7.07 bicyclic 5-6 systems: three heteroatoms 1:2aether.cmi.ua.ac.be/artikels/comprehensive...th e...

7.07Bicyclic 5-6 Systems: ThreeHeteroatoms 1:2THOMAS J. DELIA

Central Michigan University, Mount Pleasant, Ml, USA

and

DEREK T. HURSTKingston University, Kingston upon Thames, UK7.07.1 INTRODUCTION 230

7.07.2 THEORETICAL METHODS 231

7.07.3 EXPERIMENTAL STRUCTURAL METHODS 232

7.07.4 THERMODYNAMIC ASPECTS 233

7.07.5 REACTIVITY OF THE BICYCLIC RINGS AND RING SUBSTITUENTS 233

234234238238238240240240242242243244

7.07.6 RING SYNTHESES 245

7.07.6.1 Pyrrolopyridazines 2457.07.6.1.1 Pynolo[2,3-c]pyridazines 2457.07.6.1.2 Pyrrolo[2,3-d]pyridazines 2467.07.6.13 Pyrrolo[3,4-c]pyridazines 2477.07.6.1.4 Pyrrolo[3,4-d]pyridazines andpyrrolo[3,2-c]pyridazines 247

7.07.6.2 Pyrrolopyrimidines 2477.07.6.2.1 Pyrrolo[2,3-d]pyrimidines 2487.07.6.2.2 Pyrrolo[3,2-d]pyrimidines ( 9-deazapurines ) 2527.07.6.2.3 Pyrrolo[3,4-d]pyrimidines 255

7.07.6.3 Pyrrolopyrazines 2567.07.6.3.1 Pyrrolo[2,3-b]pyrazines 2567.07.6.3.2 Pyrrolo[3,4-bjpyrazines 256

7.07.6.4 Furopyridazines 2577.07.6.4.1 Furo[2,3-c]pyridazines 2577.07.6.4.2 Furo[2,3-d]pyridazines andfuro[3,4-c]pyridazines 2587.07.6.4.3 Furo[3,4-d]pyridazines 258

229

7.07.5.17.07.5.27.07.5.37.07.5.47.07.5.57.07.5.67.07.5.77.07.5.87.07.5.97.07.5.107.07.5.117.07.5.12

PyrrolopyridazinesPyrrolopyrimidinesPyrrolopyrazinesFuropyridazinesFuropyrimidinesFuropyrazinesThienopyridazinesThienopyrimidinesThienopyrazinesMiscellaneous Fused Pyrrolo SystemsMiscellaneous Fused Furo SystemsMiscellaneous Fused Thieno Systems

230 Bicyclic 5-6 Systems: Three Heteroatoms 1:2

7.07.6.4.4 Furo[3,2-c]pyridazines 2587.07.6.5 Furopyrimidines 259

7.07.6.5.1 Furo[2,3-d]pyrimidines 2597.07.6.5.2 Furo[3,4-d]pyrimidines 2627.07.6.5.3 Furo[3,2-d]pyrimidines 263

7.07.6.6 Furopyrazines 2647.07.6.6.1 Furo[2,3-b]pyrazines 2647.07.6.6.2 Furo[3,4-b]pyrazines 264

7.07.6.7 Thienopyridazines 2647.07.6.7.1 Thieno[2,3-cjpyridazines 2657.07.6.7.2 Thieno[2,3-d]pyridazines 2657.07.6.7.3 Thieno[3,4-c]pyridazines 2667.07.6.7.4 Thieno[3,4-djpyridazines 2667.07.6.7.5 Thieno[3,2-c]pyridazines 266

7.07.6.8 Thienopyrimidines 2667.07.6.8.1 Thieno[2,3-d]pyrimidines 2667.07.6.8.2 Thieno[3,4-d]pyrimidines 2687.07.6.8.3 Thieno[3,2-d]pyrimidines 269

7.07.6.9 Thienopyrazines 2707.07.6.9.1 Thieno[2,3-b]pyrazines 2707.07.6.9.2 Thieno[3,4-bjpyrazines 270

7.07.6.10 Miscellaneous fused pyrrolo systems 2707.07.6.10.1 Dioxinopyrroles ' 2707.07.6.10.2 Pyrrolooxazines 2717.07.6.10.3 Pyrrolothiazines 2727.07.6.10.4 Dithiinopyrroles 273

7.07.6.11 Miscellaneous Fused Furo Systems 2737.07.6.11.1 Furooxazines 2737.07.6.11.2 Furothiazines 275

7.07.6.12 Miscellaneous Fused Thieno Systems 2767.07.6.12.1 Thienodioxins 2767.07.6.12.2 Thienooxazines 2777.07.6.12.3 Thienothiazines 2797.07.6.12.4 Thienodithiins 280

7.07.7 IMPORTANT COMPOUNDS AND APPLICATIONS 281

7.07.1 INTRODUCTION

The subject matter of this chapter was mainly covered in two chapters in the first edition ofComprehensive Heterocyclic Chemistry (CHEC-I) <84CHEC-I(4)497, 84CHEC-I(4)973>. There are alsooccasional references to some compounds in other chapters, for example in chapters on benzofuransand benzothiophenes. In most cases the ring systems have not been studied in a systematic way,although many examples have been prepared. The systems which have attracted the most attentionare the fused diazines, and these systems are covered in the greatest detail in this chapter. Some ringsystems are not covered, either because there is little data on them or because they are more logicallycovered under other headings. Examples of these are the furodioxins. The furo[2,3-6]-l,4- (1),furo[3,4-6]-l,4- (2), 4fl-furo[3,2-rf]-l,3- (3), and 477-furo[3,4-d]-l,3-dioxin (4) have all been describedin the literature. However, all of the systems which have been described are nonaromatic and areessentially carbohydrate derivatives. Several hundred references have appeared since 1982, most ofwhich are in the journals devoted to carbohydrate chemistry. There was only one mention of afurodioxin and one mention of a thienodioxin in CHEC-I. Therefore the systems are not coveredin this chapter, and the reader is directed to the carbohydrate literature for data on them <84CHEC-1(4)973 >.

The interest in, and importance of, the compounds which are the subject of this chapter isindicated by the very large number of references (several thousand) which have been publishedsince 1982. A survey of the literature in which the two heteroatoms in the six-membered ring arenitrogen reveals a considerable variety of interest. The fused diazines were covered to some extentin CHEC-I and the pyrrolopyrimidines had been the subject of a previous review <74S837>. Notsurprisingly, the pyrrolo[2,3-J]pyrimidines and pyrrolo[3,2-J]pyrimidines, also known as 7- and 9-deazapurines, respectively, have commanded the most interest in laboratories around the world.Pyrrolopyridazines, although a much less studied subject, have also been reviewed <B-73MI 707-01).

Bicyclic 5-6 Systems: Three Heteroatoms 1:2 231

(1)

oo o

(2) (3) (4)

The oxygen and sulfur analogues, the furodiazines and thienodiazines, have attracted less interest.A brief review of the furo- and thieno[2,3-J]pyrimidines, which also included the pyrrolo[2,3-fif]pyrimidines, has been published <85RCR262>. The other six-membered ring, two heteroatom, fusedsystems have been grouped together in this chapter as miscellaneous fused pyrrolo, furo, and thienosystems (Sections 7.07.5.10 to 7.07.5.12). Apart from a few cases, there are relatively few examplesof them. All of the ring systems which are considered in this chapter are illustrated in Figures 1-5.

X = N: Pyrrolo[2,3-c]pyridazineX = O: Furo[2,3-c]pyridazineX = S: Thieno[2,3-c]pyridazine

2 N 'X 6


2N'

3


2NI

3NX 6

X = N: Pyrrolo[2,3-(flpyridazineX = O: Furo[2,3-^]pyridazineX = S: Thieno[2,3-d]pyridazine

X = N: Pyrrolo[3,4-d]pyridazineX = O: Furo[3,4-d]pyridazineX = S: Thieno[3,4-<flpyridazine

Figure 1 Fused pyridazines.

3 N2I

N1

X = N: Pyrrolo[2,3-£flpyrimidineX = O: Furo[2,3-rf]pyrimidineX = S: Thieno[2,3-rf]pyrimidine

3 NX 6

X = N: Pyirolo[3,4-t/]pyrimidineX = O: Furo[3,4-<flpyrimidineX = S: Thieno[3,4-rf]pyrimidine

X = N: Pyrrolo[3,2-d]pyrimidineX = O: Furo[3,2-d]pyrimidineX = S: Thieno[3,2-<flpyrimidine

Figure 2 Fused pyrimidines.

(5)3

(6)2

1(7)

5(3)

6(2)

7(1)

X = N: Pyrrolo[2,3-fo]pyrazineX = O: Furo[2,3-^]pyrazineX = S: Thieno[2,3-£]pyrazine

(6)3

(5)2

4(7)N

N1(4)

5(1)

X 6 (2)

7(3)

X = N: Pyrrolo[3,4-fo]pyrazineX = O: Furo[3,4-b]pyrazineX = S: Thieno[3,4-i>]pyrazine

Figure 3 Fused pyrazines.

7.07.2 THEORETICAL METHODS

Although there is a large body of literature associated with these ring systems, very little of it isrelated to fundamental properties or to structural considerations of the rings themselves. Much ofthe literature describes synthetic methods designed to create new functionality on existing ringsystems. There was no data on theoretical methods for these ring systems in CHEC-I. However


Furo[3,2-e]-l,2-oxazine

CO

O

Furo[2,3-e]-1,2-oxazine

O

Furo[2,3-t/]-l,2-oxazine X = O: Furo[3,2-e]-l,3-oxazineX = S: Furo[3,2-e]-l ,3-thiazine

oFuro[2,3-c]-l,3-oxazine X = O: Furo[2,3-</]-l,3-oxazine X = O: Furo[3,4-<fl-l,3-oxazine Furo[3,2-rf]-l,3-oxazine

X = S: Thieno[2,3-rf]-l,3-oxazine X = S: Thieno[3,4-d]-l,3-thiazine

ro

O

Thieno[3,4-rf]-l,3-oxazine Furo[3,2-fc]-l ,4-thiazine Thieno[2,3-e]-l,2-thiazine Thieno[3,4-fo]-l,4-dioxin

OI

o

Thieno[3,4-if|-1,2-dioxin

Figure 4 Fused oxazines and thiazines.

r COl,3-dioxino[4,5-fc]pyrrole l,3-dioxino[5,4-fo]pyrrole X = O: Pyrrolo[2,3-rf]-l,3-oxazine Pyrrolo[3,4-rf]-l,3-thiazine

X = S: Pyrrolo[2,3-<fl-l,3-thiazine

NN

Pyrrolo[3,4-e]-l,3-thiazine Pyrrolo[3,2-£>]-l,4-thiazine Pyrrolo[3,4-fe]-l,4-thiazine

Figure 5 Pyrrolo fused systems.

there have been some reports of the use of molecular modeling and x-ray crystallographic data topredict types of molecules as targets for synthesis (93JMC55, 93JMC1847). Structures of substratescomplexed with enzymes, such as purine nucleoside phosphorylase, have been examined by thesetechniques, and have been found to be useful.

7.07.3 EXPERIMENTAL STRUCTURAL METHODS

Much of the structural information relating to these compounds has been obtained by standardmethods, and is included in the references to their synthesis. There is nothing to merit specialdiscussion, and the more extensive reviews on the ring systems cited here, and in CHEC-I, coverthis material. The NMR spectral data of the parent ring systems, where they have been measured,are given in Table 1.

Many complex derivatives of these rings, however, particularly natural products and nucleosidederivatives, have been isolated, and their structures have been determined by a combination offunctional group manipulations, spectroscopic methods, and synthesis. Such compounds includethe nucleosides dapiramicin A <83TL495>, mycalisine A <88TL4073>, kanagawamicin <83H(20)27>, 21-C-, 3'-C- and S'-C-methylsangavamicins <92H(33)39l>. Other nucleosides which have been isolated,


Table 1 Proton NMR chemical shifts for parent ring systems.

Compound

Pyrrolo[2,3-i]pyrazinePyrrolo[2,3-6]pyrimidineFuro[2,3-rf|pyridazmeThieno[2,3-rf|pyridazineThieno[3,2-c]pyridazineThieno[3,4-rf]pyridazineThieno[2,3-(/]pyrimidineThieno[2,3-rf|pyrimidineThieno[3,2-c/|pyrimidineThieno[2,3-6]pyrazine

Solvent

d6DMSOd6DMSO

CDC13

d6DMSOCDC13

d6DMSOd6DMSO

CDCl,d6DMSO

CDC1-,

Pos. 1

9.16

2

7.958.828.047.93

9.129.019.227.83

3

6.77

7.067.569.14

7.46

4

9.049.659.598.049.169.369.189.59

5

8.43a

6.57

8.537.617.31

8.63

6

8.30"7.57

7.85

8.027.588.558.46

7

9.579.71

8.53

7.68

"Unconfirmed assignment.

and whose structures have been confirmed, are those from the marine organism Echinodictyumhypnea <83AJC165, 83BP347), the cyanobacterium Anabaena affinis strain VS-1 <93JA2504>, Strepto-myces mirabilis <87MI 707-01), and Jaspis johnnstoni <89MI 707-02).

Nonnucleoside compounds which have been fully characterized include rigidin, from the marinetunicate Eudistoma cf. rigida <9OTL4617> and echiguanines A and B from Streptomyces sp. <91MI707-03).

The complexity of many of these molecules contributes to errors in assignment of their structure.The crystal structure of an inhibitor of starfish embryonic development led to a revision of itsstructural assignment. Instead of a 4-oxo compound, the correct structure is 4-amino-7-(/?-D-ribofuranosyl)-3//-furo[3,2-d]pyrimidine <92MI 707-02). The crystal structure of compound (5), anintermediate in the enantioselective synthesis of 8-epicastanospermine has also been reported<93AX(C)40>.

There is some interest in the spectral properties of copper complexes of thieno[2,3-d]-pyrimidines<88ICA165>, and of polymers of thieno[2,3-6]pyrazines <92CC1672, 93SM960). The latter have beeninvestigated as low band-gap polymers.

7.07.4 THERMODYNAMIC ASPECTS

Interest in the thermodynamic properties of these heterocycles is focused on their biologicalattributes. Typical of this activity is a study of the conformational restrictions of sangivamicin, andits analogues, and their correlation with inhibitory activity of protein kinase C <93CPB775).

Measurements of the equilibrium binding of 7-deazaguanine analogues have also been reported<93B11374>.

7.07.5 REACTIVITY OF THE BICYCLIC RINGS AND RING SUBSTITUENTS

Relatively few fundamental reactions of these ring systems have been described and, rather thansubdivide this section into reaction types, they have been divided into sections devoted to thedifferent ring systems.


7.07.5.1 Pyrrolopyridazines

There have been few studies of the reactions of these ring systems. For example only one caseof oxidation of a partially reduced ring system to form an aromatic ring is reported. The N-methylpyrrolo[2,3-j]pyridazine (6) is converted to the aromatic compound (7) on treatment withpotassium permanganate (Equation (1)) <87JHC545>.

(i)

The reactions of pyrrolo[3,4-J]pyridazines are dominated by cleavage of the pyridazine ring.Treatment of l-chloro-5,6,7-trimethylpyrrolo[3,4-(/]pyridazine (8; R = Cl; R1 = Me) with aqueousor alcoholic bases provides a good yield of the oxo product (9) (Scheme 1). On the other hand,similar bases in DMF give the pyrrole product (10) in addition to compound (9) <84CI(L)27O>.

N-Me

NC

N-R 1 N-Me

(10)

MeO2C

(8)

OHC

(9)

N-R 1

As part of a study to explore the Diels-Alder reactions of this ring system, compound (8;R = R1 = H) was reacted with DMAD to give the pyrrole derivative (11) <85JCS(P1)899>. It appearsthat this ring cleavage is initiated by nucleophilic reaction with DMAD. Methyl propiolate behavessimilarly, whilst DEAD reacts with the pyrrole ring instead <87JCR(S)356>.

7.07.5.2 Pyrrolopyrimidines

Considerably more attention has been paid to reactions of pyrrolopyrimidines than to any otherring system covered in this chapter. Clearly, their similarity to natural purines, as they aredeazapurines, has been the cause of this interest. The discussion here will focus on the introductionof substituents at carbon and at nitrogen.

Almost without exception, the introduction of new substituents into aromatic pyrrolopyrimidines


occurs in the pyrrole portion of the system. Acylation of the dioxo compound (12; R = H) with avariety of anhydrides provides a series of 6-acyl derivatives (12; R = acyl) <88JHC1443>.

Alkylation, via the Mannich reaction, affords a mixture of 5- and 6-substituted products. Treat-ment of compound (13; R1 = R2 = R3 = H) with dimethylamine and formaldehyde leads to a mixturein which product (13; R3 = CH2NMe2, R2 = H) is favored over product (13; R3 = H, R2 =CH 2NMe 2 ) by 2 : 1 <83JHC1O23, 88JCS(P1)1637>. The 4-thio analogue behaves similarly <86JMC1749>.

The great interest in palladium-catalyzed coupling reactions prompted the reaction between the7-deazaadenine derivative (14) and mercury(II) acetate (Equation (2)). A mixture of the 5- and 6-substituted mercury compounds, (15) and (16) respectively, was obtained <9UOC5598>.

(2)

(14)

A similar reaction occurs with 2-pivaloylamino-4-oxopyrrolo[2,3-</]pyrimidine. In this case theratio of the 6-mercuri derivative to the 5-mercuri derivative was 10:1 <93H(36)1897>. Subsequentconversion of the mercuri compounds to the corresponding iodo derivatives provides the actualsubstrates for the palladium-catalyzed coupling reactions. Direct halogenation of the pyrrole ringhas also been effected. In the only position available both chlorination (sulfuryl chloride) andbromination (NBS) have been achieved on the C-nucleoside (17; R = benzoylated ribose) (Equation(3)) <90JMC2750>.

(3)

X = Cl, Br

However, bromination has also been reported to occur at C-2 of the derivative (18; R1 = H) aswell as replacing a formyl group in the pyrrole ring of the aldehyde (18; R1 = CHO). The resultingdibromo compound (18; R1 = R = Br) can be dehydrogenated to give the deazahypoxanthine (18;R2 = R1 = H) <88KFZ860>.

Many of the standard functional group interconversions are described in synthetic schemesinvolving the pyrrolopyrimidines. In order to conserve space, only a few illustrative examples areshown here. The references cited in Section 7.07.6.2 on synthesis should be consulted for furtherexamples.

Replacement of chlorine by amines has been accomplished on a variety of structures resulting in4-amino derivatives (19; R = Cl->19; R = amine) <83JHC295,84LA1972,89MI 707-01, 90ZC248). The 4-


chloro group is less reactive than a 6-bromo substituent in the derivative (19; R = Cl, R4 = Br)towards displacement by ammonia <9OMI 707-03). Displacement of a 2-chloro substituent is con-siderably more difficult. Nevertheless, hydrolysis of a 4-amino-2-chloropyrrolo[2,3-fi?]pyrimidinenucleoside is accomplished photochemically in the presence of water <91HCA1742>.

R4

More common is the replacement of chloro groups by a variety of amines. This can occur atvarious sites on simple pyrrolopyrimidines (19) where chlorine has been located <(82KFZ1338,88KFZ185), or on ring-chlorinated nucleosides (19; R2 = carbohydrate) to obtain analogues of purinenucleosides <87JHC82l, 90JHC171). Likewise, sulfur has been introduced by replacement of chlorineusing thiourea <84KFZ958>.

An alternative pathway to 4-aminopyrrolopyrimidines involves the one-pot conversion of 4-oxocompounds (20) into the desired amines (21). Primary alkyl- or aryl-amines, phosphorus pentoxideand an organic base lead to the expected products (Equation (4)) (85LA142, 85JHC859, 88CS201,88CS427).

9 R3 NHR4

(4)

Alkoxy groups are convenient substituents in the primary synthesis of fused pyrimidines. Theseallow the formation of oxo derivatives to proceed smoothly. One example of this is the hydrolysisof the 4-methoxy derivative by hot aqueous hydrochloric acid to give the 3//,5//-pyrrolo[3,2-d]pyrimidin-4-one (22) which is a deazahypoxanthine <92JCS(P1)1883>.

HN

The use of sulfur substituents at C-4 has seen limited use in preparing other derivatives. Oneunusual reaction involves treatment of a 4-thio group, as in compound (23), with chloramine togive the S-aminated product (24), which is subsequently oxidized, selectively, to the sulfinamides orsulfonamides (Equation (5)) <9OJMC122O>.

HN (5)

Whilst not strictly a functional group interconversion, the palladium-catalyzed coupling reactionis becoming more commonplace in synthesis involving halogenated rings. Thus, 5-iodopyrrolo[2,3-d]pyrimidines serve as good substrates for this process <90TL373l>.

Clearly, the most widespread nucleophilic reaction by heteroatoms is alkylation at ring nitrogenatoms. It is unsurprising that the very great interest in nucleosides of pyrrolo[2,3-</|pyrimidines, asdeaza analogues of purine nucleosides, dominates this field. Selected examples of this chemistry


include those types of substituted compounds (25)-(27) where R = H is converted into R = carbo-hydrate.

In the derivatives (25), for example, R1 and R2 may be H, Cl, MeO, NH2 in any combinationdeemed essential to allow conversion to functionality consistent with natural purine nucleosides.The use of a stereospecific sodium salt glycosylation procedure developed by Robins and co-workersaccounts for much of this synthetic activity <84JA6379, 85JMC1461,88JHC1893).

Phase-transfer-mediated glycosylation accounts for the development of the majority of nucleo-sides in this area. This technique has been exploited by Seela and co-workers (83LA876, 83JOC3119,84LA273, 85LA1360, 87LA15, 88JCS(P 1)697, 89H(29)2193>. Other workers have utilized more conventionalmethods for the synthesis of similar nucleosides <85S926, 86BCJ1915,86T199, 88TL4061).

Alkylation on ring nitrogen remains the most frequently cited reaction of a heteroatom. Due tothe considerable interest in nucleosides for their biological importance, this will be dealt with further.Standard treatment of the dioxo compound (28) with hexamethyldisilazane, followed by 1-O-acetyl-2,3,5-tri-O-benzoyl-/?-D-ribose gives the protected nucleoside (29) (Equation (6)), which can beconverted into the free nucleoside with methanolic ammonia <92JHC343>.

BzO (6)

(28)

The antiviral activity of acyclovir, with that of other similar compounds, has created significantinterest in the synthesis of acyclic sugar analogue derivatives of pyrrolo[2,3-d]pyrimidines as 5-deaza analogues. Generally, these compounds are prepared from the heterocycle via alkylation atN-7 in a manner analogous to nucleoside formation. Thus, the derivatives (25-27; R = H) arereadily converted to the derivatives (25-27; R = (substituted)alkyl). Typically, the heterocycle istreated with sodium hydride to generate the nitrogen anion which then reacts with an appropriatealkyl halide to give the desired product. In this way hydroxyethoxymethyl <83LA137, 88JMC1501,88JMC2086,89JMCl420>, l,3-dihydroxy-2-propoxymethyl (85JHC1137,89JMC402,90JMCl984>, propanoicacid <85HCA2165>, 2,3-dihydroxypropyl <82LA1940>, and phosphonomethoxypropyl <93CCC14O3,93CCC1419) analogues have been described. The isomeric ,/V-methyl derivatives of 7-deazaguanine(30) have been obtained in an unequivocal manner. Excess dimethyl sulfate affords the 3-methylderivative whilst the 7-methyl isomer is obtained by using phase-transfer-catalyzed methylation of2-amino-4-chloropyrrolo[2,3-J]pyrimidine with methyl iodide. Hydrolysis of the chloro group leadsto the guanine analogue. The 1-methyl isomer is derived by cyclization of the appropriate TV-methylated pyrimidine <84JMC981>.

Alkylation of 7-deazaadenine (31) affords mixtures of products arising from reaction at N-l andN-3 as well as the exocyclic amino group <84MI 707-02).


NH 2

7.07.5.3 Pyrrolopyrazines

There is a paucity of functional group reactions associated with the pyrrolopyrazines. A fewexamples may be found within the references describing their syntheses. However, a reaction hasbeen reported which describes the [4 + 2] cycloaddition of pyrrolopyrazines. Ring expansion of 2-phenyl-27f-pyrrolo[3,4-6]pyrazine (32) occurs through cyclocondensation of the trimethylsilyl ether(33) with, amongst other dienophiles, methyl acrylate, and a mixture of quinoxahnes (34) is obtainedin 38% yield (Scheme 2) <86JHC1641>.

N-Ph

O-TMS

N-Ph

(32)

7.07.5.4 Furopyridazines

The major reaction described for furopyridazines is ring opening. The furo[2,3-c]pyridazine (35)is converted, in 50% yield, to the chloropyridazine (36) on treatment with phosphoryl chloride inchlorobenzene with DMF as catalyst <88JOC5704>. The symmetric furo[3,4-d]pyridazine (37; R = H,Ph) is oxidatively cleaved with eerie ammonium nitrate to give the pyridazine (38) (Equations (7)and (8)) <83S1O18>.

(7)

R O

A

(37)

(8)

7.07.5.5 Furopyrimidines

Furopyrimidines undergo many of the reactions that the pyrrolopyrimidines do, although thereare fewer examples. The conversion of the oxofuro[2,3-<f]pyrimidine (39) to the (substituted)aminocompound (40) with phosphorus pentoxide and a primary amine exemplifies the type of functionalgroup interconversion which is possible (Equation (9)) <86CS337>.


NHR1

(40)

(9)

As with other nitrogen-containing heterocycles, ,/V-alkylation is a reaction of some interest. Thisis particularly true when the products are nucleosides. One interesting example of nucleosideformation arises from reaction of a suitable furo[3,4-J]pyrimidine (41) and l-0-acetyl-2,3,5-tri-benzoyl-^-D-ribose: the product formed seems to be solvent dependent. The N-1 substituted nucleo-side (42; R = tribenzoylribose) is formed in 81 % yield when the heterocycle and the protected sugarare treated with tin(IV) chloride in acetonitrile. However, use of 1,2-dichloroethane as solventaffords only 17% of this product together with 81 % of the N-1 ,N-3 disubstituted product (Equation(10)) <83CPB3074>.

O-TMS

TMS-0 N

(10)

Two examples of ring opening, followed by a recyclization step, have been reported. The Dimrothreaction of the furo[2,3-J]pyrimidine (43) has been shown to yield the product (44) <91JIC66O>. Thephotochemical ring opening of the furo[2,3-rf]pyrimidine (45) and subsequent cyclization to thespiropyrimidine (46) is an interesting reaction (Equations (11) and (12)) <87CB1433>.

(43)

NHR3

(11)

O

(12)

Furo[3,4-d]pyrimidines are ideally suited for participation in Diels-Alder reactions. The reactionof the derivatives (47) with dienophiles leads to tricyclic compounds of the type (48) <9UOC245>.There is some selectivity, since methyl acrylate forms only two regioisomeric endo products whilstother dienophiles yield both endo and exo adducts (Equation (13)).

(13)

(48)


7.07.5.6 Furopyrazines

Two reactions of note involve ring opening, followed by cyclization to a new bicyclic system. Ina classic reaction the dioxofuro[3,4-<f]pyrazine (49) undergoes reaction with 1,2-diaminoethane togive the bispyrrolopyrazine (50). Presumably other primary amines would react in a similar manner<91AP(324)185>. A less obvious process is observed in the reaction of the furo[2,3-6]pyrazine (51;R = CO2Et, CONEt2) with potassium cyanide. The product (52) probably results from cyclizationof a carboxylic acid group producing the lactone ring. The acid may be derived from initial additionof the cyanide ion to the C—C bond of the furan portion of the molecule, followed by ring openingand subsequent hydrolysis of the cyano group (Equations (14) and (15)) <83JHC365>.

(14)

(15)

(51)

7.07.5.7 Thienopyridazines

Although there is very little reported on the reactions of thienopyridazines, thieno[3,4-J]py-ridazines (53; R = CO2Et or CSNH2, R1 = Ph or 4-ClC6H4), like the comparable oxygen system,undergo Diels-Alder reactions quite readily. Dienophiles such as phenylvinyl ketone, chalcone, and/?-nitrostyrene, lead to the appropriate benzenoid compounds (54) upon loss of sulfur <93JCR(S)i30>.In another reaction, without apparent synthetic value, the dihydrothienopyridazine (55) undergoesa photochemical cleavage to form the diradical (56). This reactive intermediate is of theoreticalinterest <87TL4263>.

(16)

(17)

(55) (56)

7.07.5.8 Thienopyrimidines

The direct introduction of functional groups into the thienopyrimidine ring has been accomplishedin some cases. The 6-substituted-thieno[2,3-af]pyrimidine (57; R = CHO) has been formed, using


phosphoryl chloride-DMF, from the precursor (57; R = H). Similarly, bromine leads to compound(57; R = Br) and nitric acid produces compound (57; R = NO2) <9OJHC717>.

Halogenation of groups attached to the ring system has also been described. Bromination ofmethyl groups at the 5- or 6-positions of a series of thieno[2,3-<f]pyrimidines has been accomplishedusing NBS <87KFZ197>. Exocyclic double bonds can also be halogenated using either bromine oriodine <89KGS413>. There is greater interest in producing halogenated ring systems which canundergo nucleophilic displacements. 4-Oxothieno[2,3-J]pyrimidines (58) are treated with phos-phoryl chloride to give first the chloro compound (59; R3 = Cl) which is then substituted by a varietyof nucleophiles <85KGS925, 86PHA23, 92PHA20, 93PHA192>.

(18)

Substitutions can also occur at the 2-position of similar thienopyrimidines (86PHA23,91UC(B)618>.2-Methylthiothieno[2,3-G?]pyrimidines undergo reaction with hydrazine in an analogous manner<87KGS1131>.

Condensation between aromatic aldehydes and either 2-methyl- <87PHA131> or 4-methyl-<89YZ642> thieno[2,3-^]pyrimidines provides the corresponding vinyl-substituted derivatives. Alkyl-ation reactions have been described at both nitrogen and sulfur sites. Nucleoside (61) formationresults from the reaction of the ether (60) (Equation (19)) with an appropriately substituted ribosederivative. However, location of the carbohydrate did not occur at the desired nitrogen <85JMC423>.Reactions of other 4-oxothieno[2,3-fi?]pyrimidines also favor N-3 substitution <86PHA66l>. Similarresults occur with 2,4-dioxo compounds <86PHA66l> and disubstitution is also observed whenphase-transfer catalysis is used <83PHA135>. However, N-l substitution (63) is reported when 2,4-dioxothieno[3,4-<i]pyrimidine (62) is alkylated with 1 -bromo-2-chloroethane (Equation (20))<92SC3221>.

O-TMS

(60)

(62)

(19)

(20)

Cl

2-Thiolthieno[2,3-rf]pyrimidines can be alkylated with simple alkyl derivatives <90PHA493> or withcomplex alkyl moieties <87PHA16O>.


Several reactions involving ring opening should be noted. As expected the derivatives (64) under-go Dimroth rearrangement to form the isomers (65) (Equation (21)) <88CS195>. Loss of sulfurdioxide from compound (66) on heating leads to 2-methyl-5,6-dimethylenepyrimidin-4-one (67)(Equation (22)). This reactive species (67) has been trapped by dienophiles and by nucleophiles(93SL347, 93SL397).

NHR2

(21)

(22)

7.07.5.9 Thienopyrazines

Consistent with a sparse literature for the synthesis of thienopyrazines, there is very little of notethat can be recorded for reactions of these ring systems.

One study that could have synthetic utility is the electrochemical reduction of thieno[2,3-&]py-razines, such as the parent molecule (68) to the corresponding tetrahydro compound (69) (Equation(23)) <9UOC4840>. Thieno[3,4-6]pyrazine, as well as the oxygen analogues of both compounds,behave similarly.

XN s

(68)

(23)

(69)

7.07.5.10 Miscellaneous Fused Pyrrolo Systems

The pyrrolooxazines (70) undergo Diels-Alder cycloadditions with iV,./V-diethyl-1 -propynylamine,followed by carbon dioxide extrusion to yield pyrrolopyridines (71) <87CB1427>. The furooxazinesreact similarly (Equation (24)).

NEt2

= NEt2

MeCN, reflux

N N Ph

(24)

Ph-

(71)

The pyrrolothiazine dioxides (72), some of which show muscle relaxant properties, can be ethyl-ated (NaH/THF, reflux) to give the TV-ethyl derivatives, but all attempts to hydrolyze the nitrile tothe corresponding acid have failed <88PJS242>. The compound (73) was first reported in 1966<66AG333). Its methylation has been shown to give the 5-methyl product but prolonged reactionleads to the pyrrole (74) (Scheme 3) <87JHC425>.


R1 R2

(72)

R1 = PhCH2, PhCH2CH2, cyclohexyl, Bu and othersR2 = H, Et

Mel

/ C N SMe

~SMe

SMeN

iPh

(74)

Scheme 3

7.07.5.11 Miscellaneous Fused Furo Systems

The coverage of hetero-fused furo systems in CHEC-I was sparse, and there were few references.However, it was recorded that 4i/-furo[3,4-d][l,3]oxazine-2(l//),4-dione can be synthesized fromdiethyl 3,4-furandicarboxylate, and that it reacts with N or O nucleophiles exclusively at the N-carbonyl to give ureido or carbamato acids <8UOC3853>. The preparation and reactions of furo-oxazines have been extensively studied in particular by Gilchrist and co-workers (79CC1089,79JCS(P1)249, 79JCS(P1)258, 81JOC3853).

The furooxazines (75) react with DBU to form oxazines which can react further under theconditions of the reaction to yield pyridines (76). The compound (75; R = H, R1 = Ph) rearrangesunder acid catalysis to yield <x-(2-furyl)acetophenone oxime (Scheme 4) <79JCS(Pl)249, 83JCS(P1)1283,87JCS(Pl)2505>.

O R1dbu, CH2C12 o

oN

N R1

(75) R = Me, H; R1 = CO2Et, COMe, COPh, COEt, Ph

Scheme 4

(76)

The furooxazines obtained from the cycloaddition of a-nitrosostyrene, generated in situ fromchloroacetophenone oxime, to 2,5-dimethylfuran react further with nitrosostyrene, or with othernitrosoalkenes, to yield the tricyclic nitrones (77) (Scheme 5) <9OJCS(P1)1497>.

irx Ar

(NO

= Ph,p-NO2C6H4

Scheme 5

The tricyclic compound (79), obtained from 5-hydroxy-2-pentenolide (78), undergoes ring openingon treatment with hydrazoic acid/sodium azide to give a mixture of the two furooxazine stereo-isomers (80) and (81). These undergo the series of reactions shown in Scheme 6 <86HCA1442>.


HO

o

(78)

O

NHAc

H NHAc

AcO

AcHN,,,

AcO O O

i, H2, Pd/C, Ac2O/AcOH, RT, 1 h; ii, 20% HBr/AcOH, RT, 2 h;iii, ii then HC1, 100 °C, 1.5 h, Ac2O/pyridine, RT, 1 h

Scheme 6

7.07.5.12 Miscellaneous Fused Thieno Systems

Syntheses of thienooxazines are mentioned in CHEC-I but no reactions are discussed. The maintype of reaction of these compounds is the ring opening of the oxazine ring to yield substitutedthiophenes <53JOC138>. However, the thienooxazine (82) undergoes ring opening of the thieno ringupon refluxing with benzylamine in dichloromethane to yield the oxazine (83) (Equation (25))<88JOC850>.

PhCH 2 NH 2

CH2C12

p-MeOQjtt,

Ph

(82)

CONHCH2Ph(25)

Thieno[3,2-c][lA4,2]thiazines (84) undergo thermal [1,4] shifts to carbon, rather than a [1,2] shiftto nitrogen, on heating to > 120°C although this yields the nonaromatic 4a7/-thienothiazines (85)(Equation (26)). The properties of these compounds support their structure as being cyclic sulfur-nitrogen ylides. Their thermal stability is increased by having structural features which can stabilize,or delocalize, a positive charge on sulfur and a negative charge on nitrogen. Thus, in general, theiS-phenyl compounds are more stable than the S-methyl analogues. A similar result is observed forthe furothiazine analogues.

heat

>120"C(26)

(84) (85)


On thermolysis the S-methyl-thienothiazine (86) gives, in addition to the expected product (87),the thieno-l,3-azepine (88). When the reaction is carried out in boiling bromobenzene, the N-methylthienopyrrole (89) (9%) is also obtained <86JCS(Pl)49l>. The formation of the thiazepine canbe explained by tautomerism of compound (86) into the isomeric sulfonium ylide followed by a [1,2]nitrogen shift to the carbanionic centre in a Stevens-type rearrangement. A possible mechanism forthe formation of the TV-methylthienopyrrole is a [1,2] methyl shift from S to N followed by extrusionof sulfur <86JCS(Pl)491>.

CO->Et

(86)

Me

N

CO2Et

CO2Et

(88) (89)

The fused thiazines (84) have been shown to be photo-labile and they decompose in acetonitrileat 300 or 350 nm to yield fused pyrroles (90) (Table 2) suggesting that the RS group undergoes avery rapid [1,5] sigmatropic shift (Equation (27)) <86JCS(Pl)497>.

Table 2 Photo-decomposition of thieno[3,2-c][U4,2]thiazines (84) and related species <86JCS(P1)497>.

X

ssssoC H : C H

R

MePhPhPhPhPh

Z

CO2EtCO2EtCOMeCHOCO2EtCO2Et

Yield

508377753275

(84) (27)

The thienothiazines (86) react with DM AD in aprotic solvents at room temperature to yield 114,4-thiazocines (91) but in protic solvents 2:1 adducts are also observed (82CC1060).

R

CO2Et

(91) R = Me, Ph

7.07.6 RING SYNTHESES

7.07.6.1 Pyrrolopyridazines

7.07.6.1.1 Pyrrolo[2,3-c]pyridazines

A common method of synthesizing heterocyclic rings is intramolecular cycloaddition. Thisapproach has been successfully used with the tetrazine (92) to yield the reduced pyrrolo[2,3-c]-


pyridazine (93) (Equation (28)) <84CZ331>. One example of the synthesis of a pyrrolo[2,3-c]pyrid-azine, without the isolation of a monocyclic intermediate, has been reported when cinnamoyl-acetonitrile oxime and cyanoacetic acid hydrazide react together to give the derivative (94) (Equation(29)) <91MI 707-02).

N y N (28)

(92) (93)

NOH

CN (29)

7.07.6.1.2 Pyrrolo[2,3-d]pyridazines

Formation of the pyridazine ring occurs in a straightforward way from a suitably substitutedpyrrole. Thus the pyrrole nucleoside (95) forms the pyrrolo[2,3-fi?]pyridazine (96) on treatmentwith hydrazine <93JMC3834>. Another report describes the preparation of 4-amino-l-(/?-D-ribo-furanosyl)pyrrolo[2,3-</|pyridazine (Equation (30)) <91BMClll>. Similar pyrrole nucleosides, withan ester function at position 3 and an aldehyde at position 2, lead to 4-oxo derivatives upontreatment with hydrazine <9OJHC1989>, or 4-amino derivatives with a cyano group at position 3<92JMC526>.

NH2

NC

Eto2c ^ y \HO—1 ^ N

O I

wHO OH

(95)

(30)

Diels-Alder cycloaddition reactions with tetrazines provide a useful approach to the preparationof pyrrolo[2,3-fi?]pyridazines. Thus, the lactam acetal (97), which is in equilibrium with the cyclicketene 7V,O-acetal (98), reacts with tetrazines (99) to give the partially reduced product (100)<86CB3600>. The methylthio analogue of the acetal (97) also reacts similarly with tetrazines (Scheme7) <87JHC545>.

MeO

MeOMeO

Me Me

(97) (98)

R

(99)

Scheme 7


A synthetic approach designed to produce pyridazino[4,5-e]pyridazinones unexpectedly yieldspyrrolopyridazines, although in poor yields. The acid-catalyzed reaction between the hydrazine(101) and ketodiesters (102) results in formation of the pyrrolo[2,3-d]pyridazine (103) (Equation(31)) <92JH.C1313>.

O o

EtOOEt

(101)

R1 O

(102)

CO2Et (31)

A novel process involving displacement of fluoride provides a route to pyrrolo[2,3-<f]pyridazinesbut it is of very limited synthetic application. The highly fluorinated pyridazine (104) undergoesdisplacement of the heteroaryl fluorines by dimethylamine leading to the product (105) in 66%yield, via a postulated orthoquinoid intermediate (Scheme 8) <82CC1412>.

NMe2 CF3

(104) (105)

Scheme 8

7.07.6.1.3 Pyrrolo[3,4-c]pyridazines

An unexpected reaction which leads to pyrrolo[3,4-c]pyridazines is the action of acid on the 3-diazopyrrole (106), obtained from the corresponding amine. Although pyrrolocinnolines were thetarget compounds, the pyrrolopyridazine (107) was obtained (60%) (Equation (32)) <84H(22)2269>.However, the cinnoline product is obtained when the carbethoxy group is present instead of theacyl group at position 4 <83H(20)255>.

(32)

(106) (107)

7.07.6.1.4 Pyrrolo[3,4-dJpyridazines and pyrrolo[ 3,2-c]pyridazines

No syntheses of these two ring systems have been reported since the early 1980s and there wereno details of their synthesis in CHEC-I.

7.07.6.2 Pyrrolopyrimidines

The pyrrolopyrimidines have been much more extensively studied than the pyrrolopyridazines,and a large number of references have been extracted, some of which have been summarized forthis section.


7.07.6.2.1 Pyrrolof 2,3-dJpyrimidines

(i) Syntheses from pyrimidines

The majority of synthetic approaches to the pyrrolo[2,3-d]pyrimidine system involve a 6-amino-pyrimidine as the final precursor. The major variations of this approach either place substituentson the amine which ultimately appear in the C-5 position or place substituents on C-5 whichcondense with the 6-amino group. Examples of syntheses in which the C-5 position is unsubstitutedstart with 6-aminouracil derivatives (108) and produce the corresponding dioxopyrrolopyrimidines(109). Thus, for compound (108; R = H, R1 = Me, R2 = allyl) the monomethyl product (109;R1 = Me, R = R3 = R4 = H) is obtained <89CPB3184>. In a similar manner compound (108; R = Me,R1 = H, R2 = propargyl) leads to the 1,3,5-trimethyl compound (109; R = R4 = Me, R1 = R3 = H)<85CPB4740). This pathway provides access to other derivatives, especially N-7 nucleosides. In amore elaborate series of reactions the compound (108; R = H, R2 = CH2CO2H) has been usedto obtain the alkaloid rigidin (109; R = R1 = H, R4 = 4-hydroxybenzyl, R5 = 4-hydroxyphenyl)<93JOC403>.

(33)

R1

(108) (109)

One route which involves a C-5 substituent, and which has been extensively studied, utilizes theacetal moiety, illustrated by the general structure (110). The most common synthetic scheme beginswith the dichloro compound (110; R2 = R3 = Cl) which is converted by the appropriate amine intothe immediate precursor containing the desired substituent on the amine, very often a carbohydratemoiety. Hydrolysis of the acetal leads to simultaneous cyclization affording the derivatives (111)which, upon further manipulation, leads to deazapurine analogues of natural purines and theirnuc leos ides ( E q u a t i o n (34)) <84JMC534, 85TL2001, 85JMC1477, 86MI 707-03, 90JHC2069, 92H(34)739, 92TL2249,92BMC1279, 93JOC1696>.

(34)

(111)

The use of keto groups at C-5 of the pyrimidine ring allows the synthesis of pyrrolo[2,3-d]py-rimidines with substituents at either C-5 or C-6 in the product. These carbonyl-containing groupsare introduced either through a primary synthesis of the pyrimidine ring, or by alkylation at C-5 ofthe pyrimidine. One key intermediate structure required for elaboration into a pyrrolopyrimidine isillustrated by the precursors (112) which undergo nucleophilic displacement of one of the chlorines,followed by cyclization, to give the desired products (113) (Equation (35)) <83EJM269, 85EJM127,93H(36)1897>. Further manipulation of the ring substituents leads to structures analogous to bio-logically active molecules. 5-Chloromethylcarbonyl-2,4-dichloropyrimidine <83JHC925>, 5-formyl-2,4-dichloropyrimidine <88JMC390>, and 5-chloromethylcarbonyl-l ,6-dihydro-4-/?-D-(2,3,4,6-tetra-0-acetyl)glucopyranosylamino-l-methyl-2-methoxy-6-oxopyrimidine <86MI 707-02), all participatein similar chemistry to give N-7 substituted pyrrolo[2,3-<f|pyrimidines.

Cl

N Cl

(112)

O

(35)

(113)


The hydrazone of a 5-formylpyrimidine (114) when treated with sodium hydride and then heatedto 150°C also results in formation of a pyrrolopyrimidine (115) (Equation (36)) <89H(29)1993>. In arelated reaction, treatment of 2,4-diamino-6(l//)-oxopyrimidine (116) with methyl chloro-formylacetate gives both the pyrrolopyrimidine (117), and the furopyrimidine (118) (Equation (37))<89JCS(P 1)2375). The latter can be converted into pyrrolopyrimidine products. Pyrrolopyrimidineswith 5-amino substituents can be prepared from 5-cyanopyrimidines utilizing similar chemistry<88LA633>.

R NNHR3

R

(114)

R

(115)

(36)

O

HN

H2N N NH2

(116)

O OMe

H2N

OMe

(37)

(117)

^

(118)

NH2

Other pyrimidine precursors with unsaturated chains at C-5 have been effectively employed toachieve a variety of pyrrolo[2,3-^/]pyrimidines. The pyrimidine (119), obtained by reacting a 6-aminouracil with DMAD, upon heating, is converted into the highly oxidized pyrrolopyrimidine(120) (Equation (38)) <86H(24)927,87JHC1215). The analogous 5-allyl-6-aminouracil compounds leadto 6-methyl products <92CPB846>, whilst 5-allyl-6-chloro-2,4-dimethylpyrimidine reacts with hydra-zine to give a 7-aminopyrrolopyrimidine (85KGS678, 89AKZ530). The corresponding 5-vinyl deriva-tives form the azido compounds when treated with sodium azide. Thermal or photochemical reactionof the azide leads to 6-substituted-2,4-dimethylpyrrolo[2,3-d]pyrimidines <89CPB2933>.

CO2Me

R CO2Me R

NR!R2

CO2Me

(38)

(119) (120)

Pyrimidines bearing high nitrogen-containing substituents at C-6 have been shown to formpyrrolopyrimidines. Loss of nitrogen accompanies the cyclization step. For example, the triazolylring in compound (121) undergoes photochemical degradation leading to the 6,7-disubstitutedproduct (122) (Equation (39)) <91TL323>.

O

MeN

(AN NN

MeR1

(121)

N(39)

R2

(122)

The thermal degradation of the hydrazine (123) results in elimination of nitrogen, with con-comitant ring formation to give compound (124) (Equation (40)) <92JCS(P1)1287>.


O CO2Me

CO2Me Me

MeS N N

Me

(123)

(40)

(124)

(ii) Syntheses from pyrroles

The elaboration of a pyrimidine ring onto another aromatic ring is usually accomplished bycyclization of two adjacent functional groups, one of which is an amine moiety. The majorityof pyrrolo[2,3-J]pyrimidines developed from pyrroles have been prepared this way. 2-Amino-3-cyanopyrroles (125) serve to produce 4-aminopyrrolo[2,3-</|pyriinidines (126) (Equation (41)).Heating the pyrrole in DMF in the presence of formic acid is effective for this transformation<86JHC393, 86LA1485,87JIC713, 88H(27)186l, 88IJC(B)778>. Triethylorthoformate, followed by treatmentwith ammonia, leads to similar products <9OJMC2162>.

NC R2 NH2 R 2

R

(125)

(41)

(126)

The opportunity to introduce substituents at C-2 of the pyrrolopyrimidine is afforded by the useof 2-(substituted)amino-3-cyanopyrroles. Treatment of acylaminopyrroles (127), most commonlywith R3 = Me, with phosphorus pentoxide, an arylamine hydrochloride, and TV^-dimethyl-cyclohexylamine at elevated temperatures, gives the derivatives (128; X = NH) (Equation (42))(83LA2066,84CS73, 85CS222,85S101,88CS303,90H(31)367,93AP(326)303>. In some cases the 4-imino deriva-tive has been converted to the 4-oxo derivative (128; X = O) by hydrolysis.

NC R2

xtR3u IN

(42)

(127) (128)

Certain derivatized 2-aminopyrroles (129) also provide 4-aminopyrrolopyrimidines unsubstitutedat C-2. Thus pyrroles (129; R3 = EtO, R4 = H) yield the derivatives (130; R5 = H) <86T5869>.However, compounds (129; R3 = R4 = NH2) afford the derivatives (130; R5 = aryl or Me) whenreacted with the corresponding nitrile (Equation (43)) <87JHC425>. Reduced or partially reducedpyrroles lead to the expected reduced pyrrolopyrimidines <86CPB886,92KGS1472). Reaction betweenthe pyrroles (125) and isothiocyanates produces 4-amino-2-thiopyrrolopyrimidines (131) (Equation(44)) <9UIC396>. A similar reaction between a suitably substituted reduced pyrrole and isocyanatesgives the corresponding 2-oxo derivatives <85CB4473>.

NC R2

R3 \ /

NH2

NI

R

(43)

(129) (130)

Bicyclic 5-6 Systems: Three Heteroatoms 1:2

NH2 ,

(125)

251

(44)

NH

NH

(131)

4-Oxopyrrolopyrimidines (133) can be prepared directly from 2-amino- (or 2-(substituted)amino)-3-carboxamidopyrroles (132) (Equation (45)) <86CS347,90PHA245). Reaction of the corresponding 3-carbalkoxy derivatives with phenylisothiocyanate affords the pyrrolo[2,3-</|pyrimidine (133; R = Ph,R3 = SH) <86MI 707-04). In an unusual variation on this type of reaction, 2-triphosphoranylidene-3-carbomethoxy-4,5-dihydro-l-tosylpyrrole undergoes reaction with a series of isocyanates to givethe derivatives (133; R = alkoxy) <90LA90i>. Compounds (133) have also been prepared from 2-acylamino-3-carbomethoxypyrroles when treated with phosphorus pentoxide, an aromatic amineand triethylamine <86H(24)997>.

(45)

(133)

4-Thiopyrrolopyrimidines (135) are available directly from thioamide derivatives (134) uponheating with substituted amines (Equation (46)) <84S703>.

EtO2CHN

MeS

(134)

(46)

(135)

An unusual synthesis of a pyrrolo[2,3-d]pyrimidine without a functional group is based on thereaction of benzonitrile with jV-methyl-2-pyrrolidone. These two compounds, when heated in thepresence of sodium telluride, give low yields of 2,4-diphenyl-7-methylpyrrolo[2,3-d]pyrimidine<93JOC24l>. The yields could not be improved, thereby limiting the usefulness of the method.

A few less traditional approaches to the synthesis of pyrrolo[2,3-J]pyrimidines are worthy ofnote. Ketene S^/V-acetals (136) serve as convenient precursors to pyrrolopyrimidines which arereduced in the pyrrole ring (137) (Equation (47)). Heating compound (136) in a 1:2 ratio witharylisothiocyanates affords the dithio products (137; X = S) <83S225>, whilst similar treatment witharylisocyanates leads to the dioxo compounds (137; X = O) <85CPB4299>.

MeS N

Me

(47)

(136) (137)

Simple 2-substituted-5,6-dihydropyrrolo[2,3-fi?]pyrimidines (139) are readily obtained fromreduced pyrroles bearing a nitrogen substituent at C-2 (138). Thus compound (138; R = H, R1 = CN)is first treated with DMF diethylacetal and then with alcoholic ammonia to give the 2-aminoderivative (139; R = H, R1 =NH 2 ) (Equation (48)) <85KFZ154>. Alternatively, the precursor (138;R = Me, R1 = CO2Et) reacts with either (Me2N)2CHOEt or DMFDEA to form the 2-hydroxyderivative (139; R = Me, R2 = OH) <82KGS1553>.


(48)

R

(138) (139)

Three different approaches to the preparation of 5,6-dihydropyrrolopyrimidines (143) have beenemployed. The activated lactam (140) undergoes facile reaction with amidines to give 4-phenylaminoderivatives (143; R1 = PhNH) (Scheme 9) <83S226>.

PhHN

MeS

LiS Ni

LiR

(140) (143) (141)

CIO

(142)

Scheme 9

Lithiation of the thiolactam affords the dilithio derivative (141). Treatment of this organolithiumderivative with arylisothiocyanates, followed by methylation of the thio group and cyclization withbenzamidine, gives the derivative (143; R1 = RNH, R2 = Ph) <85H(23)2213>. Reaction of compound(142) with tetramethylguanidine, followed by sodium ethoxide, leads to a 58% yield of compound(143; R1 = R2 = Me2N, R = Me) <93IJC(B)422>.

7.07.6.2.2 Pyrrolo[3,2-d]pyrimidines (9-deazapurines)

The desire to develop efficient synthetic routes to 9-deazapurines has meant that there has beensubstantial research activity in this area, and much has been published since the early 1980s.

(i) Syn theses from pyrim idines

It is to be expected that the majority of examples involve 5-nitropyrimidines as precursors in theformation of pyrrolo[3,2-d]pyrimidines. 5-Nitro-6-alkyluracils (144), in which the acidity of thealkyl group plays an important role, have been converted into the corresponding pyrrolopyrimidines(145) (Equation (49)) by treatment with aryl aldehydes using either piperidine <82CPB3187> orpotassium hydroxide in refluxing alcohol <84JCS(Pl)583> as the base. In this case deoxygenation ofthe resulting Af-hydroxy group is effected by heating in DMF at 150°C. C-Nucleosides have beenprepared in an analogous manner commencing with the 2,4-dimethoxypyrimidine (146). Alkylationat the a-carbon using sodium hydride and 2,3-O-isopropylidene-5-O-(triphenylmethyl)-D-ribo-furanosyl chloride gives the derivative (147; R = protected carbohydrate). Reduction of the nitrogroup using 10% Pd/C catalyst gives the product (148) which, on hydrolysis of the methoxygroups and deprotection of the carbohydrate moiety, gives a mixture of nucleosides (Scheme 10)<86JOC1058>. Similarly, reduction of compound (147; R = H) leads to compound (148; R = H)<82TL4759, 83JOC1060). Treatment of 2,4-dimethoxy-6-methyl-5-nitropyrimidine with J-butoxybis


(dimethylamino)methane, followed by catalytic hydrogenation, also leads to compound (148;R = H) <83JOC1060>.

(144)

(49)

OMe

MeO

OMe

MeO

(148)

Taylor et al. have devized an improved route to 9-deazaguanine (150) <93TL4595>: a five-stepprocess starting from 2-amino-5-nitro-6(l//)-oxopyrimidine (149) results in an overall yield of 48%(Equation (50)). This modification of the Batcho-Leimgruber indole synthesis involves a key steprequiring the protection of N-3. An alternative route (Scheme 11) to 3-substituted-9-deazaguanines(153) which begins with the 4-chloropyrimidine (151) has been developed by a group at Parke-Davis<92JMC1605>. The key step involves treatment of the pyrimidine (151) with the anion of methyl 2-cyano-3-phenylpropanoate which results in the formation of the intermediate (152; Ar = Ph).

(149)

(50)

NO2 NO,

(151) (153)

A novel route to 9-deazahypoxanthine (156) proceeds through a palladium-catalyzed coupling of4-iodo-6-methyl-5-nitropyrimidine (154) with trimethyl(tributylstannylethynyl)silane to give thesilylated compound (155) (Scheme 12). Cyclization of this alkyne (155) is accomplished by treatmentwith potassium hydroxide, followed by reduction of the nitro group with palladium on carbon andheating with hydrochloric acid, which also hydrolyzes the methoxy group <92JCS(Pl)1883>. A similarapproach has been described <93CPB8l).

OMe OMe

NO2

TMS(156)


(ii) Syntheses from pyrroles

The classic approach to the formation of a fused pyrimidine ring involves cyclization of adjacentamino and cyano (or carbalkoxy) groups. The formation of pyrrolo[3,2-d] pyrimidines, commencingwith a suitably substituted pyrrole, follows this route exclusively. Virtually all of the activity usingthis approach involves the formation of C-nucleosides.

The continued interest in 9-deazaadenine derivatives is illustrated by the conversion of ribosylatedpyrroles (157; X = CN, CO2Et) into the corresponding C-nucleosides (158; R = NH2, OH) usingstandard reagents for both cyclization and deblocking of the sugar (Equation (51)) <83JOC780,93MI707-01).

(51)

(157)

OH OH

(158)

The same approach is taken to prepare 4-amino-7-((5)-2,3-dihydroxypropyl)pyrrolo[3,2-fif]py-rimidine <9UCS(P1)195>. A variation of this approach used to prepare nonnucleoside derivativesproceeds via the activated amines (159), derived from the corresponding amine and benzyl iso-thiocyanate, which is cyclized with methanolic ammonia to yield the derivatives (160) (Equation(52)) (93JMC55, 93JMC3771).

PhCOHN N

(159)

HN

H2N

(52)

(160)

(Hi) Syntheses from other rings

Rearrangement of a six-membered ring to give a five-membered ring was described in CHEC-I.Thus, pyrimido[5,4-c]pyridazine derivatives were converted into 5i/-pyrrolo[3,2-c?]pyrimidinesunder reductive conditions <78JOC2536>. Extrusion of sulfur from a pyrimidothiazine at 130°C alsogives a pyrrolo[3,2-c?]pyrimidine <71TL4185>. Pyrimido[5,4-e]-as-triazine 4-oxides (161) have beenconverted into a variety of pyrrolo[3,2-d]pyrimidines (162) (Equation (53)). These reactions involve1,3-dipolar cycloaddition of alkynic esters where the specific products depend on the esters used(79JOC3830, 82JHC1309, 85JOC2413).

(161)

(53)


7.07.6.2.3 Pyrrolo[3,4-A]pyrimidines

The use of pyrimidines as precursors for pyrrolo[3,4-<f]pyrimidines is the most common syntheticapproach. 6-Phenyl-7-(substituted)amino-pyrrolo[3,4-d]pyrimidine-2,4(l//,3//)-diones (164) arereadily obtained from the reaction of 5-formylpyrimidines (163) with arylamines (Equation (54))<89BCJ3043>. Formation of the Schiff base, followed by cyclization, is the proposed pathway. Amore traditional approach is found in the conversion of the cyanoester (165), via the amide, to thecorresponding pyrrolopyrimidine (166) (Equation (55)) <88LA643>.

O

(54)

N - R (55)

(166)

Annelation of a pyrimidine ring usually follows a pathway involving an amine function adjacentto an activated carbon moiety. The aminopyrrole carboxylic acid (167) undergoes reaction with 1-methyl-,S-phenyloxonium methylsulfate to give the tetramethylpyrrolo[3,4-J]pyrimidine (168)(Equation (56)) <88ZC334>. A similar reaction occurs with the less standard benzylidene derivative(169) and benzoyl isothiocyanate to afford the pyrrolopyrimidine (170) (Equation (57)) <89ZN(B)233>.In the case of the pyrrole (171) advantage is taken of the leaving ability of the methoxy group whenreaction with a variety of amidines leads to 2-(substituted)pyrrolo[3,4-j]pyrimidines (172) (Equation(58)) <87ZC404>.

HO2C

H2N

N-Me -Me (56)

(167) (168)

N-Bz

(169)

N-Bz (57)

(170)

MeO

(171)

(58)


7.07.6.3 Pyrrolopyrazines

7.07.6.3.1 Pyrrolo[ 2,3-bJpyrazines

Two very simple precursors combine to produce 2-arylpyrrolo[2,3-6]pyrazines. The anion derivedfrom 2-methylpyrazine (173) adds to a benzonitrile (e.g. (174)) to give the product (175) (Equation(59)). This reaction is not the favored pathway; displacement of chlorine is preferred <89TL935>although a similar reaction without the chloro substituent does provide the pyrrolopyrazine as themajor product <(81TL1219>. However, this reaction does not seem to have been investigated foradditional examples. In another simple reaction, 2-aminopyrazine (176) reacts with ethyl chloro-acetoacetate to give ethyl 6-methyl-5//-pyrrolo[2,3-6]pyrazine-7-carboxylate (177) (Equation (60))<89BSF467>.

NC

(173)

Cl

(174)

(59)

(175)

c(176) (177)

CO,Et (60)

One report of the synthesis of pyrrolo[2,3-Z>]pyrazines from a pyrrole precursor has appeared.2,3-Diiminopyrroles (178) have been cyclized to provide the tetraphenyl product (179) (Equation(61)) <88CB271>.

RNS

RN

R1

(>

NH

- R 2

R

(178)

(61)

(179)

7.07.6.3.2 Pyrrolo[3,4-b]pyrazines

Pyrazine-2,3-dicarboxylic acid anhydride (180) serves as the basis for the preparation of a seriesof pyrrolo[3,4-6]pyrazine derivatives <89JSC233>. Thus, treatment with a series of amino acids yieldscompounds of the type (181) (Equation (62)).

(62)

(180) (181)

Intermolecular cycloaddition of ethylenediimines (182) with maleimides (183) provides the cor-responding reduced pyrrolopyrazines (184) (Equation (63)) <82IJC(B)589>.

N-R1

NI

R

(182)

N-R1(63)

(184)


7.07.6.4 Furopyridazines

In Chapter 3.17 of CHEC-I only two furopyridazine systems, namely furo[2,3-d]- and furo[3,4-d]pyridazine, were discussed <84CHEC-i(4)973>. Further systems are covered in this chapter.

7.07.6.4.1 Furo[2,3-c]pyridazines

Intramolecular Diels-Alder cycloadditions have also been used in the synthesis of furo[2,3-cjpyridazines. The tetrazines (185; R = SMe, NMe2), when heated in solvents such as toluene,form the corresponding furopyridazines (186) (Equation (64)). This represents a facile method forpreparing simple derivatives which are reduced in the five-membered ring <85TL4355, 87CZ16). Analternative cycloaddition strategy leading to a partially reduced pyridazine ring commences withfuran. Treatment of furan (187) with the hydrazone (188; R = 2,4-dinitrophenyl) affords the stereo-specific product (189) in 73% yield (Equation (65)) <91T5615>.

R

N

(185) (186)

(64)

CO2Et EtO2C

O\

(187) (188) (189)

(65)

The adjacent nitrogen atoms in the furopyridazine ring systems suggest that reactions of hydra-zines would be a viable synthetic approach. The furanone (190), readily obtained from a furanedionevia a Wittig reaction, reacts with hydrazine in aqueous hydrochloric acid to produce compound(191) in 52% yield (Equation (66)) <88JOC5704>. Less acidic conditions lead to a six-membered ringvia a Michael addition reaction.

EtO2C

(66)HN

(190) (191)

The pyridazines (192) react with DMF dimethylacetal to give the intermediates (193) whichsubsequently cyclize to the furo[2,3-c]pyridazines (194) (Scheme 13) <83H(20)2347>.

CO2R1

CO2R!

NMe2

HN

(192) (193) (194)

Scheme 13


7.07.6.4.2 Furo[2,3-A]pyridazines andfuro[3,4-c]pyridazines

There have been no literature reports of these two ring systems since the early 1980s. Furo[2,3-<f]pyridazine itself is available from 2,3-dicyanofuran via the dialdehyde which is subsequentlyreacted with hydrazine. The use of the bishydrazide gives furo[2,3-rf]pyridazine-4,7-(5i/,6//)dione<56JA159, 66CR(C)313, 66CR(C)814>.

7.07.6.4.3 Furo[3,4-d]pyridazines

The synthesis of furo[3,4-fi?]pyridazines is most conveniently accomplished by treating a suitablysubstituted furan with hydrazine. Thus, the furan dicarboxylic ester (195; R = substituted phenyl)yields the aryl-substituted furopyridazine (196) when so treated (Equation (67)) <83KFZ683>.

MeO2C>=s>/" "" ' I u (67)

/ ^~^/ T TXT I / V '

R

(195) (196)

Conversion of the 2-buten-4-olides (197; R = Me) into the bromomethyl derivative (197;R = CH2Br), followed by oxidation with DMSO, leads to the dioxo compounds (198) (Equation(68)) <84KGS740>.

(68)

A simple and efficient route to these furopyridazines involves 5-aroyl-4-pyridazinecarboxylic acidderivatives (199): reaction with thionyl chloride affords the corresponding furopyridazines (200) inhigh yield (Equation (69)) <85LA167>.

Eto2c: ,XR i

R1

(197)

0(

O —/ 2

HN'I

0

XR1

(198)

01/

0

< .]

(69)

(199) (200)

One intramolecular Diels-Alder cycloaddition which does not involve a ring as a starting pointhas been described. The sequence commences with allylic /?-keto ester derivatives (201) and endswith the formation of the highly reduced furopyridazine (202; R = 2,4-dinitrophenyl or benzoyl)(Equation (70)) <89JCS(Pl)353>.

(70)

(201)

Ni

N

| H

(202)

O

w0

7.07.6.4.4 Furo[3,2-c]pyridazines

In contrast to the cycloaddition reaction of furan with hydrazones leading to furo[2,3-c]py-ridazines <91T5615>, the /?-chloroazo alkene (204) undergoes a [4 + 2] cycloaddition reaction with


furan (203) to yield a furo[3,2-c]pyridazine (205; R = Cl). The chloro group is capable of undergoingnucleophilic displacement to give other derivatives <85JCS(Pl)l74l>.

o •o

(203)

NO,

(204)

(71)

An appropriately substituted furan derivative (206; X,Y = Br, Cl), prepared from the cor-responding ketone and a hydrazine, can undergo cyclization by displacing a halogen to give afuro[3,2-c]pyridazine (207) (Equation (72)) <86M1707-05>.

RHNN

o

(72)

(206) (207)

7.07.6.5 Furopyrimidines

7.07.6.5.1 Furof2,3-d]pyrimidines

(i) Syntheses from pyrimidines

The location of the ring oxygen in furo[2,3-fif|pyrimidines suggests that pyrimidines bearing anoxygen at C-6 would serve as good candidates for developing the furan ring. Indeed, barbituricacid, and its A^N'-disubstituted derivatives, have been exploited in such synthetic schemes (Scheme14). Alkylation at C-5 of the barbituric acid derivatives (208; X = S, R = substituted-phenyl) withchloroacetic acid in the presence of triethylamine is immediately followed by cyclization to thederivatives (209; R1 = H, R2 = Me) <9OSC1O63>. Alkylation of dimethylbarbituric acid (208; R = Me)under phase-transfer conditions with 3-chloro-3-methylbut-l-yne is also followed by cyclization toform the derivatives (210) <87JHC14O9>. However, use of the 3-bromoalkyne results in disubstitutionat C-5 of the barbituric acid.

(209)

Aromatic substituents have been incorporated into the furopyrimidines (209; R1 = R2 = Ph) bytreating the thiobarbituric acids (208; X = S) with benzoin in the presence of a catalytic amount ofp-toluenesulfonic acid <90UC(B)566>. Two phenyl groups have also been introduced into the sameposition. Thus compound (208; X = O, R = Me) reacts with 1,1-diphenylethene in warm acetic acidwith manganese(II) acetate as catalyst to form the derivative (211) in 63% yield (Scheme 15). Thefuropyrimidine was not the main target of the reaction and this is the only example cited <93JOC4448>.Not unexpectedly compound (208; X = O, R = Me) condenses with substituted benzaldehydes to


give the benzylidene at C-5 in high yield. Treatment of this intermediate with phenyl isocyanideleads to the phenylamino compounds (212) <92H(34)89l>.

Ph(208)

(212) (211)

Scheme 15

Similarly, the reaction can be started with 5,5-disubstituted barbituric acid derivatives in whichone of the substituents possesses some reactive group. Thus, O-alkylation occurs in the presence ofa dibromo substituent, such as is observed with compound (213) (Equation (73)). The product (214)results from displacement of the terminal bromine by an oxy anion <92AP(325)333>. A similar resultis seen with secobarbital <92AP(325)291>. A 5-allyl-5-phenylbarbituric acid derivative, which waspreviously thought to produce an unusual tricyclic derivative upon treatment with bromine, has beenshown to follow this chemical pathway leading to a furopyrimidine <84JOC3227>. Other electrophilicreagents, such as /7-methoxyphenylselenium bromide and mercury(II) chloride, react with seco-barbital to produce 6-(substituted)furo[2,3-d]pyrimidines in an analogous manner <88SC1415>.

(73)

(213) (214)

Using similar chemistry l,3-diaryl-2-thiobarbituric acid is acylated with chloroacetyl chloride inthe presence of triethylamine. Subsequent O-alkylation under the mildly basic conditions of sodiumacetate yields the 5-oxo derivative <9lH(32)907>. It is not necessary to use barbituric acid derivativesto accomplish synthesis of furopyrimidines. Other 6-oxopyrimidines serve well in developinganalogues. For example, in a reaction similar to that described above, the acylated pyrimidine (215)undergoes cyclization to a 4-(substituted)amino compound (216) (Equation (74)) <92MI 707-03 >.

NHR1 o

jiMeS N ' "OH

(215)

NHR1

(74)

Other examples of similar chemical approaches to those described for barbituric acid derivativeshave been reported. Bromination of the derivatives (217; R = allyl) is followed by cyclization andoxidation to give the 6-methyl derivatives (218; R3 = Me) <88AKZ339>. Periodate oxidation of asimilar compound (217; R = 2,3-dihydroxypropyl) produces an unsubstituted derivative (218;R3 = H) (Equation (75)) <84MI 707-01 >.


(75)

Furo[2,3-</]pyrimidines can also be obtained from other 6-substituted-pyrimidines. For example,the 6-chloropyrimidine (219) is converted to the 6-propargyloxy compound (220) which cyclizes tothe derivative (221) upon heating <84H(22)2217>. The formation of a 6-methyl isomer is accountedfor by a Claisen rearrangement of the 6-allyloxy group (Scheme 16).

(219)

Efforts to cyclize pyrimidine nucleosides have only been marginally successful, such attemptsbeing prompted by the biological activity of many pyrimidine nucleosides. However, one suchexample is the reaction of a derivative (222; R = CH2CH2C1) with DBU in hot acetonitrile whichgives the corresponding product (223; R6 = H) in 12% yield (Scheme 17) <86CS67>. The product(223; R6 = OH) arises from reaction of compound (222; R = CH(OH)CH2I) with sodium carbonatein methanol (17.5% yield) in a reaction which was intended to replace the iodide with a methoxygroup. The latter reaction also occurs to yield 26% of the required product <9OJMC717>.

R5OR5O R5O

Scheme 17

A very low yield of a derivative (224; R7 = aryl) has been obtained in the palladium-catalyzedreaction between the precursor (222; R = O-triflate) and arylalkynes, a reaction not intended to givethe furopyrimidines <93JOC6614>. Better, but variable, yields of these derivatives are obtained whenan iodide (222; R = I) is heated to reflux in acetonitrile containing alkynes, 10% Pd/C, copper(I)iodide, and triethylamine <92IZV1449>.

(ii) Syntheses from furans

Consistent with other fused pyrimidine ring systems, the simple approach to a new pyrimidinering involves introducing a one-carbon fragment between two suitable and adjacent functionalgroups. Heating substituted 2-amino-3-cyanofurans (225) with formamide accomplishes the con-version to 4-aminofuro[2,3-fi?]pyrimidines (226) (Equation (76)) <84CCC1788>. Starting with similarlysubstituted 4,5-dihydrofurans leads to the corresponding reduced ring systems <85CB4782>.


NC R2 NH2 R 2

R1

(225)

(76)

Alkyl- or arylisothiocyanates serve to introduce sulfur at C-2 of the furopyrimidine. Hence thederivative (225) reacts with these compounds to give the 2-thio derivatives (227). Heating thesecompounds in DMF causes a Dimroth rearrangement to the isomers (228) (Scheme 18) <9UIC66O>.

(225)

NHR3

(227)

Scheme 18

A 2-acetylamino derivative of (225) forms a 2-methyl analogue of system (227) when heated withphosphorus pentoxide and a primary amine. This also undergoes a Dimroth rearrangement to a 4-(substituted)amine compound when heated in DMF <85CS227>. Phosphorus pentoxide and primaryamines react with 2-formylamino-3-carboxamidofurans to yield 4-(substituted)aminofurof2,3-fif]py-rimidines without a substituent at C-2 of the product <86CS337>.

[4 + 2] Cycloadditions can be used to produce some rather esoteric furopyrimidines. For example,the furandione (229) reacts with arylisocyanides or carbodiimides to yield compounds like (230)(Equation (77)) <91JOC235>.

Pr'

(229)

(77)

7.07.6.5.2 Furo[3,4-djpyrimidines

It is much easier to construct the furan ring on an existing ring in this system, and most of theexamples cited use this approach. Furthermore, virtually all of the syntheses lead to an oxidizedform of the furan ring. Perhaps the simplest, chemically, of the syntheses involves the pyrimidines(231). Heating these esters above 210°C provides the 5-oxofuro[3,4-J]pyrimidines (232) in yieldsranging from 50-80% (Equation (78)) <84H(22)493>. A seemingly similar pathway is observed forthe pyrimidinecarboxylic acids (233). However, reaction of these compounds with thionyl chlorideis postulated to involve the intermediates (234) which then cyclize to form the furopyrimidines (235)(Scheme 19). Evidence is presented to support the location of the sulfur and, hence, the role of theintermediate (234) <86S142>.

(78)

(231)

Ar = Ph, />-MeOC6H4,

NHAr


NHAr

263

CO2H

(233)

NHAr

(235)

An interesting, though apparently unique, example of the formation of a furopyrimidine is thatof the hemiacetal (237) from the pyrimidinecarboxaldehyde (236) (Equation (79)) <91JOC5610>.

(79)

One alternative route to furo[3,4-rf]pyrimidines proceeds via a ring interconversion. Thus thefurooxazinedione system (238) reacts with a series of primary amines to yield the corresponding 3-(substituted)furopyrimidines (239) (Equation (80)) <89EJM627>.

(80)

(238) (239)

7.07.6.5.3 Furo[3,2-A]pyrimidines

Pyrimidines with an oxygen function at C-5 represent the most efficient precursors to furo[3,2-d]pyrimidines. The formation of 5-propynyloxypyrimidines (240) allows cyclization to furo-pyrimidines (Equation (81)) (241). Treatment of compound (240; R = H) with sodium methoxidein warm DMSO gives the derivative (241; R = Me, R1 = H), whilst the methyl analogue (240;R = Me) undergoes thermal cyclization in DMSO to yield compound (241; R = R1 = Me). A parallelchemistry is described for the sulfur analogues <89JHC1851>.

(81)

(241)

The common use of amino and cyano groups ortho to each other to create a pyrimidine ring hasalso been employed. For example, the nucleoside (242), which has been synthesized from simplecarbohydrate precursors, can be treated with formamidine acetate to give the protected nucleoside(243) in 80% yield (Equation (82)). Deprotection of this compound using standard techniques leadsto the free nucleoside <90Ml 707-01).


NH2

O

(242)

(82)

7.07.6.6 Furopyrazines

There were very few references to furopyrazines in CHEC-I, and only to the furo[2,3-6]pyrazinesystem, which had been first reported in 1978 (78RTC81,78RTC151). Since then a very limited numberof further references has appeared.

7.07.6.6.1 Furo[2,3-bjpyrazines

The anions of active methylene compounds, such as A^N-diethylacetoacetamide, react withtetrachloropyrazine (244) to give the furopyrazine (245) by displacement (Equation (83)), enol-ization, and cyclization, instead of carrying out simple displacement of a chlorine. Yields of about50% are obtained <83JHC365>.

CONEt,

(83)

(244) (245)

7.07.6.6.2 Furo[3,4-b]pyrazines

The only reference to these compounds records the preparation of the furo[3,4-6]pyrazine-iV-oxides (247) from the oximes (246), which were intended to be used to make pyrazines for furtherelaboration into pteridines (Equation (84)). It is suggested that in an acidic environment theisopropylidene is cleaved thus allowing cyclization to the lactone structure <84JHC657>.

-O NOHO. X A OR

O O

(246)

(84)

7.07.6.7 Thienopyridazines

Of the five possible thienopyridazines without a nitrogen common to both rings, three types werementioned in CHEC-I and these were the [2,3-d]-, [3,2-c]-, and [3,4-d]-isomers <84CHEC-I(4)973>.


7.07.6.7.1 Thieno[2,3-c]pyridazines

Pyridazine-3-ones are relatively easy molecules to obtain. Conversion of the oxo compounds tothe corresponding 3-thiolpyridazines allows an easy access to thieno[2,3-c]pyridazines. Thus, treat-ment of compound (248; R = CN) with a-halo carbonyl compounds, such as ethyl bromoacetate orbromoacetophenone, gives the alkylthio derivative. Subsequent cyclization produces the 5-aminothienopyridazines (249; R1 = CO2Et or COPh) (Equation (85)) <9OJPR1O4, 90MI 707-04).When the derivative (248; R1 = CO2Et) is used the 5-oxothienopyridazine is obtained. An alternativeapproach involves commencing with a 3-chloro-4-cyanopyridazine and replacing the chlorine bynucleophilic reaction of an appropriately substituted alkylthiol, followed by cyclization <91M413>.

NH2

(85)

(249)

Simple pyridazine-3-thiones (e.g. (250)) undergo photoaddition to a variety of alkenes (251) togive the thienopyridazines (252) as well as dimers of the starting compounds (Equation (86))<86CPB3061>.

R1 R3

(250)

R2 R4

(251)

(86)

(252)

7.07.6.7.2 Thieno[2,3-d]pyridazines

Pyridazine-4-ones (253; R = Me) can also be used to obtain suitable thieno[2,3-d]pyridazines. TheGewald reaction, employing ethyl cyanoacetate and sulfur, leads to the tetrahydrothienopyridazines(Scheme 20) (254; R = Me; R1 = CO2Et; R2 = NHR3; R3 = various alkyl groups) <90AKZ324>. Thesame type of product (254; R = Et, Pr1, R1 = R2 = H) is produced in a [4 + 2] cycloaddition reaction.The thiophene (255; R1 = R2 = H, X = +NMe3, Y = TMS), in the presence of tributylammoniumfluoride, undergoes elimination to give 2,3-dimethylene-2,3-dihydrothiophene. This structure is wellsuited to Diels-Alder reaction with azodicarboxylate forming the cycloadduct (254) <93RTC7>.

RO2C

RO2C

Ni

N

RO2C

ORO2C

X

(253) (254)

Scheme 20

The thioamides (256; R = CN, CO2Et) undergo S-alkylation at the thioamide. Subsequent hydra-zinolysis affords the thienopyridazines (257) (Equation (87)) <87AP(320)43>. This approach seemscapable of further generalization.

NH2 NH2

N

o

(87)

(256) (257)



No syntheses of this ring system have been reported and there were no references to it in CHEC-I.

7.07.6.7.4 Thieno [ 3,4-&]pyridazines

A simple approach to thieno[3,4-</|pyridazines has been explored by several laboratories in Egypt.Commencing with a pyridazine substituted at C-4 with a cyano group and at C-5 with a methylgroup (258), the corresponding thienopyridazines (259) are obtained in good yields (Equation (88)).The reaction is carried out with sulfur in a solvent, such as ethanol, and in the presence of a base,such as triethylamine (89LA1255,90CCC2977,91MI707-01 >. A similar reaction occurs if the R substituentis attached to the other ring nitrogen. In this case a meso-ionic product results <92G503>.

CO2Et CO2Et

(88)

NH2

(258) (259)


Only thiophene derivatives have served as precursors to thieno[3,2-c]pyridazines. The thermalreaction of the 3-azidothiophene (260) to give the simple thienopyridazine (261) (Equation (89))was described in the first edition of CHEC-I <8lCC550>. It has subsequently been reported showinglow yields in addition to a variety of other products <84JCS(P1)915>. A good yield of the morecomplex thienopyridazine (263) arises from heating the thiophene (262) with piperidine in DMF(Equation (90)) <91SUL229>.

EtO2C

N3

(260)

EtO2C

N

(261)

(89)

PhHNv HON

EtO2C

NHPh

(262)

EtO2C

NHPh (90)

(263)

7.07.6.8 Thienopyrimidines

7.07.6.8.1 Thieno[2,3-&]pyrimidines

(i) Syn theses from six-membered rings

Although a large number of thieno[2,3-^/]pyrimidines have been synthesized from pyrimidineprecursors, most have evolved from pyrimidines bearing a carbonyl moiety at C-5 and an alkylatedsulfur at C-6. Either 6-thiol- or 6-chloropyrimidines may be used. In the latter case, displacementof the chlorine by a sulfur anion is commonly used. In general, pyrimidines of the type (264) are theimmediate precursors or are formed in situ. For most of the investigations the derivatives (264;R = R3 = Me; R2 = aryl) have been used. The cyclization to the products (265) can be effected by


heating the pyrimidines, or by the use of a weak base such as triethylamine, sodium acetate, orsodium carbonate <88JIC695,89PHA348,90CCC1049,91PJS4). When the C-5 substituent of the precursor(264) is an ester, the product possesses a 5-hydroxy group (265; R = OH) (Equation (91)) <89SUL20l >.Likewise, a cyano group at C-5 of the precursors (264) affords products with 5-amino substiuents(265; R = NH2) <84JCS(Pi)2447,87KGS1377,89SUL101,9OPHA216>, whilst pyrimidine-5-carboxaldehydesprovide thienopyrimidines unsubstituted at C-5 <9OJHC717>.

(91)

(264)

An alternative pathway utilizes the palladium-catalyzed replacement of an iodo group at C-5 ofthe pyrimidines (266; R2 = I) to give alkynes (266; R2 = C=C-TMS) (Equation (92)) <86CPB2719>.Replacement of the chlorine by sodium hydrogen sulfide is followed by immediate cyclization tothe thienopyrimidines (267) in yields of 53-95%.

(92)

(ii) Syntheses from five-membered rings

Virtually all of the syntheses of thieno[2,3-J]pyrimidines beginning with a thiophene precursorarise from the same synthetic strategy. Thus, thiophenes with a 2-amino- (or (substituted)amino-)function, and either a carboalkoxy, carboxamido, or a cyano group at C-3 are the preferred startingpoints. Typically, when the thiophene has a carbonyl function at C-3 (268; R = OEt or NH2)cyclization affords the 4-oxothienopyrimidines (269) (Equation (93)).

R'HN

(93)

Formamide converts 2-aminothiophenes (268; R' = H) into 4-oxothienopyrimidines (269;R1 = R2 = H) (83ZC179, 84EJM420, 90DOK32,93PHA192). If however, cyclization occurs using a cyanocompound as the one-carbon reagent, an amidine is generated at C-2 of the pyrimidine. This resultsin a product containing a substituent at C-2 which arises from the nature of the cyano compound.Thus, the derivatives (269; R1 = CH2CO2Et) form when NCCH2CO2Et is used <89IJC(B)1O39,89PHA790). The introduction of a desired substituent at C-2 of the system (269) is also accomplishedby converting the 2-amino group into the desired amide prior to cyclization. In this way a varietyof thienopyrimidines (269) have been obtained, including derivatives (269; R1 = phenyl <92MI 707-oi>, R1 = (CH2)2CO2H <89PHA860> and R1 = CO2R

5 <87JHC58l>. Acetylation of the amine andhydrazinolysis of the ester leads to the unusual thienopyrimidine (269; R1 = COCH3, R2 = NH2)<88EJM453>. Similarly, when the 2-amino group is converted to the ethoxymethylimino moiety andthen treated with aniline a thienopyrimidine (269; R' = Ph) is obtained <85IJC(B)432>.

Thieno[2,3-rf]pyrimidin-2-ylidene derivatives can be prepared by cyclization of thiophenes derivedfrom condensation of the 2-amino group and, for example, acrylonitrile <93PHA347>.

In reactions analogous to those of 2-carboxamidothiophenes, thiophenes bearing 2-(sub-stituted)urea or thiourea moieties cyclize in the presence of base to give 2,4-dioxo- or 2-thio-4-oxothieno[2,3-c?]pyrimidines bearing a variety of groups at N-3 (83HCA148, 88JMC1786, 90EJM635,91EJM807).


If 4-aminothieno[2,3-</|pyrimidines are desired, the simplest approach is to use a 3-cyano-thiophene as precursor. Formamide or triethylorthoformate are commonly used to convertthe amine (270; R1 = H) into the thienopyrimidine (271; R1 = H) (Equation (94)) <88JPR585>. Theuse of formic acid has been reported to give the 4-oxo compound instead <92MI 707-04). Guanidinereacts with the thiophene (270; R1 = H) to give only a 24% yield of product (271; R1 = NH2)<90HCA797>.

(94)

NC R3

(270)

Other 2-(substituted)amino derivatives lead to the expected 2-(substituted)-4-amino-thienopyrimidines (271) (83CPB1177,86CPB516,88CS195,89AP(322)227>. A trichloromethyl group can beintroduced at C-2 of the thienopyrimidine (271; R1 = CC13) when the thiophene (270; R1 = H) isallowed to react with trichloroacetonitrile and formamide <89ZN(B)488>. It is very likely that theintermediate is a trichloroacetamidine.

(Hi) Syntheses by transformation of another ring

The synthesis of thieno[2,3-6?]pyrimidines from other bicyclic ring systems has also beenaccomplished. Thieno[2,3-J]l,3-thiazines (272; X = S, NH) undergo reaction with primary aminesto give the corresponding N-3 (substituted)thienopyrimidines (273) (Equation (95)) (86PHA96,89UC(B)642>. A less obvious conversion occurs when 3-aminoisothiazolo[5,4-J]pyrimidines, suchas compound (274), undergo ring opening upon treatment with chloroacetone with subsequentrecyclization to the thienopyrimidine (275) (Equation (96)) <88JCR(S)46>.

(95)

NH2

COMe(96)

The exploitation of intramolecular Diels-Alder reactions has included synthetic applications inthe thienopyrimidine series as well. Thus, the 1,2,4-triazine with a tethered alkyne (276) participatesin an intramolecular cyclization, with concomitant loss of RCN, to produce the thienopyrimidine(277) (Equation (97)) <87JOC4287>. A similar reaction occurs with oxygen analogues.

(97)

N

(277)

7.07.6.8.2 Thieno[3,4-A]pyrimidines

The creation of a thiophene ring from or^o-cyano-methylpyrimidines has provided access tothieno[3,4-J]pyrimidines. Mono- or di-A^-(substituted)uracils (278) undergo reaction with elemental


sulfur to give the corresponding thienopyrazines (279) (Equation (98)) <9OMI 707-02,91 Ml 707-04). 2-(Substituted)pyrimidine-4-thiones react in the same manner with sulfur to yield 4-thiothieno[3,4-c?]pyrimidines <9OLA1215>.

(98)

(278)

The fusion of a pyrimidine onto an existing thiophene has also been described. The thiophenewith ortho-ammo and ester functions (i.e. (280; R = CO2Et)) is treated first with a series of elaborateprimary amines, which form the 4-carboxamido group. Subsequent reaction with trimethyl-aluminum leads to the dioxothienopyrimidine (281) in which the desired variation occurs at R4

(Equation (99)) <90JHCl76l>.

(99)

R2HN-WS

R1

(280)

The simpler thiophene derivative (280; R = R1 = H, R2 = CHO) is converted to a C-nucleoside(281; R1 = tribenzoylribose). Reaction with methanolic ammonia at 100°C cyclized the pyrimidinering affording no substituent at C-2, and deblocked the nucleoside <88TL3537>.

7.07.6.8.3 Thienof3,2-A]pyrimidines

3-Aminothiophene-2-carboxylates (282) undergo cyclization to the corresponding thieno[3,2-<f]pyrimidines (283), either with formamide alone <85IZV1858> or with prior reaction involving formicacid and sodium acetate (Equation (100)) <86MI 707-01 >. 3-Amino-2-cyanothiophenes are convertedto the acetamidate upon treatment with trimethylorthoacetate and acetic anhydride. The ace-tamidate leads to the thienopyrimidine when heated in a sealed vessel with sodium amide inliquid ammonia <86JHC1757>. Imidates (e.g. (284)) react with amines and hydrazines to give N-(substituted)thienopyrimidines (285) (Equation (101)) <92BSB445>. Similar thiophenes, arising fromreaction of 3-aminothiophene-2-carboxylate (282; R = Me, R1 = H) with l,l-dicyano-2-alkoxy-2-hydroxyethene, cyclize in hot DMF to give 4-oxothienopyrimidines with an exocyclic double bondat C-2 <91HCA579>.

RO2C

H2N

R1

(282)

(100)

(283)

EtO

(284)

R2

(101)


7.07.6.9 Thienopyrazines

7.07.6.9.1 Thieno[2,3-b]pyrazines

In chemistry designed to provide pteridine-based ring systems, Taylor et al. have utilized tetra-substituted pyrazines (286) to generate thieno[2,3-6]pyrazines which retain the functionality necess-ary for anellating a pyrimidine ring. When compounds (286; R = NH2, R1 = CH=CHR2) areallowed to react with thiourea in an alcoholic solvent, the fused pyrazines (287; R3 = H) are obtained(Equation (102)). If sodium sulfide is used with this pyrazine the product obtained is reduced in thethiophene ring <88JOC5839>. Displacement of the chlorine in compound (286; R = N=CHNMe2 ;R1 = CN) with an a-thiolketone in the presence of triethylamine, followed by treatment with themildly basic sodium acetate, leads to derivatives (287; R2 = CH2CO2Me, R3 = NH2) <89JA285>.

NC N R< R3

R^NJL — r FVR; (IO2)

S

(286) (287)

7.07.6.9.2 Thieno(3,4-bjpyrazines

Thieno[3,4-i]pyrazines have only been described sporadically and no new syntheses of this ringsystem have been reported since 1979. 3,4-Diaminothiophenes have been used for the synthesis ofthese compounds <77H(6)l87l, 79YZlO8l> but examples of the system are rare.

7.07.6.10 Miscellaneous fused pyrrolo systems

7.07.6.10.1 Dioxinopyrroles

There are few references to dioxinopyrroles which are compounds which do lend themselves tosystematic study. The lactam acetal of 1-methylpyrrole (288) reacts with aldehydes in anhydrousether (or in the absence of solvent) at room temperature to give the tetrahydro-l,3-dioxino[4,5-6]pyrroles (289) (Scheme 21). These lose one molecule of aldehyde when treated with alcoholicpotassium hydroxide to yield the benzhydrols (290) <83UC(B)i079>.

C JV^ * ArCHO /~T ' O ale. KOHV OMeMe / O

Me' O M e

(288) (289)

Scheme 21

The tetrahydro-l,3-dioxino[5,4-6]pyrrole (292), an intermediate in the total synthesis of ( —)-detoxinine, has been obtained from the precursor (291) (Equation (103)) (9UOC240, 93T785>. Analternative synthesis of detoxinine is that of Ohfune and Nishio who obtained it in 20% yield as aside product in the reaction of the acetal (293) with mercuric acetate in aqueous THF, followed bythe action of potassium iodide (Equation (104)) <84TL4133>.


OBu'2,2-dimethoxypropane

p-TsOH'H2O, THF, heat Boc

(292)

(103)

NHBoc

MeO,CO2Bu'

Hg(OAc)2

(293)CO2Bu'

(104)

7.07.6.10.2 Pyrrolooxazines

A number of oxazine-fused systems, including the pyrrolo[2,3-J][l,3]oxazine (295; R =PhCH2), have been obtained by reacting dichlorotriphenylphosphorane with a 1,2-aminoester(e.g. (294; R = Et)) (Equation (105)). The /-butyl ester (294; R = Bu') reacts with methyl pyru-vate in the presence of acetic acid and sodium acetate to yield the pyrrolooxazine (295; R = Me)<90MI 707-05 >.

,CO2R

(105)

PhCH2

(294) (295)

i, Ph3PX2 (X = Cl, Br), Et3N, RT to reflux, 2 h; ii, toluene or MeCN, heat

The furandione (296) reacts with diaryl or dialkylcarbodiimides to give, via the furooxazine (297),the products (298) which isomerize above 60°C to the pyrrolediones (299) (Scheme 22). Theseproducts (299) react with dimethylcarbodiimide to give pyrrolo[2,3-d][l,3]oxazinediones (300). In asimilar way 2,3-thiophenedione yields pyrrolo[2,3-c/][l,3]thiazines (301) <84CB131O>. The structures(300) and (301) were confirmed by x-ray crystallography.

O

Ph

Ph

(296)

RNCNR1

Ph

Ph

O

N

R

(299)

(297)

MeNCNMe

-RNCO

MeN

(300)

Ph

Ph

(298)

Scheme 22


(301)

There is an easy route to pyrrolooxazinediones (303) from the pyrroles (302) by simply refluxingwith carbonyl chloride in toluene (Equation (106)) <85S796>.

(302)

COC12, toluenereflux, 0.5-1 h

32-94%

(303)

(106)

7.07.6.10.3 Pyrrolothiazines

The pyrrolo[3,4-e][l,3]thiazine (305) is obtained, stereoselectively as the endo isomer, by [4 + 2]cycloaddition of the heterodiene (304) with N-phenylmaleimide in toluene at 60 °C (10 h) <89TL6923>.Af-Phenylmaleimide also reacts with 2-(dialkylhydrazono)thioacetophenones via [4 + 2] cyclo-addition to give 4-amino-3,4-dihydro-2//-l,4-thiazines which readily convert to the pyrrolothiazines(306) (Equation (107)) <92PS(70)2ll>.

Ph

JPh.

N!TMS

(304)

PhN

(305)

NPh

pRC6H4CSCH:NNMe2 +

R = H, Cl, Br

pRC6H4

(107)

(306)

Another route to pyrrolothiazines is the acid-catalyzed treatment of the pyrrolidinetrione (307)with bifunctional nucleophiles, such as thiourea and phenylthiourea, to yield the compounds (308)in yields of up to 55% (Equation (108)) <87JPR626>.

(108)

(307) (308)


Simply heating the pyrrole (309) with triethyl orthoformate (140-155 °C, 3.5 h) gives thepyrrolo[3,2-6][l,4]thiazine-l,l-dioxides (310), some of which show muscle relaxant properties<88PJS242>.

SO2CH2CN

(309)

R = PhCH2, PhCH2CH2, cyclohexyl, Bu, morpholino, pyridylmethyl; R1 = H, Et

7.07.6.10.4 Dithiinopyrroles

The 1,4-dithiino[2,3-c]pyrrole, suriclone (Rhone-Poulenc) (311), was first synthesized in the 1970s.Since then it has been widely used as an anxiolytic and many studies of its metabolism andpharmacology have been carried out. There are many patents which have been taken out onanalogues of suriclone. However, there seem to have been no reports of the chemistry of thethiinopyrrole ring system up to 1995.

7.07.6.11 Miscellaneous Fused Furo Systems

The furodioxins, and cyclic peroxides, as mentioned in Section 7.07.1, will not be dealt with here.Other furo-based systems are considered below, although there seem to be few systematic studiesof such ring systems.

7.07.6.11.1 Furooxazines

The use of a chlorooxime as the precursor to a-nitrostyrene, and its subsequent cycloaddition toproduce a furo[2,3-e]-l,2-oxazine, was referred to in CHEC-I (vol. 3, p. 1013 and <76CC58l». Muchfurther work has since been carried out on this reaction, principally by Gilchrist and co-workers.The chlorooxime (312) reacts with 3,4-dihydrofuran to yield 3-acetyl-4a,5,6,7a-tetrahydrofuro[3,2-e]-l,2-oxazine (313) which has been characterized as its 2,4-dinitrophenyl hydrazone <85JCS(Pl)2769>.Similar reactions of furan and 2,5-dimethylfuran have yielded c«-3-acetyl-4a,7a-dihydro-4//-furo[2,3-e]-l,2-oxazine (314a), and the 4a,7a-dimethyl analogue (314b) <83JCS(P1)1283>. Thisapproach to the synthesis of furooxazines has been developed using the cycloaddition of nitroso-alkenes, generated in situ from halogenooximes, to furans < 79 JCS(P 1)249,83JCS(Pl)1283,90JCS(Pl)1497>.The vinylnitroso compound (315) reacts with 2,5-dimethylfuran to yield the furooxazine (316)


(Equation (109)) <87JCR(S)180>. A similar reaction starting with the benzoylhydrazone of ethyl 3-bromo-2-oxopropanoate (317) gives a furopyridazine (318) (Equation (110)) <87JCS(Pl)2505>.

O

ciNOH

(312) (314a) R = H(314b) R = Me

CO2Et

(109)

CO2Et

(110)

(317)

Triethyl azomethinetricarboxylate (319) reacts with electron-rich alkenes in chloroform at roomtemperature to give Diels-Alder products (e.g. (320)) (Equation (111)) <84TL943>. Furooxazines(e.g. (321)) have also been obtained by reacting a-aminoesters and dichlorotnphenylphosphorane<84CB1310,85S796). The furooxazine (323) has been made by an intramolecular [4 + 2] cycloadditioninvolving an JV-acylamine and an alkene. The acetylation of compound (322; R = H) gives the ester(322; R = Ac) which on heating in refluxing o-dichlorobenzene gives the furooxazine (323) (64%)as a single stereoisomer, confirmed by high field 'H NMR spectroscopy <84JOC5058>.

EtO2C

EtO2C

NCO2Et (111)

EtO

(319) (320)

NHCOPh

(322) (323)

The oxazines (325) are formed as primary products in the photoreactions of tetrahydro[3,4-rf]isoxazoles (324), but themselves undergo cyclization to give the furooxazines (326) on furtherirradiation (Scheme 23). This reaction (325)-> (326) seems to be a concerted process involvingmigration of OR. This process seems to be similar to the classical d-7i-methane rearrangement<88CCC3171,88ZC22>.

OHCCO2R

(324) (325) (326)

Scheme 23


The tetrahydrofuro[2,3-e]-l,3-oxazin-2-one (328) has been obtained from the precursor (327) andthe structure confirmed by x-ray crystallography (Equation (112)) <88T3215>.

o1

N ™ N, N

THF, RT, 22 hH,N

O

HO OBn

(327)

OMe(112)

OBn

(328)

The reaction products of JV-alkyl(phenylmethan)imines and 4-benzoyl-5-phenylfuran-2,3-dione(329; X = O) have been confirmed as furo[3,2-e][l,3]oxazines (330) by extensive 'H and 13C NMRstudies. These compounds undergo subsequent reaction to yield pyrrolidinediones (Scheme 24). Thecompound (329; X = O) reacts with dimethyl-/»-tolylketenimine to give the furooxazine (331). Undersimilar conditions the sulfur analogue (329; X = S) gives the furothiazines (332); the structure of theproduct being confirmed by x-ray crystallography and NMR spectroscopy. This reaction is differentfrom that of the furo analogue, and is obviously more complex, since it results in a change from athiophene to a furothiazine system <84CB1310,87H(26)625>.

R N = /Ph

(329)

Me2C=N/)-Tol

(330)R = Me, Et, Prn, Bun

NI

R

p-Tol

(331)

Ph

(332)r = Ph,/)-Tol

Scheme 24

Some derivatives of 2//-furo[3,2-J][l,3]oxazine-2,6-(l/f)dione have been reported to have beenmade, but without any details <88BCJ46l>.

7.07.6.11.2 Furothiazines

Treatment of the bromomethylthiazine esters (333; X = CH2Br) with sodium acetate yields thelactone which is a furothiazinone (334; R = H). The aldehydes (333; X = CHO) react with potassiumhydroxide to give the lactones (334; R = OMe, OEt) in 80-90% yield <86PS(28)36l>.

MeO2C

CO2R

(333)

MeO2C

R = Me, Et (334)


The thiazine lactones (336) have been made by reduction of the thiazines (335) <85TL745,87T2709).A similar thiazine lactone (337) has been isolated from cultures of a cephalosporin C producingstrain of Cephalosporium acremonium <88TL21O1>.

p

o(335) (336) (337)

R = H, Me

A thiazine lactone (339) has also been made, albeit in very low yield (0.3%), by reacting 3,4-dichloro-5-hydroxy-2(5//)-furanone (338) with JV-acetylcysteine (Equation (113)). The structure ofthe product was confirmed by NMR spectroscopy <92MI 707-05).

JCi ci

N-acetylcysteine, 0.1 M phosphate buffer

" ^ M - N / (1 1 3>~ ~ u - 30-35 °C, overnight = N

U COMe

(338) (339)

7.07.6.12 Miscellaneous Fused Thieno Systems

7.07.6.12.1 Thienodioxins

The thieno[3,4-&][l,4]dioxins (341) have been obtained from the 3,4-dihydroxythiophenes (340)by the two routes shown in Scheme 25. The use of ethane-1,2-diamine allows the synthesis of thetetrahydrothieno[3,4-6][l,4]pyrazine system <9UHC1449>.

Treating the thiophenes (342; X = CO2Me) and (343; X = CO2Me) with polyphosphoric acidyields only the 4i/-thieno[3,2-Z>]-l,3-dioxin-4-one (344; X = CO2Me) (Equation (114)). Howeverthiophenes (342; X = H) and (343; X = H) give both product (345; X = H), and thienopyranone(346). Polyphosphoric acid also cyclizes the thiophenes (347) and (348) to the bicyclic products (349)and (350) (Equations (115) and (116), respectively) <85JCR(S)386>.

MeO2C

A

HO

A r - ^

CO2Me

O

.^LCO 2M,(342)

(340)

+

OH (CH2Br)2, Na2CO3

' DMF, reflux, 6 h

^ A r ' 7 3 %

Ar

\ ra (CH2OH)2, Na2CO3\ / 5 DMF, reflux^/^

CI CI\ /H

Ar-^s^Ar1

Ar = />-NO2C6H4;Ar1= [

Scheme 25

CO2Me

MeO2C o

(343)

' 70%

iy

PPA

0 0\ /M

^ S > - A r >

(341)

/r-

S '

^-CO2Me

p~CO2Me (H4)O

(344)


CO2Me^-CO2Me / = /

0 / / \

- - / o o-CO2Me \ /

277

(345) (346)

MeO2C

Br'

Br

CO2Me(115)

(347) (349)

HO2C

OCO2H

(116)

(348)

The l//,4/f-thieno[3,4-rf][l,2]dioxins (352) are obtained, as crystalline solids, by thermolysis ofthe bisallene sulndes (351) in the dark and in the presence of oxygen (Equation (117)) <85IJ1O1>.

(351)

heat, 3O2

R = H, Bu1

(117)

(352)

7.07.6.12.2 Thienooxazines

The thienooxazines (353) have been known since 1981 <81CB3188, 8UIC982). The synthetic routeto these which has been most used being the reaction of dihalotriphenylphosphoranes with a-aminoesters (cf. the synthesis of furooxazines, Section 7.07.6.11.1). The thiophene (354) reacts withdichlorotriphenylphosphorane to give the isomers (355) and (356) (Equation (118)) together withthe tricyclic compound (357), 26% of the product being (355) and (356) and 61% being (357)<81CB3188>. These reactions have been developed and general syntheses for heteroannulated 3,1-oxazin-4-ones which give high yields of these products have been formulated involving the use of/?-(./v"-triphenylphosphoranylidene)-enaminoesters with aroyl chlorides. Thus using dichloro-phenylphosphorane the thiophene (358; X = NH2) is converted to the derivative (358; X = N : PPh3)which on heating with an aroyl chloride gives the thienooxazine (359).

R,R! = (CH2)n, n = 3,4,5R2 = Me, Ph

278

PhCOHN CO2Et

JriEtO2C " \ s / ~ ~ NHCOPh

(354)


CO2Et

-NHCOPh +O_

NHCOPh

CO2Et

OPh

(355)

CO2Et

(357)

// v(358)

(118)

(359)

In a similar reaction, the bisphosphoranylideneaminothiophene (360) with an aroyl chloride givesfirst the product (361) and then the tricyclic product (362). The use of other reagents in the secondstep enables various R groups to be introduced <93T58l>.

Eto2c. ,CO2Et O CO2Et

JL x

Ph3P=N^s'

(360)

= PPh,= PPh3

(361) (362)

Thienooxazinediones (363) are obtained by reacting 2-aminothiophene-3-carboxylic acids withcarbonyl chloride. These may then be alkylated and reacted with aldehydes to yield 3-substitutedthiophenes (364) (Scheme 26) <86JCR(M)1063, 86JCR(M)2828, 86JCR(S)155, 86JCR(S)328>.

CO2H

^ N H 2

i, ii

VR

~O iii

~O QCOCH2COAr

NHMe

(363) (364)

Ar = Ph, 3,4-diMeOC6H3, 3,4-OCH2OC6H3

i, COC12, PhMe; ii, NaH-DMA, then Me2SO4; iii, ArCOCH3, Pr'2NLi

Scheme 26

Thienooxazines can also be made from 3-hydroxyisothiazoles (365) by a process involving ringopening of the isothiazole ring, followed by two ring closures (Scheme 27) <85JHC1497>.

OH

NS '

(365)

o o

I Ml i NAcS ' S '

OH

- D B U

H2O

S'

o

oOAc

O

o

Scheme 27


An example of a ring enlargement of a thienoisoxazole to yield a thienooxazine system is that of2-methyl-3/?-phenyl-2,3a,3a/?,6a/?-tetrahydrothieno[2,3-d]isoxazole-4,4-dioxide (366) which yieldscompound (367) on treatment with MCPBA (Scheme 28). This product undergoes an interestingreaction on treatment with ?-butanol in boiling toluene to give the tricyclic product (369) via thenitrone (368). The structure of compound (369) was confirmed by x-ray crystallography <86T466l>.

NMe

Ph

(366)

Ph

OH

(369)

Scheme 28

7.07.6.12.3 Thienothiazines

Thieno[3,2-c][lA\2]thiazines (371) were first reported in 1981 and were obtained by heating orirradiating the thiophenes (370) (Scheme 29) (Table 3) <81CC927, 86JCS(Pi)483>. Similar thermolysisof the azidofuran (372) gives the product (373) (Equation (119)). At higher temperatures (> 120°C)these compounds undergo thermal [1,4] shifts to yield the derivatives (374) <86JCS(Pl)49l>, and theyalso undergo photochemical rearrangements (82CC884,86JCS(Pi)497>. Attempts to make the isomericthieno[3,4-c][lA4,2]thiazines have been less successful, and the only one to be isolated (as an unstablegum) has been compound (375) (Equation (120)) <86JCS(Pl)483>.

Table 3 Synthesis of thieno[3,2-c][U4,2]thiazines(371) <81CC927, 86JCS(P1)483>.

R

MeEtCH2CH: CH2

PhPhPhPhMe

Z

CO2EtCO2EtCO2EtCO2EtCOMeCHOCNH

Yield

80300

899075904

SRheat or irradiate heat>120°C

C6H5Brorxylene

(370) (371)

Scheme 29

(374)

SMe

//Iheat

~CO2Et

N - s +Ph

(119)

(372) (373)


-N3

SR heatS

CO2Et

(120)

CO2Et

(375)

The thienothiazine system can also be obtained from the "reversed" azidothiazines. However,such reactions are not successful for the synthesis of the [3,4-c] system due to the nitrene preferentiallycyclizing to the thiophene 2-position resulting in thienopyrroles, or thienopyridines, and only thethieno[2,3-e][U4,2]thiazines are obtained <86JCS(P1)483>.

There has been considerable interest in the thienothiazine ring system from the pharmaceuticaland pharmacological view point since 1976 when tenoxicam (4-hydroxy-2-methyl-JV-2-pyridinyl-27f-thieno[2,3-c]-l,2-thiazine-3-carboxamide-1,1-dioxide) (376) was patented by Hoffmann-La Roche asan antiinflammatory agent. Since then there have been hundreds of references to analogues, and torelated compounds, and their pharmacological action, metabolism, and analytical methods for thesecompounds. It would be beyond the scope of this chapter to attempt to review these data.

OH o

(376) Tenoxicam

One of the methods which leads to a thienothiazine ring system is the reaction of the dithietane(377) with 2-amino-4,5-di(substituted)-3-thiophenecarboxamides to yield the derivatives (378)(Equation (121)) <86JAP(K)6ll5ll77>.

NC

MeO2C

CN

CO2Me

R CONH2

/ : 71

R-"\<;/^ NH2

(121)

CO2Me

(377) (378)

7.07.6.12.4 Thienodithiins

Thieno-l,4-dithiins (380) have been obtained (ca. 40% yield) from the diynes (379) (Scheme 30)(83CC1056, 87MI 707-02>. Thieno-l,4-dithiins (382) and (383) have also been obtained from 4-bromo-3-chloro-2-sulfolene (381) and the sodium salt of ethane- 1,3-dithiol (Equation (122)). These productsare oxidized by peracetic acid to yield the further S-oxides (89CC1020,92CB499).

i, KOBu', THF, -90 °C

ii, BuLi, hexane, -90 °C

R1

(379)R = TMS, Me

Scheme 30

i, CS2, -100 °C

ii, Bu'OH, HMPT,-30 °C to 30 °C

(380)R = H, Me

Br Cl

SO2

(381)

SO2

(382)

X = S, SO2

SO2

(383)

(122)


7.07.7 IMPORTANT COMPOUNDS AND APPLICATIONS

A number of derivatives of the fused diazines, particularly nucleoside derivatives, are naturallyoccurring antibiotics. Examples of such compounds are sangivamycin (384a), which is an inhibitorof protein kinase C, and the related 7-deazaadeninine antibiotics tubercidin (384b) and toyocamycin(384c), which are not <88JBC1682,89JAN102).

NH2

N

(384a) (R = CONH2) Sangivamycin(384b) (R = H) Tubercidin(384c) (R = CN) Toyocamycin

Several other ring systems covered by this chapter have other types of biological activity, forexample, the l,4-dithiino[2,3-c]pyrrole system provides suriclone (311) which is a useful anxiolyticagent. Many analogues have been synthesized and patented since the 1970s but few have beenmarketed. The thieno[2,3-c]thiazine dioxide, tenoxicam (376) is used as an antiinflammatory agentand, again, many analogues have been synthesized, a few of which have been developed.

2//-Thieno[3,2-e]-1,3-thiazines have also been patented as inhibitors of inflammation, and for theiranalgesic and antirheumatic properties (for example see <79GEP(O)283885i, 80SZP617705). Similarly, thethieno[2,3-e]-l,2-thiazines (e.g. (385)) have also been shown to have antiinflammatory properties<85EUP138223>.

OH

(385)

The 4//-thieno[3,4-(i][l,3]thiazine (386) is an intermediate in a synthesis of cephalosporin<77JAP32637, 78JAP(K)83884>.

R = phthalamido, R1 = Bu'

R2O2C \ /

(386)

Much of the chemistry of the ring systems covered in this chapter has centered on their uses asPharmaceuticals, and as synthetic analogues of natural products, or as intermediates in the synthesisof natural products. Only a few examples have been cited here. No doubt this research effort intothe synthesis and studies of biological activity will continue, unabated, in the future.

7.07 bicyclic 5-6 systems: three heteroatoms 1:2aether.cmi.ua.ac.be/artikels/comprehensive...th e...

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