malononitrile: 2mmol,

suitable base catalyst: 20 mole %, Ethanol: 20ml;

aisolated yield.

2.5.1 Selection of solvent

Our next challenge is to select appropriate solvent media for the

reaction. Among the various solvents tested such as chloroform, acetone,

acetonitrile, methanol and ethanol, the best results were obtained in ethanol.

Aqueous solvent system was found less effective in terms of isolation of

product as compared to a single solvent system.

2.5.2 Concentration of DBU

Next, we were interested to examine the effect of the amount of catalyst

on the yield of the products. Initially, we run the reaction at room temperature

without catalyst where only Knoevenagel condensation product of aldehyde

and malononitrile was observed. Addition of 5 mol% DBU drives the reaction

towards the benzopyran. However, Knoevenagel condensation product was

observed along with tetrahydrobenzo[b]pyran [TLC run in 3:7(v/v)

101

ethylacetate: petroleum ether as solvent system]. An ascending addition of

amount of DBU upto 20mole% progressed the reaction profile in terms of yield

and time and drives the reaction towards the completion. Increment in the

amount of catalyst over 20 mole % was observed without any no effect on yield

and time of reaction. So as we finalized 20mole% as an optimum amount of

DBU as a catalyst.

2.5.3 Effect of reaction temperature

To optimize the reaction temperature, we carried out the reaction at

different temperature conditions ranging from room temperature to reflux

condition. However, at reflux temperature the reaction proceeded with reduced

time and maximum yield. From the above optimization studies, the following

conditions were found to be optimum for the reaction.

Table 2.3Final parameters for the synthesis of Azolopyrimidines

Sr. No. Parameter Quantity

1. Aldehyde 1mmol

2. Malononitrile 1mmol

3. Azole 1mmol

4. DBU 20 mole%

5. Ethanol 10.0 vol

6. Reaction temperature Reflux (pre-set) oil bath

2.5.1 Preparation of different azolopyrimidines

Encouraged by this result and to understand the generally applicability

of this protocol, we have synthesized a variety of azolopyrimidines. For these

purpose different types of aromatic aldehydes containing both electron

withdrawing or donating groups were used successfully in furnishing the

product in good to excellent yields (Table 2.4). These results show that DBU

demonstrates the most excellent catalytic activity.

102

Table 2.4: DBU-mediated synthesis of triazolopyrimidines and

benzimidazolopyrimidines

Entry Compound Time

(h)

Yield

(%)

M.P.

Observed Literature

2a

NH

NCN

NH2

N

N

Cl

80 82 179-

182°C

Not

Reported

2b

NH

NCN

NH2

N

N

Cl

70 89 156-

158°C 157°C

[87]

2c

NH

NCN

NH2

N

N

F

85 83 246-

248°C

Not

Reported

2d

NH

NCN

NH2

N

N

OH

85 81 182-

184°C

Not

Reported

103

2e

NH

NCN

NH2

N

N

NCH3CH3

75 78 235-

238°C

Not

Reported

2f

NH

NCN

NH2

N

N

CF3

95 79 177-

179°C

Not

Reported

2g

NH

NCN

NH2

N

N

OCH3

95 84 113-

115°C 115°C

[87]

2h

NH

NCN

NH2

N

N

F

105 81 124-

126°C

Not

Reported

2i

NH

NCN

NH2

N

N

80 83 170-

172°C 172°C

[87]

104

2j

NH

NCN

NH2N

125 83 236–

237°C

235–

236°C[88]

2k

NH

NCN

NH2N

Cl

115 81 238°C 238°C[88]

2l

NH

NCN

NH2N

NO2

135 83 242°C 243°C[88]

2m

NH

NCN

NH2

N

N

NO2

125 79 237°C 236°C[88]

Reaction conditions: Aminoazole: 4 mmol, aldehyde: 4 mmol, Malononitrile: 4

mmol, DBU: 0.8ml, Ethanol: 40ml;

aisolated yield.

2.5.2 Mechanism and supporting evidence for the synthesis of

azolopyrimidines by using DBU as a catalyst

The multicomponent condensation of binucleophilicaminoazole,

malononitrile and aldehyde afforded the product azolopyrimidines. Formation

of azolopyrimidines can be explained by the intermediacy of

arylidenemalononitrile (indicated by TLC studies). A plausible mechanism of

the multicomponent reaction of above azolopyrimidinesgiven in Scheme 2.52is

105

confirmed by carrying out the reaction of pre-synthesized

arylidenemalononitrilederivative.

The first step involved condensation of aldehyde and malononitrile to

afford an intermediate which on Michael addition of endocyclic nitrogen

nucleophile of aminoazoleformsan intermediate. Furthermore, the

intramolecular cyclization resulted in the formationazolopyrimidines[7].

O

H

+

CN

CN

CN

NC + N

NH

NH2

CNN

NNH2 N

[1]

[2]

[3]

[4]

[5]

[6]

[7]

-H2O

Knovenagel condensation

Michael addition

N

NNH

CN

NH

N

NNH

CN

NH2

Scheme 2.52

2.6 Experimental Procedure

0.8ml of DBU (20 mole%) was added in a mixture of the aminoazole

(4mmol), aldehyde (4mmol) and malononitrile (4mmol) in ethanol (40 ml). The

reaction mixture is refluxed under stirring until completion of reaction, as

monitored by TLC. The product precipitated from the reaction mixture after

cooling wasfiltered and recrystallized from ethanol.

106

2.7 Spectral Analysis of azolopyrimidines

The structures of synthesized compounds (Table 2.4) were confirmed on the basis of IR, 1H NMR,

13C NMR and mass

spectroscopic data. The spectroscopic data (Table 2.5) were in full agreement with the literature values.

Table 2.5 Spectral analysis of DBU catalyzed azolopyrimidines

Entry Spectrum Spectrum

No. Structure Elucidation of azolopyrimidines

2b

IR (KBr) 2.1 νmax= 3497- 3184, 2197, 1662, 1632, 1534 cm -1

1H NMR(DMSO-d6+CDCl3) 2.2

δ = 5.306 (s, 1H, CH), 6.975 (s, 2H, NH2), 7.279-7.351(m, 4H,Ar-H),

7.524 (s, 1H, NH), 8.65 (s, 1H, triazolic proton) ppm

Mass 2.3 m/z = 273.1(M+1)

2i

IR (KBr) 2.4 3427- 3053, 2186, 1679, 1639, 1599 cm -1

1H NMR (DMSO-d6+CDCl3) 2.5

δ = 5.327(s, 1H, CH), 7.202 (s, 2H, NH2), 7.269-7.404 (m, 5H,Ar-H),

7.702 (s, 1H, NH), 8.775 (s, 1H, triazolic proton) ppm

13CNMR (DMSO-d6+CDCl3) 2.6

δ = 54.43, 56.49, 119.48, 126.49, 128.48, 129.17, 143.64, 147.46, 152.34,

154.42 ppm

2j

IR (KBr) 2.7 νmax= 3435-3056, 2189, 1679, 1631, 1602 cm -1

1H NMR (DMSO-d6+CDCl3) 2.8

δ = 5.195 (s, 1H, CH), 6.816 (s, 2H, NH2*), 6.965-7.016 (t, 1H,Ar-H),

7.079- 7.129 (t, 1H,Ar-H), 7.206-7.365 (m, 6H,Ar-H), 7.600-7.626 (d,

1H,Ar-H), 8.579 (s, 1H, triazolic proton) ppm

107

13CNMR (DMSO-d6+CDCl3) 2.9

δ = 53.68, 62.40, 112.85, 116.53, 119.63, 120.34, 123.80, 126.34, 128.31,

129.16, 129.73, 143.37, 144.04, 149.57, 152.20 ppm

Mass 2.10 m/z = 288.1 (M+1)

2k

IR (KBr) 2.11 νmax= 3427-3053, 2186, 1679, 1639, 1600 cm -1

1H NMR (DMSO-d6+CDCl3) 2.12

δ = 5.242 (s, 1H, CH), 6.859 (s, 2H, NH2), 6.969-7.019 (t, 1H,Ar-H),

7.082-7.133 (t, 1H,Ar-H), 7.210-7.236 (d, 1H,Ar-H), 7.280-7.7.308 (d,

2H,Ar-H), 7.405-7.433 (d, 2H,Ar-H), 7.602-7.628 (d, 1H,Ar-H), 8.592 (s,

1H, triazolic proton) ppm

13CNMR (DMSO-d6+CDCl3) 2.13

δ = 53.03, 61.93, 112.89, 116.59, 119.48, 120.42, 123.86, 128.38, 129.15,

129.70, 132.89, 142.25, 143.99, 149.69, 152.03 ppm

Mass 2.14 m/z = 322.1 (M+1)

2l

1H NMR (DMSO-d6+CDCl3) 2.15

δ = 5.226 (s, 1H, CH), 6.792 (s, 2H, NH2), 6.984-7.638 (m, 8H,Ar-H and -

NH), 8.645 (s, 1H, triazolic proton) ppm

13CNMR (DMSO-d6+CDCl3) 2.16

δ = 151.88, 149.65, 143.72, 142.03, 133.06, 129.62, 129.01, 128.29,

123.76, 120.35, 116.44, 112.83, 95.98, 61.82, 53.18 ppm

2h

IR (KBr) 2.17 νmax= 3416-3127, 2186, 1652, 1598 cm -1

1H NMR (DMSO-d6+CDCl3) 2.18

δ = 5.290 (s, 1H, CH), 6.832 (s, 2H, NH2), 6.932-7.342 (m, 4H, Ar-H),

7.471 (s, 1H, -NH) , 8.617 (s, 1H, triazolic proton) ppm

13CNMR (DMSO-d6+CDCl3) 2.19 δ = 154.08, 151.94, 147.42, 145.78, 130.66, 130.55, 122.20, 119.05,

108

115.21, 114.93, 113.46, 113.18, 68.69, 56.31, 54.25 ppm

Mass 2.20 m/z = 257.2 (M+1)

2c IR (KBr) 2.21 νmax= 3497-3185, 2195, 1661, 1600 cm

-1

Mass 2.22 m/z = 257.2 (M+1)

2f IR (KBr) 2.23 νmax= 3369-3243, 2189, 1645, 1605 cm

-1

Mass 2.24 m/z = 307.1 (M+1)

2d IR (KBr) 2.25 νmax= 3442-3351, 2204, 1610, 1597, 1549 cm

-1

Mass 2.26 m/z = 254.9 (M+1)

2a IR (KBr) 2.27 νmax= 3438-3304, 2183, 1651, 1581, 1521 cm

-1

Mass 2.28 m/z = 273.1 (M+1)

2e IR (KBr) 2.29 νmax= 3359-3272, 2210, 1659, 1615, 1563, 1523 cm

-1

Mass 2.30 m/z = 282.1 (M+1)

2g

IR (KBr) 2.31 3368 - 3264, 2184, 1683, 1622, 1507 cm -1

1H NMR (DMSO-d6+CDCl3) 2.32

δ = 3.828 (s, 3H, -OCH3), 5.220 (s, 1H, methine -CH), 6.713 (brs, 2H,

NH2), 6.808-6.836 (m, 2H, Ar-H), 7.220 (m, 2H, Ar-H) , 7.451 (s, 1H, -

NH), 8.449 (s, 1H, triazolic proton) ppm

Mass 2.33 m/z = 266.9 (M+1)

2m IR 2.34 νmax= 3429, 3241, 3077, 2183, 1656, 1521, 1350,1275, 1159 cm

-1

Mass 2.35 m/z = 282.1 (M+1)

109

2.8 Conclusion

In conclusion, an efficient synthesis of triazolopyrimidines, asbuilding

blocks in herbicidal drugs and pharmaceuticals, synthesis has been developed

via a multicomponent condensation reaction between 3-amino-1,2,4-triazole,

malononitrile and aldehyde using DBU as a novel catalyst. The advantages this

methodology is short reaction time, enhanced yield, high selectivity and

operational simplicity render this method an attractive for the rapid synthesis of

triazolopyrimidines.

110

DKS-248

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

-1.0

0

2

4

6

8

10

12

14

16

18

20

22

24

25.5

cm-1

%T

3497.10

3184.392196.74

1899.82

1804.87

1661.64

1534.16

1485.11

1411.34

1364.13

1288.83

1217.011156.32

1090.25

1013.24

968.02

907.28

821.90

785.56732.20

617.20558.07

2913.16

3120.44

NH

NCN

NH2

N

N

Cl

Spectrum 2.1: IR spectrum of 5-amino-7-(4-chlorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

111

NH

NCN

NH2

N

N

Cl

Spectrum 2.2: 1HNMR spectrum of 5-amino-7-(4-chlorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

112

Spectrum 2.3: Mass spectrum of 5-amino-7-(4-chlorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

NH

NCN

NH2

N

N

Cl

113

DKS-345

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

23.0

26

28

30

32

34

36

38

40

42

44

46

48

50

52

53.9

cm-1

%T

3427.00

3327.65

3216.91 2918.53

2186.43

1679.45

1639.501599.77 1468.83

1442.64

1403.01

1246.07

1158.09

1091.10814.95

736.28

538.83497.97

3053.22

NH

NCN

NH2

N

N

Spectrum 2.4: IR spectrum of 5-amino-7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

114

NH

NCN

NH2

N

N

Spectrum 2.5: 1H NMR spectrum of 5-amino-7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

115

Spectrum 2.6: 13

C NMR spectrum of 5-amino-7-phenyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

NH

NCN

NH2

N

N

116

DKS-341

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

3.6

5

10

15

20

25

30

35

38.1

cm-1

%T 3434.63

3321.81 3055.852878.92

2188.87 1679.20

1601.64

1465.241441.27

1402.20

1245.03

1162.00

1103.47

1026.28

921.75

796.47

733.08

700.84

527.96

479.35

Spectrum 2.7: IR spectrum of 2-amino-4-phenyl-1,4-dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile

NH

NCN

NH2N

117

Spectrum 2.8: 1H NMR spectrum of 2-amino-4-phenyl-1,4-dihydropyrimido[1,2-a]benzimidazole-3-

carbonitrile

NH

NCN

NH2N

118

NH

NCN

NH2N

Spectrum 2.9: 13

C NMR spectrum of 2-amino-4-phenyl-1,4-dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile

119

TIC: from Sample 8 (DKS- 341) of Data23.08.2012.wiff (Turbo Spray) Max. 2.6e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

5.0e8

1.0e9

1.5e9

2.0e9

2.5e9

In

te

ns

it

y,

..

.

1.11

1.93 4.472.96 4.12 4.813.232.21 2.50 2.74 3.820.880.59

+EMS: Exp 1, 1.256 min from Sample 8 (DKS- 341) of Data23.08.2012.wiff (Turbo Spray) Max. 5.0e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

5.0e7

In

te

ns

it

y,

..

.

288.0

134.0

286.1

135.1308.0

340.3290.2 435.1210.1 227.0149.2 369.5237.0182.0 378.1166.1

+ER (286.06,287.14) FT(2,2): Exp 2, 1.275 min from Sample 8 (DKS- 341) of Data23.08.2012.wiff ... Max. 9.1e7 cps.

260 265 270 275 280 285 290 295 300 305 310 315m/z, Da

0.0

2.0e7

4.0e7

6.0e7

8.0e7

9.1e7

In

te

ns

it

y,

..

.

288.1

286.1

289.1

287.2

290.1286.5 292.0

+EPI (288.10) Charge (+1) CE (25.7097) FT (171.545): Exp 4, 1.301 min from Sample 8 (DKS- 34... Max. 1.4e6 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e5

4.0e5

6.0e5

8.0e5

1.0e6

1.2e6

1.4e6

In

te

ns

it

y,

..

.

133.6

132.0222.1155.2

288.1

92.2

128.3107.0 137.293.7 119.3 210.0 271.1

80.3

Spectrum 2.10: Mass spectrum of 2-amino-4-phenyl-1,4-dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile

NH

NCN

NH2N

120

DKS-345

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

23.0

26

28

30

32

34

36

38

40

42

44

46

48

50

52

53.9

cm-1

%T

3427.00

3327.65

3216.91 2918.53

2186.43

1679.45

1639.501599.77 1468.83

1442.64

1403.01

1246.07

1158.09

1091.10814.95

736.28

538.83497.97

3053.22

Spectrum 2.11: IR spectrum of 2-Amino-4-(4-chlorophenyl)-1,4-dihydropyrimido[1,2-a]benzimidazole-3-carbonitrile

NH

NCN

NH2N

Cl

121

Spectrum 2.12: 1H NMR spectrum of 2-amino-4-(4-chlorophenyl)-1,4-dihydropyrimido[1,2-a]benzimidazole-3-

carbonitrile

NH

NCN

NH2N

Cl

122

Spectrum 2.13:

13C NMR spectrum of 2-amino-4-(4-chlorophenyl)-1,4-dihydropyrimido[1,2-a]benzimidazole-3-

carbonitrile

NH

NCN

NH2N

Cl

123

TIC: from Sample 7 (DKS- 345) of Data23.08.2012.wiff (Turbo Spray) Max. 5.3e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

1.0e9

2.0e9

3.0e9

4.0e9

5.0e9

In

te

ns

it

y,

..

.

1.16

2.642.21 4.800.20 4.393.982.98 4.570.34 3.332.11 3.61

+EMS: Exp 1, 1.145 min from Sample 7 (DKS- 345) of Data23.08.2012.wiff (Turbo Spray) Max. 6.5e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

5.0e7

6.0e7

In

te

ns

it

y,

..

.

322.0

324.0

133.9

344.0

346.2320.2256.0136.1 292.3 434.9107.0 237.2 277.1 355.2 373.3 401.3

+ER (321.99,324.06) FT(2,2): Exp 2, 1.164 min from Sample 7 (DKS- 345) of Data23.08.2012.wiff ... Max. 1.2e8 cps.

295 300 305 310 315 320 325 330 335 340 345 350m/z, Da

0.00

2.00e7

4.00e7

6.00e7

8.00e7

1.00e8

1.20e8

In

te

ns

it

y,

..

.

322.1

324.0

323.1

325.0

320.3 326.1

+EPI (322.12) Charge (+1) CE (27.6827) FT (51.0007): Exp 4, 1.184 min from Sample 7 (DKS- 34... Max. 4.7e6 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e6

2.0e6

3.0e6

4.0e6

4.7e6

In

te

ns

it

y,

..

.

133.6

132.1

256.1

189.1 322.192.0

131.0107.2

144.193.8 162.1 305.080.0 210.1 286.0220.1

NH

NCN

NH2N

Cl

Spectrum 2.14: Mass spectrum of 2-Amino-4-(4-chlorophenyl)-1,4-dihydropyrimido[1,2-a]benzimidazole-3-

carbonitrile

124

NH

NCN

NH2N

NO2

Spectrum 2.15: 1H NMR spectrum of 2-amino-4-(4-nitrophenyl)-1,4-dihydropyrimido[1,2-a]benzimidazole-3-

carbonitrile

125

NH

NCN

NH2N

NO2

Spectrum 2.16: 13

C NMR spectrum of 2-amino-4-(4-nitrophenyl)-1,4-dihydropyrimido[1,2-a]benzimidazole-3-

carbonitrile

126

DKS-235

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450.0

6.0

8

10

12

14

16

18

20

22

24

26

28

30

32.8

cm-1

%T

3126.68

2185.71

1805.02

1652.06

1524.18

1487.43

1369.21

1321.851284.21

1249.881210.84

1153.23

1027.41969.27

940.36

906.88872.64

785.93

733.95

701.73

622.18

530.33507.29

3368.13

3280.21

Spectrum 2.17: IR spectrum of 5-amino-7-(3-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

NH

NCN

NH2

N

N

F

127

NH

NCN

NH2

N

N

F

Spectrum 2.18: IR spectrum of 5-amino-7-(3-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

128

NH

NCN

NH2

N

N

F

Spectrum 2.19: IR spectrum of 5-amino-7-(3-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

129

TIC: from Sample 12 (DKS- 237) of Data23.08.2012.wiff (Turbo Spray) Max. 3.9e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

1.0e9

2.0e9

3.0e9

3.9e9

In

te

ns

it

y,

..

.

0.72

0.084.420.50 1.34

1.44 2.05 2.481.65 2.20 4.212.82 4.893.13

+EMS: Exp 1, 0.632 min from Sample 12 (DKS- 237) of Data23.08.2012.wiff (Turbo Spray) Max. 7.3e6 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e6

4.0e6

6.0e6

7.3e6

In

te

ns

it

y,

..

.

321.0

343.4256.9

340.4227.2

249.1279.2

286.0 365.2148.9 209.0173.0 338.0 371.4 436.0

203.0 403.1236.0 307.2133.1 288.2 345.0273.0 419.3

+ER (321.11,257.01) FT(2,5.72958): Exp 2, 0.651 min from Sample 12 (DKS- 237) of Data23.08.2... Max. 1.9e7 cps.

245 250 255 260 265 270 275 280 285 290 295 300 305 310 315 320 325 330m/z, Da

0.0

5.0e6

1.0e7

1.5e7

1.9e7

In

te

ns

it

y,

..

.

321.1

257.1

322.0

258.1323.1255.1 327.1261.0 321.5

+EPI (257.07) Charge (+1) CE (23.9099) FT (250): Exp 4, 0.681 min from Sample 12 (DKS- 237) o... Max. 8.1e5 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e5

4.0e5

6.0e5

8.0e5

In

te

ns

it

y,

..

.

67.6

190.982.4

76.9

73.8 257.2

85.9124.1

95.0 198.1173.0 240.157.1 134.097.1

NH

NCN

NH2

N

N

F

Spectrum 2.20: Mass spectrum of 5-amino-7-(3-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

130

DKS-237

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0 5.0

10

15

20

25

30

35

40

45 47.0

cm-1

%T

3497.00

3185.49

3116.17

2917.85

2194.88

1892.98

1661.09 1600.14

1529.79 1508.18

1484.83

1364.98

1313.78 1285.52

1219.02 1156.49

1114.64 1096.44

1013.42 967.83

911.32

836.17

790.79 775.43

732.62 673.80

629.93 568.51

515.09

NH

NCN

NH2

N

N

F

Spectrum 2.21: IR spectrum of 5-amino-7-(4-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

131

TIC: from Sample 12 (DKS- 237) of Data23.08.2012.wiff (Turbo Spray) Max. 3.9e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

1.0e9

2.0e9

3.0e9

3.9e9

In

te

ns

it

y,

..

.

0.72

0.084.420.50 1.34

1.44 2.05 2.481.65 2.20 4.212.82 4.893.13

+EMS: Exp 1, 0.632 min from Sample 12 (DKS- 237) of Data23.08.2012.wiff (Turbo Spray) Max. 7.3e6 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e6

4.0e6

6.0e6

7.3e6

In

te

ns

it

y,

..

.

321.0

343.4256.9

340.4227.2

249.1279.2

286.0 365.2148.9 209.0173.0 338.0 371.4 436.0

203.0 403.1236.0 307.2133.1 288.2 345.0273.0 419.3

+ER (321.11,257.01) FT(2,5.72958): Exp 2, 0.651 min from Sample 12 (DKS- 237) of Data23.08.2... Max. 1.9e7 cps.

245 250 255 260 265 270 275 280 285 290 295 300 305 310 315 320 325 330m/z, Da

0.0

5.0e6

1.0e7

1.5e7

1.9e7

In

te

ns

it

y,

..

.

321.1

257.1

322.0

258.1323.1255.1 327.1261.0 321.5

+EPI (257.07) Charge (+1) CE (23.9099) FT (250): Exp 4, 0.681 min from Sample 12 (DKS- 237) o... Max. 8.1e5 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e5

4.0e5

6.0e5

8.0e5

In

te

ns

it

y,

..

.

67.6

190.982.4

76.9

73.8 257.2

85.9124.1

95.0 198.1173.0 240.157.1 134.097.1

NH

NCN

NH2

N

N

F

Spectrum 2.22: Mass spectrum of 5-amino-7-(4-fluorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

132

DKS-238

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

8.0

10

15

20

25

30

35

40

45

49.5

cm-1

%T

3369.28

3243.49

2897.29

2188.87

1644.84

1578.45

1520.331485.22

1439.10

1365.10

1329.25

1293.76

1172.17

1122.951078.34

968.54

910.05814.15

793.96

763.31

727.79

699.27643.57

622.84

588.78

543.26

503.96

NH

NCN

NH2

N

N

CF3

Spectrum 2.23: IR spectrum of 5-amino-7-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-

6-carbonitrile

133

TIC: from Sample 13 (DKS- 238) of Data23.08.2012.wiff (Turbo Spray) Max. 1.5e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0Time, min

0.0

5.0e8

1.0e9

1.5e9

In

te

ns

it

y,

..

.

3.42 4.301.15 2.150.69 3.87 4.511.901.72 2.524.953.00 4.121.480.60 3.693.14

+EMS: Exp 1, 0.976 min from Sample 13 (DKS- 238) of Data23.08.2012.wiff (Turbo Spray) Max. 2.5e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

5.0e6

1.0e7

1.5e7

2.0e7

2.5e7

In

te

ns

it

y,

..

.

307.1329.0

227.0340.4 435.4209.2149.2 295.1 305.4 383.5 394.8241.0 345.1281.3185.0169.1136.9

+ER (307.15,329.08) FT(3.58478,30.3416): Exp 2, 0.996 min from Sample 13 (DKS- 238) of Data2... Max. 1.9e7 cps.

280 285 290 295 300 305 310 315 320 325 330 335 340 345 350 355m/z, Da

0.0

5.0e6

1.0e7

1.5e7

1.9e7

In

te

ns

it

y,

..

.

307.1

308.1329.0

330.0305.1 309.1

331.0

+EPI (307.08) Charge (+1) CE (26.8106) FT (250): Exp 3, 1.017 min from Sample 13 (DKS- 238) o... Max. 1.0e6 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.00

2.00e5

4.00e5

6.00e5

8.00e5

1.00e6

In

te

ns

it

y,

..

.

65.569.0

241.082.0

70.9221.2

86.0 174.0307.1

309.157.1 161.2 247.287.1 134.0127.063.1 181.0 203.2 287.2267.0223.1

NH

NCN

NH2

N

N

CF3

Spectrum 2.24: Mass spectrum of 5-amino-7-[3-(trifluoromethyl)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-

6-carbonitrile

134

NH

NCN

NH2

N

N

OH

DKS-239

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450.0

27.0

28

30

32

34

36

38

40

42

44

46

48

50

52

54.1

cm-1

%T 3441.89

3351.18

3239.33

2204.21

1610.041549.11

1488.77

1383.32

1156.78

761.67

533.53

Spectrum 2.25: IR spectrum of 5-amino-7-(2-hydroxyphenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

135

TIC: from Sample 15 (DKS- 239) of Data23.08.2012.wiff (Turbo Spray) Max. 2.5e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

5.0e8

1.0e9

1.5e9

2.0e9

2.5e9

In

te

ns

it

y,

..

.

0.94

0.073.102.302.02 2.58 4.00 4.463.382.74

+EMS: Exp 1, 1.161 min from Sample 15 (DKS- 239) of Data23.08.2012.wiff (Turbo Spray) Max. 4.2e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

In

te

ns

it

y,

..

.

153.1

253.1

340.3275.2268.1 371.0290.2

444.1337.2210.0 227.0 295.1 344.4155.0383.3169.3121.2107.2

+ER (253.05,275.11) FT(2,2.86044): Exp 2, 1.180 min from Sample 15 (DKS- 239) of Data23.08.2... Max. 5.1e7 cps.

225 230 235 240 245 250 255 260 265 270 275 280 285 290 295m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

5.0e7

In

te

ns

it

y,

..

.

253.1

275.0255.1253.5

+EPI (253.07) Charge (+1) CE (23.6779) FT (2): Exp 3, 1.189 min from Sample 15 (DKS- 239) of D... Max. 2.9e7 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

5.0e6

1.0e7

1.5e7

2.0e7

2.5e7

2.9e7

In

te

ns

it

y,

..

.

253.2

236.0

211.0225.4171.0

254.9

NH

NCN

NH2

N

N

OH

Spectrum 2.26: Mass spectrum of 5-amino-7-(2-hydroxyphenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

136

DKS-240

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

0.0

2

4

6

8

10

12

14

16

18

20

22

24

26.0

cm-1

%T

3304.15

2183.53

1798.75

1651.89 1521.381481.05

1370.40

1283.561260.05

1205.72

1177.401151.58

1111.62

1038.35

970.32903.02

869.78

824.50

794.23

761.83

732.63

702.09

672.21

634.11609.07

545.87513.11

450.35

422.38

Spectrum 2.27: IR spectrum of 5-amino-7-(2-chlorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

NH

NCN

NH2

N

N

Cl

137

TIC: from Sample 10 (DKS- 240) of Data23.08.2012.wiff (Turbo Spray) Max. 5.7e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

1.0e9

2.0e9

3.0e9

4.0e9

5.0e9

5.7e9

In

te

ns

it

y,

..

.

0.77

0.08 0.30 2.851.19 2.732.28 4.684.441.86 3.23 3.703.06 3.961.530.56

+EMS: Exp 1, 0.685 min from Sample 10 (DKS- 240) of Data23.08.2012.wiff (Turbo Spray) Max. 1.2e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.00

2.00e6

4.00e6

6.00e6

8.00e6

1.00e7

1.20e7

In

te

ns

it

y,

..

.

337.0

340.3273.1

343.4331.4 359.2

295.1284.2

262.3

264.0 435.4210.1 361.0342.0281.8149.0129.0 227.2 236.8 411.1326.2 369.1307.9192.0159.1 405.2117.1

+ER (337.05,273.13) FT(2,4.22104): Exp 2, 0.704 min from Sample 10 (DKS- 240) of Data23.08.2... Max. 2.0e7 cps.

270 275 280 285 290 295 300 305 310 315 320 325 330 335 340 345m/z, Da

0.0

5.0e6

1.0e7

1.5e7

2.0e7

In

te

ns

it

y,

..

.

337.0

339.1

273.0 340.2

338.1343.3275.0

271.0 331.3341.0326.2 337.4

+EPI (273.03) Charge (+1) CE (24.8359) FT (250): Exp 4, 0.734 min from Sample 10 (DKS- 240) o... Max. 5.0e5 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e5

2.0e5

3.0e5

4.0e5

5.0e5

In

te

ns

it

y,

..

.

83.3 171.1

79.8

66.1 71.9237.1 273.1207.1

75.6189.185.9

57.1 214.187.6 195.0162.1231.1 256.0140.2

94.8

Spectrum 2.28: Mass spectrum of 5-amino-7-(2-chlorophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

NH

NCN

NH2

N

N

Cl

138

NH

NCN

NH2

N

N

NCH3CH3

DKS-241

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

1.0

5

10

15

20

25

30

35

40

45

48.7

cm-1

%T

3358.87

3271.80

3183.28

2913.94

2814.02

2209.86

2191.35 1658.881615.84

1563.14

1523.661482.03

1419.17

1388.54

1361.94

1260.271231.81

1198.641179.61

1065.24

968.18

944.53

929.53

817.15

788.52730.25

623.20

601.03

564.21520.22

Spectrum 2.29: IR spectrum of 5-amino-7-[4-(dimethylamino)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a] pyrimidine-

6-carbonitrile

139

TIC: from Sample 9 (DKS- 241) of Data23.08.2012.wiff (Turbo Spray) Max. 5.1e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0Time, min

0.0

1.0e9

2.0e9

3.0e9

4.0e9

5.0e9

In

te

ns

it

y,

..

.

1.11

1.63 1.82 3.952.60 3.312.930.52 2.262.024.07 4.854.574.383.50 3.82

+EMS: Exp 1, 0.770 min from Sample 9 (DKS- 241) of Data23.08.2012.wiff (Turbo Spray) Max. 6.1e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

5.0e7

6.0e7

In

te

ns

it

y,

..

.

282.0

265.2

304.1

340.4161.0 284.3122.2 198.1 216.1331.3107.2 237.1 267.4

169.1 351.2 393.4301.1 435.2148.8

+ER (282.15,265.17) FT(2,10.8756): Exp 2, 0.789 min from Sample 9 (DKS- 241) of Data23.08.20... Max. 5.7e7 cps.

240 245 250 255 260 265 270 275 280 285 290 295 300 305 310m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

5.0e7

5.7e7

In

te

ns

it

y,

..

.

282.1

283.1

284.1271.1 280.2270.1 278.4266.1

+EPI (266.12) Charge (+1) CE (24.4347) FT (250): Exp 4, 0.819 min from Sample 9 (DKS- 241) of ... Max. 1.3e5 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e4

4.0e4

6.0e4

8.0e4

1.0e5

1.2e5

In

te

ns

it

y,

..

.

266.3

154.2

211.1 239.2182.2

NH

NCN

NH2

N

N

NCH3CH3

Spectrum 2.30: Mass spectrum of 5-amino-7-[4-(dimethylamino)phenyl]-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

140

DKS-242

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 450.0

6.0

8

10

12

14

16

18

20

22

24

26

28

30

32

34.3

cm-1

%T

3368.00

3263.81

3131.97

2839.22

2184.40

1908.31

1756.73

1682.96 1507.121485.32

1370.32

1307.241251.60

1210.02

1177.87

1147.94

1119.92

1059.59

1026.29

964.32

881.08

838.30

822.18798.46

771.62

730.23

678.51

636.35

581.37546.24

524.10

Spectrum 2.31: IR spectrum of 5-amino-7-(4-methoxyphenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

NH

NCN

NH2

N

N

OCH3

141

NH

NCN

NH2

N

N

OCH3

Spectrum 2.32: IR spectrum of 5-amino-7-(4-methoxyphenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

142

TIC: from Sample 14 (DKS- 242) of Data23.08.2012.wiff (Turbo Spray) Max. 7.7e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5 5.0Time, min

0.0

2.0e9

4.0e9

6.0e9

7.7e9

In

te

ns

it

y,

..

.

0.83

1.651.43 2.05 2.282.812.682.490.08 3.12 3.48 4.463.87 4.35 4.62 4.920.17

+EMS: Exp 1, 0.849 min from Sample 14 (DKS- 242) of Data23.08.2012.wiff (Turbo Spray) Max. 7.2e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

2.0e7

4.0e7

6.0e7

7.2e7

In

te

ns

it

y,

..

.

266.9

333.0

289.1

355.2

282.2270.2 334.7153.1

290.5203.2 371.0252.4 411.2364.2223.9169.2109.1

+ER (268.15,266.87) FT(2,2): Exp 2, 0.868 min from Sample 14 (DKS- 242) of Data23.08.2012.wiff... Max. 1.2e8 cps.

240 245 250 255 260 265 270 275 280 285 290 295m/z, Da

0.00

2.00e7

4.00e7

6.00e7

8.00e7

1.00e8

1.20e8

In

te

ns

it

y,

..

.

267.0268.0

267.3

269.1

266.4270.1

271.0

+EPI (267.00) Charge (+1) CE (24.4859) FT (5.42183): Exp 3, 0.877 min from Sample 14 (DKS- 2... Max. 2.6e7 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

5.0e6

1.0e7

1.5e7

2.0e7

2.5e7

In

te

ns

it

y,

..

.

266.9

252.1224.2

85.1

183.2

212.3184.2228.6 257.2134.2 187.9

172.8 223.2280.2

NH

NCN

NH2

N

N

OCH3

Spectrum 2.33: Mass spectrum of 5-amino-7-(4-methoxyphenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

143

DKS-247

Date: Wednesday, June 27, 2012

4000.0 3600 3200 2800 2400 2000 1800 1600 1400 1200 1000 800 600 400.0

0.0

5

10

15

20

25

30

35

40

46.0

cm-1

%T

3428.89

3241.31

3077.55

2183.44

1791.99

1656.581586.71

1571.14

1521.33

1488.70

1350.74

1318.181294.76

1275.14

1213.091191.25

1159.59

1099.24

999.90967.93

899.41

882.12

824.38

793.71

743.65

730.91

716.65

688.15

666.91

643.47

625.29

522.59

494.19

421.10

NH

NCN

NH2

N

N

NO2

Spectrum 2.34: IR spectrum of 5-amino-7-(3-nitrophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-

carbonitrile

144

TIC: from Sample 16 (DKS- 247) of Data23.08.2012.wiff (Turbo Spray) Max. 3.7e9 cps.

0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 4.5Time, min

0.0

1.0e9

2.0e9

3.0e9

3.7e9

In

te

ns

it

y,

..

.

0.96

0.620.36 3.011.99 4.303.83 4.062.222.39 2.68 3.38 3.60

+EMS: Exp 1, 0.969 min from Sample 16 (DKS- 247) of Data23.08.2012.wiff (Turbo Spray) Max. 6.9e7 cps.

100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

5.0e7

6.0e7

6.9e7

In

te

ns

it

y,

..

.

282.0

283.1

304.1

169.2 236.0 326.2297.0340.4227.3 403.7284.9185.2 255.2153.1 391.3136.0

+ER (282.01,283.11) FT(2,2): Exp 2, 0.988 min from Sample 16 (DKS- 247) of Data23.08.2012.wiff... Max. 1.2e8 cps.

255 260 265 270 275 280 285 290 295 300 305 310m/z, Da

0.00

2.00e7

4.00e7

6.00e7

8.00e7

1.00e8

1.20e8

In

te

ns

it

y,

..

.

282.0

283.1

284.1

282.7 286.0

+EPI (282.08) Charge (+1) CE (25.3604) FT (2.32903): Exp 3, 0.996 min from Sample 16 (DKS- 2... Max. 4.9e7 cps.

60 80 100 120 140 160 180 200 220 240 260 280 300 320 340 360 380 400 420 440m/z, Da

0.0

1.0e7

2.0e7

3.0e7

4.0e7

4.9e7

In

te

ns

it

y,

..

.

236.0282.1

224.285.1

182.0197.2 220.1 238.2156.1 284.2

NH

NCN

NH2

N

N

NO2

Spectrum 2.35: Mass spectrum of 5-amino-7-(3-nitrophenyl)-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile

145

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