Fluorinated Î²-Enamino Esters as Versatile Synthetic Intermediates

Chapter 34

Downloaded by UNIV OF MASSACHUSETTS AMHERST on March 1, 2017 | http://pubs.acs.org Publication Date: July 21, 2005 | doi: 10.1021/bk-2005-0911.ch034

Fluorinated β-Enamino Esters as Versatile Synthetic Intermediates: Synthesis of Fluorinated β-Amino Acids and Uracils Santos Fustero*, Juan F. Sanz-Cervera*, Julio Piera, María Sánchez-Roselló, Diego Jiménez, and Gema Chiva Departamento de Química Orgánica, Universidad de Valencia, Avenida Vicente Andrés Estellés s/n, E-46100 Burjassot, Spain

β-Enamino esters are versatile synthetic intermediates that can be prepared with a diversity of methods. The reactivity of these compounds both in the asymmetric synthesis of fluorinated β-amino acids and in the preparation of heterocyclic systems such as fluorinated uracils and thiouracils has been studied.

Introduction In Nature, the great majority of molecules, including proteins and nucleic acids as well as most biologically active compounds, contain nitrogen. Therefore, developing new synthetic methods for the construction of nitrogenous molecules has defined the frontiers of organic synthesis since its very beginning. In this context, the past few decades have seen a concerted effort to develop building blocks for this purpose. One such group of building blocks is comprised of the β-enamino esters (1,2), an important class of molecules which have proven their utility as valuable and versatile intermediates for the synthesis of biologically active compounds such as α and β-amino acids,

© 2005 American Chemical Society

Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.

593


594 conformationally restricted peptide analogs, heterocyclic derivatives, and alkaloids, these last generally through aza-annulation processes. One of the keys to the versatility of these compounds is the various reactions in which they can be prepared. Thus, in addition to the classic condensation reaction between β-keto esters and amines, other routes, including the nucleophilic addition of acid derivative enolates to nitriles or imidoyl halides, the Michael addition of amines to alkynoates, and the reaction of imines with activated carbonic acid derivatives, have all been undertaken with more or less success (i, 2). In the course of our ongoing study of the synthesis and reactivity of 1,3difunctionalized derivatives (3), we became interested in the development of new strategies for the synthesis offluorine-containingnitrogen derivatives such as acyclic and cyclic β-amino acids as well as biologically active heterocyclic systems like fluorinated uracils and thiouracils, all starting from a common intermediate, namelyfluorinatedβ-enamino esters (Figure 1).

Figure 1. Fluorinated β-enamino esters as starting materials for the preparation ofβ-amino acids and (thio)uracils.

In contrast to their non-fluorinated counterparts, v-fluorinated β-enamino esters have received far less attention in the past. A survey of the literature reveals that relatively few methodologies have been developed for the synthesis of these derivatives. Some of the most recent and useful procedures described include:

Synthesis of fluorinated β-enamino esters. Condensation of fluorinated β-keto esters and amines. In this context, Soloshonok has very recently described an improved synthesis of fluorinated β-enamino esters 2 and 3 which takes into account the chemo- and regioselectivity in the reactions of highly electrophilic fluorine-


595


containing β-keto esters 1 and aliphatic (4) and aromatic amines (5) (Figure 2). The process is highly dependent on the reaction conditions and can be applied on a large-scale. These systems are useful key intermediates for the preparation both of enantiomerically pure fluorinated β-amino acids 4 by biomimetic transamination processes (6) and of biologically interesting heterocyclic systems such as 2-trifluoromethyl 4-quinolinones 5 by intramolecular cyclizations (5). R

Θ ®X X ν H tr N XT' Âr 3

F C^ ^ r s ^ U J b t - γ Y _ ^ R^NH Ο 3

V

F

OH

aC NH Ο 2

FC

OEt

3

ο

Α Γ

2

4

ο 1

ArNH X 3

OEt r v Ar .NH Ο

H

C

F

3

Figure 2. Condensation reaction offluorinated β-keto esters and amines.

Michael addition of amines tofluorinatedalkynoates. Abarbri et al. have recently used this well-known reaction for the preparation of optically active perfluoroalkyl-oxazepin-7-ones 6 by reaction of perfluoro-2-alkynoates 7 with bifunetional heteronucleophiles such as optically active amino alcohols 8 (7) (Figure 3). The global two-step process involves an intermolecular Michael addition that generates 9, followed by lactone formation. -C0 Et

R,

2

£

H

"

X o H 2 N

F

0°C

H

I Toluene, C0 Et 9(78-96%) 2

6(74-87%)

Ο

Figure 3. Michael addition of amines tofluorinatedalkynoates.

In a similar fashion, (£)- or (Z)-perfluoroalkyl β-enamino esters had been previously obtained quantitatively through direct addition of primary or secondary aliphatic amines to ethyl perfluoroalkynoates without the need for a catalyst (8).


596


Wittig reaction of fluorinated amides* JV-Arylfluorinatedβ-imino/enamino esters 10 can be obtained easily and in excellent yields by reacting fluorinated JV-aryl substituted amides 11 with phosphoranes 12 (9) (Figure 4). These enamines are precursors of synthetically and biologically important heterocycles such as indole 13 and quinolone 14 derivatives, both of which can be obtained from a common intermediate. Thus, an intramolecular Heck reaction in N atmosphere provided indole derivatives in moderate yields. Quinolones were prepared under similar reaction conditions except that the reactions were performed under CO atmosphere. The overall transformation implies a sequential Wittig-Heck reaction. 2

13(44-54%)

14(54-77%)

Figure 4. Wittig reaction offluorinatedamides.

Intramolecular Wittig type rearrangement of imino (thio)ethers. This strategy, described in 1998 by Uneyama for iminoethers 15, provided a-hydroxy-P-imino-y-fluorinated esters 16 in good yields (>80%) (Figure 5). Compounds 15 were converted into 16 after treatment with a base at low temperature via Wittig rearrangment (10). The best results were obtained when lithium 2,2,6,6-tetramethylpiperidide (LTMP) was used as base and when the reaction temperature was kept between -105°C and -70°C for 1 h. Compounds 16 are precursors of racemic a-hydroxy-P-amino-y-fluorinated acids 17 through stereoselective reduction processes.


597

A R

ΑΓ

N-

Ν·

NBase

π

R Ô^C0 R F

J OH 16

RF

2

*-

15

NH I2

R F ^ V ^ OH 17


Figure 5. Intramolecular Wittig type rearrangement of imino (thio)ether

The same author studied an extension of the O-Wittig rearrangement to the corresponding thio-analogues with unexpected results (11) (Figure 6). The starting thioglycolates 18 were prepared in good yieldsfromfluorinatedimidoyl chlorides. Compounds 18 were next subjected to the base-catalyzed (LDA) Wittig type rearrangement. The reaction proceeded at a higher temperature (-40°C) and with a longer reaction time (9 h) than those of oxygen analogues. Surprisingly, a facile desulfurization was observed, affording β-enamino esters 19 bearing no sulfur moiety. N' Jjj^

A R

HSCH C0 R 2

2

N* t

^

Bas

HN'

A R

e|

Ρ /k^C0 R 2

r

f

Cl Et N,THF,0°C 3

r

p

s

18

C

0

2

R

-S

R

F

8

19

Figure 6. Preparation offluorinatedthioglycolates and their desulfurization t β-enamino esters.

Ester enolate condensation withfluorinatedimidoyl halides or nitriles. This strategy represents one of the simplest as well as one of the most efficient and general routes to fluorinated β-enamino esters 20. In 1997, we described the condensation reaction between lithium ester enolates and imidoyl chlorides 21 (12,13). Subsequent treatment of alkyl esters with 2.0 equivalents of lithium diisopropylamide (LDA) in THF, followed by addition at -78°C of a variety of fluorinated JV-alkyl or JV-aryl imidoyl chlorides provided, after standard workup, the corresponding fluorinated β-enamino esters 20, which were isolated as a mixture of imino and enamino tautomers (Figure 7). In general, the process works well, with good yields (64-95%) being obtained regardless of the nature of the starting materials. No excess of starting material is necessary with the exception of L D A , for which a two-fold excess should be used in order to ensure the presence of the intermediate 22, which results in a significant improvement of the chemical yield.


598

N

R

F

'

R

l

II

AXI

LDA(2.0equiv)

"NLi Ο

(

+

n

R

I 3

O

R

2

THF,-78*C

*

R ^ V ^ OR F

R

21 NH Clsat.

Ν

Ο

NH

4

Rp^yÔR


3

22

R

2

^

Ο

R p ' ^ ' ^ O R

3

R

2QE

2

3

20/

Figure 7. Ester enolate condensation withfluorinatedimidoyl halides.

In order to demonstrate the scope of this approach, we extended the process to other β-enamino acid derivatives, such as fluorinated β-enamino amides derived from chiral nonracemic acyclic and cyclic amides. Thus, compounds 21 reacted with a range of chiral amides to afford the enamino tautomers exclusively and in good yields. Some representative examples are shown in Figure 8.

">i

PMP

ι ~s- ο

r Î

•"> Ϊ

«ΑΛ^, XA /T *Αφ*· * A \ y F!C

N

°2 94%

40%

—OBoc

*—- O P M B

85%

82%

Figure 8. Fluorinated β-enamino amides derivedfromchiral nonracemic acyclic and cyclic amides.

In the same vein, we have also reported a simple route to JV-substituted Cprotected β-enamino acid derivatives 23 by reacting 2-alkyl-A -oxazolines 24 (X=0) and 2-alkyl-A -thiazolines 24 (X=S) with imidoyl chlorides 21 (Figure 9). Thus, azaenolates derived from 2-alkyl-A -oxa(thia)zolines react with compounds 21 under the same conditions as described above to provide the enamino tautomers 23 in good yields (14,15). 2

2

2


599

2

R C(C1)=NR (21)

R

x

F

LDA (2.0 equiv), THF, -78 C

NH

N - V

G

e

1

r 23

(60-92%)

r

1

R C = N (25)


24 (X= 0,S)

NH

F

LDA (1.0 equiv), THF, -78°C (60-93%)

i>

Ν

2

X

RF 1

r 27

2

Figure 9. Preparation of A -oxazoline protected β-enamino esters.

The reactivity offluorinatednitriles in this kind of process was also studied. We found that lithium ester enolates and lithium azaenolates derived from 2alkyl-A -oxazolines condensed smoothly withfluorinatedaromatic and aliphatic nitriles 25 to afford excellent yields offluorinatedβ-enamino acid derivatives 26 (16) (Figure 10) and 27 (17) (Figure 9). In this case, only one equivalent of LDA was necessary to ensure the success of the process. 2

Ο

£l

ι. LDA (1.0 equiv),

«.NH Clsat. 4

25

NH Ο 2

^ 26

(>95%)

Figure 10. Ester enolate condensation withfluorinatednitriles.

In turn, compounds 26 and 27 have been used as starting materials for the preparation of racemic and chiral nonracemic fluorinated β-amino acid derivatives (15) and heterocycles such as uracils and thiouracils (see below).

Reactivity and applications offluorinatedβ-enamino esters. Synthesis offluorinatedβ-amino acids through reduction offluorinatedβenamino esters. Although the chemo- and stereoselective reduction of chiral non-racemic βenamino ester derivatives constitutes a simple and attractive route to enantiopure



600

β-amino acids, very few examples of this strategy being used for preparing enantiopure fluorinated β-amino acids have been reported (6). In 1999, our group described a new and efficient two-step procedure for the diastereoselective synthesis of racemic (18) and chiral non-racemic syn-a-alkylβ-Αηο^Ι^Ι-β-βιηΐηο esters 29 (13). In this protocol, a chiral auxiliary group was used in the alcohol moiety of the ester. The condensation reaction yielded optically active fluorinated enamino esters 28, which were then reduced with NaBH /ZnI in an aprotic, non-chelating solvent (CH C1 ) to give the corresponding fluorinated β-amino esters 29. The best asymmetric induction was achieved with (-)-8-phenylmenthol as the chiral auxiliary. While the yields were high, a mixture of both diastereomers was obtained in all cases. These could, however, be separated by means of column chromatography. With few exceptions, the syn diastereomer was predominant, with the diastereomeric excesses ranging between moderate and good (d.e. up to 96%). In addition, the researchers found that the amino group could be easily deprotected with CAN. Thus, the use of (-)-8-phenylmenthol as a chiral auxiliary allowed for the preparation of optically active β-amino acids 30 in good yields (Figure 11). 4

2

2

„PMP Ν

PMP Ο

+

R / X l

Γ

l,LDA(2equivQ OR*

R

ZnI /NaBH 2

4

CH C1 * 2

2

2 8 (67-85%)

S

f

1

9

l.CAN

NH2 Ο

χΛ Α

D

Ο

R / T " U R *

4

(R*=8-phenylmentyl) PMP

S

NH

2. aq. NH C1

2

•

ν

X OR* 2.HC1 R* 29 (75-85%) (d.e. up to 96%)

Jl

Χ

RF^>TÔH R 30

F

RF=CF , R*=Me 3

50% yield., e.e. >99%

2

Figure 11. Chemo- and stereoselective reduction ofchiral non-racemic β-enamino ester derivatives for the preparation of enantiopure β-amino acids.

An explanation for the stereochemical outcome of the reduction of chiral βenamino esters 28 (R = CF , R = Me) could involve the participation of two diastereomeric chelate models, in which the hydride attack is conditioned by the presence of the 8-phenyl group of the chiral auxiliary (1,5-asymmetric induction, Figure 12). 2

F

3



601

(2R,3fl,R*)-29

(2S,3S,/?*)-29

major

minor

Figure 12. A possible explanation for the stereochemical outcome of the reduction of chiral β-enamino esters 28.

Considering that several well-known amino acid drugs (i.e. Captopril and its trifluoromethylated analogue) contain a thiol group and that isoserine derivatives display an important biological activity, Uneyama et al. focused on the synthesis of fluorinated isoserine analogs. In the course of their work, they were able to achieve the diastereoselective synthesis of both diastereomers of racemic S-tert-butyl-p-itrifluoromethyOisocysteine (19) by coupling fluorinated imidoyl chloride 31 with the enolate 32 to provide β-imino esters 33 in good yields. To suppress the desulfurization during the Wittig-type rearrangement (see Figure 6 above), S-terf-butyl protection of the sulfur moiety was necessary (11) (Figure 13). The conversion of compounds 33 into the corresponding fluorinated βamino acid diastereomers syn-34 and anti-34 was achieved by means of sterocontrolled reduction with hydride via either the chelated intermediate or the non-chelated Felkin-Ahn intermediate, respectively. For this purpose, NaBH in CH C1 and in the presence of ZnBr led to the preferential reduction of the imino moiety, affording the syn product exclusively. It was deemed convenient to stop the reaction when ca. 20% of die starting material was still present, as prolonged reaction times led to the appearance of alcohol as a result of the ester group reduction. In contrast, reduction of compounds 33 with NaBH in a solvent that traps sodium ions to generate naked borohydride [e.g. THF/di(ethyleneglycol)dimethylether] gave a mixture of both diastereoisomers, with the anti being predominant, in a proportion of 11:89 syn.anti. 4

2

2

2

4


602 ,Ar Ν"" X FC CI

.AT +

Θ r-BuS^^CÛ^-Bu

C0 *-Bu 2

3

Si-Bu

32

31

33 Ar = p-C H OCH , 80% p-C H Cl, 92% 6

4

6


T

.PMP

HN

.PMP

HN

C0 /-Bu

C0 r-Bu

+

2

2

F

S/-Bu

3

C

S/-Bu

33

3

4

.PMP

A^CO^-Bu : Sf-Bu anti-34

syn-34

Figure 13. Uneyama's synthesis of isoserinefluorinatedanalogs.

Both diastereomers 34 were easily deprotected by first removing the PMP group by means of C A N oxidation, followed by /-butyl group removal through acid-catalyzed hydrolysis (Figure 14). Additionally, the deprotection of the Stert-butyl group was achieved in two steps. First, the C-S bond was cleaved with o-nitrobenzenesulfenyl chloride to give the unsymmetrical disulfide 35 in 88% yield. This compound was then reduced with NaBH to afford the thiol 36 in 64% yield. 4

HN FC

„PMP

NH

CAN

«A^CO^-Bu

3

H NNH 2

2

syn/anti-34

HN FC

Jk^CCty-Bu Si-Bu syn-34

HN

2-Nbs-Cl 3

88%

MeOH S/-Bu

62% (syn) 68% {ami)

CH C0 H rt,24h

Bu

3

.PMP

3

+

F C

Sf-Bu

NH cr

aq. HC1

2

3

F,C J k ^ C 0 H 2

S/-Bu

99% (syn) 99% (anti)

.PMP NaBH

FC 3

2

HN 4

CHCl -MeOH rt, lh

FC

.PMP

Αγ-CO^-Bu

3

3

V

2-Nbs

35

64%

SH syn-36

Figure 14. Deprotection reactions of isoserinefluorinatedanalogs.

Cyclic β-amino acids represent an interesting class of compounds because of their potential as therapeutic agents. Cyclic β-amino acids are also useful intermediates in the synthesis of natural products, β-peptides, and peptidomimetics. While the chemistry of their non-fluorinated derivatives has received a great deal of attention in the past few years (20), very little is known



603

about their fluorinated counterparts. Although the literature includes several examples of β-amino acids with seven-membered rings, no fluorinated sevenmembered β-amino acids have been described until recently. Our group described the first diastereoselective preparation of fluorinated seven-membered β-amino acid derivatives through Ring-Closing Metathesis (RCM) (21, 22) (Figure 15). The first step of the synthesis consisted of the condensation between the imidoyl chloride 37 and the enolate of ester 38. This yielded compound 39, which appeared as a mixture of enamino and imino tautomers. Although a variety of reagents were used to reduce compound 39, no stereoselectivity was achieved. Thus, column chromatography was used to separate the syn-40 and anti-40 diastereomers (in 1:1 ratio), which were then submitted to an R C M reaction with second-generation ruthenium catalyst (fflMes)(PCy )Cl Ru=CHPh (23) to yield the respective seven-membered β-amino esters 41 in low yields. 3

F

2

F

,Ar OH

3

3

4

F

F

37a Ar=/?-MeOC H (80%) 37b Ar=o-MeOC H (82%) 37c Ar=/7-FC H (50%)

H N-Ar 2

Ο

2. aq. NH4CI

3h

CC1 , D,

Ν

1. LDA (2 equiv.) /THF/-78°C

Ph P, Et N

6

6

4

6

4

39 (tautomers)

4

PMP

N

F

NH !

t

Ο U

PMP^ Second generation ρ y OEt ruthenium catalyst V^-\>C0 Et (15mol%) F-7 \ x m

H

2

2

,ΡΜΡ Ν Ο

CH C1 (2· 10" M),

\ = /

40°C

cis-41a (27%)

2

l.NaCNBH THF/TFA/ 0°C. 3

2

(syn/anti 1:1)

+ 2.aq.NH Cl 4

P

70%

M

\ NH

39a

Ο

Second generation P M P x ruthenium catalyst «NH rntVifninm nntnlve* _ (15mol%) OEt • F CH C1 (2Î0- M), t ) 40°C trans-4U (27%) F

2

2

2

N

=

=

/

\anti-40a

Figure 15. Diastereoselective preparation ofseven-membered β-amino acid derivatives 41 by means ofRing-Closing Metathesis (RCM).


604

Since neither the diastereoselectivity nor the yields for this approach were satisfactory, the reactions were next performed in inverse order. Thus, compounds 39 were cyclized by reaction with eitherfirst-generationruthenium catalyst catalysts (PCy ) Cl Ru=CHPh (24) or second-generation ruthenium catalyst (fflMes)(PCy )Cl Ru=CHPh (the latter gave slightly better yields under milder conditions) to furnish the cyclized imino esters 42 in 60-90% yield, depending on the substituents (Figure 16). These compounds were then reduced with NaCNBH /TFA in a completely stereoselective fashion to give the cis diastereomer 41 in 72-90% yield. 3


3

2

2

2

3

Figure 16. MM and diastereoselective reduction of compound 39.

Finally, it was possible to either deprotect the amino group by means of PMP removal with CAN, or hydrogenate the double bond with hydrogen and a palladium on charcoal catalyst, with both procedures producing very high yields of 43 or 44, respectively (Figure 17).

Figure 17. Deprotection reactions on compound 41a.

Synthesis of fluorinated iso(thio)cyanates.

uracils

from

β-enamino

esters

and

Our research group has developed several strategies for using β-enamino esters as starting materials in the synthesis offluorinateduracils. In some cases,


605

the synthesis is applicable for obtaining non-fluorinated compounds as well, but quite often it is precisely the differential reactivity of fluorinated organic compounds that makes the synthesis possible. The two main strategies involved are the reaction of ester enolates withfluorinatednitriles and the reaction of Δ oxazolin-C-protected β-enamino ester enolates withfluorinatednitriles. In the first uracil synthesis developed by our group from β-enamino esters (25), compounds 26 are condensed with iso(thio)cyanates 45 to furnish the corresponding (thio)uracils after treatment with NaH in DMF. This condensation leads to the i\T-acylation of the enamine, which then undergoes a cyclization to yield the (thio)uracils 46. When isocyanates were used, the corresponding uracils were obtained in good yields (64-90%), with the yields for the thiouracils being slightly lower (64-70%). In this way, 20 new fluorinated (thio)uracils 46 were easily prepared in only two steps and in high yieldsfromfluorinatednitriles, esters, and iso(thio)cyanates (Figure 18).


2

Figure 18. Reaction of compounds 26 with iso(thio)cyanates 45.

1

Interestingly, the direct halogenation of uracils at C-5 when R = H does not seem to be possible. For this reason, the halogenation with either N chlorosuccinimide (NCS) or N-bromosuccinimide (NBS) of the corresponding β-enamino esters is a useful approach to C-5 chlorinated or brominated uracils. Unfortunately, we have not been successful in our efforts at direct fluorination or iodination with a variety of reagents. Thus far, then, we have only been able to introduce a CI or a Br atom into this position easily and in good yields (26). Although the procedure for the uracil synthesis outlined above appears to be general, there is one notable exception: the reaction of β-enamino esters 26 with 2-chloroethyl isocyanate 45a did not provide the desired uracils 46, and only an ill-defined mixture of products were formed (Figure 19). This type of compound remains, however, an interesting target, since the chlorine atom would allow the introduction of functionality in that position through nucleophilic substitution reactions. The failure of this particular reaction may reside in the strongly basic medium, which could cause an HC1 elimination in the isocyanate. In the next section, we will discuss the strategy we developed for the synthesis of this particular kind of uracils.



606

Figure 19. β-Enamino esters 26 fail to condense with 2-chloroethylisocyan 45a.

Our original two-step uracil synthesis, however, seemed a good candidate for solid-phase methodology not only due to its high yields, but also for the ease with which diversity can be introduced into the molecule. For instance, diversity can be easily introduced into groups R (from different esters), R (from different iso(thio)cyanates), R (from different fluorinated nitriles), and X (using either an isocyanate or an isothiocyanate), thereby facilitating the preparation of small libraries of fluorinated uracils for their subsequent biological evaluation. The literature contains a single precedent of the synthesis of uracils in solid-phase, but in that example the diversity introduced was reduced and only difficult to separate mixtures of isomeric, non-fluorinated uracils were obtained (27). By the same token, there are also very few examples of solid-phase parallel syntheses of fluorinated compounds (28), a fact that makes the search for new solid-phase syntheses for organofluorinated compounds even more appealing. Our solid-phase synthesis of fluorinated uracils as outlined in Figure 20 is directly adapted from that described above (29). Thus, Wang resin 47 was first acetylated to afford its acetylated counterpart 48. Next, the ester enolate of this acetylated resin was formed with an excess of LDA in THF at -50°C, which was then treated with difluorophenylacetonitrile at -78°C for 3 h to afford resin 49, which was finally treated with an excess of NaH in DMF at 0°C, followed by reaction with several different iso(thio)cyanates 45. This sequence led to the formation of the uracils with concomitant cleavage from the resin, which precluded the need for a specific cleavage step (30). With this procedure, C-6difluorobenzylated uracils 46 (X=0) were obtained in good yields (67-89%) and with high purity (65-99%). In contrast, the corresponding C-6difluorobenzylated thiouracils 46 (X=S) prepared with thioisocyanates instead of isocyanates were obtained in lower yields (55-63%) and with lower purity (61-73%), as had been the case in the previous solution synthesis. Although we only used one ester and one nitrile in our study, it should be possible to use many different esters and nitriles, which in turn would facilitate the preparation of small libraries of (thio)uracils. 1

F


2

607

Ο

1. L D A / T H F , -50 °C

A c 0 / Pyridine 2

2. P h C F C N / - 7 8 ° C

25 °C, 15 h.

2

Wang resin (47)

3, NH C1 sat. 4

48

X


R

l

Ο ] NH

N ^ N H

NaH, D M F , 0 °C F F -EtOH 46 (X=0,S)

49

Figure 20. Solid phase synthesis of fluorinated uracils via β-enamino

esters.

Thus, our first uracil synthesis from β-enamino esters allows for the simple and efficient preparation offluorinated(thio)uracils with a methodology that can be easily adapted to solid-phase methodology.

2

Synthesis of fluorinated uracils from A -oxazolin-C-protected β-enamino esters and triphosgene. Our second uracil synthesis (31) allows for the preparation of C-6 fluoroalkylated N-3 alkylated pyrimidin-2,4-diones 50 (Figures 21 and 22) from 2~alquil-A -oxazolines andfluorinatednitriles. In this synthesis, the A -oxazolin-C-protectedfluorinatedenamino esters 27 were reacted with triphosgene (32) to give a mixture of isomeric oxazolopyrimidinones 51 and 52 in yields ranging from 70 to 95%. (Figure 21). 2

2

^

N

N

H

2

O'T^^RF R 2

7

C1 C^CC1 3

V .

3

E t N , T H F , rt

N

O ^ V ^ R

3

(x=ci,occi )

F

* \ A *

5

1

N

O'^f^R

R

3

(70-95%)

A ^

R 5

1

2

Figure 21. Reaction of compounds 27 with triphosgene.



608 While the pyrimidinone derivatives 51 were the predominant products of the condensation reaction, their isomers 52 were formed in all instances as well. In several cases, both compounds 51 and 52 were isolated and purified, but in some instances only 51 was isolated. Because of the similarities between isomeric compounds 51 and 52, their structural elucidation was only possible through X-ray diffraction analysis. It is worth noting that, unlike our first uracil synthesis, this alternative method is also useful for the preparation of non-fluorinated uracils, as the oxazoline aza-enolates are reactive enough to furnish the corresponding protected β-amino esters through reaction with non-fluorinated nitriles (33). In contrast, ester enolates will not react with non-fluorinated nitriles. The final step in this synthesis consisted of an oxazoline ring-opening reaction by a nucleophile (Figure 22), a reaction for which there are several precedents in the literature (34,35). We studied the reactivity of pyrimidinones 51 and 52 with nucleophiles such as MeOH, EtOH, H 0 , AcOH, and HC1, under basic or acidic conditions, to give compounds 50 (Figure 22). 2

RONa/ROH, THF

R2

Ο R 51

1

52

R

R

Method A

/-~0

Nu

1

2

Ο Ν

NH

HCl/Dioxane, THF 50

MethodB

(Nu = OR; OH; OAc;Cl)

Figure 22. Ring-opening reaction ofpyrimidinones 51 and/or 52 with nucleophiles. Synthesis of uracils 50.

Compounds 51 and 52 underwent oxazoline ring opening under basic conditions in refluxing THF; subsequent hydrolysis with aq. NH C1 solution furnished uracils 50 (Method A, Figure 22). The ring-opening reaction can be carried out under milder acidic conditions as well. Thus, when compounds 51 and/or 52 were dissolved in THF and treated with 4M HC1 in dioxane at room temperature, subsequent hydrolysis with aq. NH C1 solution also afforded uracils 50 (Nu = CI; Method B, Figure 22). It is remarkable that the same uracil 50 was obtained as a reaction product regardless of whether compound 51, 52, or a mixture of 51+52 was used. In all cases it was observed that the ringopening reaction in acidic medium proceeded faster (0.5-2 h) and with better yields (80-98%) than the corresponding reactions under basic conditions (5-7 h; 72-80%). In resume, this method provides a straightforward synthesis of 4

4


609

fluorinated and non-fluorinated uracil derivatives 50 from A -oxazolines and fluorinated and non-fluorinated nitriles in only three steps with satisfactory chemical yields. The ring-opening reaction of intermediate oxazolopyrimidinones 51 and 52 by a number of different nucleophiles allows the preparation of a variety of potentially interesting analogues.


2

Acknowledgements We thank the Ministerio de Ciencia y Tecnologia and the Generalitat Valenciana of Spain for financial support (BQU2003-01610 and GRUPOS03/193, respectively).

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