Regiocontrolled synthesis of 3-substituted-6-trifluoromethyl-4(3H)-pyrimidinones

TETRAHEDRON

Pergamon

Tetrahedron 57 (2001) 2689±2700

Regiocontrolled synthesis of

3-substituted-6-tri¯uoromethyl-4(3H)-pyrimidinones

Colin M. Tice^pand Lois M. Bryman

Rohm and Haas Company, 727 Norristown Road, Spring House, PA 19477-0904, USA

Received 17 October 2000; accepted 8 January 2001

AbstractÐDirect reaction of a variety of N-monosubstituted benzamidines with 4,4,4-tri¯uoroacetoacetate esters substituted at the

2-position with methyl, ethyl or methoxy afforded moderate to good yields of herbicidal 3-substituted-6-tri¯uoromethyl-4(3H)-pyrimidi-

nones. Lower yields were obtained with the corresponding 4,4-di¯uoroacetoacetate esters and the reaction failed with non¯uorinated

b-ketoesters. In addition to benzamidines, 3- and 4-pyridylcarboxamidines reacted successfully. The reaction tolerated propyl, allyl,

1. Introduction

sought an alternate route to 1a which would be suitable

for the preparation of 500 g quantities.

Pyrimidinones of general structure 1 (Fig. 1) bearing an

aromatic or heteroaromatic group at R²and a propargyl

group at R³are inhibitors of zeta-carotene desaturase¹and

possess interesting herbicidal activity.²Among this class of

compounds, analogs with di¯uoromethyl and, especially,

tri¯uoromethyl groups at the 6-position of the pyrimidinone

ring, e.g. 1a (Scheme 1) proved to possess superior

herbicidal activity. Our original route to 1a (Method A) is

shown in Scheme 1. Reaction of benzamidine hydrochloride

(3) with ethyl 2-tri¯uoroacetylbutanoate (4a) proceeded in

satisfactory yield to afford 5a.³An extensive effort to

optimize the propargylation of 5a was undertaken but the

2. Results and discussion

Incorporation of the propargyl group into the benzamidine

building block prior to reaction with the b-keto ester

appeared to offer an alternative route to pyrimdininones

including 1a, avoiding the troublesome propargylation reac-

tion (Scheme 2). However, examination of the literature was

not encouraging. Sitte and Paul reported in 1969 that reac-

tion of a concentrated solution of N-propylbenzamidine (7c)

and methyl acetoacetate (4c) in methanol at room tempera-

ture for two weeks afforded the pyrimidinone 1c (R²Ph,

R³n-Pr, R⁵H, R⁶Me) in 64% yield (Scheme 3) but,

they stated that the reaction failed when the b-keto ester

used was substituted with an alkyl group at the a-position.⁷

To provide the most herbicidally active compounds which

bear an ethyl group at R⁵an a-ethyl-b-ketoester is required.

Our own investigations of the reactions between N-propyl

benzamidine (7c) or N-propargyl benzamidine (7a) and

various b-ketoesters, including 4b and 4c (Scheme 4),

con®rmed Sitte and Paul's ®ndings. Presumably, formation

of enamine intermediate 9 (Scheme 5) required for ring

closure is disfavored for steric reasons when R⁵is a non-

hydrogen substituent leading to failure of the reaction.

Somewhat more encouraging results were reported by

Huber et al. who successfully reacted the cyclic amidine

2-iminopiperidine (7n, Scheme 7) with a cyclic b-keto

ester to afford a fused tricyclic pyrimidinone.⁸Presumably,

the cyclic nature of both of the reactants in this example

enforced conformations favoring ring closure over other

possible reactions.

1

best ratio, based on H NMR and GC of the crude product,

of the desired N-propargyl compound 1a to the undesired

O-propargyl compound 6a that could be obtained was ca.

1:4.^4,5This result was obtained using propargyl bromide as

alkylating agent, sodium methoxide as base and methanol as

solvent.⁶Under these conditions, propargylation of 5a was

incomplete and separation of 1a from the unreacted 5a and

from 6a required careful chromatography. Therefore, we

Figure 1. 2-Aryl-4(3H)-pyrimidinone regioisomers.

Keywords: pyrimidones; amidines; keto acids and derivatives; herbicides.

Corresponding author. Tel.: 11-215-641-7446; fax: 11-215-619-1617;

e-mail: colin_tice@rohmhass.com

p

Furthermore, during the course of investigating the

PII: S0040-4020(01)00042-4

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C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

Scheme 1. Synthesis of 1a and 1b by base catalyzed propargylation (Method A). 1a R⁵Et, R⁶CF₃, 1b R⁵Et, R⁶Et. (a) NaOAc, xylenes, re¯ux, Dean

Stark trap. (b) HCxCCH₂Br, NaOMe, MeOH, re¯ux.

from 7a, and 13, presumably via 12 (Scheme 6).¹¹The

imidazoles 11 and 13 were both isolated and characterized;

however, the putative intermediate N,N⁰-bis(propargyl)-

benzamidine (12) was not isolated. Similar reactions of

N-propargylamidines have been reported previously by

Deryckere et al.¹²

Despite these discouraging results, we reasoned that when

the b-ketoester used is a tri¯uoromethyl ketone, e.g. 4a,

direct pyrimidinone synthesis (Scheme 2) might be work-

able. The well-known electrophilicity of tri¯uoromethyl

ketones might shift the equilibria in the ®rst two steps of

ring formation (Scheme 5) to the right in favor of formation

of enamine 9 (R⁶CF₃), despite the unfavorable steric inter-

actions present in this intermediate, and allow the desired

reaction to occur under conditions mild enough to avoid

rapid decomposition of 7a. We were pleased to ®nd that

on our ®rst attempt, reaction of 7a (generated in situ from

ethyl benzimidate hydrochloride (10) and propargylamine,

Scheme 7, Method B1) with 4a in THF at 508C for 24 h

afforded 1a in 26% yield. The crude reaction product also

contained the imidazoles 11 and 13 and the unpropargylated

pyrimidinone 5a. A plausible route for the formation 5a is

shown in Scheme 6. This version of Method B, in which the

amidine 7 was generated in situ from an imidate, is referred

to as Method B1 below.

Scheme 2. Direct synthesis of pyrimidinones (Method B).

Scheme 3. Sitte and Paul pyrimidinone synthesis (see Ref. 7).

Scheme 4. b-Ketoesters used and their preparation. Method C: R⁶CO₂Et,

NaH, toluene, re¯ux. Method D: (i) (R⁶CO)₂O, pyridine, 108C, (ii) EtOH.

4a R⁵Et, R⁶CF₃, Method C or D; 4b R⁵Et, R⁶Et, Reference 18;

4c R⁵Me, R⁶H, Commercially available; 4d R⁵Me, R⁶CF₃, Method;

4e R⁵H, R⁶CF₃, Commercially available; 4f R⁵OMe, R⁶CF₃,

Method C; 4g R⁵Cl, R⁶CF₃, Commercially available; 4h R⁵Et,

R⁶CHF₂, Method D; 4i R⁵H, R⁶CHF₂, Method C; 4j R⁵OMe,

R⁶CHF₂, Method C; 4k R⁵Me, R⁶CO₂Et, Commercially available.

In principle, reaction of 7a with 4a could also produce the

regioisomer 2 (Fig. 1). In our work, only a single regio-

isomer was ever detected. The structure 1a was initially

assigned based on the precedent of the work of Sitte and

Paul.⁷The fact that the same product is also produced

by propargylation of 5a also favors structure 1a over 2,

since alkylation of pyrimidinones typically occurs at the

3-position to a greater extent than at the 1 position.^4a,bThe

carbonyl group of 1a absorbs at 1674 cm²¹which is typical

preparation⁹and reactions of N-propargylbenzamidine (7a),

we discovered that it began to decompose over the course of

several days at room temperature, and more rapidly when

heated or exposed to acid, to afford imidazole 11,¹⁰directly

Scheme 5. Proposed mechanism of the reaction of N-monosubstituted amidines with b-ketoesters.

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

2691

Scheme 6. Side reactions of N-propargylbenzamidine.

Scheme 7. Synthesis of 1 by Methods B, B1 and B2 (for de®nitions of R², R³, R⁵and R⁶in 1 see Table 2). Method B: c. CH₂Cl₂or THF, 40±608C, 3 d. Method

B1: a. R³NH₂, NaHCO₃, 258C, 4 h, CH₂Cl₂. c. CH₂Cl₂, re¯ux, 3 d. Method B2: b. (i) 0.1 equiv. NaOMe, MeOH, 258C. (ii) R³NH₂.HCl. c. CH₂Cl₂or THF, 40±

608C, 3 d. 7a R²Ph, R³CH₂CxCH, Method B1; 7b R²Ph, R³CH₂CHCH₂, Method B1; 7c R²Ph, R³CH₂CH₂CH₃, Method B1; 7d R²3-Cl-Ph,

R³CH₂CxCH, Method B2; 7e R²3-F-Ph, R³CH₂CxCH, Method B2; 7f R²3,5-diCl-Ph, R³CH₂CxCH, Method B2; 7g R²3,5-diF-Ph,

R³CH₂CxCH, Method B2; 7h R²2-pyridyl, R³CH₂CxCH, Method B2; 7i R²3-pyridyl, R³CH₂CxCH, Method B2; 7j R²5-Br-3-pyridyl,

R³CH₂CxCH, Method B2; 7k R²4-pyridyl, R³CH₂CxCH, Method B2; 7l R²2-Cl-4-pyridyl, R³CH₂CxCH, Method B2; 7m R²2,6-diCl-4-pyridyl,

R³CH₂CxCH, Method B2; 7n R²-R³±(CH₂)₄±, Method B; 7o R²Ph, R³Ph, Method B.

of N³alkylated pyrimidinones. The carbonyl groups of N¹

alkylated pyrimidinones typically occur below 1670 cm^{21 4a}

An X-ray crystal structure of the closely related compound

1b, which has very similar spectral characteristics to 1a, was

obtained and con®rmed the presence of the propargyl group

at N³.

Extensive efforts to optimize the synthesis of 1a by Method

B1 were undertaken and selected results are shown in Table

1. Five solvents were studied for the cyclization step

(Entries 1±5). The best yields (50±60%) of 1a with the

smallest amounts of 5a were obtained with CH₂Cl₂and

acetonitrile. Signi®cantly lower yields of 1a and greater

.

Table 1. Effect of varying conditions on the yield and purity of 1a

Entry

Solvent

Additives

T (8C)

t (h)

Yield 1a^a(%)

Yield 5a^b(%)

1

2

3

4

5

6

7

8

9

CH₂Cl₂

MeCN

DMF

MeOH

EtOAc

MeCN

CH₂Cl₂

±

40

60

80

40

72

26

8

60

57

47

38

29

53

40

63

56

5

4

3

5

2

5

6

7

±

Ê

4 A sieves

H₂O

72

a

After chromatography.

Estimated by integration of the H NMR signals for the ortho protons on the phenyl rings of 1a and 5a.

b

1

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C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

amounts of 5a were produced when DMF, methanol and

especially ethyl acetate were used as solvents. Acetonitrile

was employed as solvent to examine the effect of tempera-

ture. At 808C, no further product was produced after 8 h and

the yields of 1a and 5a were 40 and 5%, respectively (Entry

7) while at 408C, the reaction required 72 h to reach a point

at which no further product was produced and the yields of

1a and 5a were 57 and 4%, respectively (Entry 2). The crude

products from Entries 1±7 all appeared to contain some

unreacted 7a and 4a at the end of the reaction. Reasoning

that water and ethanol produced in the course of the reaction

might be preventing the reaction from proceeding further

products 11 and 13 and any unreacted 7a and 10. Unreacted

4a could be recovered by trituration of the crude product

with hexanes. Washing the crude product with aqueous

sodium hydroxide failed to remove 5a from the crude

product, presumably due to the insolubility of the sodium

salt of 5a in water; instead, ¯ash chromatography on activity

III basic alumina was employed and afforded 1a that was

90±95% pure. This procedure routinely afforded 50±55%

yields of 1a on a 1 mol scale.

Once this methodology was established for 1a, preparation

of a variety of related analogs allowed us to investigate the

scope of the reaction (Table 2). Two general methods were

employed to prepare the b-ketoesters 4a, 4f, 4h±4j that

were not commercially available (Scheme 4). In Method

C, the appropriate ethyl ester 14 was reacted with ethyl

tri¯uoroacetate or ethyl di¯uoroacetate using 2.2 equiv. of

sodium hydride.¹³This was the preferred method when

working at a 0.5 mol or smaller scale. Because of the

hazards of sodium hydride, for larger scale work a modi-

®cation of the method of Zard et al. using the acid chloride

and either tri¯uoroacetic anhydride or di¯uoroacetic

anhydride was employed (Method D).¹⁴Distillation of the

crude products from Methods C and D effected partial

puri®cation, but in general, b-ketoesters 4 were dif®cult to

separate from esters 14 (unreacted in Method C or produced

in situ from ethanolysis of 15 in Method D). In addition, the

keto±enol equilibria in 4 complicated the interpretation of

Ê

by forming the hydrate and/or hemiacetal of 4a, 4 A mol-

ecular sieves were added to the reaction mixture to remove

water and this did effect a slight increase in yield (Entry 8),

while deliberate addition of water appeared to cause a slight

decrease in yield (Entry 9). In large scale runs, a moisture

trap was employed to remove water. The presence of

residual tri¯uoroacetic acid in some batches of 4a had a

deleterious effect on the yield. The ®nal conditions selected

for the large scale preparation of 1a were as follows: ethyl

benzimidate hydrochloride and propargylamine were

reacted in CH₂Cl₂in the presence of NaHCO₃to afford a

solution of 7a. An excess of b-keto ester 4a (1.25±

1.5 equiv.) was immediately added and the mixture was

placed in a 408C oil bath and stirred for 72 h with a moisture

trap. The reaction mixture was diluted with ether and

washed with aqueous HCl to remove the imidazole by-

Table 2. Pyrimidinones 1 synthesized

Pyrimidinone

Precursors

R²

R³

R⁵

R⁶

Method

Yield (%)

b-Ketoester

Amidine (nitrile or imidate)

1a

1b

1c

1d

1e

4a

4b

4a

4d

4e

4f

4h

4i

4j

4g

4e

4k

7a (10)

7b (10)

7g (10)

7i (16g)

7j (16j)

7k (16k)

7l (16l)

7m (16m)

7a (10)

7c (10)

7o

Ph

CH₂CuCH

CH₂CHvCH₂

CH₂CuCH

n-Pr

Et

CF₃

Et

B1

B2

B1

B

53^a

0^a

CF₃

CHF₂

CF₃

CO₂Et

55^a

53^b

25^b

23^b

36^b

14^b

59^a

72^a

44^c

33^b

41^b

83^c

22^b

32^b

30^b

46^b

33^b

45^b

12^b

3^b

3,5-di-F-Ph

3-Pyridyl

5-Br-3-pyridyl

4-Pyridyl

2-Cl-4-pyridyl

2,6-di-Cl-4-pyridyl

Ph

1f

1g

1h

1i

1j

1k

1l

1m

1n

1o

1p

1q

1r

Et

Me

H

Ph

CH₂CuCH

7l (16l)

7m (16m)

7n

2-Cl-4-pyridyl

2,6-di-Cl-4-pyridyl

B2

B

±(CH₂)₄±

7e (16e)

7f (16f)

7j (16j)

7l (16l)

7m (16m)

7l (16l)

7a (10)

7e (16e)

7m (16m)

7a (10)

7m (16m)

7a (10)

7o

3-F-Ph

CH₂CuCH

Ph

B2

B1

B2

B1

B2

B1

B

3,5-diCl-Ph

5-Br-3-pyridyl

2-Cl-4-pyridyl

2,6-diCl-4-pyridyl

2-Cl-4-pyridyl

Ph

3-F±Ph

2,6-diCl-4-pyridyl

Ph

2,6-di-Cl-4-pyridyl

Ph

2-Pyridyl

Ph

1s

1t

1u

1v

1w

1x

1y

1z

1aa

1ab

1ac

1ad

OMe

Et

H

OMe

Cl

H

Me

29^a

11^b

0^a

0^c

7h (16h)

7a (10)

CH₂CuCH

B2

B1

0^b

0^a

a

Yield calculated based on ethyl benzimidate hydrochloride (10).

Yield calculated based on the nitrile precursor 16.

Yield based on amidine precursor 7.

b

c

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

2693

Table 3. ¹H NMR of aromatic protons in selected pyrimidinones

1

their H NMR spectra; however, the major peaks in the

spectra corresponded to those expected based on the

literature values for the keto forms.¹⁵The purity of these

intermediates was estimated by GC.

Compound

(aromatic region)

R³

¹H NMR

1a

1b

1c

1k

1ae

6a

CH₂CuCH

CH₂uCH

CH₂CHvCH2

CH₂CH₂CH₃

CH₂OCH₃

n/a

7.48±7.56 (3H), 7.64±7.74 (2H)

7.40±7.60 (5H)

7.45±7.55 (3H), 7.60±7.70 (2H)

7.45±7.55 (3H), 8.40±8.50 (2H)

Two different methods were also employed to prepare the

desired N-monosubstituted amidines 7a±m (Scheme 7); 7n

and 7o were commercially available. In Method B1, Step 1,

benzamidines 7a±c without any substituents on the benzene

ring were prepared from ethyl benzimidate by treatment

with the appropriate amine as described above.⁹These

amidines were used immediately without isolation or

characterization. In Method B2, Step 1, benzamidines

with electron withdrawing substituents 7e±g and pyridine-

carboxamidines 7h±m were prepared in one pot from the

corresponding nitriles 16 as follows: the appropriate nitrile

16 was ®rst treated with a catalytic quantity of sodium

methoxide in methanol to convert it to the imidate and

then with a slight excess of amine hydrochloride to afford

the amidine.¹⁶The nitriles used were either commercially

available or prepared from the corresponding carboxylic

acids via the carboxamides using standard methods.¹⁷

Since 2-chloropyridines are susceptible to displacement by

methoxide, it was found to be important to hold the time for

the generation of the imidate to a minimum with nitrile

16m. A reaction time of 2 h was found satisfactory. The

N-substituted pyridine carboxamidines 7h±7m were

found to be qualitatively more stable than the benzamidines

7a±g and they could be stored for a few days before

use. Amidines 7d±m were characterized by ¹H NMR

spectroscopy but no attempt was made to rigorously purify

them.

Scheme 8. Methoxymethylation. (a) P₂O₅, (MeO)₂CH₂, CHCl₃, rt, 18 h.

reaction failed entirely when pyridine-2-(N-propargyl-

carboxamidine) 7h was employed (1ac). Possibly intra-

molecular hydrogen bonding between the pyridine

nitrogen and one of the amidine NHs lowers the reactivity

of 7h. The effects of variations in R³on product yields are

unclear from these reactions although the increased yield

observed with 7c (R³propyl) compared to 7a (R³pro-

pargyl) is consistent with the role of the decomposition of

N-propargyl benzamidine 7a depicted in Scheme 6 (1k vs

1j). As expected from the work of Huber et al.,⁸excellent

results were obtained when the cyclic amidine 2-imino-

piperidine (7n) was employed (1o).

The reactions of 4 and 7 to produce 1 shown in Table 2 were

run at 40±608C in THF or methylene chloride for 3 d. In

certain instances, the reactions were terminated earlier if ¹H

NMR of an aliquot of the crude reaction mixture indicated

that the starting amidine had been consumed. Yields were

calculated based on ethyl benzimidate hydrochloride (10)

for pyrimidinones made by Method B1, on nitriles 16 for

compounds made by Method B2 or on the commercially

available amidine in the cases of 7n and 7o. The clearest

trend apparent in Table 2 is that yields were lower when the

less electrophilic di¯uoromethyl ketoesters 4h and 4i were

employed than with the corresponding tri¯uoromethyl

ketoesters 4a and 4e (1a vs 1v; 1t vs 1x). As expected,

the reaction failed when ethyl 2-propionylbutanoate (4b,

Scheme 4) was used.⁷It also failed when diethyl oxalo-

propionate (4k, Scheme 4) was employed despite the

electron withdrawing carboethoxy group at R⁶in this

b-ketoester (1ad). Somewhat better yields were obtained

when the a-methoxyketoesters 4f and 4j were used than

with the corresponding a-methyl or ethyl keto esters 4d,

4a or 4h (1u vs 1m, 1h; 1y vs 1v). The reaction failed to

give the desired pyrimidinones when the a-chloro ketoester

4g was used (1aa, 1ab). Presumably, the introduction of an

additional electrophilic site into the ketoester component

leads to the predominance of alternate reaction pathways.

The overall yields of the pyrimidinone product were lower

with the electron withdrawing chloropyridyl amidines 7l

and 7m than with 7a (1h, 1i vs 1a; 1z vs 1y); however, it

is unclear whether the yield of amidine formation or of ring

formation is responsible for this drop. Interestingly, the

1

In the H NMR spectra of 1a and 1b (R³propargyl), the

ortho protons on the phenyl ring appear 0.15 ppm down®eld

from the meta and para protons (Table 3). By contrast, in 1c

(R³allyl) and 1k (R³propyl) the ortho protons are coin-

cident with the meta and para protons. We attributed this

difference to the slightly greater steric demands of the allyl

(sp²CH at b-position) and propyl (sp³CH₂at b-position)

groups compared to the propargyl group (sp C at b-position)

forcing the phenyl ring to rotate further out of the plane of

the pyrimidinone rings thus moving the ortho protons

further into the shielding cone of the heterocyclic ring.

The X-ray structure of 1b showed a 43.98 angle between

the plane of the phenyl and pyridmidinone rings. In the

O-propargyl compound 6a, in which the phenyl and

pyrimidinone rings are expected to be coplanar, the ortho

protons are separated from the meta and para protons by

0.95 ppm. In 1ae (R³CH₂OMe, sp³O at b-position,

preparation shown in Scheme 8), the ¹H NMR of the

aromatic region is very similar to that of 1a and 1b. It is

possible that this subtle conformational effect plays a role in

the level of herbicidal activity of these pyrimidinones: 1a,

1b and 1ae are substantially more active than 1c or 1k.²⁰

3. Conclusions

We have developed a method for the regiocontrolled synth-

esis of 3-substituted-6-tri¯uoromethyl-4(3H)-pyrimidinones

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C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

from N-monosubstituted amidines and tri¯uoroacetoacetate

esters in moderate yields under mild conditions (Scheme 7).

This method is more convenient and affords better yields of

this type of compound than alkylation of a 3-unsubstituted

pyrimidinone precursor (Scheme 1). Not unexpectedly,

reaction yields are lower when amidines with electron with-

drawing substituents are employed. The main limitation

encountered in the tri¯uoroacetate reactant was the lack of

tolerance for a chlorine at the a-position.

(350 mL) and washed with aqueous sodium hydroxide

(3£75 mL) and brine (2£75 mL). The ether layer was

dried over MgSO₄and evaporated to dryness under reduced

pressure to leave a solid (8.9 g) which was puri®ed by ¯ash

chromatography on a silica gel column eluted with 20%

ethyl acetate in hexanes to afford 6a (2.4 g, 13%) as an

1

off-white solid, mp 83±878C. H NMR (200 MHz, CDCl₃)

d 1.20 (t, 3H, J7.5 Hz), 2.53 (t, 1H, J2.5 Hz), 2.79 (q,

2H, J7.5 Hz), 5.20 (d, 2H, J2.5 Hz), 7.45±7.55 (3H),

8.40±8.50 (2H); IR (nujol mull) 3280. Anal. Calcd for

C₁₆H₁₃F₃N₂O: C, 62.74; H, 4.28; N, 9.15. Found: C,

62.68; H, 4.15; N, 8.80. Additional 6a present in mixed

fractions was not isolated. Further elution of the column

afforded 1a (1.9 g, 10%), mp 113±1158C. ¹H NMR

(300 MHz, CDCl₃) d 1.23 (t, 3H, J7.4 Hz), 2.42 (t, 1H,

J2.3 Hz), 2.77 (q, 2H, J7.4 Hz), 4.61 (d, 2H, J2.3 Hz),

7.50±7.60 (3H), 7.70±7.80 (2H); ¹³C NMR (75 MHz,

CDCl₃) d 13.4, 19.8, 37.7, 73.8, 77.8, 121.9 (q), 128.7,

129.3, 131.5, 133.7, 146.4 (q), 158.3, 162.5; ¹⁹F NMR

(282 MHz, CDCl₃) d 265.5; IR (CDCl₃) 3308, 1674,

1549. Anal. Calcd for C₁₆H₁₃F₃N₂O: C, 62.74; H, 4.28; N,

9.15. Found: C, 62.49; H, 4.10; N, 9.03.

4. Experimental

4.1. General

Unless otherwise state all reagents were purchased from

commercial sources and used without further puri®cation.

All reactions were conducted under a nitrogen atmosphere.

Solvents were removed on a rotary evaporator under house

vacuum (20±50 mm Hg). Melting points were determined

on a Hoover capillary melting point apparatus and are

1

uncorrected. H NMR spectroscopy was performed on a

Bruker DPX300 or a Varian XL200. Chemical shifts are

reported in ppm down®eld from internal tetramethylsilane.

4.1.2. 5,6-Diethyl-2-phenyl-3-(prop-2-ynyl)-4(3H)-pyri-

midinone (1b) via 5,6-diethyl-2-phenyl-4(3H)-pyrimidi-

none (5b). A stirred mixture of benzamidine hydrochloride

(21.7 g, 0.14 mol), ethyl 2-propionylbutanoate (21.64 g,

0.13 mol),¹⁸anhydrous sodium acetate (11.30 g, 0.14 mol)

and xylenes (350 mL) was heated at re¯ux with a Dean±

Stark trap for 5.5 h. The mixture was poured onto ice and

allowed to stand overnight. The mixture was ®ltered and the

solid collected was washed with water and dried in a

vacuum oven to afford 5b (14.5 g, 49%) as an off-white

¹³C and ¹⁹F NMR were performed on a Bruker DPX300. ¹³

C

NMR chemical shifts are referenced to the central line of

CDCl₃at 77.0 ppm and ¹⁹F NMR chemical shifts are

referenced to CCl₃F at 0 ppm. Infra red spectra were

recorded on

a Perkin±Elmer Model BMC spectro-

photometer or a Mattson Genesis-II FTIR. Mass spectra

were obtained on a Hewlett Packard 5970 GC±MS.

Elemental analyses were performed by Robertson±Microlit

Labs.

1

solid, mp 170±1738C. H NMR (300 MHz, DMSO-d₆) d

1.06 (t, 3H, J7.4 Hz), 1.22 (t, 3H, J7.5 Hz), 2.51 (q,

2H, J7.4 Hz), 2.60 (q, 2H, J7.5 Hz), 7.5±7.6 (3H),

8.1±8.2 (2H); ¹³C NMR (75 MHz, CDCl₃) d 11.3, 11.7,

16.4, 25.2, 121.3, 125.8, 126.1, 126.9, 129.5, 131.0, 151.9,

161.6; IR (nujol) 1650. Anal. Calcd for C₁₄H₁₆N₂O: C,

73.66; H, 7.06; N, 12.27. Found: C, 73.58; H, 6.93; N, 12.35.

4.1.1. 5-Ethyl-2-phenyl-3-(prop-2-ynyl)-6-(tri¯uoromethyl)-

4(3H)-pyrimidinone (1a) via 5-ethyl-2-phenyl-6-

(tri¯uoromethyl)-4(3H)-pyrimidinone (5a). Method A. A

stirred mixture of benzamidine hydrochloride (23.7 g,

0.15 mol), ethyl 2-(tri¯uoroacetyl)butanoate (30.00 g,

0.15 mol), anhydrous sodium acetate (13.60 g, 0.16 mol)

and xylenes (30 mL) was heated at re¯ux with a Dean±

Stark trap for 7.5 h. The mixture was poured onto ice and

allowed to stand overnight. The mixture was ®ltered and the

solid collected was washed with water and dried in a

vacuum oven to afford 5a (17.7 g, 44%) as a light brown

Sodium metal (1.65 g, 71.7 mmol) was dissolved in metha-

nol (200 mL) and 5b (13.60 g, 59.6 mmol) was added

followed by 80% propargyl bromide in toluene by weight

(9.76 mL, 87.6 mmol). The mixture was heated at re¯ux for

2 h and the bulk of the solvent was removed under reduced

pressure. The residue was taken up in ethyl acetate

(200 mL), washed with 1 M aqueous NaOH (3£100 mL)

and dried over MgSO₄. Removal of the solvent under

reduced pressure left a yellow solid (14.4 g). Flash chroma-

tography on silica gel (250 g) eluting with methylene

chloride afforded 1b (5.7 g, 36%) as an off-white solid,

1

solid, mp 2508C (dec). H NMR (300 MHz, d₆DMSO) d

1.12 (t, 3H, J7.4 Hz), 2.61 (q, 2H, J7.4 Hz), 7.6±7.8

(3H), 8.1±8.2 (2H), 13.3 (1H); ¹⁹F NMR (282 MHz, d₆

DMSO) d 264.3; IR (nujol) 1650. Anal. Calcd for

C₁₃H₁₁F₃N₂O: C, 58.21; H, 4.13; N, 10.44. Found: C,

58.32; H, 3.94; N, 10.19.

1

mp 101±1038C. H NMR (300 MHz, CDCl₃) d 1.18 (t,

To a stirred suspension of 5a (16.2 g, 60 mmol) in methanol

(200 mL) was added 25% by weight sodium methoxide in

methanol (20.9 mL, 91.4 mmol), followed by 80% pro-

pargyl bromide in toluene by weight (13.5 mL,

120 mmol). The mixture was heated at re¯ux for 5.5 h.

The bulk of the solvent was removed under reduced pres-

sure and the residue was suspended in 1 M aqueous sodium

hydroxide (200 mL) and extracted with ether (4£100 mL).

The combined ether extracts were dried over MgSO₄and

evaporated under reduced pressure to afford a light brown

solid (17.7 g). This material was redissolved in ether

3H, J7.5 Hz), 1.26 (t, 3H, J7.6 Hz), 2.33 (t, 1H, J

2.4 Hz), 2.63 (q, 2H, J7.5 Hz), 2.64 (q, 2H, J7.6 Hz),

4.56 (d, 2H, J2.4 Hz), 7.48±7.56 (3H), 7.64±7.74 (2H);

¹³C NMR (75 MHz, CDCl₃) d 13.6, 13.7, 19.7, 28.0, 36.9,

72.9, 78.8, 124.4, 128.5, 129.2, 130.7, 134.9, 157.0, 162.4,

162.9; IR (nujol) 3205, 1650. Anal. Calcd for C₁₇H₁₈N₂O: C,

76.69; H, 6.77; N, 10.53. Found: C, 76.25; H, 6.65; N, 10.34.

4.1.3. General procedure used for optimization of the

synthesis of 1a by method B1. Method B1. All reactions

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

2695

summarized in Table 1 were run using ethyl benzimidate

hydrochloride (10, 1.86 g, 10.0 mmol) and powdered

sodium bicarbonate (0.84 g, 10.0 mmol) in the solvent

speci®ed (6 mL). The mixture was stirred for 0.5 h at

room temperature and propargylamine (0.70 mL,

10.2 mmol) was added. The mixture was stirred for 3±4 h

to afford a solution containing 7a. Ethyl 2-tri¯uoroacetyl-

butanoate (4a, 3.18 g, ,12.5 mmol assuming 85% purity)

was added. The mixture was stirred in an oil bath at the

speci®ed temperature T for t h (see Table 1). The progress

of the reactions was monitored by reverse phase HPLC

using a C-18 column eluted with 70% acetonitrile and

30% water containing 25 mM ammonium acetate with UV

detection at 254 nm. Compounds 1a, 5a and 13 were sepa-

rated and detected under these conditions. N-propargyl-

benzamidine (7a) and imidazole 11 were detected but

were not resolved from each other under these conditions.

Ethyl 2-tri¯uoroacetylbutanoate (4a) and propargylamine

were not detected. Reactions were run until no further

change in the HPLC trace could be discerned. The reaction

mixtures were diluted with ether, washed with 5% aqueous

HCl and 5% aqueous NaOH and dried over MgSO₄. The

crude neutral products obtained in this way were examined

by ¹H NMR. The % of 5a in the crude product was estimated

based on comparison of the integration of the ortho protons

of the phenyl rings of 5a and 1a. The crude neutral product

was subjected to ¯ash chromatography on activity III

neutral alumina (30 g) eluting with ether (200 mL). Ca.

25 mL fractions were collected and fractions containing

1a were pooled and evaporated under reduced pressure to

crude 1a (49.05 g) was puri®ed by ¯ash chromatography on

a column of activity III neutral alumina (100 g) packed in

ether. The column was eluted with ether to afford 1a (37.3 g,

53%) as a white solid, mp 113±1158C.

The following compounds were prepared following Method

B1 as described above.

4.1.5. 5-Ethyl-2-phenyl-3-(prop-2-enyl)-6-(tri¯uoromethyl)-

4(3H)-pyrimidinone (1c). Mp 73±768C. ¹H NMR

(300 MHz, CDCl₃) d 1.22 (t, 3H, J7.4 Hz), 2.76 (dq,

2H, J1.6, 7.4 Hz), 4.55 (dt, 2H, J5.3, 1.4 Hz), 4.96

(dd, 1H, J17.2, 0.9 Hz), 5.22 (dd, 2H, J9.4, 0.9 Hz),

5.88 (m, 1H), 7.40±7.60 (5H); ¹³C NMR (75 MHz,

CDCl₃) d 13.4, 19.8, 49.6, 118.7, 122.1 (q), 128.5, 129.0,

129.2, 131.0, 131.7, 134.3, 146.9 (q), 158.9, 162.8; ¹⁹F

NMR (282 MHz, CDCl₃) d 265.4; IR (CDCl₃) 1660.

Anal. Calcd for C₁₆H₁₅F₃N₂O: C, 62.33; H, 4.90; N, 9.09.

Found: C, 61.98; H, 4.94; N, 8.89.

4.1.6. 5-Methyl-2-phenyl-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1j). Mp 143±1458C. ¹H

NMR (300 MHz, CDCl₃) d 2.33 (q, 3H, J2.1 Hz), 2.42

(t, 1H, J2.4 Hz), 4.63 (d, 2H, J2.4 Hz), 7.50±7.60 (3H),

7.70±7.78 (2H); ¹³C NMR (75 MHz, CDCl₃) d 10.9, 37.3,

73.4, 77.5, 121.4 (q), 123.2, 128.2, 128.7, 130.9, 133.1,

146.2 (q), 157.6, 162.4; ¹⁹F NMR (282 MHz, CDCl₃) d

265.8; IR (CDCl₃) 3300, 1670. Anal. Calcd for

C₁₅H₁₁F₃N₂O: C, 61.65; H, 3.79; N, 9.59. Found: C,

61.44; H, 3.56; N, 9.63.

1

afford 1a whose purity was con®rmed by H NMR. No

attempt was made to isolate or quantify the basic products

from these runs.

4.1.7. 5-Methyl-2-phenyl-3-(propyl)-6-(tri¯uoromethyl)-

4(3H)-pyrimidinone (1k). Oil. ¹H NMR (300 MHz,

CDCl₃) d 0.77 (t, 3H, J7.5 Hz), 1.64 (m, 2H), 2.30 (q,

3H, J2.1 Hz), 3.90 (m, 2H), 7.42±7.56 (5H) ¹³C NMR

(75 MHz, CDCl₃) d 10.3, 10.4, 21.0, 47.8, 121.2 (q),

122.4, 127.4, 128.1, 129.7, 133.7, 145.4 (q), 157.8, 162.4;

¹⁹F NMR (282 MHz, CDCl₃) d 265.8; IR (CDCl₃) 1660,

1540; MS (EI) m/z 296, 295, 254. Anal. Calcd for

C₁₅H₁₅F₃N₂O: C, 60.81; H, 5.10; N, 9.45. Found: C,

61.20; H, 5.11; N, 9.47.

4.1.4. 5-Ethyl-2-phenyl-3-(prop-2-ynyl)-6-(tri¯uoromethyl)-

4(3H)-pyrimidinone (1a) from 4a and 10. A 1 L 4-neck

¯ask, equipped with a condenser, mechanical stirrer and

thermometer, maintained under a slight positive nitrogen

pressure, was charged with ethyl benzimidate hydrochoride

(10, 46.54 g, 0.25 mol) and methylene chloride (150 mL).

To the stirred suspension was added powdered sodium

bicarbonate (21.03 g, 0.25 mol). The mixture was stirred

for 0.5 h and propargylamine (17.0 mL, 0.25 mol) was

added rapidly. A 108C exotherm occurred. The mixture

was stirred for 3.75 h at room temperature to afford a solu-

tion containing 7a and ethyl 2-tri¯uoroacetylbutanoate (4a,

81.20 g, 0.38 mol) was added. A 108C exotherm occurred.

The mixture was placed in an oil bath maintained at 408C

and stirred for 3 d. The mixture was diluted with ether

(800 mL) and washed with 5% aqueous HCl (2£250 mL)

and with saturated aqueous NaHCO₃(250 mL), and dried

over MgSO₄. Removal of the solvent under reduced pres-

sure with a room temperature water bath afforded a mixture

of 1a, unreacted 4a and residual solvents as a pasty yellow

solid (95.15 g). The crude product was triturated with

hexanes (2£100 mL) to afford crude 1a (45.59 g). The

mother liquors were evaporated under reduced pressure

with a room-temperature water bath to leave a yellow liquid,

which was taken up in hexanes (20 mL) and placed in the

freezer overnight. Filtration of this mixture afforded addi-

tional crude 1a (3.46 g). The ®ltrate was evaporated under

reduced pressure with a room-temperature water bath to

leave recovered 4a (30.91 g) as an orange oil. The combined

4.1.8. 6-(Di¯uoromethyl)-5-ethyl-2-phenyl-3-(2-propynyl)-

4(3H)-pyrimidinone (1v). H NMR (300 MHz, CDCl₃) d

1

1.24 (t, 3H, J7.4 Hz), 2.40 (t, 1H, J2.4 Hz), 2.77 (q, 2H,

J7.4 Hz), 4.60 (d, 2H, J2.4 Hz), 6.56 (t, 1H, J54.2 Hz),

7.50±7.60 (3H), 7.70±7.80 (2H); ¹³C NMR (75 MHz,

CDCl₃) d 13.7, 18.9, 73.8, 78.1, 114.3 (t), 128.6, 128.7,

129.3, 131.3, 134.0, 150.1 (t), 158.5, 162.5; ¹⁹F NMR

(282 MHz, CDCl₃) d 2116.8 (d); IR (CDCl₃) 3300, 1660.

Anal. Calcd for C₁₆H₁₄F₂N₂O: C, 66.66; H, 4.89; N, 9.72.

Found: C, 66.54; H, 4.95; N, 9.67.

4.1.9. 6-(Di¯uoromethyl)-5-methoxy-2-phenyl-3-(2-pro-

pynyl)-4(3H)-pyrimidinone (1y). Mp 131±1338C. ¹H

NMR (200 MHz, CDCl₃) d 2.38 (t, 1H, J2.5 Hz),

4.10 (s, 3H), 4.60 (d, 2H, J2.5 Hz), 6.79 (t, 1H,

J54 Hz), 7.50±7.60 (3H), 7.65±7.75 (2H); ¹³C NMR

(75 MHz, CDCl₃) d 37.2, 60.7, 73.4, 77.3, 109.5 (t),

128.2, 128.7, 130.8, 133.4, 141.6 (t), 143.2, 155.3, 158.4;

IR (CDCl₃) 3300, 1670. Anal. Calcd for C₁₅H₁₂F₂N₂O₂:

C, 62.07; H, 4.17; N, 9.65. Found: C, 61.91; H, 3.86; N,

9.53.

2696

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

4.1.10. 2-Chloropyridine-4-(N-prop-2-ynyl)carboxami-

dine (7l). Method B2, Step 1. To a stirred suspension of

2-chloro-4-cyanopyridine¹⁹(5.77 g, 41.7 mmol) in metha-

nol (50 mL) was added 25% by weight sodium methoxide

in methanol (0.81 g, 3.8 mmol). The mixture was stirred for

18 h and propargylamine hydrochloride (4.35 g, 47.5 mmol)

was added. The mixture was stirred for 4 h and evaporated

under reduced pressure to remove methanol. The residue

was partitioned between ether (150 mL) and 5% aqueous

HCl (2£75 mL). The combined aqueous layers were

carefully basi®ed to pH ,12 by addition of 50% aq

NaOH and extracted with ethyl acetate (2£90 mL). The

combined ethyl acetate extracts were dried over MgSO₄

and concentrated under reduced pressure with the water

bath at (408C to afford crude 7l (8.34 g, 107%) as an

amber oil which solidi®ed on standing. The crude product

4.12 (d, 2H, J2.5 Hz), 5.80±6.40 (2H), 7.35 (dd, 1H,

J6.5, 8.0 Hz), 7.75 (t, 1H, J6.5 Hz), 8.22 (d, 1H,

J8.0 Hz), 8.54 (d, 1H, J6.5 Hz).

4.1.17. Pyridine-3-(N-prop-2-ynyl)carboxamidine (7i).

¹H NMR (200 MHz, CDCl₃) d 2.32 (t, 1H, J2.5 Hz),

4.11 (d, 2H, J2.5 Hz), 5.00±5.60 (2H), 7.30 (dd, 1H,

J5.5, 7.5 Hz), 7.98 (br d, 1H, J5.5 Hz), 8.62 (br d, 1H,

J7.5 Hz), 8.84 (br s, 1H).

4.1.18. 5-Bromopyridine pyridine-3-(N-prop-2-ynyl)car-

boxamidine (7j). H NMR (200 MHz, CDCl₃) d 2.31 (d,

1

1H, J2.5 Hz), 3.90±4.20 (2H), 4.12 (d, 2H, J2.5 Hz),

8.20 (br s, 1H), 8.75 (s, 1H), 8.80 (s, 1H).

4.1.19. Pyridine-4-(N-prop-2-ynyl)carboxamidine (7k).

¹H NMR (200 MHz, CDCl₃) d 2.32 (t, 1H, J2.5 Hz),

4.05 (d, 2H, J2.5 Hz), 5.96 (s, 2H), 7.50 (d, 2H,

J7.5 Hz), 8.55 (d, 2H, J7.5 Hz).

1

was used without further puri®cation. H NMR (200 MHz,

CDCl₃) d 2.32 (1H, t, J2.5 Hz), 4.08 (2H, d, J2.5 Hz),

5.50±5.90 (2H), 7.48 (d, 1H, J7.5 Hz), 7.60 (s, 1H), 8.38

(d, 1H, J7.5 Hz).

4.1.20. 2-(2-Chloro-4-pyridyl)-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1s). Method B2, Step 2. A

mixture of crude 7l (8.34 g, (41.7 mmol), ethyl tri¯uoro-

acetoacetate (10.24 g, 55.6 mmol) and dichloromethane

(20 mL) was placed in a 608C oil bath and the mixture

was heated at re¯ux for 2 d. The mixture was cooled, diluted

with ether (150 mL), washed with 5% aqueous HCl

(2£50 mL) and 5% aqueous NaOH (2£50 mL) and dried

over MgSO₄. Removal of the solvent under reduced pres-

sure left a yellow solid (8.37 g). The crude product was

recrystallized from methanol (30 mL) to afford 1s (6.31 g,

48%) as a white solid. Mp 125±1268C. ¹H NMR (300 MHz,

CDCl₃) d 2.54 (t, 1H, J2.2 Hz), 4.64 (d, 2H, J2.2 Hz),

6.93 (s, 1H), 7.65 (dd, 1H, J5.0, 1.4 Hz), 7.74 (d, 1H,

J1.4 Hz), 8.63 (d, 1H, J5.0 Hz); ¹³C NMR (75 MHz,

CDCl₃) d 36.9, 75.2, 76.8, 113.2, 120.4 (q), 121.2, 123.6,

143.2, 151.0, 151.4 (q), 152.9, 158.9, 160.3; ¹⁹F NMR

(282 MHz, CDCl₃) d 272.1; IR (CDCl₃) 3300, 1690.

Anal. Calcd for C₁₃H₇ClF₃N₃O: C, 49.78; H, 2.25; N,

13.40. Found: C, 49.89; H, 2.05; N, 13.34.

4.1.11. 2,6-Dichloropyridine-4-(N-2-propynyl)carboxa-

midine (7m). To a stirred suspension of 2,6-dichloropyri-

dine-4-carbonitrile (66.44 g, 0.38 mol) in methanol

(800 mL) was added 25% by sodium methoxide in methanol

by weight (28.30 g, 38.4 mmol). The mixture was stirred at

room temperature for 2 h and solid propargylamine hydro-

chloride (42.28 g, 0.46 mol) was added. The mixture was

stirred for 3 h and evaporated to dryness under reduced

pressure (bath temp ,408C). The solid residue was treated

with cold 10% aqueous NaOH (1 L) and extracted with

ethyl acetate (2£800 mL). The combined organic extracts

were washed with 10% aqueous NaOH (200 mL), dried over

MgSO₄and evaporated to dryness under reduced pressure to

afford crude 7m (89.18 g, 103%) as a yellow solid. ¹H NMR

(200 MHz, CDCl₃) d 2.32 (t, 1H, J2.5 Hz), 4.08 (d, 1H,

J2.5 Hz), 4.90±5.70 (2H), 7.57 (s, 2H).

The following crude amidine intermediates were prepared

under similar conditions.

4.1.12. 3-Chloro-N-prop-2-ynylbenzamidine (7d). ¹H

NMR (200 MHz, CDCl₃) d 2.28 (t, 1H, J2.5 Hz), 4.08

(d, 2H, J2.5 Hz), 5.0±5.6 (2H), 7.20±7.55 (3H), 7.61 (s,

1H).

The following pyrimidinones were prepared in a similar

fashion.

4.1.21. 2-(3,5-Di¯uorophenyl)-5-ethyl-3-(prop-2-ynyl)-6-

(tri¯uoromethyl)-4(3H)-pyrimidinone (1d). Mp 88±908C.

¹H NMR (200 MHz, CDCl₃) d 1.25 (t, 3H, J7.5 Hz), 2.48

(d, 1H, J2.5 Hz), 2.77 (q, 2H, J7.5 Hz), 4.62 (d, 2H,

J2.4 Hz), 6.98±7.15 (m, 1H), 7.30 (m, 2H); ¹³C NMR

(75 MHz, CDCl₃) d 12.8, 19.3, 37.0, 74.1, 76.9, 106.7

(m), 111.8 (d), 121.3 (q), 130.0, 135.7 (m), 145.7 (q),

154.3, 161.5, 164.5; ¹⁹F NMR (282 MHz, CDCl₃) d

265.8, 2107.2; IR (CDCl₃) 3300, 1650; Anal. Calcd for

C₁₆H₁₁F₅N₂O: C, 56.15; H, 3.24; N, 8.18. Found: C, 56.21;

H, 3.13; N, 8.09.

4.1.13. 3-Fluoro-N-prop-2-ynylbenzamidine (7e). ¹H

NMR (200 MHz, CDCl₃) d 2.30 (t, 1H, J2.5 Hz), 4.09

(d, 2H, J2.5 Hz), 5.30±5.70 (2H), 7.05±7.20 (1H),

7.30±7.50 (3H).

1

4.1.14. 3,5-Dichloro-N-prop-2-ynylbenzamidine (7f). H

NMR (200 MHz, CDCl₃) d 2.30 (t, 1H, J2.5 Hz), 4.07

(d, 2H, J2.5 Hz), 7.50±7.65 (2H), 7.38 (br s, 1H), 7.50

(br s, 2H).

1

4.1.15. 3,5-Di¯uoro-N-prop-2-ynylbenzamidine (7g). H

NMR (200 MHz, CDCl₃) d 2.30 (t, 1H, J2.5 Hz), 4.08

(d, 2H, J2.5 Hz), 5.15±5.50 (2H), 6.80±6.95 (1H),

7.10±7.30 (2H).

4.1.22. 5-Ethyl-2-(3-pyridyl)-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1e). Mp 116±1188C. ¹H

NMR (300 MHz, CDCl₃) d 1.24 (t, 3H, J7.4 Hz), 2.44

(t, 1H, J2.4 Hz), 2.78 (br q, 2H, J7.4 Hz), 4.64 (d, 2H,

J2.4 Hz), 7.50 (dd, 1H, J4.9, 7.9 Hz), 8.10 (m, 1H), 8.82

(dd, 1H, J4.9, 1.5 Hz), 9.02 (d, 1H, J2.2 Hz); ¹³C NMR

(75 MHz, CDCl₃) d 12.9, 19.5, 37.1, 74.2, 77.1, 121.4 (q),

4.1.16. Pyridine-2-(N-prop-2-ynyl)carboxamidine (7h).

¹H NMR (200 MHz, CDCl₃) d 2.31 (t, 1H, J2.5 Hz),

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

2697

1

123.5, 129.7, 129.9, 135.9, 145.5 (q), 149.0, 152.0, 155.3,

161.8; ¹⁹F NMR (282 MHz, CDCl₃) d 265.5; IR (CDCl₃)

3300, 1670. Anal. Calcd for C₁₅H₁₂F₃N₃O: C, 58.63; H,

3.94; N, 13.68. Found: C, 58.38; H, 3.99; N, 13.40.

988C. H NMR (200 MHz, CDCl₃) d 2.35 (br s, 3H), 2.47

(t, 1H, J2.5 Hz), 4.60 (d, 2H, J2.5 Hz), 7.60 (dd, 1H,

J5.0, 1.4 Hz), 7.70 (d, 1H, J1.4 Hz), 8.62 (d, 1H,

J5.0 Hz); ¹³C NMR (75 MHz, CDCl₃) d 11.1, 36.8,

74.4, 76.4, 119.1, 121.0 (q), 123.2, 125.1, 142.9, 145.9

(q), 150.2, 152.1, 153.7, 161.5; ¹⁹F NMR (282 MHz,

CDCl₃) d 265.9; IR (CDCl₃3300, 1665, 1530. Anal.

Calcd for C₁₄H₉ClF₃N₃O: C, 51.31; H, 2.77; N, 12.82.

Found: C, 51.28; H, 2.75; N, 12.89.

4.1.23. 2-(5-Bromo-3-pyridyl)-5-ethyl-3-(prop-2-ynyl)-6-

(tri¯uoromethyl)-4(3H)-pyrimidinone (1f). Mp 123±

1258C. ¹H NMR (200 MHz, CDCl₃) d 1.23 (t, 3H,

J7.5 Hz), 2.52 (t, 2H, J2.5 Hz), 2.78 (q, 2H,

J7.5 Hz), 4.65 (d, 2H, J7.5 Hz), 8.28 (t, 1H, J2 Hz),

8.91 (d, 1H, J2 Hz), 8.96 (d, 1H, J2 Hz); ¹³C NMR

(75 MHz, CDCl₃) d 12.9, 19.5, 36.9, 74.5, 76.7, 120.7,

121.3 (q), 130.4, 130.7, 138.5, 146.2 (q), 146.9, 153.1,

153.8, 161.5; ¹⁹F NMR (282 MHz, CDCl₃) d 265.3; IR

(CDCl₃) 3300, 1710. Anal. Calcd for C₁₅H₁₁BrF₃N₃O: C,

46.65; H, 2.87; N, 10.88. Found: C, 46.43; H, 2.78; N, 10.58.

4.1.29. 2-(2,6-Dichloro-4-pyridyl)-5-methyl-3-(prop-2-

ynyl)-6-(tri¯uoromethyl)-4(3H)-pyrimidinone (1n). Mp

131±1348C. H NMR (200 MHz,) d 2.35 (br s, 3H), 2.55

1

(t, 1H, J2.5 Hz), 4.60 (d, 2H, J2.5 Hz), 7.65 (s, 2H); ¹³C

NMR (75 MHz, CDCl₃) d 11.1, 36.8, 74.8, 76.3, 121.0 (q),

121.8, 125.8, 145.0, 146.3 (q), 151.4, 152.7, 161.5; ¹⁹F

NMR (282 MHz, CDCl₃) d 265.9; IR (CDCl₃) 3300,

1675. Anal. Calcd for C₁₄H₈Cl₂F₃N₃O: C, 46.43; H, 2.23;

N, 11.60. Found: C, 46.20; H, 2.03; N, 11.49.

4.1.24. 5-Ethyl-2-(4-pyridyl)-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1g). Mp 114±1168C. ¹H

NMR (200 MHz, CDCl₃) d 1.25 (t, 3H, J7.5 Hz), 2.48

(t, 1H, J2.5 Hz), 2.80 (q, 2H, J7.5 Hz), 4.63 (d, 2H,

J2.4 Hz), 7.69 (d, 2H, J3.0 Hz), 8.86 (d, 2H, J

3.0 Hz); ¹³C NMR (75 MHz, CDCl₃) d 12.8, 19.4, 36.9,

74.2, 76.8, 121.3 (q), 122.2, 130.2, 140.4, 145.8, 150.5,

155.3, 161.5; ¹⁹F NMR (282 MHz, CDCl₃) d 265.4; IR

(CDCl₃) 3300, 1670. Anal. Calcd for C₁₅H₁₂F₃N₃O: C,

58.63; H, 3.94; N, 13.68. Found: C, 58.58; H, 3.99; N, 13.60.

4.1.30. 5-Methyl-2,3-tetramethylene-6-(tri¯uoromethyl)-

4(3H)-pyrimidinone (1o). H NMR (300 MHz, CDCl₃) d

1

1.92 (m, 2H), 2.00 (m, 2H), 2.22 (q, 3H, J2.1 Hz), 3.00 (t,

2H, J6.9 Hz), 3.97 (t, 3H, J6.3 Hz); ¹³C NMR (75 MHz,

CDCl₃) d 9.9, 18.2, 21.1, 29.9, 43.0, 121.2 (q), 120.2, 145.4

(q), 157.0, 162.5; ¹⁹F NMR (282 MHz, CDCl₃) d 265.9; IR

(CDCl₃) 1650, 1540; MS(EI) m/z 232, 217, 203, 192. Anal.

Calcd for C₁₀H₁₁F₃N₂O: C, 51.73; H, 4.78; N, 12.06. Found:

C, 51.85; H, 4.74; N, 12.03.

4.1.25. 2-(2-Chloro-4-pyridyl)-5-ethyl-3-(prop-2-ynyl)-6-

(tri¯uoromethyl)-4(3H)-pyrimidinone (1h). Mp 82±848C.

¹H NMR (300 MHz, CDCl₃) d 1.23 (t, 3H, J7.4 Hz), 2.51

(t, 1H, J2.4 Hz), 2.77 (q, 2H, J7.4 Hz), 4.62 (d, 2H,

J2.4 Hz), 7.63 (dd, 1H, J5.0, 1.3 Hz), 7.72 (s, 1H),

8.61 (d, 1H, J5.0 Hz); ¹³C NMR (75 MHz, CDCl₃) d

13.2, 19.9, 37.3, 74.9, 77.7, 121.3, 121.6 (q), 123.8, 131.2,

143.6, 146.2 (q), 150.9, 152.9, 154.4, 161.7; ¹⁹F NMR

(282 MHz, CDCl₃) d 265.5; IR (CDCl₃) 3295, 1670.

Anal. Calcd for C₁₅H₁₁ClF₃N₃O: C, 52.72; H, 3.24; N,

12.30. Found: C, 52.55; H, 3.16; N, 12.10.

4.1.31. 2-(3-Fluorophenyl)-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1p). Mp 71±748C. ¹H

NMR (200 MHz, CDCl₃) d 2.43 (t, 1H, J2.5 Hz), 4.61

(d, 2H, J2.5 Hz), 6.90 (s, 1H), 7.25±7.4 (m, 1H), 7.45±

7.6 (m, 2H); ¹³C NMR (75 MHz, CDCl₃) d 36.9, 74.0, 76.8,

111.7, 115.7 (m), 118.2 (m), 120.2 (q), 123.9, 130.8, 134.5,

151.1 (q), 160.5, 160.8 (m), 164.0; ¹⁹F NMR (282 MHz,

CDCl₃) d 271.8, 2110.8; IR (CDCl₃) 3300, 1685. Anal.

Calcd for C₁₄H₈F₄N₂O: C, 56.77; H, 2.72; N, 9.46. Found:

C, 56.80, H, H, 3.00; N, 9.32.

4.1.26. 2-(2,6-Dichloro-4-pyridyl)-5-ethyl-3-(prop-2-ynyl)-

6-(tri¯uoromethyl)-4(3H)-pyrimidinone (1i). Mp 129±

1318C. ¹H NMR (200 MHz, CDCl₃) d 1.24 (t, 3H,

J7.5 Hz), 2.53 (t, 1H, J2.5 Hz), 2.78 (q, 2H,

J7.5 Hz), 4.63 (d, 2H, J2.5 Hz), 7.68 (s, 2H); ¹³C

NMR (75 MHz, CDCl₃) d 12.7, 19.4, 36.7, 74.7, 76.2,

121.1 (q), 121.8, 131.3, 145.0, 145.6 (q), 151.5, 152.9,

161.0; ¹⁹F NMR (282 MHz, CDCl₃) d 265.3; IR (CDCl₃)

3300, 1670. Anal. Calcd for C₁₅H₁₀Cl₂F₃N₃O: C, 47.90; H,

2.68; N, 11.17. Found: C, 48.16; H, 2.66; N, 10.92.

4.1.32. 2-(3,5-Dichlorophenyl)-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1q). Mp 149±1528C. ¹H

NMR (300 MHz, CDCl₃) d 2.49 (t, 1H, J2.4 Hz), 4.62

(d, 2H, J2.4 Hz), 6.91 (s, 1H), 7.59 (t, 1H, J1.9 Hz),

7.66 (d, 2H, J1.9 Hz); ¹³C NMR (75 MHz, CDCl₃) d

37.2, 74.8, 77.0, 112.7, 120.5 (q), 127.1, 132.0, 135.6,

136.3, 151.5 (q), 160.0, 160.7; ¹⁹F NMR (282 MHz,

CDCl₃) d 271.8; IR (CDCl₃) 3300, 1690. Anal. Calcd for

C₁₄H₇Cl₂F₃N₂O: C, 48.44; H, 2.03; N, 8.07. Found: C,

48.19; H, 2.25; N, 7.98.

4.1.27. 2,3-Diphenyl-5-methyl-6-(tri¯uoromethyl)-4(3H)-

1

pyrimidinone (1l). Mp 146±1478C. H NMR (300 MHz,

4.1.33. 2-(5-Bromo-3-pyridyl)-3-(prop-2-ynyl)-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1r). Mp 119±1218C. ¹H

NMR (300 MHz, CDCl₃) d 2.51 (t, 1H, J2.4 Hz),

4.65 (d, J2.4 Hz), 6.93 (s, 1H), 8.28 (dd, 1H, J2.1,

1.8 Hz), 8.91 (d, 1H, J2.1 Hz), 8.96 (d, 1H, J1.8 Hz);

¹³C NMR (75 MHz, CDCl₃) d 36.5, 74.7, 76.3, 112.3,

119.9 (q), 120.6, 130.2, 138.3, 146.5, 150.9 (q), 153.3,

158.2, 160.1; ¹⁹F NMR (282 MHz, CDCl₃) d 271.8;

IR (CDCl₃) 3300, 1680. Anal. Calcd for C₁₃H₇BrF₃N₃O:

C, 43.60; H, 1.97; N, 11.73. Found: C, 43.37; H, 1.90; N,

11.54.

CDCl₃) d 2.34 (q, 3H, J2.1 Hz), 7.05±7.40 (10H); ¹³C

NMR (75 MHz, CDCl₃) d 11.0, 121.5 (q), 123.6, 127.9,

128.3, 128.9, 129.0, 129.1, 129.9, 133.8, 136.8, 146.5 (q),

157.1, 163.2; ¹⁹F NMR (282 MHz, CDCl₃) d 265.8; IR

(CDCl₃) 1670, 1540; MS (EI) m/z 330, 329, 301. Anal.

Calcd for C₁₈H₁₃F₃N₂O: C, 65.45; H, 3.97; N, 8.48.

Found: C, 65.38; H, 3.85; N, 8.43.

4.1.28. 2-(2-Chloro-4-pyridyl)-5-methyl-3-(prop-2-ynyl)-

6-(tri¯uoromethyl)-4(3H)-pyrimidinone (1m). Mp 96±

2698

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

4.1.34. 2-(2,6-Dichloro-4-pyridyl)-3-(prop-2-ynyl)-6-(tri-

¯uoromethyl)-4(3H)-pyrimidinone (1t). Mp 149±1528C.

¹H NMR (300 MHz, CDCl₃) d 2.47 (t, 1H, J2.4 Hz),

4.55 (d, 2H, J2.4 Hz), 6.84 (s, 1H), 7.59 (s, 1H); ¹³C

NMR (75 MHz, CDCl₃) d 36.9, 75.5, 76.6, 113.5, 120.3

(q), 122.1, 145.1, 151.4 (q), 152.0, 157.8, 160.0; ¹⁹F NMR

(282 MHz, CDCl₃) d 271.9; IR (CDCl₃) 3300, 1700. Anal.

Calcd for C₁₃H₆Cl₂F₃N₃O: C, 44.85; H, 1.74; N, 12.07.

Found: C, 44.56; H, 1.61; N, 11.87.

0.5 h. The mixture was heated at re¯ux for 3 h, cooled

and poured into 18% aqueous HCl (300 mL). The layers

were separated and the aqueous layer was extracted with

ether (300 mL). The combined organic layers were washed

with 5% aqueous HCl (100 mL) and brine (100 mL), and

dried over MgSO₄. Removal of the solvent on a rotary

evaporator left crude 4a (79.91 g) as a brown oil. This

product was combined with crude 4a (83.27 g) from a

second run at the same scale distilled through a short

Vigreaux column at 60 mm Hg to afford 4a (84.88 g,

44%) as a straw colored liquid boiling from 60±858C. The

purity was estimated to be 85% by GC. ¹H NMR (300 MHz,

CDCl₃) d 0.98 (3H, t, J7.4 Hz), 1.28 (3H, t, J7.2 Hz),

2.02 (2H, m), 3.77 (1H, t, J7.2 Hz), 4.22 (2H, q,

J7.2 Hz); ¹³C NMR (75 MHz, CDCl₃) d 11.7, 14.3,

21.6, 54.9, 62.5, 115.5 (q), 167.5, 187.4; ¹⁹F NMR

(282 MHz, CDCl₃) d 278.7 (major), 284.4 (minor).

4.1.35. 2-(2-Chloro-4-pyridyl)-5-methoxy-3-(prop-2-ynyl)-

6-(tri¯uoromethyl)-4(3H)-pyrimidinone (1u). Mp 126±

1288C. ¹H NMR (200 MHz, CDCl₃) d 2.52 (t, 1H,

J2.5 Hz), 4.17 (s, 3H), 4.61 (d, 2H, J2.5 Hz), 7.60 (dd,

1H, J5.0, 1.4 Hz), 7.68 (d, 1H, J1.4 Hz), 8.60 (d, 1H,

J5.0 Hz); ¹³C NMR (75 MHz, CDCl₃) d 36.8, 60.7, 74.7,

76.1, 120.4 (q), 120.9, 123.3, 137.1 (q), 142.9, 144.5, 150.0,

150.1, 152.1, 157.9; ¹⁹F NMR (282 MHz, CDCl₃) d 266.7; IR

(CDCl₃) 3300, 1680, 1585. Anal. Calcd for C₁₄H₉ClF₃N₃O₂: C,

48.93; H, 2.64; N, 12.23. Found: C, 48.94; H, 2.53; N, 12.25.

4.1.40. Ethyl 2-methoxy-2-(tri¯uoroacetyl)acetate (4f).

Reaction of sodium hydride (60% in oil, 40.21 g,

1.0 mol), ethyl tri¯uoroacetate (72 mL, 0.60 mol) and

ethyl methoxyacetate (14f, 47 mL, 0.40 mol) as described

above afforded crude 4f (66.46 g). Distillation at 20 mm Hg

4.1.36. 6-(Di¯uoromethyl)-5-ethyl-2-(3-¯uorophenyl)-3-

(2-propynyl)-4(3H)-pyrimidinone (1w). Mp 90±928C. H

1

NMR (300 MHz, CDCl₃) d 1.23 (t, 3H, J7.4 Hz), 2.42 (t,

1H, J2.4 Hz), 2.77 (tq, 2H, J1.5, 7.4 Hz), 4.62 (d, 2H,

J2.4 Hz), 6.56 (t, 1H, J54.0 Hz), 7.27 (m, 1H), 7.44 (m,

1H), 7.50±7.60 (3H); ¹³C NMR (75 MHz, CDCl₃) d 13.0,

18.2, 36.7, 77.2, 113.1 (t), 115.4 (m), 117.7 (m), 123.8,

128.4, 130.4, 135.0, 149.1 (t), 156.5, 160.5, 161.6, 163.8;

¹⁹F NMR (282 MHz, CDCl₃) d 2111.1, 2116.9 (d); IR

(CDCl₃) 3300, 1660. Anal. Calcd for C₁₆H₁₃F₃N₂O: C,

62.74; H, 4.28; N, 9.15. Found: C, 62.60; H, 4.19; N, 8.85.

through a Vigreaux column afforded 4f (45.77 g, 53%). H

NMR (CDCl₃) d 1.32 (3H, t, J7 Hz), 3.50 (3H, s), 4.07

(1H, s), 4.33 (2H, q, J7 Hz).

4.1.41. Ethyl 2-(di¯uoroacetyl)acetate (4i). Reaction of

sodium hydride (40.14 g, 1.0 mol), ethyl di¯uoroacetate

(45.0 mL, 0.45 mol) and ethyl acetate (37.5 mL, 0.38 mol)

following the procedure described above afforded a mixture

of crude 4i and toluene (78.43 g). The crude product was

distilled through a short Vigreaux column at 10 mm Hg to

1

4.1.37. 2-(2,6-Dichloro-4-pyridyl)-6-(di¯uoromethyl)-3-

(2-propynyl)-4(3H)-pyrimidinone (1x). Mp 129±1318C.

¹H NMR (200 MHz, CDCl₃); (2.52 (t, 1H, J2.5 Hz),

4.61 (d, 2H, J2.5 Hz), 6.39 (t, 1H, J54 Hz), 6.88 (s,

1H), 7.64 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) d 36.2,

63.5, 74.8, 111.1, 112.4, 121.7, 145.1, 151.7, 155.5 (t),

156.8, 160.1; ¹⁹F NMR (282 MHz, CDCl₃) d 2122.8 (d);

IR (CDCl₃) 3300, 1685, 1520; MS (EI) m/z 330, 294. Anal.

Calcd for C₁₃H₇Cl₂F₂N3O: C, 47.30; H, 2.14; Cl, 21.48; F,

11.51; N, 12.73; O, 4.85.

afford 4i (15.67 g, 25%) boiling 55±808C. H NMR was

comparable to that in the literature.²¹

4.1.42. Ethyl 2-(di¯uoroacetyl)-2-methoxyacetate (4j).

Reaction of sodium hydride (40.34 g, 1.0 mol), ethyl

di¯uoroacetate (40.0 mL, 0.40 mol) and ethyl methoxy-

acetate (14f, 47.0 mL, 0.40 mol) following the procedure

described above afforded crude 4j (26.97 g). The crude

product was distilled through a short Vigreaux column at

1

10 mm Hg to afford 4j (5.57 g, 34%) boiling 85±958C. H

NMR (CDCl₃) d 1.38 (3H, t, J7.1 Hz), 3.59 (1H, s), 3.67

(3H, s), 4.23 (2H, q, J7.1 Hz), 6.65 (1H, t, J53.7 Hz);

MS (EI) 196, 168, 150, 122.

4.1.38. 2-(2,6-Dichloro-4-pyridyl)-6-(di¯uoromethyl)-5-

methoxy-2-phenyl-3-(2-propynyl)-4(3H)-pyrimidinone

(1z). Mp 149±1528C. ¹H NMR (200 MHz, CDCl₃) d 2.53 (t,

1H, J2.5 Hz), 4.18 (s, 3H), 4.59 (d, 2H, J2.5 Hz), 6.81 (t,

1H, J54 Hz), 7.65 (s, 2H); ¹³C NMR (75 MHz, CDCl₃) d

36.6, 60.8, 74.8, 76.3, 108.8 (t), 121.9, 141.0 (t), 144.3,

145.2, 149.9, 151.4, 157.5; ¹⁹F NMR (282 MHz, CDCl₃) d

2122.1 (d); IR (CDCl₃3300, 1675. Anal. Calcd for

C₁₄H₉Cl₂F₂N₃O₂: C, 46.69; H, 2.52; Cl, 19.69; F, 10.55;

N, 11.67. Found: C, 46.52, H, 2.67; N, 11.51.

4.1.43. Ethyl 2-(tri¯uoroacetyl)butanoate (4a). Method D.

To a stirred solution of butanoyl chloride (15a, 50 mL,

0.48 mol) in methylene chloride (300 mL) was added

tri¯uoroacetic anhydride (70.1 mL, 0.50 mol). The mixture

was cooled to ca. 108C in an ice bath and pyridine (80 mL,

0.99 mol) that had been dried over NaOH pellets was added

dropwise such that the temperature did not rise above 128C.

The mixture was stirred for an additional 15 min in the ice

bath and at room temperature for 3 h. The mixture was

recooled to below 08C and ice cold absolute ethanol

(80 mL) was added dropwise such that the temperature

did not rise above 08C. The mixture was allowed to stir

overnight at room temperature, washed with 10% aqueous

HCl (3£), water (1£) and saturated aqueous sodium

bicarbonate (3£), and dried over MgSO₄. The solvent was

removed under reduced pressure with a room temperature

4.1.39. Ethyl 2-(tri¯uoroacetyl)butanoate (4a). Method C.

Sodium hydride (60% in oil, 46.11 g, 1.15 mol) was washed

with hexanes (3£80 mL) and suspended in toluene

(200 mL). A mixture of ethyl tri¯uoroacetate (80 mL,

0.67 mol) and ethanol (0.5 mL) was added dropwise over

10 min to the stirred mixture. The mixture was heated to

808C and a solution of ethyl butanoate (14a, 60 mL,

0.45 mol) in toluene (50 mL) was added dropwise over

C. M. Tice, L. M. Bryman / Tetrahedron 57 (2001) 2689±2700

2699

water bath to afford of crude 4a (63.15 g, 62%) which had

a similar H NMR to the distilled sample produced by

Method C.

1H), 7.42 (m, 3H), 7.60 (m, 2H); ¹³C NMR (75 MHz,

CDCl₃) d 9.6, 34.3, 73.6, 78.0, 125.0, 126.4, 128.6, 128.7,

128.8, 130.6, 147.4; IR (CDCl₃) 3300; MS (EI) m/z 196,

181, 157. HRMS (EI) Calcd for C₁₃H₁₂N₂196.0996.

Found 196.0997.

1

4.1.44. Ethyl 2-(di¯uoroacetyl)butanoate (4h). Reaction

of di¯uoroacetic anhydride²²(10.03 g, 57.5 mmol),

butanoyl chloride (15a, 6.0 mL, 57.8 mmol), pyridine

(9.3 mL, 115.4 mmol) and ethanol (12 mL, 200 mmol) as

described above afforded crude 4h (5.74 g, 51%). This

material was used in subsequent reactions without further

Acknowledgements

We are indebted to Dr Tianlan Zhang for analytical support

and to Dr Karen Anderson Evans for critically reading the

manuscript.

1

puri®cation. H NMR (CDCl₃) d 0.98 (3H, t, J7.5 Hz),

1.28 (3H, t, J7.1 Hz), 1.99 (2H, m), 3.76 (1H, t,

J6.9 Hz), 4.22 (2H, q, J7.1 Hz), 5.90 (1H, t,

J53.7 Hz); ¹³C NMR (75 MHz, CDCl₃) d 11.9, 14.5,

21.2, 54.7, 62.2, 109.8 (t), 168.6, 195.2; ¹⁹F NMR

(282 MHz, CDCl₃) d 2128.4.

References

4.1.45. 5-Ethyl-3-methoxymethyl-2-phenyl-6-(tri¯uoro-

methyl)-4(3H)-pyrimidinone (1ae). To a stirred solution

of 5a (3.62 g, 13.5 mmol) in chloroform (100 mL) and

dimethoxymethane (100 mL) was added powdered phos-

phorus pentoxide (37.88 g, 267 mmol). The mixture was

stirred vigorously overnight and quenched by cautious addi-

tion of 5% aqueous NaOH (100 mL). The mixture was

allowed to cool to room temperature and extracted with

ethyl acetate (2£150 mL). The combined organic extracts

were washed with brine (100 mL), dried over MgSO₄and

concentrated under reduced pressure to afford an off-white

solid (4.06 g). This material was puri®ed by ¯ash chromato-

graphy on silica gel (50 g), eluting with 0, 25, 50 and 75%

ether in hexanes (200 mL of each) to afford 1ae (2.76 g,

1. Burdge, E. L. Pest Manag. Sci. 2000, 56, 245±248.

2. Tice, C. M. US 5300477, 1994 (Chem. Abstr. 122:31543).

3. Pinner, A. Chem. Ber. 1889, 22, 1612±1635.

4. Examination of the literature indicates that the ratio of N and

O alkylation products of pyrimidinones depends on the reac-

tion conditions and the substituents on the pyrimidinone ring:

(a) Brown, D. J.; Hoerger, E.; Mason, S. F. J. Chem. Soc.

1955, 211±217. (b) Neelakantan, P.; Rani, R.; Rahman,

M. F.; Bhalerao, U. T. Ind. J. Chem. Sect. B 1985, 24,

1180±1181. (c) Shimizu, S.; Ogata, M. J. Org. Chem. 1988,

53, 5160±5163. (d) Atwal, K. S.; Ahmed, S. Z.; Bird, J. E.;

Delaney, C. L.; Dickinson, K. E. J.; Ferrara, F. N.; Hedberg,

A.; Miller, A. V.; Moreland, S.; O'Reilly, B. C.; Schaeffer,

T. R.; Waldron, T. L.; Weller, H. N. J. Med. Chem. 1992, 35,

4751±4763. (e) Nicolai, E.; Cure, G.; Kirchner, M.; Teulon,

J. M.; Versigny, A.; Cazes, M.; Virone-Oddos, A.; Caussade,

F.; Cloarec, A.; Eur Eur. J. Med. Chem. 1995, 30, 365±376.

(f) Hori, M.; Ohtaka, H. Chem. Pharm. Bull. 1993, 41, 1114±

1117. (g) Leonard, N. J.; Curtin, D. Y. J. Org. Chem. 1946, 11,

341±348.

1

65%) as a white solid, mp 85±878C. H NMR (200 MHz,

CDCl₃) d 1.25 (t, 3H, J7.5 Hz), 2.75 (q, 2H, J7.5 Hz),

4.51 (s, 3H), 5.20 (s, 2H), 7.45±7.55 (3H), 7.60±7.70 (2H);

¹³C NMR (75 MHz, CDCl₃) d 13.0, 19.4, 58.2, 76.5, 121.5

(q), 128.5, 129.0, 130.9, 133.4, 146.2 (q), 148.5, 159.0,

163.3; ¹⁹F NMR (282 MHz, CDCl₃) d 264.8; IR (CDCl₃)

1665. Anal. Calcd for C₁₅H₁₅F₃N₂O₂: C, 57.69; H, 4.84; N,

8.97. Found: C, 57.66; H, 4.81; N, 8.94.

5. Interestingly methoxymethylation of 5a under acid conditions

(P₂O₅, MeOCH₂OMe, CHCl₃) afforded predominantly the

N-methoxymethyl compound 1ae, (Scheme 8). Fuji, K.;

Nakano, S.; Fujita, E. Synthesis 1975, 276±277.

4.1.46. 4-methyl-2-phenylimidazole (11) and 4-methyl-2-

phenyl-3-(prop-2-ynyl)imidazole (13). Ethyl benzimidate

hydrochloride (1.86 g, 10.0 mmol) was suspended in aceto-

nitrile (6 mL) and powdered sodium bicarbonate (0.84 g,

10.0 mmol) was added. The mixture was stirred for 0.5 h

and propargylamine (0.69 mL, 10.0 mmol) was added. The

mixture was heated at re¯ux for 16 h, cooled, diluted with

ethyl acetate (150 mL), washed with water (50 mL) and

dried over MgSO₄. Removal of the solvent under reduced

pressure left a yellow solid (1.32 g) which was puri®ed by

¯ash chromatography on a silica gel column (30 g) eluted

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was triturated twice with 1:1 ether/hexanes (20 mL) to

afford 11 (0.89 g, 56%) as an off-white solid, identical by

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1

TLC and H NMR to a commercially obtained sample. H

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Article Doi

Regiocontrolled synthesis of 3-substituted-6-trifluoromethyl-4(3H)-pyrimidinones

DOI: 10.1016/S0040-4020(01)00042-4

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Article abstract of DOI:10.1016/S0040-4020(01)00042-4

Full text of DOI:10.1016/S0040-4020(01)00042-4

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