The first fluoroalkylation of amino acids and peptides in water utilizing the novel iodonium salt (CF3so2)2NI(Ph)CH2CF3

Article abstract of DOI:10.1039/a805879b

The novel iodonium salt (CF₃SO₂)₂NI(Ph)CH₂CF₃ is a powerful alkylating reagent which can be utilized in water to trifluoroethylate amino acids and peptides.

Full text of DOI:10.1039/a805879b

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The first fluoroalkylation of amino acids and peptides in water utilizing the
novel iodonium salt (CF3SO2)2NI(Ph)CH2CF3
Darryl D. DesMarteau*† and Vittorio Montanari
Department of Chemistry, Box 341905, Clemson University, Clemson, SC 29634-1905, USA
The novel iodonium salt (CF3SO2)2NI(Ph)CH2CF3 is a
powerful alkylating reagent which can be utilized in water to
trifluoroethylate amino acids and peptides.
Bis(trifluoromethylsulfonyl)imide, (CF3SO2)2NH (2), origi-
nally devised for establishing the existence of Xe–N bonds,5 is
one of the strongest acids known in the gas phase.6 Derivatives
of the acid typically have unusual properties as exemplified by
the N-fluoro compound which is a powerful fluorinating
reagent.7,8 Perfluoroionomers and ionene polymers made in this
laboratory, containing the repeating (RfSO2NXSO2R’f) unit (X
= H or other cation) have high potential in solid polymer
electrolyte fuel cells and polymer lithium batteries, and are
promising superacid catalysts.9 In connection with this re-
search, it is useful to synthesize novel salts of 2 as model
compounds for structure and reactivity studies. The first
iodine(III) compound we prepared, [Ph2I]+[N(SO2CF3)2]2 (3),
is a stable, low-melting compound (67 °C) and a strong
arylating agent.10 Encouraged by this result, a high-yield
synthesis of 1 was developed.‡ We found that 1 immediately
transfers the trifluoroethyl group to nucleophiles, such as
aniline, in organic solvents. Surprisingly 1, which is very
slightly soluble in water, is hydrolyzed only slowly. This fact
led us to investigate fluoroalkylation reactions in water as a
solvent. Using simple amines as model compounds, we
observed high yields of trifluoroethylamines from 1 equiv. each
of 1, substrate, and NaHCO3.
Fluorine-containing amino acids have been actively investi-
gated in view of their high potential for biological studies and
medical applications.1 In particular, the use of 19F NMR as a
sensitive mechanistic probe has been intensively studied.2
Synthetic routes to fluorinated amino acids normally involve
several steps using fluorinated building blocks, mostly obtained
by the conversion of carbon–heteroatom bonds to C–F bonds. A
more direct approach to the introduction of fluorine into
biochemically significant substrates might involve fluoroalk-
ylations.3 Cysteine and related amino acids and peptides can be
alkylated by alkyl halides or esters if both the substrate and
alkylating reagent can be solubilized in mixed water–organic
solvents or in liquid ammonia.4 However, simple fluorine
containing alkyl halides and esters are of low reactivity in
analogous alkylations. Increasing the reactivity by incorpora-
tion of fluoroalkyl groups into iodonium salts such as
CF3CH2I(Ph)O3SCF3 is successful3 but until now such com-
pounds could not be employed in aqueous media or basic
solvents since they are instantly destroyed under these condi-
tions.
Based on this novel result, our goal became the alkylation of
amino acids. The reactive side-chain of cysteine and lysine were
considered, anticipating that the products would be of interest
In contrast the novel iodonium salt (CF3SO2)2NI(Ph)CH2CF3
(1) is unexpectedly stable to water. Herein we report the first
fluoroalkylations in aqueous media and the application of 1 to
the alkylation of representative biochemically significant sub-
strates (Scheme 1).
for biochemical studies. S-Trifluoroethyl- -cysteine (4) was
L
readily obtained in 60–90% isolated yields.§ Fig. 1 shows the
X-ray crystal structure of 4.¶
Under the same conditions the commercially available Na-
SO2CF3
–N
Z-protected -lysine unexpectedly reacted with 3 equiv. of 1 to
L
give the ester (CF3CH2)2N(CH2)4CH(NH-Z)COOCH2CF3 (5).
SO2CF3
Hydrolysis of 5 in 37% HCl gave Ne-bis(trifluoroethyl)-
hydrochloride (6) in 60% overall yield.
L
-lysine
1 eq. substrate
I+
1 eq. CsHCO3
Compounds 4 and 6 are modified in the side-chains but are
otherwise normal amino acids: they can be converted into the
Fmoc-protected acyl fluorides in good overall yield. This form
of protection–activation is very useful in the assembly of
peptides of any size according to many literature examples.11
By means of these acyl fluorides the unlikely event of extensive
racemization under our alkylation conditions could be easily
ruled out: reaction with (R)- or (S)-phenethylamine gave
CH2CF3
1
CF3SO2
I
N–Cs+
+
CF3SO2
NH2
CO2H
NH2
CF3CH2S
HO2C
C(O)
H
N
4
CF3CH2S
C(O)NHCH2CO2H
7
O
(CF3CH2)2N
OCH2CF3
NHZ
conc. HCl
5
O
(CF3CH2)2N
OH
NH2•HCl
6
Scheme 1 Reaction of 1 with cysteine Na-Z-lysine and glutathione and the
Fig. 1 Crystal structure of S-trifluoroethylcysteine 4 showing one of the two
trifluoroethylated products obtained
unique molecules in the unit cell
Chem. Commun., 1998
2241

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91.45(2)°; V = 832.2(6) Å3; Dcalc = 1.622 g cm23; Z = 4 (2 unique); m =
0.40 mm21; empirical absorption correction (0.94–1.00); Mo-Ka radiation
diastereoisomeric amides that are clearly distinguishable by 1H
and 19F NMR.12
with graphite monochromator, l
= 0.71073 Å; Rigaku AFC7R dif-
A different approach to the use of 1 is the direct reaction with
a peptide having unprotected side-chains. We tested the reaction
on glutathione (GSH, g-Glu-Cys-Gly) because of its bio-
chemical relevance and commercial availability in preparative
amounts. Under the same conditions used for the preparation of
4, we obtained complete conversion to a mixture of the desired
S-trifluoroethylglutathione (7) and oxidized glutathione (8) in
an 8:2 ratio. Compound 7 was separated from 8 by precipitation
from water–ethanol.
In summary, we have reported that 1 reacts rapidly in water,
under mildly alkaline conditions, with unprotected cysteine and
glutathione, and with Na-protected lysine, to give the novel
amino acids 4 and 6, and tripeptide 7.
The covalent polar residue CF3CH2 can now be readily
introduced into a variety of peptide building blocks or into
suitable preassembled peptides. These results provide inter-
esting potential for modifying the bioactivity of peptides and as
probes for biochemical reactions.
The promise of 1 for the synthesis of other useful compounds,
such as fluorine-tagged ligands for metal complexes,13 is
obvious, considering that the successful reactions described
above were those with the greatest potential for failure, in our
view. In fact, recent results show that the bis-fluoroalkylation
observed with lysine is a general and facile reaction.14
Financial support of this research by the National Science
Foundation is gratefully acknowledged. Crystallographic data
were supplied by W. T. Pennington and G. Schimek.
fractometer; 2119 measured reflections (Rint = 1.61%); 1676 reflections
used with F > 2s(F); 2qmax = 55°; 217 parameters; non-H atoms refined
anisotropically; H atoms fixed in calculated positions (C–H = 0.96 Å); full-
matrix least-squares refinement; R
= 4.68%/Rw = 5.93%. CCDC
182/1019.
1 Biomedical Frontiers of Fluorine Chemistry, ed. I. Ojima, J. R.
McCarthy and J. T. Welch, ACS Symposium Series 639, 1996;
Fluorine-containing Amino Acids, ed. V. P. Kukhar and V. A.
Soloshonok, Wiley, New York, 1995.
2 Some recent papers: L. M. McDowell, M. S. Lee, R. A. McKay, K. S.
Anderson and J. Schaefer, Biochemistry, 1996, 35, 3328; H. Duewel, E.
Daub, V. Robinson and J. F. Honek, ibid., 1997, 36, 3404; I. Ojima,
S. D. Kuduk, S. Chakravarty, M. Ourevitch and J. P. Begue, J. Am.
Chem. Soc., 1997, 119, 5519; R. A. Komoroski, Anal. Chem., 1994, 66,
1024.
3 T. Umemoto, Chem. Rev., 1996, 96, 1757.
4 V. du Vigneaud, L. F. Audrieth and H. S. Loring, J. Am. Chem. Soc.,
1930, 52, 4500; M. D. Armstrong and J. D. Lewis, J. Org. Chem., 1950,
15, 749; M. J. Brown, P. D. Milano, D. C. Lever, W. W. Epstein and
D. C. Poulter, J. Am. Chem. Soc., 1991, 113, 3176; C. C. Yang, C. K.
Marlowe and R. Kania, ibid., 1991, 113, 3177.
5 J. Fouropulos, Jr., and D. D. DesMarteau, J. Am. Chem. Soc., 1982, 104,
4260.
6 I. A. Koppel, R. W. Taft, F. Anvia, S.-Z. Zhu, L.-Q. Hu, K. Sung, D. D.
DesMarteau, L. M. Yagupolski, Y. L. Yagupolski, N. V. Ignatev, N. V.
Kondratenko, A. Y. Volkonskii, V. M. Vlasov, R. Notario and P. C.
Maria, J. Am. Chem. Soc., 1994, 116, 3047.
7 D. D. DesMarteau and M. Witz, J. Fluorine Chem., 1991, 52, 7.
8 W. Ying, D. D. DesMarteau and Y. Gotoh, Tetrahedron, 1996, 52,
15.
9 D. D. DesMarteau, J. Fluorine Chem., 1995, 72, 203.
10 From the reaction of 3 with aniline (2 equiv.) in boiling water,
diphenylamine was isolated in 30% yield. Only trace amounts are
obtained under the same conditions with diphenyliodonium bromide:
F. M. Beringer, A. Brierley, M. Drexler, E. M. Gindler and C. C.
Lumpkin, J. Am. Chem. Soc., 1953, 75, 2708.
Notes and References
† E-mail: fluorin@clemson.edu
‡ Bis(trifluoromethylsulfonyl)imide was obtained from its lithium salt (HQ-
115™, 3M Co., St. Paul, MN) by vacuum sublimation from H2SO4 (see ref.
7). The other starting material CF3CH2I(OCOCF3)2, a hygroscopic solid
that melts at 39–40 °C without decomposition, was prepared by oxidation of
CF3CH2I with 50% H2O2 (available from Aldrich, Inc.) in TFAA under N2
(3–5 d, RT). The preparation of 1 is simple, but anhydrous conditions must
be maintained throughout the reaction. In a typical small-scale reaction, 2
(1.40 g, 5 mmol) was added under N2, in one portion, into a solution of
CF3CH2(OCOCF3)2 (2.16 g, 5 mmol) in CFC 113 (20 mL). This addition is
endothermic. After 10 min, benzene (0.43 ml, 5 mmol) was rapidly added
with ice–water cooling. The reaction mixture was allowed to return to 25 °C
during 30 min and then stirred at 25 °C for 6 h. The volatiles were removed
under vacuum and the residue was stirred with ice–water (50 ml) for 15 min.
The precipitate was collected on a glass frit and freeze-dried to yield 1, 1.28
g (46%) as a white powder, mp 77–79 °C. On a larger scale (up to 30 g of
1) we have routinely obtained yields greater than 70%.
11 L. A. Carpino, M. Beyermann, H. Wenschuh and M. Bienert, Acc.
Chem. Res., 1996, 29, 268, and refs. therein.
12 S-CF3CH2-FMOC-
in water–NaHCO3–CH2Cl2.10 The same reaction was carried out on
S-CF3CH2-Fmoc-( )-Cys-F, prepared from racemic cysteine.
S-CF3CH2-Fmoc-
-Cys-NHCHMePh was a single product by 1H and
19F NMR. S-CF3CH2-Fmoc-(
)-Cys-NHCHMePh was clearly a 1:1
mixture of two compounds [dF(CHCl3–CFCl3) 266.99, 267.00].
Because the starting material for 6 is only available in the form, 6 was
converted into Ne(CF3CH2)2-Na-Fmoc-
-Lys-F, which was reacted
L
-Cys-F was reacted with (2)-(S)-phenethylamine
D,L
L
D,L
L
L
separately with (2)-(S)- and (+)-(R)-phenethylamine. Each amide was
identified by NMR. Equal amounts of the two amides were combined,
and the mixture showed two compounds by both 1H and 19F NMR
[dF (CHCl3–CFCl3) 270.83, 270.86].
All other materials are commercially available and were used as received.
The novel products 4–7 were fully characterized by 1H, 19F and 13C NMR
and elemental analysis.
§ Typical procedure. Cysteine (606 mg, 5 mmol), CsHCO3 (968 mg, 5
mmol), and 1 (3.2 g, 5.6 mmol) were added into a degassed mixture of pH
10 buffer (Hydrion, Na2CO3–NaHCO3, 20 mL) and CH2Cl2 (10 mL) at 5 °C
under nitrogen with rapid stirring. The reaction mixture was allowed to
return to 23 °C during 30 min. The aqueous phase was separated,
neutralized and evaporated to a crystalline solid. This solid was refluxed
twice in 30 mL CH3CN to extract the Cs salt of 2. The resulting powder was
suspended in 10 mL water at pH 7, filtered through a syringe filter to remove
insoluble cysteine and slowly evaporated to yield crystalline 4 (874 mg,
13 K. Severin, R. Bergs and W. Beck, Angew. Chem., Int. Ed., 1998, 37,
1086.
14 Ms J. Sayers, NSF-SURP 1997, obtained from 4-aminobutyric acid
(GABA)
and
1
under
the
same
simple
conditions
(CF3CH2)2N(CH2)3CO2CH2CF3 in very high yield (NMR). A non-
volatile, easily isolated analog was obtained from GABA phenylethyl
ester hydrochloride. The yield of (CF3CH2)2N(CH2)3CO2C2H4Ph was
70%, representing more than 80% per alkylation step: D. D. DesMar-
teau, J. Sayers and V. Montanari, manuscript in preparation.
25
82%), [a]D 215 (c 0.37, 4 M HCl).
¶ Crystal data of 4: formula, C5H8F3NO2S; M
= 203.2; monoclinic;
P21(#4); T = 25 °C; a = 9.503(3), b = 5.166(3), c = 16.957(3) Å, b =
Received in Corvallis, OR, USA, 27th July 1998; 8/05879B
2242
Chem. Commun., 1998