Electrochemical fluorination of 1-ethylpiperazine and 4-methyl- and/or 4-ethylpiperazinyl substituted carboxylic acid methyl esters

Journal of Fluorine Chemistry 108 (2001) 21±35

Electrochemical ¯uorination of 1-ethylpiperazine and

4-methyl- and/or 4-ethylpiperazinyl substituted

carboxylic acid methyl esters^$

Takashi Abe^a,*, Hajime Baba^b, Irina Soloshonok^a

^aDepartment of Chemistry, National Industrial Research Institute of Nagoya, Hirate-cho 1-1, Kita-ku, Nagoya 462-8510, Japan

^bDepartment for New Refrigerants Research, Research Institute of Innovative Technology for the Earth (RITE),

c/o NIRIN, Hirate-cho 1-1, Kita-ku, Nagoya 462-8510, Japan

Received 14 March 2000; received in revised form 26 September 2000; accepted 7 November 2000

Abstract

Electrochemical ¯uorination (ECF) of 1-ethylpiperazine and eight methyl esters of 4-methyl- and/or 4-ethylpiperazinyl substituted

carboxylic acids were studied. Corresponding per¯uoro(4-¯uoro-1-ethylpiperazine) was obtained from 1-ethylpiperazine in a small yield

along with per¯uoro(1-methyl-3-ethylimidazolidine), per¯uoro[2-(N⁰,N⁰-di¯uoroaminoethyl)-N,N-diethylamine)] and per¯uorotriethyla-

mine. The corresponding mono-basic per¯uoroacid ¯uorides with a per¯uoro(4-alkylpiperazinyl) group were obtained in fair to good yields

from the ¯uorination of methyl esters of 4-alkylpiperazinyl-substituted carboxylic acids. Yields of the targeted per¯uoro(4-alkylpiperazinyl)

group containing per¯uorocarboxylic acid ¯uorides varied depending on both the type of N-alkyl (alkyl CH₃or C₂H₅) group at the 4-

position and the (o-methoxycarbonylalkyl) group at the 1-position of the piperazine ring of the substrate. Higher yields of per¯uoroacid

¯uorides were obtained by the ECF of 4-ethyl substituted piperazine derivatives than of the 4-methyl substituted piperazine derivatives

when 4-alkylpiperazines with the same carboxylic acid ester group were ¯uorinated electrochemically. Spectroscopic data as well as

physical properties are described for new per¯uoro(1,4-dialkylpiperazines) and N-containing per¯uorocarboxylic acids with a

Keywords: Electrochemical ¯uorination; Per¯uoroacid ¯uorides; Per¯uoropiperazines; Per¯uoromono-basic acids

1. Introduction

We have previously shown that the ECF of two methyl

esters of 4-methylpiperazinyl substituted carboxylic acids

(methyl 2-(4-methylpiperazinyl)propionate, methyl 3-(4-

methylpiperazinyl)-2-methylpropionate) resulted in fair to

good yields of the corresponding per¯uoroacid ¯uorides

with a per¯uoropiperazine ring [8,9]. Furthermore, we have

shown in a previous paper that per¯uoro[1,4-bis(o-¯uoro-

carbonylmethyl)piperazine] could be obtained by the ECF

of 1,4-bis(2-hydroxyethyl)piperazine [10].

We have now embarked on the preparation of various

per¯uorocarboxylic acids with a per¯uoropiperazine ring by

ECF because little data are available on the ECF of piper-

azine derivatives with a functional group [11±14].²Though

results of the ECF of methyl 2-(4-methylpiperazinyl)pro-

pionate (4) [8] and 3-(4-methylpiperazinyl)-2-methylpro-

Electrochemical ¯uorination (ECF) is a very important

method for the production of per¯uoro-compounds¹with a

hetero-atom [1±3]. Although the ECF of several per¯uoro(1,

4-dialkylpiperazines) including various per¯uoroheterocyc-

lic compounds were reported by Russian chemists in 1965

[4], it was not until 1975 that the synthesis of per¯uoro(1,4-

di¯uoropiperazine), a per¯uoroderivative of piperazine, was

done by the ECF of piperazine by Banks et al. [5].

However, a need still exists for developing new per¯uor-

ocarboxylic acids especially those with a hetero-atom such

as S, N, and O, because per¯uorocarboxylic acids are

important starting materials for products such as agrochem-

icals and pharmaceuticals [6,7].

^$Electrochemical fluorination of N-containing carboxylic acids. Part 7.

^*Corresponding author. Tel.: 81-52-911-2998; fax: 81-52-916-2802.

E-mail address: abe@nirin.go.jp (T. Abe).

¹The prefix of ``F-'' in this paper designates ``perfluoro-'' (all C±H

bonds are replaced by C±F bonds).

²It has been shown in brief by one of authors (TA) that F-[1,4-bis(1-

fluorocarbonylethyl)piperazine] was obtained by the ECF of 1,4-bis(1-

methoxycarbonylethyl)piperazine [13]. It was stated in brief that

F-[1,4-bis(2-fluorosulfonylethyl)piperazine] was prepared by the ECF of

1,4-bis(2-fluorosulfonylethyl)piperazine [14].

PII: S 0 0 2 2 - 1 1 3 9 ( 0 0 ) 0 0 3 9 7 - 3

22

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

pionate (6) [9] have already been reported, these two

samples were also examined in order to identify the by-

products in detail under the same conditions as those applied

for other samples for the purposes of comparison.

We herein report the results of the ECF of 1-ethylpiper-

azine (1) and the following eight derivatives of 4-methyl-

and/or 4-ethylpiperazines with a o-(methoxycarbonylalkyl)

group at the 1-position of the piperazine ring (2±9):

c-C₂H₅N(C₂H₄)₂NH (1), c-CH₃N(C₂H₄)₂NCH₂CH₂C(O)-

OMe (2), c-C₂H₅N(C₂H₄)₂NCH₂CH₂C(O)OMe (3),

c-CH₃N(C₂H₄)₂NCH(CH₃)C(O)OMe (4), c-C₂H₅N(C₂-

H₄)₂NCH(CH₃)C(O)OMe (5), c-CH₃N(C₂H₄)₂NCH₂CH-

(CH₃)C(O)OMe (6), c-C₂H₅N(C₂H₄)₂NCH₂CH(CH₃)C(O)-

OMe (7), c-CH₃N(C₂H₄)₂NCH(CH₃)CH₂C(O)OMe (8),

c-C₂H₅N(C₂H₄)₂NCH(CH₃)CH₂C(O)OMe (9).

Scheme 1.

were different. The expected per¯uoro(4-¯uoro-1-ethylpi-

perazine) (10) was obtained at a small yield (GC yield

1:7%) together with per¯uoro(1-methyl-3-ethylimidazoli-

dine) (11) [16], per¯uoro[2-(N⁰,N⁰-di¯uoroaminoethyl)-

N,N-diethylamine)] [molecular formula: (C₂F₅)₂NCF₂-

CF₂NF₂] (12) and per¯uorotriethylamine (13) (major pro-

duct) through the ECF of 1, as shown in Scheme 2.

The second major product other than cleaved products

was the ring-contracted compound 11 instead of 10 which

was desired in this case. Though, an attempt to improve the

yield of the corresponding per¯uoro(4-¯uoro-1-methylpi-

perazine) by the ECF of 1-methylpiperazine was made

successfully by raising the initial substrate concentration

(from 5.1 to 8.2%) in anhydrous hydrogen ¯uoride (AHF)

[15] with the yield increasing from 0.8 to 6.8%, changing of

the solute concentration did not produce the same effect in

the case of 1 (see Section 3). Therefore, it was expected that

some correlation would be observed from the results of the

comparative ECF study where methyl esters of 4-alkylpi-

perazinyl substituted carboxylic acids were ¯uorinated by

changing the N-alkyl group (alkyl CH₃or C₂H₅) at

the 4-position of the piperazine ring, because it is known that

the ECF yield of the tertiary amines of the type of CH₃-

NR₁(R₂) (R₁ C_nH_2n1, R₂ C_mH_2m1; n, m > 2) can be

raised considerably by replacing the N-CH₃group with other

higher N-alkyl groups of the starting material [17].

We have investigated the ECF of 1,4-dialkylpiperazine

derivatives which have a methyl and/or an ethyl group at the

4-position of the piperazine ring and a carboxylic acid

methyl ester group at the 1-position. The results of the

¯uorination of (4-alkylpiperazinyl) substituted n- and/or

iso-propionic acid methyl esters [alkyl CH₃(2, 4),

C₂H₅(3, 5)], and those of methyl 3-(4-alkylpiperazinyl)-

2-methylpropionate [alkyl CH₃(6), C₂H₅(7)] and methyl

2. Results and discussion

We have shown that the ECF of N-(2-hydroxylethyl)pi-

perazine does not produce per¯uoro(4-¯uoropiperazinyl-

acetyl ¯uoride) as the expected product due to the extensive

cleavage of the C±N bond of the secondary amine. Instead,

per¯uoro(N,N-diethylamino-acetyl ¯uoride) was formed as

the cleaved product (Scheme 1) [10].

However, it has been shown that the ECF of 1-methylpi-

perazine yielded the corresponding per¯uoro(4-¯uoro-1-

methylpiperazine) (GC yield 6:8%), which retained

its original structure, together with per¯uoro(N,N-diethyl-

methylamine) (14.8%), per¯uoro(1,3-dimethylimidazoli-

dine) (2.6%) and per¯uoro[2-(N⁰,N⁰-di¯uoroaminoethyl)-

N-methyl,N-ethylamine)] [molecular formula: C₂F₅(CF₃)-

NCF₂CF₂NF₂] (2.0%) [15]. Among these products,

per¯uoro(1,3-dimethylimidazolidine) was formed as a

result of the ring isomerization of the piperazine ring during

¯uorination.

In order to investigate the process of the ECF of 1-

alkylpiperazine in more detail, we have examined the

ECF of 1-ethylpiperazine (1) under almost comparable

conditions to those applied in the ECF of 1-methylpiper-

azine. It was found that almost the same types of products as

those obtained from 1-methylpiperazine were formed

through the ECF of 1, though their distribution patterns

Scheme 2.

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

23

Table 1

Results of the fluorination of 2, 3, 4 and 5

Run

1

Sample g

(mol)

Current

passed (A h)

Fluorinated

product (g)

Fluorinated products^c(yield %)

(2) 39.5 (0.212)

233

9.5^a(19.9)^b

(C₂F₅)₂NCF₃(32) (5.0), (C₂F₅)₃N (13) (3.5), CF₃

CF₃(33) (3.8),

(C₂F₅)₂NCF₂CF₂C(O)F (16) (4.0), CF₃

(14) (8.0)

C₂F₅(17) (5.8), CF₃

CF₂CF₂C(O)F

2

3

4

(3) 39.7 (0.198)

(4) 39.7 (0.213)

(5) 39.2 (0.196)

233

211

209

6.5^a(30.2)^b

6.7^a(16.0)^b

5.1^a(30.1)^b

(CF₃)₂NC₂F₅(31) (2.3), 32 (1.1), (CF₃)₂NCF₂CF₂C(O)F (36) (0.7), 13 (4.9), 16 (6.1), 17

(4.2), C₂F₅C₂F₅(18) (12.8), C₂F₅CF₂CF₂C(O)F (15) (14.3)

31 (1.6), 32 (1.7), (CF₃)₂NCF(CF₃)C(O)F (38) (1.6), 13 (3.2), 33 (0.4), 17 (6.4),

CF₃

31 (2.9), 32 (0.7), 39 (1.2), 13 (2.7), 17 (1.0), 18 (12.4), C₂F₅

(15.7), C₂F₅CF(CF₃)C(O)OCF₃(22) (0.9)

CF(CF₃)C(O)F (19) (7.5), CF₃

CF(CF₃)C(O)OCF₃(20) (0.5)

CF(CF₃)C(O)F (21)

^aProducts obtained in a cold trap.

^bProducts obtained as cell drainings.

^cArranged in order of the elution time on GC.

3-(4-alkylpiperazinyl)butyrate [alkyl CH₃(8), C₂H₅(9)]

are summarized in Tables 1 and 2, respectively.

obvious difference was observed in the yields of the targeted

per¯uoroacid ¯uorides between those with a per¯uoro(4-

methylpiperazinyl) group and those with a per¯uoro(4-

ethylpiperazinyl) group. Characteristically, the yields of

the per¯uoroacid ¯uorides were almost double that when

were obtained from the ECF of 4-ethylpiperazinyl substi-

tuted substrate as compared with those from 4-methylpiper-

azinyl substituted substrate.

It was found that the desired per¯uoro(4-alkylpiperazinyl)

substituted per¯uoro(carboxylic acid ¯uorides) could be

obtained in fair yields by the ECF of corresponding car-

boxylic acid methyl esters with a 4-alkylpiperazinyl group

[alkyl CH₃(2, 4, 6, 8), C₂H₅(3, 5, 7, 9)]. Although

almost the same kind of the products and distribution pattern

of the cleaved by-products were obtained through ECF of 4-

alkylpiperazine derivatives in the case where an identical

carboxylic acid group was attached at the 1-position, an

For example, the corresponding per¯uoro[3-(4-methylpi-

perazinyl)propionyl ¯uoride] (14) and per¯uoro[3-(4-ethyl-

piperazinyl)propionyl ¯uoride] (15) were obtained together

Table 2

Results of the fluorination of 6, 7, 8 and 9

Run

1

Sample g

(mol)

Current

passed (A h)

Fluorinated

product (g)

Fluorinated products^c(yield %)

(6) 39.7 (0.199)

239

10.0^a(40.2)^b

iso-C₃F₇C(O)F (42) (7.2), (CF₃)₂NCF₂CF(CF₃)C(O)F (43) (4.3), 33 (0.8), 17 (1.3),

(C₂F₅)₂NCF₂CF(CF₃)C(O)F (27) (14.5), CF₃

CF₃CF₂CF(CF₃)C(O)F (23) (22.1)

42 (2.8), 31 (2.1), 38 (3.2), 27 (2.3), C₂F₅

C₂F₅CF₂CF(CF₃)C(O)F (25) (37.5)

C₃F₇(n) (44) (3.4),

2

3

(7) 40.0 (0.187)

(8) 40.5 (0.203)

232

229

6.6^a(53.1)^b

C₃F₇(n) (46) (5.2),

12.0^a(26.9)^b

n-C₃F₇C(O)F (48) (4.7), 32 (4.4), 13 (3.7), 17 (3.5), CF₃

CF₃CF(CF₃)CF₂C(O)F (24) (10.9), CF₃

48 (trace), 32 (1.8), 13 (3.4), 18 (11.0), C₂F₅

C₂F₅CF(CF₃)CF₂C(O)F (26) (20.2), C₂F₅

C₃F₇(i) (49) (3.8),

(30) (4.5)

4

(9) 40.3 (0.188)

237

7.1^a(56.1)^b

C₃F₇(i) (28) (9.5),

(29) (9.7)

^aProducts obtained in a cold trap.

^bProducts obtained as cell drainings.

^cArranged in order of the elution time on GC.

24

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

Scheme 3.

with cleaved products in yields as shown in Scheme 3 by the

¯uorination of 2 and 3.

Other major by-products obtained were per¯uoro[3-(N,N-

diethylamino)propionyl ¯uoride] (16) and per¯uoro(4-

methyl-1-ethylpiperazine) (17) from 2, and 16 and per-

¯uoro(1,4-diethylpiperazine) (18) from 3, respectively. In

the case of the ¯uorination of 3, it was found that not only the

yield of the targeted 15 but also that of 18, which resulted

from the a-bond scission of the carboxylic acid, also

increased as compared with that of the corresponding 17

from 2. Among the targeted compounds (14 and 15), com-

pound 15 is a known compound which has been ®led in the

patent literature [12]. Previously, compound 15 has been

isolated as a cleaved by-product from the ¯uorination of 1,4-

bis(b-propionyl chloride)piperazine dihydrochloride.

We have reported that various kinds of per¯uoro[2-(cyclic

amino)propionyl ¯uoride] could be obtained together with a

small amount of per¯uoro[methyl 2-(cyclic amino)propio-

nate] by the ECF of methyl esters of 2-(cyclic amino)pro-

pionic acid [8] (Scheme 4).

Scheme 4.

the cleavage of the a-bond to the carbonyl group is generally

observed. While, in the ECF of acyclic tertiary amines with

a branched alkyl group [alkyl N-CHR₁(R₂); R₁

C_nH_2n1, R₂ C_mH_2m1; n, m > 2], the very easy cleavage

of the C±C bond at the site of either a C±R₁bond or a C±R₂

bond (b-bond from the amine) is widely acknowledged [17].

Therefore, compound 18 from the ECF of 5, which is a

tertiary amine with a branched propionic acid methyl ester,

is thought to be formed due to a complex effect consisting of

the a-bond scission at the carboxylic acid site and the b-

bond scission at the amine site.

In accordance with these observations, a pair of the

targeted per¯uorocarboxylic acid derivatives, speci®cally,

per¯uoro[2-(4-methylpiperazinyl)propionyl ¯uoride] (19)

and per¯uoro[methyl 2-(4-methylpiperazinyl)propionate]

(20), and per¯uoro[2-(4-ethylpiperazinyl)propionyl ¯uor-

ide] (21) and per¯uoro[methyl 2-(4-ethylpiperazinyl)pro-

pionate] (22) were obtained by the ¯uorination of 4 and

5, respectively. For example, several products including 21

and 22 were obtained in the ¯uorination of 5 as shown in

Scheme 5.

The formation of per¯uoro(methyl esters) such as per-

¯uoro[methyl 2-(4-ethylpiperazinyl)propionate] (22) can be

easily identi®ed by studying spectroscopic data (¹⁹F NMR

and IR). The CF₃O signal of the ester group was observed in

the ¹⁹F NMR spectra of 22 as a singlet at 59.4 ppm, and the

IR spectra exhibited characteristic n(C=O) bands which split

into two peaks at 1854 and 1840 cm ¹. The values for

n(C=O) bands of the corresponding per¯uoroacid ¯uoride

(21), which similarly split into two peaks at 1898 and

1881 cm ¹, are slightly higher than those of the per¯uor-

o(methyl ester) (22). The mass spectra of 22 were consider-

Among the products, considerable quantities of per-

¯uoro(1,4-diethylpiperazine) (18) was formed as a cleaved

product resulting from the C±C bond scission. In the ECF of

carboxylic acids (acid halides, methyl esters and amides),

ably different from those of 21. The base peak was the CF₃

ion at m/e 69 for 19, while that of 20 was the C₂F₅ion at m/

e 119.

Scheme 5.

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

25

Scheme 6.

Relatively good yields of per¯uoroacid ¯uorides were

obtained from the ECF of 4-alkylpiperazines with a n- and/

or an iso-butyric acid group at the 1-position of the piper-

azine ring as compared with those obtained from 4-alkylpi-

The targeted per¯uoro[3-(4-methylpiperazinyl)butyryl

¯uoride] (24) and per¯uoro[3-(4-ethylpiperazinyl)butyryl

¯uoride] (26) were obtained in fair yields together with

cleaved and cyclization products by the ¯uorination of

methyl 3-(4-methylpiperazinyl)butyrate (8) and methyl 3-

(N-ethylpiperazinyl)butyrate (9).

As a typical example, the reaction pathway for each of the

¯uorination products from the ECF of 9 can be explained as

shown in Scheme 7.

perazines with

a n- and/or an iso-propionic acid

group. Furthermore, the kinds of products obtained from

the ECF of 4-alkylpiperazines with an iso-butyric acid group

and/or a n-butyric acid one differed from each other. Rela-

tively simple kinds of ¯uorinated products were formed

from the ECF of the former substrates. In contrast, a com-

plex mixture of cleaved products and a cyclization product

as well as the targeted per¯uoroacid ¯uoride were obtained

from the ECF of the latter substrates. For example, the

per¯uoro[(4-ethylpiperazinyl)-2-methylpropionyl ¯uoride]

(25) was formed at a yield as high as 37.5% together with

cleaved products by the ECF of methyl 3-(4-ethylpiperazi-

nyl)-2-methypropionate (7) as is shown in Scheme 6. The

yield of 25 was almost doubled that of per¯uoro[(4-methyl-

piperazinyl)-2-methylpropionyl ¯uoride] (23) obtained from

the ECF of 4-methylpiperazinyl substituted substrate (6).

Per¯uoro[3-(N,N-diethylamino)-2-methylpropionyl

¯uoride] (27) was formed due to the C±N bond scission

between the 3- and 4-position of the piperazine ring in a

small yield (2.3%) as a cleaved product from 7. This

compound was also obtained from 6 as a common cleaved

product at a higher yield (yield 14:5%) than that obtained

from 7. Therefore, in the case of the ECF of 7 having a 4-

ethylpiperazinyl group, the degree of the C±N bond scission

at the 4-position of the piperazine ring was considerably

lower than the case of 6 with a 4-methylpiperazinyl group,

which resulted in an increased amount of the formation of

the corresponding per¯uoroacid ¯uoride.

Among them, per¯uoro(1,4-diethylpiperazine) (18) and

per¯uoro[4-ethyl-1-(iso-propyl)piperazine]

(28)

were

formed as major cleaved products. Compound 28 was

formed as a result of the a-bond scission of the carboxylic

acid skeleton. Compound 18 is thought to be formed due to

the b-bond scission (from the side of the amine) of the

butyric acid skeleton as is shown in Scheme 5 by looking at

the cleavage pattern of the products from ECF of 5 which

resulted in per¯uoro(1,4-diethylpiperazine) (18) as the main

cleaved product. Another major product obtained was the

per¯uoro[3-(4-ethylpiperazinyl)oxolane] (29) which is a

speci®c product from the ECF of the substrate with a ±

CH(CH₃)CH₂C(O)OMe group. We have shown that per-

¯uoroalkylamines bearing a per¯uorooxolane group are

formed in the ¯uorination of a series of methyl 3-(dialky-

lamino)butyrates as a result of the intramolecular cyclization

[9]. Corresponding per¯uoro[3-(4-methylpiperazinyl)oxo-

lane] (30) was similarly formed as the expected cyclization

product (Y 4:5%) by the ¯uorination of 8. The yields of

these cyclization products (29 and 30) amounted to almost

half of those of the corresponding per¯uoroacid ¯uorides (26

and 24), respectively. Accordingly, it can be concluded that

this cyclization is one of the major reasons for lowered yield

Scheme 7.

26

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

14 (A form) < 24 (C form) < 23 (D form). The comparison of

the ECF yields in a series of per¯uoro[4-ethylpiperazinyl]

group substituted per¯uoroacid ¯uorides showed the same

increasing order of the yield as was observed in that for

per¯uoro[4-methylpiperazyniyl] group substituted per¯uor-

oacid ¯uorides; 15 (A form) < 21 (B form) < 26 (C form) <

25 (D form).

Scheme 8.

Our study on the preparation of N-containing per¯uor-

oacid ¯uorides is in progress and the results of the ECF of

piperazines with bis(o-methoxycarbonylalkyl) groups at the

1- and 4-positions of the piperazine ring will be reported in a

subsequent paper.

of the targeted per¯uoroacid ¯uorides in the case of the

¯uorination of those substrates with a 4-alkylpiperazinyl

group.

It has been reported by Moore and co-workers at 3M Co.

that there is a relationship between the structure and the ECF

yield for substrates which have a dialkylamino-substituted

ether structure [18]. They found that good product yields

were obtained when an iso-propyl group was incorporated

into the ether linkage (I and II) compared with the case

where the N and O atoms are separated by three methylene

groups (III) (Scheme 8).

Similarly we have found that there is a correlation

between the yields of the desired per¯uoroacid ¯uoride

and the structure of the substrate consisting of (N,N-dialky-

lamino) substituted carboxylic acids with respect to both the

dialkylamino-group and the carboxylic acid skeleton [8,9].

The cyclic amino group substituted carboxylic acids result in

higher yields of per¯uoroacid ¯uoride than those from

acyclic amino group substituted carboxylic acids. Further-

more, good yields of the corresponding per¯uoro(N,N-dia-

lkylamino) substituted per¯uoroacid ¯uorides are obtained

in the case of iso-butyric acid (the precursor for D form in

Scheme 9) compared with those of n-/iso-propionic acid (the

precursor for A and B forms) and n-butyric acid (the

precursor for C form) as the substrate in regard to the

structure of the carboxylic acid bearing a N,N-dialkyla-

mino-group. Generally, the following order of increasing

yields was observed as shown in Scheme 9.

3. Experimental details

Boiling points were uncorrected. The 1-ethylpiperazine

(1) was used as commercial grade. Methyl esters of 2-(4-

alkylpiperazinyl)propionic acids were prepared by the reac-

tion of corresponding 4-alkylpiperazine with methyl 2-bro-

mopropionate in the presence of Na₂CO₃and small

quantities of H₂O according to the method described in

the literature [19]. Methyl esters of 3-(4-alkylpiperazinyl)-

propionic acids, methyl esters of 3-(4-alkylpiperazinyl)-2-

methylpropionic acids, and methyl esters of 3-(N-alkylpi-

perazinyl)butyric acids were prepared by the Michael

reaction of corresponding 1-alkylpiperazine with

methyl acrylate, methyl methacrylate and methyl crotonate,

respectively.

The substrates synthesized for ¯uorination had the fol-

lowing boiling points: methyl 3-(4-methylpiperazinyl)pro-

pionate (2), bp 103±1048C/5 mmHg; methyl 3-(4-

ethylpiperazinyl)propionate (3), bp 1078C/3 mmHg; methyl

2-(4-methylpiperazinyl)propionate (4), bp 798C/5 mmHg;

methyl 2-(4-ethylpiperazinyl)propionate (5), 868C/

3 mmHg; methyl 3-(4-methylpiperazinyl)-2-methylpropio-

nate (6), 267±1708C/15 mmHg; methyl 3-(4-ethylpiperazi-

nyl)-2-methylpropionate (7), 1428C/17 mmHg; methyl 3-(4-

methylpiperazinyl)butyrate (8), 1328C/19 mmHg; methyl 3-

(4-ethylpiperazinyl)butyrate (9), 1348C/17 mmHg.

So, it has become possible to determine the relationship

between the yields of corresponding per¯uoroacid ¯uorides

and the structure of the substrate by studying the data, in

which 4-methyl and/or ethylpiperazinyl groups bearing one

of four kinds of (methoxycarbonylalkyl) groups are ¯uori-

nated. It was found that, in accordance with the general rule

shown in Scheme 9, the following order of the increasing

yield was obtained for the series of per¯uoro[4-methylpi-

perazinyl] substituted per¯uoroacid ¯uorides; 19 (B form),

Purity of anhydrous hydrogen ¯uoride (AHF) (Daikin

Industries Co.) was more than 99.8%. The electrolytic

¯uorination apparatus and operating procedures were simi-

lar to those described previously [20]. Analytical GLC work

was carried out with a Shimadzu GC-14B gas chromato-

graph using stainless steel columns (3 mm diameter) packed

Scheme 9.

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

27

with 25% Fomblin YR on Chromosorb PAW (6.4 m). For a

semi-preparative work, a GASUKURO LL-75 modi®ed gas

chromatograph using stainless steel columns (10 mm dia-

meter) packed with 30% KelF wax on Chromosorb PAW

(4.9 m), and a Varian model 920 GC using an aluminum

column (3/8 in. diameter) packed with 20% Fomblin YR on

Chromosorb PAW (20 ft) were used. The carrier gas was

helium in all cases. Infrared spectra were measured on a

Shimadzu FTIR-8000PC spectrometer using a 6 cm gas cell

with KBr windows. ¹⁹F NMR spectra were measured on a

Varian Unity Inova 300 spectrometer (282.238 MHz for ¹⁹F

of 11, 10 and 12 are shown below. ¹⁹F NMR data of 10 are

shown in Table 3 together with those of other new com-

pounds isolated in this study.

Per¯uoro(3-methyl-1-ethylimidazolidine) (11): bp 76.0±

20

77.08C (reported bp 70±758C) [16], d₄

n_D< 1:28. IR (gas): 1366 (vs), 1340 (s), 1304 (ms),

1.7653,

20

1248 (vs), 1219 (s), 1188 (ms), 1077 (m), 1008 (w), 1922

(m), 824 (w), 748 (w), 709 (w), 665 (w). MS: 347 [M F]

(15.8), 297 C₅F₁₁N₂(22.2), 259 C₅F₉N₂(6.6), 214

C₄F₈N (3.4), 209 C₄F₇N₂(13.5), 164 C₃F₆N (59.3),

119 C₂F₅(33.6), 114 C₂F₄N (100), 100 C₂F₄(13.4), 69

1

and 299.95 MHz for H, respectively). Chemical shifts for

CF₃(96.9), 50 CF₂(11.1).

Per¯uoro(4-¯uoro-1-ethylpiperazine) (10) (nc): bp 85.0±

¹⁹F and ¹H NMR spectra were reported relative to CFCl₃and

TMS, respectively. Positive shifts are down®eld from the

reference (CFCl₃and TMS). MS spectra were measured on a

Shimadzu GC/MS-QP5000 and a Shimadzu GC/MS-

QP1100EX instruments ®tted with a capillary column (Neu-

tra Bond-1, 30 m long, 0.25 mm i.d., 1.5 mm thick) at 70 eV.

Elemental analyses were performed by Mikroanalytisches

20

85.58C, d₄1.8030, n_D< 1:2835. IR (gas): 1381 (m),

1334 (s), 1287 (ms), 1247 (vs), 1229 (vs), 1183 (s), 1140 (w),

1120 (w), 1071 (s), 970 (m), 951 (ms), 824 (m), 734 (m), 706

(w), 665 (w), 626 (w). MS: 347 [M F] (4.9), 297

C₅F₁₁N₂(4.2), 259 C₅F₉N₂(1.5), 209 C₄F₇N₂(16.8),

164 C₃F₆N (42.3), 159 C₃F₇(4.1), 145 CF₃N₂(11.0),

119 C₂F₅(100), 114 C₂F₄N (99.6), 100 C₂F₄(40.7), 95

È

Laboratorium Beller in Gottingen, Germany.

C₂F₃N (7.1), 69 CF₃(88.9), 50 CF₂(19.0). Analysis:

Calc. for C₆F₁₄N₂: C, 19.67%; F, 72.7%. Found: C, 19.72; F,

72.4%.

Per¯uoro[2-(N⁰,N⁰-di¯uoroaminoethyl)-N,N-diethyla-

mine) (12) (nc): bp 95.0±95.58C, d₄

n_D< 1:2800. IR (gas): 1348 (w), 1816 (m), 1286 (vs),

1241 (vs), 1171 (m), 1158 (m), 1109 (ms), 1050 (w), 939

(w), 879 (m), 841 (w), 788 (w), 755 (w), 742 (w). MS: 302

3.1. Fluorination of 1-ethylpiperazine at a lower solute

concentration (1)

20

Sample 1 (28.6 g, 0.250 mol) was charged into a cell

containing 420 ml electrolytically puri®ed AHF, and the

solution was subjected to ¯uorination with an anodic current

density of 3.2 A/dm², a cell voltage of 5.7±5.8 V, and a cell

temperature of 7±88C over a period of 690 min (261 A h). At

the ®nal stage of the ¯uorination, the voltage reached 6.2 V.

The ef¯uent gases from the cell were passed over NaF

pellets and then condensed in a trap cooled to 788C. The

gaseous products which did not condense in the 788C trap

were then bubbled through a ¯uoropolymer bottle contain-

ing water and a gas washing bottle containing an aqueous

solution of a mixture of K₂CO₃, KOH and KI. All products

except new ones were identi®ed by comparison of their

infrared spectra and GLC retention times with those of

authenticated samples. New compounds were separated

from the other products by use of semi-preparative GLC,

and their structures were determined on the basis of their

spectral data (IR, ¹⁹F NMR and MS) and elemental analysis

(carbon and ¯uorine).

The products (21.1 g) condensed in the 788C trap con-

sisted of per¯uoro(N,N-dimethylethylamine) (31) (3.3 g),

per¯uoro(N,N-diethylmethylamine) (32) (5.6 g), per¯uoro-

triethylamine (13) (9.1 g), per¯uoro(3-methyl-1-ethylimida-

zolidine) (11) [16] (0.7 g), per¯uoro(4-¯uoro-1-ethyl-

piperazine) (10) (0.1 g) and unidenti®ed products (2.3 g)

(products are arranged in order of elution on GC). Cell

drainings (24.2 g) consisted of 32 (1.3 g), 13 (18.1 g), 11

(2.1 g), 10 (1.4 g), per¯uoro[2-(N⁰,N⁰-di¯uoroaminoethyl)-

N,N-diethylamine)] (12) (0.9 g) and unidenti®ed products

(0.4 g). The GC yield of 10 was 1.7%. ¹⁹F NMR data of 11

were the same as those of the reported one [16]. The

physicochemical properties and spectral data (IR and MS)

1.8075,

20

[M CF₂NF₂] (1.1), 247 C₄F₉N₂(1.3), 214 C₄F₈N

(8.9), 195 C₂F₅N₂(3.2), 164 C₃F₆N (15.3), 119 C₂F₅

(100), 114 C₂F₄N (10.7), 100 C₂F₄(11.4), 76 N₂F₂

(1.3), 69 CF₃(66.5), 50 CF₂(6.8). ¹⁹F NMR: d 18.1 (m,

2F, NF₂), 81.8 (m, 6F, (CF₃CF₂)₂NCF₂), 86.2 (m, 2F,

(CF₃CF₂)₂NCF₂), 89.9 (m, 4F, (CF₃CF₂)₂NCF₂),

112.0 (m, 2F, ±CF₂NF₂). Analysis: Calc. for C₆F₁₆N₂:

C, 17.82%; F, 75.3%. Found: C, 17.92; F, 75.0%.

3.2. Fluorination of 1-ethylpiperazine (1) at a higher

solute concentration

Sample 1 (40.2 g, 0.352 mol) was ¯uorinated similarly

under the following conditions: 3.2 A/dm², 5.6±5.8 V, 7±

88C, 846 min (321 A h). The work-up gave the following

products in the 788C trap (18.1 g): 31 (3.3 g), 32 (5.8 g),

13 (6.7 g), 11 (0.4 g), and unidenti®ed products (1.9 g). Cell

drainings (29.2 g): 32 (1.3 g), 13 (21.4 g), 11 (3.3 g), 10

(1.6 g), 12 (1.2 g) and unidenti®ed products (0.4 g). The GC

yield of 11 was 1.3%.

3.3. Fluorination of methyl 3-(4-methylpipera-

zinyl)propionate (2)

Sample 2 (39.5 g, 0.212 mol) was ¯uorinated similarly

under the following conditions: 3.2 A/dm², 5.8±6.4 V, 7±

88C, 638 min (233 A h). The work-up gave the following

products in the 788C trap (9.5 g): 32 (3.4 g), 13 (1.8 g),

28

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

Table 3

¹⁹F NMR of compounds 10, 14, 15, 21, 22, 24, 25, 26, 28, 29, 30, 34, 37, 40, 44, 45, 46, 47, 49, 50 and 51

Compound

Formula

Chemical shift^a,b

J (Hz)^b

10

a

b

c

d

e

87.1 (quintet)

97.2 (quintet)

89.6 (broad)

109.6

a±c 8.7

b±c 17.2

107.7 (s)

14

15

a

b

c

d

e

f

52.4 (quintet)

93.5 (quartet)

90.6 (m)

a±b 13.8

b±a 13.8

91.0 to 91.4 (m)

118.9 (double quintet)

26.0 (m)

e±f e±c 10.4

a

b

c

d

e

f

86.8 (quintet)

96.6 (quintet)

92.4 (m)

a±b 6.8

b±c 18.9

92.2 (m)

119.8 (double quintet)

26.3 (m)

f±d 8.8, f±g 8.5

g

21

22

24

25

a

b

c

d

e

f

86.1 (quintet)

93.8, 97.7

87.2, 95.4

87.1, 93.5

75.8 (m)

a±c 7.1

J_AB 238

J_AB 192

J_AB 191

140.8 (m)

24.9 (m)

g

a

b

c

d

e

f

86.0 (m)

93.3, 98.0

86.3, 96.2

86.3, 94.0

75.8 (m)

J_AB 238

J_AB 189

J_AB 190

142.3 (m)

59.1 (s)

g

a

b

c

d

e

f

52.9 (quintet)

89.8, 92.8

84.9, 87.6

76.1 (m)

a±b 11.9±13.8

J_AB 191

J_AB 189

158.2 (quintet)

112.0, 112.9

25.8

e±c 20.6±24.0

J_AB 271

g

a

b

c

d

e

f

87.0 (m)

96.9 (quintet)

92.9

b±c 18.9

J_AB 243

92.6

82.7, 86.6

73.3 (m)

177.2 (m)

33.8

g

h

26

a

b

c

d

e

f

85.2 (m)

94.9 (quintet)

88.0, 90.3

86.8, 88.9

75.9

b±c 18.9

J_AB 193

J_AB 179

158.1 (m)

112.3, 112.9

25.9

g

h

J_AB 276

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

29

Table 3 (Continued )

Compound

Formula

Chemical shift^a,b

J (Hz)^b

28

a

b

c

d

e

f

85.2 (quintet)

95.0 (quintet)

89.4 (m)

a±c 8.5±8.8

b±c 18.9

88.0 (m)

77.3 (quintet)

160.5 (quintet)

e±d 8.6

f±d 24.1

29

a

86.1 (quintet)

95.6, 96.2

a±c 6.8

b

J_AB 238 (F₁±c 18.9±

20.6; F₂±c 17.2±20.9)

J_AB 200

c

d

e

f

90.4, 91.6

90.4 (m)

136.0 (m)

70.4, 83.5

117.2, 127.4

79.8, 91.3

J_AB 135

J_AB 250

J_AB 127

g

h

30

a

b

c

d

e

f

52.8 (quintet)

91.7, 92.9

89.4, 90.1

135.4 (m)

a±b 13.0

J_AB 189

J_AB 192

117.2, 127.4

70.1, 83.3

80.0, 91.4

J_AB 257

J_AB 133

J_AB 127

g

34

a

b

c

d

e

f

52.5 (quintet)

93.7 (quintet)

90.7 (m)

a±b 12.1

b±a 13.8

91.7 (quintet)

119.7 (quintet)

d 3.99 (s)

d±c 18.9

e±c 11.3

37

a

b

c

d

e

f

86.9 (quintet)

96.7 (quintet)

92.6

a±c 8.5

b±c 18.9

b±a 13.8

92.3

92.9 (quintet)

120.6 (quintet)

d 3.98 (s)

e±d 17.2±18.9

f±d 8.5

g

40

a

b

c

d

e

f

86.0 (m)

93.3, 98.2

86.3, 96.3

86.0, 94.5

76.7 (m)

J_AB 238

J_AB 206

J_AB 197

142.4 (m)

d 4.00 (s)

g

44

45

a

b

c

d

e

f

52.4 (quintet)

93.7 (quintet)

90.8 (m)

a±b 13.8

b±a 13.8

91.1 (m, broad)

127.5 (quintet)

81.3 (triplet)

e±c 10.4±11.9

f±d 8.8±10.2

a

b

c

d

e

f

52.3 (quintet)

93.9, 94.8

90.7, 92.1

83.8, 84.7

73.6 (m)

a±b 13.8

J_AB 195

J_AB 190

J_AB 239

178.7 (m)

g

d 3.97 (s)

30

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

Table 3 (Continued )

Compound

Formula

Chemical shift^a,b

J (Hz)^b

46

a

b

c

d

e

f

86.8 (quintet)

96.7 (quintet)

92.7 (m)

a±c 7.1

b±c 18.9

92.3 (m)

92.0 (m)

128.3 (quintet)

81.3 (triplet)

f±d 10.4

g

g±e 8.8±10.4

47

a

b

c

d

e

f

81.7 (quintet)

97.0 (quintet)

92.8 to 92.9 (m)

84.5, 85.7

73.6 (m)

a±c 7.1±8.5

b±c 17.2±20.6

J_AB 237

g

h

178.9 (m)

d 3.96 (s)

49

50

a

b

c

d

e

52.4 (quintet)

91.5

a±b 12.1±13.8

87.7

77.4 (double quintet)

160.9 (heptet)

d±c 10.2, d±e 3.4

e±d 3.4

a±b 13.5

J_AB 195

J_AB 196

a

b

c

d

e

f

52.9 (quintet)

87.7, 95.3

85.0, 89.5

75.3 (m)

158.3 (triple triplet)

114.1 (m)

e±c 22.3±26.8

g

d 3.98 (s)

51

a

b

c

d

e

f

85.1 (quintet)

93.4 (F₁), 96.5(F₂)

86.7, 91.6

a±c 8.7

J_AB 239, F₂-c 18.9

J_AB 190

85.1, 90.1

75.1 (m)

J_AB 195

158.3 (quintet)

114.2 (double quartet)

d 3.98 (s)

f±d 20.6±27.9

g±e g±f 10.4

g

h

a

¹⁹F chemical shifts in ppm relative to internal CCl₃F (negative shifts are upfield) and ¹H chemical shifts in ppm relative to TMS.

^bOnly obvious chemical shifts and coupling constants are given.

per¯uoro(1,4-dimethylpiperazine) (33) (1.2 g), per¯uoro[3-

(N,N-diethylamino)propionyl ¯uoride] (16) [21] (0.4 g),

per¯uoro(4-methyl-1-ethylpiperazine) (17) (0.6 g) and uni-

denti®ed products (2.1 g). Cell drainings (19.9 g): 13 (1.0 g),

33 (1.8), 16 (2.9 g), 17 (4.9 g), per¯uoro[3-(4-methylpiper-

azinyl)propionyl ¯uoride] (14) (7.5 g) and unidenti®ed pro-

ducts (1.8 g). The GC yield of 14 was 8.0%. Spectral data

(IR and MS) of 14 are shown below. ¹⁹F NMR data of 14 are

shown in Table 3.

(64.8), 114 C₂F₄N (39.3), 100 C₂F₄(39.2), 95 C₂F₃N

(2.5), 81 C₃F₃(1.2), 76 C₂F₂N (2.3), 69 CF₃(100), 50

CF₂(6.8).

Further characterization of 14 was conducted in a form of

the methyl ester. Methyl ester (34) of 14 were prepared by

mixing about 5 g of cell drainings with 2 ml of methanol.

The reaction was completed within a few minutes. The lower

layer of the reaction mixture was separated by means of

semi-preparative GC to give 34.

Per¯uoro[3-(4-methylpiperazinyl)propionyl

¯uoride]

Methyl

(34) (nc) had bp 171.0±171.78C, d₄1.7675 and n_D

per¯uoro[3-(4-methylpiperazinyl)propionate]

20

(14) (nc): IR (gas): 1886 n(C=O) (ms), 1358 (vs), 1338

(m), 1311 (vs), 1268 (ms), 1230 (vs), 1180 (ms), 1121 (m),

1092 (w), 1077 (w), 986 (w), 959 (ms), 896 (w), 800 (w),

1.3223. IR (capillary ®lm): 2968 (w) n(CH), 1789 n(C=O)

(s), 1444 (w), 1351 (s), 1302 (vs), 1269 (s), 1217 (s), 1166

(vs), 1087 (m), 1071 (m), 1015 (m), 954 (s), 894 (m), 853

(w), 826 (w), 792 (m), 729 (m), 744 (m), 679 (w). MS: 437

742 (w), 731 (w), 691 (w). MS: 425 [M F] (0.7), 347

[M CF₂C(O)F] (9.6), 259 C₅F₉N₂(7.7), 214 C₄F₈N

(0.9), 209 C₄F₉N₂(1.4), 171 C₄F₅N₂(3.1), 164 C₃F₆N

[M F] (0.6), 347 [M CF₂C(O)OCH₃] (7.8), 259

C₅F₉N₂(4.5), 171 C₄F₅N₂(1.8), 164 C₃F₆N (7.3),

(15.9), 147 C₂F₅N₂(3.4), 145 C₃F₅N (1.8), 119 C₂F₅

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

31

159 C₂F₄C(O)CH₃, C₃F₅N₂(8.3), 145 C₃F₅N (2.4), 131

Pe¯uoro[3-(4-ethylpiperazinyl)propionyl ¯uoride] (15)

[12]: IR (gas): 1885 n(C=O) (m), 1340 (s), 1304 (s), 1270

(ms), 1252 (vs), 1214 (m, sh), 1185 (s), 1121 (w), 1102 (w),

1068 (m), 987 (w), 956 (m), 824 (w), 796 (w), 731 (w), 662

C₃F₅(14.0), 119 C₂F₅(15.2), 114 C₂F₄N (19.5), 100

C₂F₄(27.8), 97 C₂F₃O (3.2), 95 C₂F₃N (1.3), 81 C₂F₃

(8.1), 76 C₂F₂N (1.2), 69 CF₃(43.7), 59 [C(O)OCH₃]

(100), 50 CF₂(2.6). Analysis: Calc. for C₉F₁₅N₂O₂H₃: C,

23.68%; F, 62.5%. Found: C, 23.80%; F, 62.3%. ¹⁹F NMR

data of 34 are shown in Table 3.

(w). MS: 475 [M F] (0.8), 425 [M CF₃] (1.2), 397

[M CF₂C(O)F] (10.8), 309 C₆F₁₁N₂(3.8), 259

C₅F₉N₂(4.9), 214 C₄F₈N (1.4), 171 C₄F₅N₂(3.8),

Compound 14 was derivatized into an amide of p-meth-

oxyaniline for further characterization also: into a 100 ml

polytetra¯uoroethylene beaker, was placed 0.23 g

(1.9 mmol) of p-methoxyaniline dissolved in 10 ml of

dichloromethane and 0.23 g (2 mmol) of triethylamine,

and compound 14 (1.01 g, 2 mmol) which was isolated

by preparative GC was added dropwise while shaking.

The mixture was left standing in the draft overnight. The

residue was dissolved in a mixture of hexane and acetonitrile

(1:1) and analyzed by TLC. The crude product was puri®ed

by column chromatography (hexane/acetonitrile as eluent)

to give per¯uoro[3-(4-methylpiperazinyl)propionyl]-p-

methoxyanilide (35) as white crystals (0.52 g, 46% yield).

Per¯uoro[3-(4-methylpiperazinyl)propionyl]-p-methoxya-

nilide (35) (nc) had mp 82.3±83.08C. IR (KBr): 1701

164 C₃F₆N (15.4), 147 C₃F₅O (2.8), 145 C₃F₅N

(1.6), 119 C₂F₅(100), 114 C₂F₄N (33.4), 100 C₂F₄

(32.6), 95 C₂F₃N (1.8), 76 C₂F₂N (1.9), 69 CF₃(45.8),

50 CF₂(4.4).

Methyl ester (37) of 15 were prepared in a similar manner

as explained for 14.

Methyl per¯uoro[3-(4-ethylpiperazinyl)propionate] (37)

(nc) had bp 181.2±181.78C, d₄²⁰1.7712 and n_D²⁰1.3193. IR

(capillary ®lm): 2968 n(CH) (w), 1788 n(C=O) (s), 1444 (w),

1333 (s), 1297 (vs), 1260±1227 (s±vs), 1200±1166 (s±vs),

1101 (w), 1063(s), 1015 (s), 951 (s), 821 (s), 756 (s), 739 (s),

726 (m), 696 (m), 676 (m), 656 (ms), 623 (m), 613 (w). MS:

447 [M C(O)OCH₃] (0.5), 397 [M CF₂C(O)OCH₃]

(8.6), 309 C₆F₁₁N₂(2.1), 259 C₅F₉N₂(4.3), 214 C₄F₈N

(1.3), 171 C₄F₅N₂(2.9), 164 C₃F₆N (10.2), 159 C₃F₅N₂

(11.9), 149 C₃F₅O (1.0), 145 C₃F₅N (2.7), 131 C₃F₅

n(C=O) (ms). MS: 547 [M 1] (0.9), 149 C(O)NHPh-

(22.1), 119 C₂F₅(52.8), 114 C₂F₄N (24.7), 100 C₂F₄

OCH₃(54.6), 134 C(O)NHPhO (22.5), 122 NHPhOCH₃

(100), 119 C₂F₅(17.2), 114 C₂F₄N (19.1), 100 C₂F₄

(40.3), 97 C₂F₃O (5.4), 95 C₂F₃N (1.6), 81 C₂F₃(12.0),

(17.2), 95 C₂F₃N (18.3), 69 CF₃(54.1), 52 CF₂H₂

76 C₂F₂N (1.4), 69 CF₃(32.3), 59 [C(O)OCH₃] (100),

(23.3), 51 CF₂H (11.9) 50 CF₂(8.4). ¹⁹F NMR (CDCl₃):

50 CF₂(3.7). Analysis: Calc. for C₁₀F₁₇N₂O₂H₃: C,

d

52.4 (quintet, 3F, J_F 13:8 Hz, CF N), d 90.5 [m,

23.72%; F, 63.8%. Found: C, 23.80%; F, 63.7%. ¹⁹F

NMR data of 37 are shown in Table 3.

F

3

4F, c-CF₃N(CF₂CF₂)₂N], d 91.2 [quintet, 2F, J_F

18:9 20:9 Hz, NCF₂CF₂C(O)O)], d 93.6 [quartet, 4F,

11.9±13.8 Hz, c-CF₃N(CF₂CF₂)₂N], d 120.8 (quintet,

F

3.5. Fluorination of methyl 2-(4-methylpiperazinyl)-

propionate (4)

1

2F, J_F 10:4 Hz, NCF CF C(O)O), H NMR (CDCl ):

F

2

3

d 7.90 (s, 1H, NH), d 7.45 (d, 2H), d 6.91 (d, 2H), d 3.81 (s,

3H, OCH₃). Analysis: Calc. for C₁₅F₁₅N₃O₂H₈: C, 32.91%;

F, 52.10%. Found: C, 33.04%; F, 51.9%.

Sample 4 (39.7 g, 0.213 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.6±6.7 V, 7±

88C, 575 min (211 A h). The work-up gave the following

products in the 788C trap (6.7 g): 31 (0.9 g), 32 (1.2 g),

per¯uoro[2-(N,N-dimethylamino)propionyl ¯uoride] (38)

[22] (1.0 g), 13 (1.7 g), 33 (0.3 g), 17 (0.5 g) and unidenti-

®ed products (1.1 g). Cell drainings (16.0 g): 13 (0.9 g),

per¯uoro(4-methyl-1-ethylpiperazine) (17) (5.2 g), per-

¯uoro[2-(4-methylpiperazinyl)propionyl ¯uoride] (19)

(7.1 g), per¯uoro[methyl 2-(4-methylpiperazinyl)propio-

nate] (20) (0.6 g) and unidenti®ed products (2.2 g). The

GC yields of 19 and 20 were 7.5 and 0.5%, respectively.

Spectral data (IR, Mass and ¹⁹F NMR) of 19 and 20, and

the methyl ester of per¯uoro[2-(4-methylpiperazinyl)pro-

pionic acid] have been reported in our previous paper [8].

Therefore, the physical property (mp) and spectral data (IR,

3.4. Fluorination of methyl 3-(4-ethylpiperazinyl)pro-

pionate (3)

Sample 3 (39.7 g, 0.198 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.8±6.1 V, 7±

88C, 638 min (233 A h). The work-up gave the following

products in the 788C trap (6.5 g): 31 (1.2 g), 32 (0.7 g),

per¯uoro[3-(N,N-dimethylamino)propionyl ¯uoride] (36)

[22] (0.4 g), 13 (2.4 g), 17 (0.4 g), per¯uoro(1,4-diethylpi-

perazine) (18) (0.5 g) and unidenti®ed products (0.9 g). Cell

drainings (31.8 g): 13 (1.2 g), 16 (0.5 g), 17 (3.1 g), 18

(11.3 g), per¯uoro[3-(4-ethylpiperazinyl)propionyl ¯uor-

ide] (15) (14.0 g) and unidenti®ed products (1.7 g). The

GC yield of 15 was 14.3%. Spectral data (IR and MS) of

15 will be shown below as no data except the bp (86±888C/

0.6 mmHg) and mp (56±598C) of per¯uoro[3-(4-ethylpiper-

azinyl)propionic acid] which was derived by a hydrolytic

reaction of 15 are described in the patent literature [12]. ¹⁹F

NMR data of 15 are shown in Table 3.

1

MS and ¹⁹F and H NMR) of p-methoxyanilide (39) of

per¯uoro[2-(4-methylpiperazinyl)propionic acid], which

was prepared in a similar manner as explained for 14, will

be reported.

Per¯uoro[2-(4-methylpiperazinyl)propionyl]-p-methox-

yanilide (39) (nc) had mp 124.0±124.58C (55% yield). IR

(KBr disk): 1705 n(C=O) (s). MS: 547 [M 1] (0.7), 149

32

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

C(O)NHPhOCH₃(30.7), 134 C(O)NHPhO (9.7), 122

Methyl per¯uoro[2-(4-ethylpiperazinyl)propionate] (40)

(nc) had bp 180.0±180.78C, n_D²⁰1.3212 and d₄²⁰1.7808. IR

(capillary ®lm): 2968 n(CH) (w), 1789 (s) n(C=O), 1443 (m),

1408 (w), 1340±1225 (s±vs), 1175 (vs), 1125 (s), 1084 (ms),

1067 (ms), 1046 (s), 951 (s), 932 (w), 919 (w), 842 (w), 820

(ms), 841 (w), 820 (w), 792 (w), 776 (m, sh), 739 (s), 719

(w), 689 (w), 676 (w), 668 (w), 641 (w), 624 (w). MS: 487

NHPhOCH₃(100), 119 C₂F₅(22.1), 114 C₂F₄N (12.5),

100 C₂F₄(12.8), 95 C₂F₃N (15.7), 77 C₂F₂NH (11.4), 69

CF₃(42.9), 53 ? (11.1), 52 CF₂H₂(19.1), 51 CF₂H

(10.3). ¹⁹F NMR (CDCl₃): d 52.8 (triple triplet, 3F,

J_F 8:8 and 10.2 Hz, CF N), d 85.6, 99.3 [4F,

F

3

J_AB 192 Hz, c-C₂F₅N(CF₂CF₂)₂N], d

83.4,

94.8

[4F, J_AB 189 Hz, c-C₂F₅N(CF₂CF₂)₂N], d 73.7 [m,

[M F]

(0.5), 447 [M C(O)OCH₃]

(0.9), 309

1

3F, NCF(CF₃)], d 133.6 [m, 1F, NCF(CF₃)]. H NMR

C₆F₁₁N₂(2.2), 214 C₄F₈N (2.2), 195 C₄F₇N (2.8),

(CDCl₃): d 7.88 (s, 1H, NH), d 7.43 (d, 2H), d 6.92 (d, 2H), d

3.82 (s, 3H, OCH₃). Analysis: Calc. for C₁₅F₁₅N₃O₂H₈: C,

32.91%; F, 52.1%. Found: C, 33.03%; F, 52.2%.

164 C₃F₆N (7.4), 159 [C₂F₄C(O)OCH₃] (1.2), 145

C₃F₅N (1.8), 131 C₃F₅(12.9), 119 C₂F₅(21.1), 114

C₂F₄N (7.7), 100 C₂F₄(13.9), 97 C₂F₃O (1.8), 81 C₂F₃

(3.9), 69 CF₃(14.5), 59 [C(O)OCH₃] (100), 50 CF₂

3.6. Fluorination of methyl 2-(4-ethylpiperazinyl)pro-

pionate (5)

(1.6). Analysis: Calc. for C₁₀F₁₇N₂O₂H₃: C, 23.72%; F,

63.8%. Found: C, 23.85%; F, 63.6%.

Per¯uoro[2-(4-ethylpiperazinyl)propionyl]-p-methoxya-

nilide (41) (nc) had mp 105.5±106.08C (60% yield). IR (KBr

Sample 5 (39.2 g, 0.196 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.8±6.3 V, 7±

88C, 572 min (209 A h). The work-up gave the following

products in the 788C trap (5.1 g): 31 (1.5 g), 32 (0.4 g), 38

(0.7 g), 13 (1.6 g), 17 (0.3 g), 18 (0.2 g) and unidenti®ed

products (0.4 g). Cell drainings (30.1 g): 13 (0.4 g), 17

(0.5 g), 18 (11.2 g), per¯uoro[2-(4-ethylpiperazinyl)propio-

nyl ¯uoride] (21) (15.2 g), per¯uoro[methyl 2-(4-ethyl-

piperazinyl)propionate] (22) (1.0 g) and unidenti®ed

products (1.8 g). The GC yields of 21 and 22 were 15.7

and 0.9%, respectively.

disk): 1712 n(C=O) (ms). MS: 597 [M 1] (0.5), 221 ?

(0.9), 164 C₃F₆N (0.8), 150 C₃F₆(1.0), 149 C₈H₇NO₂

(32.8), 134 C₂F₅NH (8.9), 123 C₇H₉NO₂(7.9), 122

C₇H₈NO₂(100), 119 C₂F₅(35.7), 114 C₂F₄N (12.4),

100 C₂F₄(15.2), 95 C₂F₃N (16.0), 77 C₂F₂NH (10.6), 69

CF₃(25.2), 53 ? (11.0), 52 CF₂H₂(20.5), 51 CF₂H

(10.5). ¹⁹F NMR (CDCl₃): d 73.8 (m, 3F, NCF(CF₃), d

84.2, 85.5 (2F, J_AB 184 Hz, CF₃CF₂N) d 85.4,

97.5 [4F, J_AB 203 Hz, c-C₂F₅N(CF₂CF₂)₂N],

d

84.1, 94.4 [4F, J_AB 195 Hz, c-C₂F₅N(CF₂CF₂)₂N],

Spectral data (IR and Mass) of 21 and 22 including the

physicochemical properties for the former one are shown

below. ¹⁹F NMR data of 21 and 22 are shown in Table 3.

Per¯uoro[2-(4-ethylpiperazinyl)propionyl ¯uoride] (21)

d

85.7 [quintet, J_F 8:8, CF CF N], d 134.3 [m,

F

3

2

1

1F, NCF(CF₃)]. H NMR (CDCl₃): d 7.86 (s, 1H, NH), d

7.43 (d, 2H), d 6.92 (d, 2H), d 3.82 (s, 3H, OCH₃). Analysis:

Calc. for C₁₆F₁₇N₃O₂H₈: C, 32.16%; F, 54.1%. Found: C,

32.12%; F, 54.2%.

20

(nc) had bp 138.5±139.58C, n_D1.3007 and d₄1.8386.

IR (gas): 1898 (m) and 1881 (ms) n(C=O), 1326 (s), 1302 (s),

1247 (vs, broad), 1185 (vs), 1135 (m), 1107 (w), 1186 (w),

1071 (w), 1053 (ms), 1044 (ms), 981 (m), 955 (m), 824 (w),

3.7. Fluorination of methyl 3-(4-methylpiperazinyl)-2-

methylpropionate (6)

810 (w), 741 (ms), 697 (w). MS: 475 [M F] (0.7), 447

[M COF] (4.0), 425 [M CF₃] , 309 C₆F₁₁N₂(4.3),

259 C₅F₉N₂(1.2), 214 C₄F₈N (9.4), 171 C₄F₅N₂(1.6),

Sample 6 (39.7 g, 0.199 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.8±6.1 V, 7±

88C, 656 min (239 A h). The work-up gave the following

products in the 788C trap (10.0 g): per¯uoro(iso-propionyl

¯uoride) (42) (3.1 g), per¯uoro[3-(N,N-dimethylamino)-2-

methylpropionyl ¯uoride] (43) [9] (2.2 g), 33 (0.5 g), 17

(1.0 g), per¯uoro[3-(N,N-diethylamino)-2-methylpropionyl

¯uoride] (27) [9] (0.9 g) and unidenti®ed products (2.3 g).

Cell drainings (40.2 g): 43 (0.9 g), 27 (12.1 g), per¯uoro[4-

methyl-1-(propyl)piperazine] (44) (3.1 g), per¯uoro[3-(4-

164 C₃F₆N (19.7), 145 C₃F₅N (1.8), 126 C₃F₄N (0.5),

119 C₂F₅(100), 114 C₂F₄N (26.5), 100 C₂F₄(31.9), 95

C₂F₃N (2.1), 76 C₂F₂N (2.8), 69 CF₃(50), 50 CF₂

(5.6).

Per¯uoro[methyl 2-(4-ethylpiperazinyl)propionate] (22)

(nc): IR (gas): 1854 (m) and 1840 (m) n(C=O), 1324 (m),

1289 (ms), 1256 (vs), 1219 (m), 1185 (ms), 1153 (ms), 1107

(w), 1089 (w), 1054 (w), 1019 (w), 955 (w), 824 (w), 788

(w), 741 (w). MS: 491 [M F]

(0.2), 447

(0.5), 309

[M C(O)OCF₃]

(2.0), 397 C₇F₁₅N₂

methylpiperazinyl)-2-methylpropionyl

¯uoride]

(23)

C₆F₁₁N₂(6.3), 259 C₅F₉N₂(0.3), 214 C₄F₈N (3.0),

(21.7 g) and unidenti®ed products (2.4 g). The GC yield

of 23 was 22.1%.

195 C₄F₇N (1.8), 164 C₃F₆N (6.3), 145 C₃F₅N (1.5),

119 C₂F₅(30.2), 114 C₂F₄N (7.7), 100 C₂F₄(12.7), 76

Spectral data (IR, MS and ¹⁹F NMR) of 23 have been

reported in our previous paper [9]. Therefore, physicochem-

ical properties and spectral data of 44 and methyl per-

¯uoro[3-(4-methylpiperazinyl)-2-methylpropionate] (45),

which had not been characterized yet, will be described.

¹⁹F NMR data of 44 and 45 are shown in Table 3.

C₂F₂N (1.1), 69 CF₃(100), 50 CF₂(5.3).

Methyl ester (40) and p-methoxyanilide (41) of per-

¯uoro[2-(4-methylpiperazinyl)propionic acid] were pre-

pared in a similar manner as explained for 16. ¹⁹F NMR

data of 40 are shown in Table 3.

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

33

Per¯uoro[4-methyl-1-(propyl)piperazine] (44) (nc) had

C₂F₄(69.0), 95 C₂F₃N (2.1), 76 C₂F₂N (1.8), 69 CF₃

20

bp 121.2±121.88C, n_D1.2874 and d₄1.8386. IR (gas):

1359 (s), 1311 (s), 1273 (ms), 1233 (vs), 1179 (ms), 1151

(w), 1136 (w), 1102 (w), 1076 (w), 979 (m), 959 (ms), 895

(100), 50 CF₂(5.7).

Per¯uoro[4-ethyl-1-(propyl)piperazine] (46) (nc) had bp

137.0±137.68C, n_D²⁰1.2883 and d₄²⁰1.8384. IR (gas): 1340

(s), 1307 (s), 1271 (s), 1252 (vs), 1235 (s), 1184 (s), 1137

(w), 1108 (w), 1070 (ms), 978 (ms), 956 (ms), 824 (w), 793

(w), 796 (w), 739 (ms), 666 (w), 626 (w). MS: 447 [M F]

(2.1), 347 [M C₂F₅] (13.1), 259 C₅F₉N₂(11.1), 214

C₄F₈N (2.4), 209 C₄F₇N₂(1.3), 171 C₄F₅N₂(2.8), 169

(w), 741 (ms), 665 (w), 647 (w). MS: 497 [M F] (1.8),

C₃F₇(34.7), 164 C₃F₆N (13.3), 145 C₃F₅N (2.0), 121

447 [M CF₃] (2.8), 397 C₇F₁₃N₂(11.7), 359 C₇F₁₃N₂

(2.0), 309 C₆F₁₁N₂(9.5), 264 C₅F₁₀N (2.0), 259 C₅F₉N₂

C₃F₃N₂(2.0), 119 C₂F₅(16.3), 114 C₂F₄N (30.7), 100

C₂F₄(46.7), 95 C₂F₃N (2.2), 76 C₂F₂N (1.7), 69 CF₃

(7.7), 214 C₄F₈N (5.1), 171 C₄F₅N₂(6.1), 169 C₃F₇

(65.9), 164 C₃F₆N (26.7), 145 C₃F₅N (3.2), 119 C₂F₅

(100), 50 CF₂(4.0). Analysis: Calc. for C₈F₁₈N₂: C,

20.60%; F, 73.1%. Found: C, 20.58%; F, 73.0%.

Methyl per¯uoro[3-(4-methylpiperazinyl)-2-methylpro-

pionate] (45) had bp 179.5±180.08C, n_D1.2874 and

d₄1.8386. IR (capillary ®lm): 2969 n(CH) (w), 1793

(97.3), 114 C₂F₄N (55.4), 100 C₂F₄(83.7), 95 C₂F₃N

(3.1), 81 C₂F₃(1.3), 76 C₂F₂N (2.8), 69 CF₃(100), 50

20

CF₂(7.7). Analysis: Calc. for C₉F₂₀N₂: C, 20.93%; F,

73.6%. Found: C, 20.83%; F, 73.3%.

20

(ms) and 1780 (m) n(C=O), 1443 (w), 1351 (s), 1301

(vs), 1262 (s), 1226 (vs), 1164 (s), 1090 (m), 1070 (w),

1045 (m), 1034 (m), 1019 (w), 968 (m), 953 (s), 892 (m), 852

(m), 808 (w), 780 (m), 743 (w), 729 (w), 701 (w), 620 (w).

For the further characterization of 25, it was derivatized

into the corresponding methyl ester (47) similarly. It was a

compound like sherbet at room temperature.

Methyl per¯uoro[3-(4-ethylpiperazinyl)-2-methylpropio-

nate] (47) (nc) had bp 192.0±192.58C. IR (capillary ®lm):

2969 n(CH) (w), 1792 and 1980 n(CO) (ms), 1443 (w), 1335

(s), 1295 (s), 1250±1245 (s±vs), 1226 (s), 1201 (m), 1165 (s),

1099 (w), 1065 (s), 1046 (m), 1034 (m), 967 (w), 951 (s),

823 (m), 807 (w), 780 (m), 755 (w), 739 (ms), 697 (w),

MS: 347 [M CF(CF₃)C(O)OCH₃] (2.3), 259 C₅F₉N₂

(2.2), 209 C₃F₆C(O)OCH₃, C₄F₇N₂(5.5), 197 C₄F₇N₂

(2.0), 169 C₃F₇(2.8), 164 C₃F₆N (4.1), 150 C₃F₆(9.1),

145 C₃F₅N (1.1), 131 C₃F₅(3.6), 119 C₂F₅(4.8), 114

C₂F₄N (12.9), 100 C₂F₄(10.8), 81 C₂F₃(10.4), 69 CF₃

(31.5), 59 [C(O)OCH₃] (100), 50 CF₂(1.4). Analysis:

Calc. for C₁₀F₁₇N₂O₂H₃: C, 23.72%; F, 63.8%. Found: C,

23.70%; F, 63.8%.

674 (w), 642 (m). MS: 397 [M CF(CF₃)C(O)OCH₃]

(1.9), 309 C₆F₁₁N₂(0.8), 259 C₅F₉N₂(1.6), 209

C₃F₇C(O)OCH₃, C₄F₇N₂(7.7), 197 C₃F₇N₂(2.4), 169

C₃F₇(3.3), 164 C₃F₆N (4.9), 159 C₃F₅N₂(1.1), 150

C₃F₆(10.5), 145 C₃F₅N (1.0), 131 C₃F₅(4.1), 119

C₂F₅(18.6), 114 C₂F₄N (14.7), 100 C₂F₄(11.6), 81

3.8. Fluorination of methyl 3-(4-ethylpiperazinyl)-2-

methylpropionate (7)

C₂F₃(11.9), 69 CF₃(21.3), 59 [C(O)OCH₃] (100), 50

CF₂(1.4). Analysis: Calc. for C₁₁F₁₉N₂O₂H₃: C, 23.74%;

F, 64.9%. Found: C, 23.90%; F, 65.2%.

Sample 7 (40.0 g, 0.187 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.6±6.0 V, 7±

88C, 632 min (232 A h). The work-up gave the following

products in the 788C trap (6.6 g): 42 (1.2 g), 31 (1.1 g), 43

(2.1 g) and unidenti®ed products (2.2 g). Cell drainings

(53.1 g): 27 (1.9 g), per¯uoro[4-ethyl-1-(propyl)piperazine]

(46) (5.0 g), per¯uoro[3-(4-ethylpiperazinyl)-2-methyl-

propionyl ¯uoride] (25) (38.2 g) and unidenti®ed products

(8.0 g). The GC yield of 25 was 37.5%.

¹⁹F NMR data of 46 and 47 are shown in Table 3.

3.9. Fluorination of methyl 3-(4-methylpiperazinyl)buty-

rate (8)

Sample 8 (40.5 g, 0.203 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.9±6.1 V, 7±

88C, 619 min (229 A h). The work-up gave the following

products in the 788C trap (12.0 g): per¯uoro(propionyl

¯uoride) (48) (2.1 g), 32 (2.9 g), 13 (2.7 g), 17 (0.9 g) and

unidenti®ed products (3.4 g). Cell drainings (26.9 g): 17

(2.0 g), per¯uoro[4-methyl-1-(iso-propyl)piperazine] (49)

(3.2 g), per¯uoro[3-(4-methylpiperazinyl)butyryl ¯uoride]

(24) (10.9 g), per¯uoro[3-(4-methylpiperazinyl)oxolane]

(30) (4.6 g) and unidenti®ed products (6.2 g). The GC yield

of 24 was 10.9%.

Spectral data (IR and MS) of 24 and physicochemical

properties and spectral data (IR and Mass) of 30 and 49 are

shown below. ¹⁹F NMR data of 49 isolated by preparative

GC revealed that it contained small quantities of per-

¯uoro[4-methyl-1-(propyl)piperazine] (43). ¹⁹F NMR data

of 24, 49 and 30 are shown in Table 3.

Physicochemical properties and spectral data (IR and MS)

of 25 and 46 are shown below. ¹⁹F NMR data of 25 and 46

are shown in Table 3.

Per¯uoro[3-(4-ethylpiperazinyl)-2-methylpropionyl ¯uo-

20

ride] (25) had bp 138.5±139.58C, n_D1.3005 and d₄

1.8512. IR (gas): 1890 (m) and 1875 (m) n(CO), 1340

(s), 1230 (s), 1271 (s), 1252 (vs), 1184 (ms), 1155 (w),

1069 (ms), 1011 (w), 988 (w), 970 (w), 955 (m), 824 (w),

789 (w), 756 (w), 741 (m), 692 (w), 630 (w). MS:

525 [M F] (0.3), 475 [M CF₃] (2.3), 397 [M

C₂F₄C(O)F] (4.3), 309 C₆F₁₁N₂(1.5), 259 C₅F₉N₂

(3.9), 214 C₄F₈N (1.5), 197 C₄F₇N₂(22.3), 171

C₄F₅N₂(1.8), 169 C₃F₇(32.9), 164 C₃F₆N (14.2),

150 C₃F₆(3.2), 145 C₃F₅N (1.9), 131 C₃F₅(2.3), 128

C₄F₄N₂(2.4), 119 C₂F₅(51.8), 114 C₂F₄N (33.8), 100

34

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

Per¯uoro[3-(4-methylpiperazinyl)butyryl ¯uoride] (24)

C, 23.81%; F, 63.5%. ¹⁹F NMR data of 50 are shown in

Table 3.

(nc): IR (gas): 1886 n(CO) (ms), 1413 (w), 1360 (vs),

1296 (s), 1270 (s), 1227 (vs), 1199 (m), 1177 (ms), 1124

(w), 1092 (w), 1075 (w), 1031 (w), 960 (ms), 928 (w), 897

3.10. Fluorination of methyl 3-(4-ethylpiperazinyl)butyrate

(9)

(m), 855 (w), 788 (w), 732 (m). MS: 425 [M F] (0.8),

397 [M C(O)F] (4.9), 359 C₇F₁₃N₂(0.4), 309

C₆F₁₁N₂(1.5), 264 C₅F₁₀N (3.2), 259 C₅F₉N₂(1.9),

Sample 9 (40.3 g, 0.188 mol) was ¯uorinated similarly

under the following conditions; 3.2 A/dm², 5.9±6.0 V, 7±

88C, 656 min (237 A h). The work-up gave the following

products in the 788C trap (7.1 g): 48 (trace), 32 (1.1 g), 13

(2.4 g), 18 (0.3 g) and unidenti®ed products (3.3 g). Cell

drainings (56.1 g): 18 (9.3 g), per¯uoro[4-ethyl-1-(iso-

propyl)piperazine] (28) (9.3 g), per¯uoro[3-(4-ethylpipera-

zinyl)butyryl ¯uoride] (26) (20.7 g), per¯uoro[3-(4-ethylpi-

perazinyl)oxolane] (29) (10.0 g) and unidenti®ed products

(6.8 g). The GC yield of 26 was 20.2%.

214 C₄F₈N (5.7), 197 C₃F₇N₂(1.3), 171 C₄F₅N₂(1.3),

169 C₃F₇(6.6), 164 C₃F₆N (18.6), 145 C₃F₅N (2.2), 131

C₃F₅(1.5), 119 C₂F₅(52.3), 114 C₂F₄N (18.1), 100

C₂F₄(21.7), 95 C₂F₃N (2.1), 76 C₂F₂N (2.3), 69 CF₃

(100), 50 CF₂(4.7).

Per¯uoro[4-methyl-1-(iso-propyl)piperazine] (49) (nc)

20

had bp 121.0±121.68C, n_D1.2895 and d₄1.8564. IR

(gas):1413 (w), 1360 (vs), 1320±1272 (vs), 1245±1229 (vs),

1176 (m), 1149 (w), 1075 (w), 1060 (w), 978 (m), 959 (s),

897 (w), 857 (w), 796 (w), 740 (m), 730 (w), 629 (w), 546

Spectral data (IR and MS) of 26 and physicochemical

properties and spectral data (IR and Mass) of 28 and 29 are

shown below. ¹⁹F NMR of 26, 28 and 29 are shown in

Table 3.

(w). MS: 447 [M F] (3.2), 397 [M CF₃] (19.9), 359

C₇F₁₅N₂(3.6), 309 C₆F₁₁N₂(3.9), 264 C₅F₁₀N (12.7),

259 C₅F₉N₂(3.3), 214 C₄F₈N (10.6), 171 C₄F₅N₂(1.8),

169 C₃F₇(4.4), 164 C₃F₆N (29.7), 145 C₃F₅N (3.1), 119

Per¯uoro[3-(4-ethylpiperazinyl)butyryl ¯uoride] (26)

(nc): IR (gas): 1886 n(C=O) (m), 1323 (ms), 1292 (s),

1254 (vs), 1182 (ms), 1072 (w), 1030 (m), 955 (m), 928

C₂F₅(66.2), 114 C₂F₄N (29.2), 100 C₂F₄(47.7), 95

C₂F₃N (2.6), 81 C₂F₃(1.2), 76 C₂F₂N (3.5), 69 CF₃

(100), 50 CF₂(5.8). Analysis: Calc. for C₈F₁₈N₂: C,

20.60%; F, 73.4%. Found: C, 20.50%; F, 73.1%.

Per¯uoro[3-(4-methylpiperazinyl)oxolane] (30) (nc) had

(w), 826 (w), 741 (m). MS: 525 [M F] (0.4), 475

[M CF₃] (0.7), 447 [M CF₂C(O)F] (4.2), 425

C₈F₁₆N₂O (0.2), 359 C₇F₁₃N₂(0.4), 309 C₆F₁₁N₂

(2.8), 264 C₅F₁₀N (3.3), 214 C₄F₈N (6.4), 197

20

bp 145.0±145.58C, n_D1.3055 and d₄1.8756. IR (gas):

1360 (s), 1316 (s), 1254 (s), 1227 (vs), 1186 (ms), 1124 (w),

1084 (m), 1073 (w), 1011 (w), 972 (m), 927 (w), 8976 (w),

C₃F₇N₂(1.2), 171 C₄F₅N₂(1.5), 169 C₃F₇(5.5), 164

C₃F₆N (14.9), 150 C₃F₆(1.3), 145 C₃F₅N (1.5), 131

C₃F₅(1.5), 119 C₂F₅(100), 114 C₂F₄N (20.3), 100

764 (w), 732 (w). MS: 428 [M CF₃] (3.7), 378 C₇F₁₄N₂

(11.4), 321 C₇F₁₁N₂(1.1), 295 C₆F₁₁N (4.7), 264

C₂F₄(23.2), 95 C₂F₃N (1.6), 76 C₂F₂N (2.1), 69 CF₃

C₅F₁₀N (4.0), 245 C₅F₉N (7.3), 221 C₅F₇N₂(1.3),

(57.8), 50 CF₂(4.4).

Per¯uoro[4-ethyl-1-(iso-propyl)piperazine] (28) (nc) had

214 C₄F₈N (4.6), 176 C₄F₆N (7.7), 169 C₃F₇(2.4),

20

164 C₃F₆N (9.9), 152 ? (1.8), 150 C₃F₆(7.3), 145

bp 137.3±137.98C, n_D1.2929 and d₄1.8734. IR (gas):

1324 (s), 1290 (vs), 1268 (vs), 1247 (vs), 1204 (ms), 1180

(s), 1147 (w), 1123 (w), 1086 (w), 1072 (w), 1041 (m), 978

(m), 956 (m), 826 (w), 796 (w), 741 (ms), 729 (m), 676 (w),

C₃F₅N (21.9), 131 C₃F₅(10.1), 119 C₂F₅(35.6), 114

C₂F₄N (21.0), 100 C₂F₄(74.4), 95 C₂F₃N (3.2), 81

C₂F₃(2.3), 76 C₂F₂N (4.2), 69 CF₃(100), 50 CF₂

(6.1). Analysis: Calc. for C₉F₁₈N₂O: C, 21.86%; F, 69.2%.

Found: C, 21.76%; F, 69.1%.

621 (w). MS: 497 [M F] (0.7), 447 [M CF₃] (5.9),

387 C₇F₁₅N₂(2.7), 309 C₆F₁₁N₂(4.4), 259 C₅F₉N₂

(3.5), 214 C₄F₈N (5.0), 171 C₄F₅N₂(2.7), 169 C₃F₇

For the further characterization of 24, it was derivatized

into the methyl ester (50) similarly.

Methyl per¯uoro[3-(4-methylpiperazinyl)butyrate] (50)

(23.0), 164 C₃F₆N (18.8), 145 C₃F₅N (1.9), 119 C₂F₅

(76.2), 114 C₂F₄N (33.1), 100 C₂F₄(43.4), 95 C₂F₃N

(2.2), 76 C₂F₂N (2.3), 69 CF₃(100), 50 CF₂(4.8).

Analysis: Calc. for C₉F₂₀N₂: C, 20.93%; F, 73.6%. Found:

C, 20.91%; F, 73.3%.

20

(nc) had bp 185.5±185.88C, n_D1.3262 and d₄1.7971.

IR (capillary ®lm): 2969 n(CH) (w), 1792 n(C=O) (s), 1444

(w), 1411 (w), 1352 (s), 1340±1171 (vs), 1070 (ms), 1050

(m), 1034 (m), 955 (s), 895 (ms), 881 (w), 853 (w), 817 (m),

776 (m), 729 (ms), 691 (w), 673 (w), 627 (m), 576 (w). MS:

Per¯uoro[3-(N-ethylpiperazinyl)oxolane] (29) (nc) had

20

bp 159.5±160.08C, n_D1.3065 and d₄1.8986. IR (gas):

1312 (m, broad), 1254 (vs), 1236 (s, sh), 1188 (ms), 1128

(w), 1190 (w), 1067 (w), 1011 (w), 968 (w), 923 (w), 826

447 [M C(O)OCH₃] (0.3), 397 [M CF₂C(O)OCH₃]

(6.1), 309 C₆F₁₁N₂(1.1), 264 C₅F₁₀N (1.5), 259 C₅F₉N₂

(1.1), 214 C₄F₈N (2.7), 209 C₃F₆C(O)OCH₃, C₄F₇N₂

(w), 762 (w), 741 (w). Mass: 525 [M F] (1.2), 478

C₉F₁₈N₂(2.0), 428 C₈F₁₆N₂(6.7), 295 C₆F₁₁N (2.1),

(8.0), 181 C₄F₇(1.2), 164 C₃F₆N (6.7), 150 C₃F₆(7.8),

264 C₅F₁₀N (5.1), 245 C₅F₉N (4.7), 214 C₄F₈N (4.3),

145 C₃F₅N (2.1), 131 C₃F₅(2.9), 119 C₂F₅(15.8), 114

C₂F₄N (13.1), 100 C₂F₄(10.9), 95 C₂F₃N (1.1), 81

195 C₄F₇N (16.0), 176 C₄F₆N (5.4), 169 C₃F₇(2,5), 164

C₃F₆N (14.6), 150 C₃F₆(8.3), 145 C₃F₅N (13.8), 131

C₂F₃(2.1), 76 C₂F₂N (1.1), 69 CF₃(36.3), 59

[C(O)OCH₃] (100), 50 CF₂(1.6). Analysis: Calc.

for C₁₀F₁₇N₂O₂H₃: C, 23.72%; F, 63.8%. Found:

C₃F₃(10.3), 119 C₂F₅(100), 114 C₂F₄N (34.5), 100

C₂F₄(86.7), 81 C₃F₃(2.7), 76 C₂F₂N (5.0), 69 CF₃

T. Abe et al. / Journal of Fluorine Chemistry 108 (2001) 21±35

35

[3] F.G. Drakesmith, in: R.D. Chambers (Ed.), Organofluorine Chem-

istry, Technique and Synthons, Topics in Current Chemistry,

Springer, Berlin, 1997, pp. 197±242.

(85), 50 CF₂(7.7). Analysis: Calc. for C₁₀F₂₀N₂O: C,

22.06%; F, 69.9%. Found: C, 22.03%; F, 69.8%.

For the further characterization of 26, it was derivatized

into the methyl ester (51) similarly.

[4] S.A. Mazalov, S.I. Gerasimov, S.V. Sokolov, V.L. Zolatavin, Zh.

Obshch. Khim. 35 (1965) 485.

Methyl per¯uoro[3-(4-ethylpiperazinyl)butyrate] (51)

[5] R.E. Banks, P.A. Carson, R.N. Haszeldine, J. Chem. Soc., Perkin I

(1973) 1111.

20

(nc) had bp 199.0±199.58C, n_D1.3253 and d₄1.8216.

IR (capillary ®lm): 2968 n(CH) (w), 1792 n(C=O) (s), 1444

(w), 1350±1230 (s±vs), 1173 (vs), 1111 (m, sh), 1068 (ms),

1034 (ms), 951 (s), 917 (w), 855 (w), 825 (ms), 817 (ms),

776 (m), 740 (ms), 675 (w), 691 (w), 675 (w), 620 (w), 567

[6] R.E. Banks, Fluorocarbons and Their Derivatives, MacDonald & Co.

Ltd, London, 1970.

[7] Organofluorine Chemistry. Principles and Commercial Applications,

R.E. Banks, B.E. Smart, J.C. Tatlow (Eds.), Plenum Press, New York,

1994.

[8] T. Abe, E. Hayashi, H. Fukaya, H. Baba, J. Fluorine Chem. 50 (1990)

173.

(w), 541 (w). MS: 447 [M CF₂C(O)OCH₃] (3.3), 309

C₆F₁₂N₂(1.8), 264 C₅F₁₀N (1.5), 214 C₄F₈N (2.2), 209

[9] T. Abe, H. Fukaya, E. Hayashi, Y. Hayakawa, M. Nishida, H. Baba, J.

Fluorine Chem. 66 (1994) 193.

C₃F₆C(O)OCH₃(6.9), 164 C₃F₆N (7.9), 150 C₃F₆(7.2),

145 C₃F₅N (2.4), 131 C₃F₅(2.5), 119 C₂F₅(31.2), 114

[10] T. Abe, I. Soloshonok, H. Baba, A. Sekiya, J. Fluorine Chem. 99

(1999) 51.

C₂F₄N (16.0), 100 C₂F₄(12.7), 81 C₂F₃(1.7), 76

[11] 3M Co., Britain Patent 1,146,312 (1966).

[12] R.A. Guenthner, US Patent 3,471,484 (1969).

[13] T. Abe, JP Patent 1,451,067 (1988).

C₂F₂N (1.0), 69 CF₃(20.8), 59 [C(O)OCH₃] (100),

50 CF₂(3.4). Analysis: Calc. for C₁₁F₁₉N₂O₂H₃: C,

23.74%; F, 64.9%. Found: C, 23.85%; F, 64.5%. ¹⁹F

NMR data of 51 are shown in Table 3.

[14] W.M. Grootaert, US Patent 5,285,002 (1994).

[15] H. Baba, T. Abe, E. Hayashi, Nihon Kagaku Kaishi J. Chem. Soc.

Jpn. (1986) 1249.

Â

[16] P. Sartori, D. Velayutham, N. Ignatev, M. Noel, J. Fluorine Chem. 83

(1997) 1.

Acknowledgements

[17] T. Abe, E. Hayashi, H. Baba, S. Nagase, Nihon Kagaku Kaishi J.

Chem. Soc. Jpn. (1985) 1980.

This investigation was supported by the New Energy and

Industrial Technology Development Organization (NEDO).

Authors wish also thank to Ms. J. Tachibana for taking

NMR, Mass and IR spectra.

[18] G.G.I. Moore, J.C. Hansen, T.M. Barrett, J.E. Waddell, K.M. Jewell,

T.A. Kestner, R.M. Payfer, J. Fluorine Chem. 32 (1986) 41.

[19] T.C. Moore, M. Boyle, V.M. Thorn, J. Chem. Soc. (1929) 39.

[20] T. Abe, S.K. Pandey, H. Baba, Electrochemical fluorination of N-

containing carboxylic acids. Part 6, J. Fluorine Chem. 105 (2000)

149.

References

[1] S. Nagase, in: P. Tarrant (Ed.), Fluorine Chemistry Reviews, Vol. 1,

Marcel Dekker, New York, 1967, p. 77.

[21] T. Abe, E. Hayashi, H. Fukaya, Y. Hayakawa, H. Baba, J. Fluorine

Chem. 57 (1992) 101.

[2] N.L. Weinberg (Ed.), Technique of Electroorganic Synthesis. Part II,

Techniques of Chemistry. Vol. V, Wiley, New York, 1995, pp. 1±82.

[22] T. Abe, E. Hayashi, H. Baba, H. Fukaya, J. Fluorine Chem. 48 (1990)

257.

Article Doi

Electrochemical fluorination of 1-ethylpiperazine and 4-methyl- and/or 4-ethylpiperazinyl substituted carboxylic acid methyl esters

DOI: 10.1016/S0022-1139(00)00397-3

Source and publish data:

Authors:

Article abstract of DOI:10.1016/S0022-1139(00)00397-3

Full text of DOI:10.1016/S0022-1139(00)00397-3

Products guided by the article

R&D Labs maybe for 109421-51-4

Relevant to this article

Hot Product