Fluorinated Heterocycles - ACS Publications - American Chemical

Chapter 13

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Syntheses of Fluorinated 1,3-Oxazoles 1,3,4-Oxadiazoles, 1,3,4-Thiadiazoles, and Oxazolo[4,5-d]pyrimidines V. S. Brovarets, O. P. Mityukhin, Α. V. Golovchenko, and B. S. Drach Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanskaya Str. 1, 02660, Kyiv-94, Ukraine

The preparation of fluorine-containing azole and azine heterocyclic systems that posses additional pharmacophoric groups is often a difficult process. As our approach, we have carried out cyclization of fluorinated 2-acylamino-3,3dichloroacrylonitriles. The sequence allows retention of the nitrile group, or this group can be used for further transformation.

In order to obtain fluorine-containing analogues of heterocyclic substances designed for the study of different types of bioactivity, mainly two basic approaches are used. These include reaction of halogen-substituted heterocycles with inorganic nucleophilic fluorinating agents or, alternatively, cyclization of fluorinated organic precursors. Areas of applications for the two approaches in general do not overlap and they are developed independently. During the last few years, cyclization of various fluorine-containing reagents have been studied with special intensity. Electrophilic reagents for this application were synthesized recently in our laboratory through addition of fluorine-containing carboxamides to chloral (Figure 1). The sequence of reactions ( 1 )—*(2)—*(3)~*(5) is similar to transformations of ordinary non-fluorinated chloral amides, which were synthesized and studied previously (/). O f special interest here is the obtaining of fluorinated 2-acylamino-3,3-dichloroacrylonitriles (2), which we have abbreviated A D A N . F

© 2009 American Chemical Society

In Fluorinated Heterocycles; Gakh, A., et al.; ACS Symposium Series; American Chemical Society: Washington, DC, 2009.

281

282

H

V

N

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r ^ ,

Q

Q

—

V

-

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t ^ ' q

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2 (ADAN ) F

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-

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^ > = 0

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H II

—

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°oA)Alk

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5

R = CH F, CHF , CF , CF CF CF CHF , C F C H , C H F-4, C H OCHF -4. F

2

3

2

2

2

2

2

2

6

5

6

4

6

4

2

Figure 1

R = C H F , C H F , C F et al., N R ' R = NHAlk, N A I k , N H A r ; R = Alk, Ar. 2

F

2

2

3

2

3

Figure 2


283 Although derivatives (3-5) are also suitable for the syntheses of heterocyclic compounds, they are not considered in this article in detail, and our main attention is devoted to cyclization reactions based on A D A N . We have established that A D A N , like non-fluorinated 2-acylamino-3,3-dichloroacrylonitrile (7-5), react under ordinary conditions with various primary and second amines to give substituted 5-amino-4-cyano-l,3-oxazoles (6). These heterocyles contain fluorinated alkyl or aryl residues in position 2 of the oxazole rings (Figure 2). The A D A N reaction with a hydrazine hydrate proceeds in a similar manner to produce the 5-hydrazino-4-cyano-1,3-oxazole derivatives (7). We also successfully synthesized the fluorine-containing derivatives of 5-mercapto-4cyano-l,3-oxazoles using the sequence of transformations (2)-*(8)—>(9), presented on the Figure 2. Formation of oxazole rings as a result of removal of a alkylthio- or arylthiogroups from the generalized structure F

F


F

RS

Î X

where X=CN, CO(0)OAlk, P(0)(OAlk) and other electron-withdrawing substituents, has been studied recently with several non-fluorinated enamides (4,5). Such cyclocondensations are also characteristic for several of the fluorinated enamidonitriles [see transformation (8)—*(9) in Figure 2, unpublished results]. The readily accessible reagents A D A N were applicable not only for the synthesis of substituted oxazoles, but also for the preparation of new types of fluorine-containing derivatives of 1,3,4-oxadiazoles. Reagents (2) were first converted into substituted 5-hydrazino-4-cyano-1,3-oxazole (7) and their analogues (14). Subsequent treatment with acylating agents initiates the successive transformations: (7)-+(10)—^(11)—•(12)—>(13) (Figure 3). 2

F

Similar transformations ( 14)—>( 15)—•( 16) —>(17) or (18) are shown in Figure 4. Formation of the 1,3,4-oxadiazole system presented in Figures 3 and 4 occurs due to ring transformation (10)—> —>(13) (15)-* —•(17) and (15) —• —•(18). A n important factor in this rearrangement is prototropic destabilization of the oxazole ring. Intermediate prototropic tautomers (11) and (16) contain a non-aromatic oxazoline ring and are capable of ring transformations at elevated temperatures in pyridine or acetic acid. The structure of the recyclization products (13,17,18) were confirmed by combination of spectral methods, by X-Ray analysis of compounds (13) and (18) ((5), and also by chemical transformations presented on the Figure 5. We tried to convert compounds (17) into amino acids (19), but they are easily decarboxylated. However, we did manage to modify compounds (17) by



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CH C(Q)OH Δ Downloaded by EAST CAROLINA UNIV on August 29, 2013 | http://pubs.acs.org Publication Date: January 1, 2009 | doi: 10.1021/bk-2009-1003.ch013

3

Γ

t

X = P(0)(OAlk)

Χ= C(0)OAlk

2

Ν-Ν

N~N

Η

Ο 0

OÔAlk

R or R| = CF , CF C H , et al. F

3

2

6

OA

5

Χ = C(0)OAlk, P(0)(OAlk) .

17(61-72%)

18(63-77%)

2

Figure 4

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286 CN R'N=C=S

Ν - / „ „ // \ \ H R-r\ > - N

NIL

/

23

NHR

N

O

HNHR

24

1

N-N

N-N

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R

NH

NH

2


CN

CN

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NHR

-Y

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NH

2

26

25

CH,C(0)OH, Δ

R = FCH , F CH, F C et al; F

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2

H R ^ N ^ ^

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1

R = Alk, Ar.

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Figure 6

their conversion into (21) and (22). As is shown in Figure 5, these transformations involve intermediate (20) containing an azlactone ring which is readily cleaved by water or alkyl esters of glycine to give derivatives of alphaamino acids (21, 22). Starting from 5-hydrazino-4-cyanooxazoles (7), we synthesized not only the 1,3,4-oxadiazole derivatives but also the related derivatives of 1,3,4-thiadiazole (Figure 6). For this purpose, compounds (7) were heated in dioxane with alkyl- or arylisothiocyanates. The resulting compounds (25) are then converted into compounds (26). The latter, when heated in acetic acid, gave compounds (27). We propose that initial cleavage of the 5-aminooxazole ring of compound (26) occurs and that this is followed by decarboxylation. It is interesting that A D A N (2) reacts with benzamidine in a totally different way compared to the reaction with amines. Here, [2+3] condensation takes place resulting in compounds (28) which after acid hydrolysis produces imidazolones (29). When heated in pyridine compounds (29) are converted to substituted oxazolo[4,5-^pyrimidines (31). Probably, in such an intricate transformation, intermediate spiro-compounds play an important part [see transformations (29)->(30)->(31) on Figure 7]. F


287 c i ^ c i

Ν*

1

Η

HN^NH

2

Ν 2a

2

Ar


Ο

Ar

Ν Η 28

Ar

J^CHCl/

Η,Ο, Η

N

Ar

Ν Η 29

Py, Δ

N

V y Y

Py

Rp

U KΝ T Η

i l

γ-ο

ΗΝΟ

CI 30

'

*

Ο R = CHF , CF , C F C H et a l F

2

3

2

6

31

5

Figure 7

R = CHF , C F C F C H et al. F

2

3

2

6

5

Nu = AlkNH, Alk N, ArNH, AlkS, ArS. 2

Figure 8


288 It should be noted that compounds (31) have been little investigated and are unlikely to be obtained by other methods. The presence of the oxazolopyrimidine fragment in the final products (31) is supported by the fact that the structures of similar non-fluorinated compounds analogous to (31) were confirmed by X-ray analysis (7). Compounds (31) are attractive starting points for the synthesis of other derivatives of oxazolo[4,5-^-pyrimidine using simple transformation (31)—>(32)—>(33) or (34) presented on Figure 8. Thus, based on the availability of reagents A D A N , we have successfully synthesized a series of derivatives of oxazole (A, B), 1,3,4-oxadiazole (C), 1,3,4-thiadiazole (D) and oxazolo-[4,5-c/]pyrimidines (E, F, G) containing fluorinated substituents. These compounds should be of interest as leads for the development of various bioregulators (see Figure 9). In conclusion, we have reviewed briefly the most recent results of our research on heterocyclizations of fluorinated 2-acylamino-3,3-dichIoroacrylonitriles. Only a small portion of this work has been previously published (8,9), but more detailed publications will be forthcoming.


F

R = CH F, CHF . CF , CF CF CF CHF , C F C H , C H F-4, C H OCHF -4 F

2

2

3

2

2

2

2

2

6

5

6

4

6

4

Figure 9


2

289

References 1.

2.


3. 4. 5. 6. 7. 8. 9.

Drach, B.S.; Brovarets, V.S.; Smolii, Ο.Β. Syntheses of Nitrogen -Containing Compounds on the Basis of Amidoalkylating Agents; Naukova Dumka: Kiev, 1992. Oxygen- and Sulfur-containing Heterocycles; Kartsev, V . G . , Ed.; IBS Press: Moscow, 2003, v. 1 ; pp 52-66. Matsumura, K . ; Saraie, T.; Nashimoto, N. Chem. Pharm. Bull. 1976, 24, 924-940. Matsumura, K.; Miyashito, O.; Shimadzu, H . Chem. Pharm. Bull. 1976, 24, 948-959. Pilyo, S.G.; Brovarets, V.S.; Vinogradova, T.K.; Golovchenko, A . V . ; Drach, B.S. Zh. Obshch. Khim. 2002, 72, 1818-1827. Golovchenko, A . V . ; Pilyo, S.G.; Brovarets, V.S.; Chernega, A . N . ; Drach, B.S. Zh. Obshch. Khim. 2005, 75, 461-467. Sviripa, V . M . ; Gakh, A . A . , Brovarets, V . S . ; Gutov, A . V . ; Drach, B.S. Synthesis, 2006, 20, 3462-3466. Drach, B.S.; Miskevich, G.N. Zh. Org. Khim., 1978, 14, 501-507. Pilyo, S.G.; Brovarets, V.S.; Vinogradova, T.K.; Chernega, A . N . ; Drach, B.S. Zh. Obshch. Khim. 2001, 71, 310-315.


Fluorinated Heterocycles - ACS Publications - American Chemical

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