CROATICA CHEMICA ACTA CCACAA 59 (1) 153-163 (1986)

CCA-1633YU ISSN 0011-1643'

UDC 547.772Original Scientific Paper

Base-Catalyzed Rearrangement of 2-Vinylpyrazolium Salts into1,2- Dihydropyrimidines

Jose EIguero*Instituto de Quimica Medica, C.S.I.C., Juan de la ,Cierva 3, 28006 Madrid, Spain

and

Antonio de la Hoz and Carmen PardoDepartamento de Quimica Organica, Facultad de Quimica, Universidad Complutense,

28040 Madrid, Spain

Received June 6, 1985

The ring transformation of 2-viny1pyrazolium salts into dihy-dropyrimidines is the 1ast step of a process which starts fromneutra1 pyrazoles. G1obally,it results in the insertion of a :::'CE--CHOH-E (E = C02Me) fragment between the two nitrogenatoms of a l-substituted pyrazole. The dihydropyrimidines formedwere identified spectroscopically (iH and i3C NMR) and therelative configuration of the two chiral centres established bythe X-ray structure analysis of a picrate. Finally, a plausiblemechanism for the formation and epimerization of dihydropyrimi-dines is proposed.

INTRODUCTION

In arecent report- on the non-aromatie behaviour of aromatie azoles,we described the reaetion between N-substituted pyrazolium fluoroboratesand aeetylenie esters. The reaetion yields 2-vinylpyrazolium fluroborates bythe Michael addition of the corresponding pyrazole to the activated triplebond.

These vinylpyrazolium salts (I) were unknown. In an attempt to studytheir reaetivity, this paper deseribes the reaetion of salts (J) with nucleophiles(aqueous potassium earbonate and alcohols).

RESULTS AND DISCUSSION

When (la), (Ib) and (le) are treated with an aqueous solution of potassiumearbonate they undergo a rearrangement leading to a mixture of two eom-pounds, one being slightly predominant. They have been identified as the

* To whom correspondence shou1d be addressed.

154 J. ELGUERO ET AL.

two diastereoisomers of the dihydropyrimidine (II). We were not able toseparate the diastereoisomers either by chromatography (column or HPLC)or by fractional crystallization.

(1)Q, Rl'H.R~CHJ

J 5Q, R 'CHJ,R ,H

s. RJ,R5'CHJ

The structure of the dihydropyrimidines (II) was established by analyticaland spectroscopic data. Thus, both microanalysis and mass, spectrometryindicate that (II) have a molecular formula resulting from the addition ofan OH- to the cation (l). Moreover, in the mass spectra fragments appearcorresponding to the loss of CHOH-C02Me (base peak) and C02Me fromthe molecular ion.

The IR spectra of (II), recorded in KBr, present bands at 2080-3600cm? (VOH strongly associated) and at 1735-1740 and 1715-1720 crrr? (non--conjugated ester groups).

Proton NMR spectra of (II) and of some of their salts are summarizedin Table 1. One of the diastereoisomers (the less abundant one) showsthe methoxy signal of one of the ester groups clearly shielded with regardto the other three methoxy signals (one of the same diastereoisomer andtwo of the other). At the same time, the mixture of diastereoisomers showsthe ortho protons of the more abundant compound deshielded comparativelywith the remaining protons of the phenyl groups. Signals corresponding tothe exocyclic CH appear as broad singlets due to residual 3J coupling withthe OH (addition of trifluoroacetic acid or deuterium oxide causes disap-pearance of the OH signals and the narrowing of the CH singlets).

Table II contains the carbon-13 chemical shifts of compounds (Ila), (Ilb)and (Ilc) (Ilb decomposes partialy in deuteriochloroform solution) and thoseof the picrate (Vc) of the last compound. The signals of the pyrimidine ringare consistent with literature values for similar compounds.š Most signalsare »doublets« of different intensity, as expected from a mixture of diaste-reoisomers. It is noteworthy that the picrate (Vc) shows only one signalfor each carbon.

When 2-vinylpyrazolium salts (I) are treated with methanol or ethanolat room temperature, the »pyrazolium-pyrimidine« rearrangement takes place.The tetrafluoroborate (IIlc) , on treatment with an aqueous solution of etha-nolamine, yields the free dihydropyrimidine (IVe).

111-"""--- ",f;;"~-,Rl 5 I~,R,CHJ' ,CHJ,R ,H Ph 8~e

" R,CHJ,RJ'R5,CH] (I JI)

Q, R'CH{H] ,RJ,Ft,CHJ

(IV)

TA

BLE

I

Pro

ton

NM

RS

pect

raof

the

Dih

ydro

pyrim

idin

es(II);

<5(ppm

from

TM

S),

J(H

z)

'o 1'1 ;::l...,

inle.

O1'1

~::r::

iii'po.

o.cl)

cl)i

Ph

lI:iEl

:>El

tnO

""

11

O.....

•I

U::r::

::r::~

po.~

""O

O~

~~

Uul

.~::r::

OU

O>-,

>-,>-,

H L: ><:m

ajor

7.75

5.27

1.66

3.71

,3.

724.

40_.

7.10

-7.5

4(3H

),8.

0(2H

)3.

50.

70.

5t<

Ila

DCC13

'tj

min

or7.

645.

191.

633.

41,

3.68

4.95

-7.

10-7

.54(

5H)

3.6

0.7

0.5

><: ~Il

bD

CCb

maj

or2.

135.

206.

603.

71,

3.71

4.73

-7.

20-7

.64(

5H)

-7.

0-

~m

inor

2.11

5.16

6.60

3.44

,3.

654.

997.

20-7

.64(

5H)

7.0

N-

--

oun

der

t< H qIl

bTFAA

-2.

535.

85Ph

3.77

,3.

835.

23-

7.55

(6H

)-

7.0

-~

Ilc

DCCb

maj

or2.

105.

181.

623.

64,

3.68

4.40

{3.8

47.

20-7

.66(

3H),

7.92

(2H

)-

0.7

-ul

min

or2.

065.

101.

593.

39,

3.66

4.95

4.10

7.20

-7.6

6(5H

)0.

7~

--

r-m

ajor

1.95

5.19

1.52

3.55

,3.

584.

277.

25-'-

7.50

(3H

),7.

75(2

H)

-0.

7>-l

Ilc

DM

SO-d

6-

-ul

min

or1.

925.

101.

493.

32,

3.53

4.62

-7.

25-7

.50(

5H)

-0.

7Il

cTFAA

2.48

5.80

2.08

3.77

,3.

825.

18-

7.20

-7.8

7(5H

)Vc

DM

SO-d

6-

2.33

5.80

1.87

3.47

,3.

654.

78-

7.50

(5H

)VI

cD

MSO

-d6

-2.

355.

781.

883.

47,

3.63

4.82

-7.

48(5

H)

VIlc

DCCb

-2.

375.

451.

903.

28,

3.87

5.20-

7.47

(5H

)

~ en <:"n

f-'

<:Jl

o'l

TA

BLE

II

Car

bon-

13N

MR

Spe

ctra

ofth

eD

ihyd

ropy

rimid

ines

(II):

a(p

pmfrom

TM

S)

'o c ;::l....,

o~

isom

erC

-2C-4

C-5

C-6

R3RS

OCH

3CH

OH

C=O

Php-

a>EJ

:>o

'o:-<

Uen

M t"' PH

aD

CC13

maj

or84

.715

9.4

97.6

152.

6-

20.8

52.5

71.8

171.

3{1

28.9

,12

9.0,

131.

8,q M

min

or84

.015

8.7

96.8

153.

5-

20.6

52.4

,52

.872

.917

0.3

131.

913

2.1,

Ci:

139.

4~

maj

or84

.716

8.2

98.2

143.

226

.553

.1,

53.5

72.2

171.

6{1

28.7

,12

9.3,

129.

6O

lIb'

DCC13

-m

inor

85.1

167.

597

.014

3.2

26.0

52.7

72.2

170.

9M

-..,

maj

or84

.216

7.1

98.8

151.

623

.820

.652

.2,

52.4

72.1

171.

1,17

1.5{

128.

6,12

8.9,

129.

0,;,.

He

DCCh

131.

7,13

1.8,

132.

1,r'

min

or85

.116

6.9

97.6

152.

523

.820

.552

.4,

52.6

73.0

170.

4,17

2.5

Ci:

139.

6V

eD

MSO

-d6

-80

.516

6.3b

97.9

165.

0"21

.019

.254

.1,

52.6

69.0

169.

4e

nTh

iseo

mpo

und

deeo

mpo

ses

onstan

ding

,so

me

sign

als

are

tent

ativ

ely

assign

ed.

bTh

eas

sign

emen

tof

thes

esign

als

may

bein

verte

d.C

Com

plex

grou

pof

sign

als

whi

chin

elud

esth

ose

ofth

epi

eryl

grou

p.

I~

TA

BLE

III

Pro

ton

NM

RS

peet

raof

the

Dih

ydro

pyiri

mid

ines

(III)

and

(IV

);so

Lven

t:D

CC

L 8,

1\(ppm

from

TM

S)

'o s:: ;:::s oisom

erR3

H-5

R5

CH

OR

OCH

3R

Ph@: o U lI

Ibm

ajor

2.55

5.86

"un

der

Ph4.

473.

72,

3.92

3.10

7.12

-7.7

0(6H

)m

inor

2.50

5.69

"un

der

Ph4.

683.

40,

3.87

3.55

7.12

-7.7

0(6H

)

IlIe

maj

or2.

505.

882.

034.

233.

77,

3.87

3.03

7.07

-8.0

7(5H

)m

inor

2.43

5.73

1.93

4.60

3.47

,3.

833.

477.

07--8.

07(5

H)

IlId

maj

or2.

425.

791.

944.

223.

68,

3.80

1.13

",3.

10-4

.02

7.01

-7.7

3(3H

),7.

85(2

H)

min

or2.

375.

621.

854.

603.

35,

3.76

0.96

",2.

04-2

.72

7.01

-7.7

3(5H

)

IVe

maj

or2.

105.

201.

604.

183.

68,

3.72

2.70

7.00

-8.1

0(5H

)m

inor

2.05

5.08

1.60

4.37

3.28

,3.

723.

477.

00-8

.10(

5H)

n3J

R'_H

(5)=

7.0

Hz;

"3JC

H3-C

H2=

7.0

Hz.

'" < I-< Z ~ ~ ;d ;,. N O r- a ~ ul ;,. r- ..., ul '-' ~ --l

158 :1. ELGUERO ET AL.

The salts (III) and the free base (IVe) are oily mixtures of the twodiastereoisomers, whose characteristic proton NMR spectra are given inTable III. When (IVe) is dissolved in 32% tetrafluoroboric acid and thesolution is evaporated to dryness, salt (IIIe) is recovered.

Transformation of N-vinylpyrazolium salts (I) into the corresponding1,2-dihydropyrimidines (II) and (III) is due to expansion of the pyrazole ring.Probably this expansion starts from the intermediate carbanion, formed bynucleophilic addition to the exocyclic double bond, according to the followingscheme.

Two chiral centres are created in the reaction. As a consequence, thedihydropyrimidines (II) and (III) are a mixture of RR(SS) and RS(SR) diaste-reoisomers. Both diastereoisomers are in equilibrium through an open-chainvalence tautomer. This explains why it is impossible to separate the mixtureor even modify the proportions.

Using deuterium oxide, either in the basic or neutral conditions, theexocyclic CH proton of (Ile) or its salts does not exchange. This observationis in favour of the open-chain intermediate and against another possibleepimerization mechanism (see below) which would begin with the loss ofthe aforementioned proton.

RR(SS) RS(SR)

When the dihydropyrimidine (lIc) is protonated . (trifluoroacetic, tetra-fluoroboric or picric acid) only one diastereoisomeric salt, (Ve)-(VIIc), isobtained (see Tables I and II). The great effect observed on C-6 in thecarbon-13 NMR spectra indicates that the salt has the delocalized structurecorresponding to protonation on N-3.

(Vc)

• (Vile)

2-VINYLPYRAZOLIUM SALTS 159Molecular models shown that the salt is likely to have the RS(SR)

diastereoisomeric structure*, since only in this case can two stabilizinghydrogen bonds be formed (Figure 1).

HiO~"HHC J'h I3~ oEĐ ,H C N H C-OCH3 'HI J

Figure 1. Molecular model of salts (Vc)-(VIlc) showing the two intramolecularhydrogen bonds.

I

(a) 3.75356 362

3.64 3.50 6(ppm)

I

J ~(b) ).87 3.75 3.67 3.50 3.27 6 (ppm)

3.39

(c) 3.87 375 3.50 327 6 (ppm)

Figure 2. Proton NMR spectra of (Ilc): a) in DCC13; b) in DCCb + a small quantityof CF3C02H; c) in DCC13 + a large quantity of CF3C02H (or of VIlc in DCC13).

* The protonation of N-3 changes the absolute configuration as a consequenceof the Cahn-Jngcld-Prelog rules. However, (Ilc) RR(SS) and (VIlc) RS(SR), on onethe hand, and (Ilc) RS(SR) and (VIle) RR(SS), on the other hand, have anidentical disposition of the substituents.

160 J. ELGUERO ET AL.

When the picrate (Vc) is treated with ethanolamine, the free base (Ilc)is recovered. A proton NMR spectrum shows that both diastereoisomers arepresent in the proportions identical to those in the starting compound. Insalts (III), the absence of the OH group prevents the formation of doublechelate and a mixture of diastereoisomers is observed.

It is possible to follow the transformation of the dihydropyrimidine(Ilc) into its salt (VIlc) by proton NMR. In the zone of methoxy signals thefree base shows four singlets (Table I and Figure 2) in deuteriochloroform.By adding a few drops of trifluoroacetic acid the less intense signals shiftedto a new position, which they have in the salt (VIlc) , and the intensity ofthe two other signals decreased.

This experiment proves that the high field methoxy signal belongsto the diastereoisomer with the same relative configuration as the salt whichis formed by direct protonation [(Ilc) RR(SS) + 1-1+ ~ (VIlc) RS(SR)]. Theother diastereoisomer (Ilc) RS(SR), or its salt (VIlc) RR(SS), epimerizes throughthe open-chain tautomer. Thus, the high field methoxy group correspondsto the RR(SS) diastereoisomer and the deshielded ortho protons to the RS(SR)one. The examination of molecular models supports these : facts.

(II c)RR(SS)

Major iscmer

Figure 3. Molecular models of the two diastereoisomers of dihydropyrimidine (Ilc).

In the RS(SR) diastereoisomer both ester groups are near the orthoprotons and this can resul t in a deshielding of these protons. On the otherhand, one methoxy group of the RR(SS) diastereoisomer in a particularconformation is above the phenyl ring with the resulting shift to highfields.

The final proof of the RS(SR) relative configuration of the salts(Vc)-(VIlc) and, consequently, of that of the dihydropyrimidines (II), wasobtained by the X-ray determination of the molecular structure of thepicrate (VC).3

In order to prove that the signle crystal sample of (Vc) was representa-tive of the whole compound, that is, that precipitate was formed exclu-sively by the RS(SR) diastereoisomer, the following experiment was carriedout.' A powder diagram was record ed on a SIEMENS DSOO diffractometerusing the CuKa radiation (A.= 1.54178 A) and a nickel filter. The angularpositions of the diffraction maxima were compared with those obtainedtheoretically (LSUCRE program) from the structural data of the salt (Vc).Since all the lines obtained experimentally concide with the theoretical ones,it is possible to conclude that the whole sample is formed exclusively byRS(SR) crystals.

The reaction described here, (1)~ (II) or (II!), is not the first reportedexample of a pyrazole ring expansion to a pyrimidine derivative. However,literature examples concern quite different reactions, for instance, that of

2-VINYLPYRAZOLIUM SALTS 161

Figure 4. Molecular structure of picrate (Vc).

N-benzyl pyrazoles and indazoles with strong bases as amide or hydrideat 150°C;5 the oxidation of N-amino pyrazoles and indazoles with leadtetraacetate,? and the insertion of chlorocarbenes into N-unsubstituted pyra-zoles and indazoles.?

ph

ph ph Ph Ph _ PPhhLo")Nlf1. ~ DePh)(~ "N'CH Ph)(~ ~'CH2o J "'-.J

More related to our reaction is the behaviour of isoxazolium salts indiluted basic medium" or that of mesoionic pyrazolobenzotriazoles when theyare allowed to react with dimethyl acetylenedicarboxylate."

~~E

DMAD ~ a::UN

CONCLUSION

In 1974 Abjean-? described the following sequence of reactions that wasremarkable in several aspects: it could be the first and sole xample of dienicbehaviour of an aromatic pyrazole and also a rather attractive way of obta-ining a-aminopyridines from the easily accesible pyrazoles.

162 J. ELGUERO ET AL.

In fact we have demonstrated (Ref. 1 and the present work) that bothconclusions are wrong. The correct sequence reaction is represented below.

5~IERJ(NXCHOH-EI •

Ph

(li G, b.c)

A possible explanation for Abjean's errcr;" when he assigned amino-pyridine structure to the dihydropyrimidines (II), could be that he record edthe proton NMR spectra in trifluoroacetic acid, the conditions in which onlyone diastereoisomer, (VIle), is observed.

EXPERIMENT AL

M.p.s were determ!ned on a Buchi 510 apparatus and are uncorrected. IRspectra were recorded on a Perkin-Elmer 257 spectrometer and the mass spectraon a Varian MAT-71l. Proton NMR spectra were recorded on Varian T-60A andHX-100 spectrometers, and the carbon-13 spectra on a Varian FT-80 spectrometer.Microanalyses were performed at Centro Nacional de Quimica Organica (C.S.I.S.,Madrid).

Reaetion of 2-VinyLpymzoLium TetrafLuoroborates (l) with AqueousPotassium Carbonate

GeneraL procedure. - To asaturated solution of salt (I) in water, a 10°':0aqueous potassium carbonate solution was added dropwise. The mixture becameyellow and at pH = 9 a white solid precipitated. The solid was filtered off andthoroughly washed with water. Recrystallization from benzene yield pure (II).

2 -( H ydroxymethoxycarbony Lmeth y L)- 6 -meth y L-2 -methoxyca r b on y L-l-pheny L--1,2-dihydropyrymidine (Ila)

Yield: 270/0, m. p. 164-166 DC (decomp.).AnaL C16H1SN205(318.33) calc'd.: C 60.37; H 5.70; N 8.80%.

found: C 60.57; H 5.99; N 8.64%.

2-(HydroxymethoxycarbonyLmethyL)-4-methyL-2-methoxycarbonyL--1-phenyL-l,2-dihydropyrimidine (lIb)

Yield: 64010, m. p. 118-:t20 DC.AnaL C16HlSN205 (318.33) calc'd.: C 60.37; H 5.70; N 8.80010.

found: C 60.59; H 5.98; N 8.77010.

2-VINYLPYRAZOLIUM SALTS 1632-(Hydroxymethoxycarbonylmethyl)-4,6-dimethyl-2-methoxycarbonyl-l-phenyl--1,2-dihydropyrimidine (Ilc)

Yie1d: 47010,m. p. 160-161 DC (decomp.).AnaL C17H20N205 (332.36) ca1c'd.: C 61.43; H 6.06; N 8.43010.

found: C 61.19; H 6.11; N 8.56010.

Reaction of 2-Vinylpyrazolium Tetrafluoroborates (1) with Alcohols

General procedure. - A solution of 1.5 mmo1 of (I) in 50 ml of the anhydrousa1coho1 was stirred at room temperature for 12 days. After removing the solventin vacuo, compcund (III) was obtained as an orange oil.

Preparation of picrate (Vc). - A concentrated solution of picric acid in boilingethanol was added to a concentrated solution of (Ilc) in boiling ethanol. Afterfiltration of the hot mixture, picrate (Vc) crystallized on cooling, M. p. 173-175 DC(ethanol).

AnaL C23H23NS012(561.46) ca1c'd.: C 49.20; H 4.13; N 12.47%found: C 48.96; H 4.34; N 12.42010

Preparation of 1,2-dihydropyrimidines (Ilc) and (IVc) from its saLts. - AfterWeimer and Kaye.'!

REFERENCES

1. A. del a H o z, E. Die z - Bar r a, C. Par d o, J. El g u e r 0, J. P. D e-cl e r c q, G. G e rrna i n, and M. Van Me e r s s c h e, Tetrahedron 39 (1983)2193.

2. C h. K ash ima, M. S h i m i z u, A. Kat o h, and Y. O m ote, J. Chem.Soc. Per kin Trans I (1983) 1799.

3. E. G u t i e r r e z - P u e b 1a, A. M o n g e, C. R u i z - Val e r o, and A. R o-d r i g u e z - RoI dan, Acta Cryst. C 41 (1985) 411.

4. E. G u t i e r r e z - P u e b 1a et al., persona1 communication. We greatly acknow-ledged the realization of this experiment.

5. a) N. F i n c h and H. N. G e s c h w end, J. Org. Chem. 36 (1971) 1463. b)B. A. Ter tov, P. P. O n i s h c h e n k o, and V. Y. B e s s o n o v, Khim.GeteroskL Soedin (1974) 1410; C. A. 82 140068. c) B. A. Ter tov and Y. G.B oga c h e v, Khim. Geteroski: Soedin (1981) 119; C. A. 94 208798.

6. a) B. M. Ad g e r, S. Bra d b u r y, M. K e ati n g, C. W. R e e s, R. C.S tor r, and M. T. W i Il i a m s, J. Chem. Soc. Perkin Trans I (1975) 31. b) A.O s h a w a, H. Ara i, H. O h n i s h i, and H. 19 eta, J. Chem. Soc. Chem.Comm. (1980) 1182.

7. a) R. L. J o n e s and C. W. R e e s, J. Chem. Soc. (C) (1969) 2251. b) R. E.B u s b y, J. Par ric k, S. M. H. R i z u i, and C. J. Ga n v i Il e - S h a w,J. Chem. Soc. Perkin Trans I (1979) 2786. c) H. C. van der Pal a s, RingTransformations of HeterocycLes, Academic Press, London, 1973, VolI, pp. 274-275.

8. J. F. K i n g and T. Du r s t, Can. J. Chem. 40 (1962) 882, and Ref. 7c, pp. 329.9. A. Al b i n i, G. F. Bet t i net t i, G. M i n o 1i, and R. O b e r t i, J. Chem.

Research (S) (1980) 404, (M) (1980) 4801.10. F. A bje a n, C. R. Acad. Sci. Ser. C 278 (1974) 359.11. C. N. W e ime r and A. Kay e, J. Org. Chem. 14 (1949) 868.

POVZETEKPotom baz katalizirana premestitev 2-vinilpirazolijevih soli v 1,2-dihidropirimidine

Jose Elguero, Antonio de la Hoz in Carmen Pardo

Pretvorba 2-vinilpirazolijevih soli v dihidropirimidine je zadnja stopnja po-stop ka, pri katerem izhajamo iz nevtra1nih pirazolov, V celoti je pos1edica vklju-čitve dela >CE-CHON-E (E = COOMe) med dva dušikova atoma pri l-substitu-iranem pirazo1u. Nastale dihidropirimidine smo identificirali spektroskopsko (,H inJ3C NMR) in relativno konfiguracijo dveh kiraInih centrov smo ugotovili s pomočjorentgenske analize pikrata. Predlagani so tudi ustrezni mehanizmi za nasta nek inepimerizacijo dihidropirimidinov.