Ethyl trifluoroacetate: a powerful reagent for differentiating amino groups

Tcrmkdmn Lrtrrr. Vol. 36. No. 41. pp. 7357-7360. 1995 ElsevielscienceLtd Printedin GUI Britain

Pergamon

oa4c4039/% s9.50400

0040-4039(95)016554

Ethyl Trifluoroacetate: A Powerful Reagent for Differentiating Amino Groups Daqiang Xu, Kapa Prasad *, Oljan Repic, and Thomas J. Blacklock Chemical Research and Development, Technical R & D Sandor Research Institute, Sandoz Pharmaceutical Corporation, 59 Route IO, East Hanover, NJ 07936, USA

Abstract:

Selective protection of primary aminesin the presenceof secondaryaminesand monofunctionatizadon of symmetric

primary and secondary diamines using ethyl trifluoroacetateis described. Effective differentiationof primary. secondary and tertiary alkyl-substituted primary amines from one another by ethyl trilluoroacetate acylation is also demonstrated. These result are explained on the basis of steric and electronic effects of the subwale amines.

The trifluoroacetyl

(Tfa) group has been widely used as an amine protecting

due to the ease of its removal under mild conditions. used

for this purp0se.t

Trifluoroacetic

group in organic synthesis

anhydride is the reagent

most widely

As this reagent is too reactive, all types of amino groups gets acylated under these

conditions. Ethyl trifluoroacetate. a mild trifuoroacetyl transferring agent. on the other hand was used in few instances for differentiating amino groups. 2 As there is no detailed study3 on the scope of this acyl transfer, we undertook a systematic investigation. and the details of these results are presented in this paper. We found that ttifluoroacetylation of primary amines can be conveniently achieved by simple mixing

of the amine and a stoichiomeuic amount of ethyl trifluoroacetate under neutral conditions at 0 T.

The

reaction normally goes to completion in a few minutes, and the product is isolated by evaporation of the solvent and the liberated ethanol. presence of secondary amines

H&

-NH2

These mild conditions offer exclusive primary amine acylation in the

as exemplified by equations 1 and 2.

I qcFgzooEl

HsC,

THF. 0 “c. IO min

#

WNHTfa

(Es J)

Ii >95%

# H2N-

mNH2

$o~~m;. . 7357

T,a,,,,,/\/

MeNHTfa

(Eq2)

The obsenred selectivity is attributed to the differences in steric demand of primary and secondary amincs in accotxiance with aminolysis of esters. 5 The steric influence of substituents on the amino group is clearly demons~ted

by competition experiments using r-. i-. and n-bu~~amines

(Eqs 3 & 4). The high

selectivity and mild conditions makes this trifluoroacetylation protocol a powerful tool for the differentiation of primary, secondary and tertiary alkyl-substituted primary amines.

H3+,NH~

H3k.+,JJH3

~~~CQOQO

e

H3eN”Tfa

+

H3vNHTf3 0%

+

CH3

l

H3C

CH3

Wi

31

H3C CH3

NH2 I eq CF$XOEt H3C-NH2

H3C-7’ +

dioxme, I5 “C

-

H3-NHTfa+

“3C’-fNHTfa

C”3

cEq4 CY

The reaction of ethyl trifluoroacetate with symmetric diamines is even mom interesting. selectivities are realized for mono-t~fluo~acetylation

Excellent

of all 1.2-diamines studied except for rrans-1,2-

diaminocyclohcxanc (see the Table). Even the highly reactive ethylenediamine offered moderate selectivity at 0 ‘C (entry 2). and the selectivity is improved IO the synthetically useful range of 12.6~1 (93% of mono- vs. 7% of bis-trifluoroacetate) when the acylation is run at -70 OC (entry 3). The stark differences in seiectivity among cis- and rranr-diaminocyclohexanes 4. 5, and 6).

and the 1.2-diphenylethylenediamine

While both cis-di~in~yclohexane

selectivity for mono-trifluoroacylation,

are most intriguing (entries

and 1,2-diphenylethyIenediamine

(runs-diaminocyclohexane

give extremely high

shows statistical distribution of all the

possible products in the reaction mixture after the addition of one equivalent of ethyl trifluoroacetate, with the starting diamine, the monoacylated product and the bisacylated product in the ratio of roughly 1:2:t. This clearly indicates the cooperative nature of the two nitmgens in the aminolysis i.e., general base catalysis by the other nitrogen via in~ol~~ar

hydrogen bonding likely accounting for the selectivity (see Scheme).6 When

the two nitrogens are farther apart, this intramolecular polarization becomes less entropically favored, and the attacking nitrogen also becomes more sterically crowded. This explains the reduced selectivities for mono~fluoroacetylation

in the series from ethylenediaminc,

entries 1,7,8 and 9).

propane&amine. piperazine to hexanediamine (c$

7359

Table substrate

EW

Mono/EWb

Rxn Temp

Solvents

H

1

HP-el-N-cna

2

3

H,N-

NHz

a

4

43.7

RT

THF

3.0

o”c

MeCN

12.6

-70 “C

EtOH

68.0

0°C

MeCNIEtOH

1.8

0°C

THF

o”c

THF

8.3

RT

THF

5.8

RT

THF

NH2 NH2

5

6

> load m H,C.NV

7

N.=“a

H

H

n MN

8 H,C.

9

Nr\ H

NH

/. w&)4

N-CH, ”

RT

a) The ratio of monouifluotwcylated product and the bistrifluoroacyliltcd product upon complete reaction with 1 equivalent of ethyl trifluoroacetatc;b) The ratioswcrc dctcrrnincdby GC usinga DEand were conficd

I column

by ‘H NMR spcc~ra after Ihe completion of tbc rcrtions: c) Solvents wcrc chosen

for solubility and GC considcntions; d) No funhcr rykion

was observed even wilh excess ethyl

lrifiuoroilcewtc.

Scheme:

(n = O,l,...)

7360

The intramolecular equations

catalysis assumption

5 and 6. The secondary

trifluoroacetylated

is further supported

by the competition

studies illustrated in

amino group in N.N’.N’-trimethylpropanediamine

over the one in N.N’-dimethylpropanediamine

probably

is more selectively

due to higher basicity of the

trimethyl analog.

Id

HsC’

C&t

-N’

HaC’ 1 q CFsccxxt

H

#

W

*N’ Tfa

MeCN. RT H&v

35.2

I

)

_

H,CvN/CH”

/CH3 w

(Eq 5) 1.0

I

ifa

(1:l)

CH3

HsK#m’ H3KN-NHCH3

H

I

H

Tfa

M&N, RT

H3kN/,,+.N/cH3

(Eq 6)

“3k.N~N/CH3

H

I

1.0

I

eqCFICCCEt

3.7

I

CH3

I

Tfa

CH3

(1:l)

In conclusion, trifluoroacetate

we have

for differentiating

to the steric and electronic

demonstrated

the

broad

scope

amino groups from one another.

of trifluoroacetylations

This trifluoroacetylation

influences of the amines and, therefore, promises

with

ethyl

is highly sensitive

a wide variety of applications

in

synthetic organic chemistry for selective amino group functionalizations. Rcfcrenccs and Notes: 1.

Green, T. W. and Wuts. P. G. M. Prorecrive Groups in Organic Synrhesis John Wiley & Sons, Inc.

2.

(a) Mitchinson,

New York, 1991. 1994. 2613.

A; Gelding.

(b) Rizo, J.; Albericio.

Aviron-Violet. 3.

B.T.; Griffin, R.J.;

O’Sullivan. M. C. J. Chem. Sot., Gem.

F.; Giralt. E. and Pedroso. Terruhedron Lem. 1992.33,

finding

397. (c)

P. and GervaJs. C. US Patent 4943679.

Recently, O’Sullivan and Dalrymple reported (Terruhedron earlier

Commun.

(ref.

2 (a)) on the differentiation

Len. 1995.36.3451)

of primary

amines

the extension of th:ir

in spermidine

to other

polyamines. 4. 5.

The

products

(a) MC. Arnett,

obtained

as described

have

purities

of 1

98%.

determined

E.; Miller, J. G. and Day, A. R. J. Am. Chem. Sot. 1950, 72.5635.

73‘5393. 6.

Werner,

B. H. H. and Fischer,

E. 0. Anger. Chem. Int . Ed. Engl. 1968,7,817.

(Received in USA 5 July 1995;accepted 2 August 1995)

by tH

NMR.

(b) ibid, 1951,