Increasing the N-H acidity: Introduction of highly electronegative groups into the hydrazine molecule

Article abstract of DOI:10.1055/s-2005-871928

Various hydrazine derivatives containing combinations of trifluoroacetyl, trifluoromethanesulfonyl, and 2,4-dinitrophenyl groups were prepared. Synthetic strategy is studied in terms of using protecting groups and direct acylation. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2005-871928

LETTER
1939
Increasing the N–H Acidity: Introduction of Highly Electronegative Groups
into the Hydrazine Molecule
I
ntroduction of Hig
l
hly Electronegati
k
ve
G
roups in
s
to the
H
yd
e
razine Mol
i
e
cule Bredikhin,a Olga Tšubrik,a Rannar Sillard,b Uno Mäeorg*a
a
Institute of Organic and Bioorganic Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
Fax +372(7)375245; E-mail: uno.maeorg@ut.ee
b
Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171-77 Stockholm, Sweden
Received 21 April 2005
accessible via subsequent acylation of hydrazine. Howev-
er, only symmetrical 1,2-bis(trifluoroacetyl)hydrazine (1)
was obtained this way and the reported procedures are
based on the use of anhydrous hydrazine (which is explo-
sive and prohibited in many states for now) or afforded
contaminated product.3c,9 Tris(trifluoroacetyl)hydrazine
was never described earlier. Tetrakis(trifluoroacetyl)hy-
drazine was presumably isolated by Young from 0.14 mol
scale time-consuming reaction, carried out in a bomb be-
tween Hg salt of the compound 1 and trifluoroacetylanhy-
dride.3c Structure of the product was not confirmed and
thus the process is unsuitable as an example of modern
synthetic technique.
Abstract: Various hydrazine derivatives containing combinations
of trifluoroacetyl, trifluoromethanesulfonyl, and 2,4-dinitrophenyl
groups were prepared. Synthetic strategy is studied in terms of using
protecting groups and direct acylation.
Key words: acylations, hydrazines, neighboring-group effects,
protecting groups, sulfonamides
Modern synthesis enables the attachment of different sub-
stituents to the hydrazine skeleton, thus allowing design
of compounds with predetermined properties.1,2 Contrary
to common aryl-, alkyl- and acyl-substituted hydrazines,
there are only few studies concerning derivatives which
bear highly electronegative substituents.3 Fluorinated
imides have found usage in fuel cells and as components
in solid polymer electrolyte systems.4 In the same way,
similar class of hydrazine derivatives potentially possess
unusual electrochemical properties. Introduction of tri-
fluoromethanesulfonyl group might have positive effect
on the biological activity of hydrazine-based pharmaceu-
ticals: firstly, it increases the solubility, secondly, the tri-
flyl-containing analogues were found to inhibit carbonic
anhydrases.5 Also, derivatized hydrazines can be used as
precursors of the amines with different substitution
pattern, as trifluoroacetyl-activated N–N bond is easily
cleaved by SmI2.6
In our studies, direct derivatization of electron-deficient 1
using standard acylation procedure (CF3CO)2O/DMAP/
MeCN was found to be impossible. Therefore, the com-
pounds 2 and 3 were obtained by stepwise deprotonation
with n-BuLi and subsequent acylation with (CF3CO)2O or
CF3COCl. The last reagent can be easily prepared by add-
ing trifluoroacetic anhydride dropwise to pyridinium
chloride;10 the resulting gas was passed directly into the
solution of Li salt of 1 or 2.11 After evaporation of sol-
vents, crude products 2 (85% yield) and 3 (40%) were
subjected to NMR and MS analysis. Magnetic inequiva-
lence of the CF3CO groups and C–F splitting causes the
appearance of two CF3 quartets in the ratio of 1:2 (the
same goes for carbonyl signals) in the 13C NMR spectrum
The correlation between acidities of hydrazine and simi-
larly substituted ammonia derivatives can be useful in
prediction of the potential of the compounds for the
Mitsunobu-type alkylations, etc.7 Recently, quantum
chemical calculations afforded the pKa of 1,1,2-tris(tri-
flyl)hydrazine to be about 0.4 in DMSO, which reaches
that of sulfuric acid.8 Obviously, NH acids of this type
could be of high interest for synthetic chemists as well. In
order to determine pKa values experimentally, we have
started to develop a general synthetic approach to this
kind of compounds, testing the extent of substitution to
which the protecting groups strategy can be readily ap-
plied.2
13
of 2. Under the same circumstances, C NMR spectrum
of 3 contains only one CF3 quartet. Attempts to purify 2
by sublimation in vacuo induced its decomposition and
formation of CF3CONHNHCOCF3 (most probably due to
the disproportionation).
Previously published synthesis of 5c employ either a mul-
tistep synthesis with hydrazinolysis on its end,3b harsh re-
action conditions or anhydrous hydrazine as a reagent.8,12
A recent study has also demonstrated instability of this
compound and its disposition towards disproportion-
ation.13 Our synthesis started with compounds 4a and 4b
which were easily obtained in 96–100% yields by reacting
Boc- and Z-protected hydrazines with trifluoroacetic an-
hydride in MeCN or CH2Cl2.14 Depending on what pro-
tecting group we chose to use (Cbz or Boc), either
CF3CONHNH2 as a free base 5c (94% yield) or salts 5a
and 5b (78% and 100% yields) were obtained (ESI-
HRMS: m/z calcd for C2H4F3N2O: 129.0276: found:
129.0270 [MH]+). Contrary to the substance 5c, the
Our work was aimed at the introduction of CF3CO substit-
uent in different combinations as shown in Scheme 1. One
may think that di-, tri- and tetrasubstituted compounds are
SYNLETT 2005, No. 12, pp 1939–1941
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1
.0
8
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Advanced online publication: 07.07.2005
DOI: 10.1055/s-2005-871928; Art ID: G14205ST
© Georg Thieme Verlag Stuttgart · New York

1940
A. Bredikhin et al.
LETTER
1. BuLi, –80 °C
2. CF3COCl
1. BuLi, –80 °C
2. CF3COCl
CF3CO
CF3CO
H
CF3CO
CF3CO
COCF3
(CF3CO)2O
N2H4 ×H2O
CF3CONHNHCOCF3
N
N
N N
Na2CO3
CH2Cl2, 0 °C, 0.5 h
THF
THF
COCF3
COCF3
1
2
3
CF3CONHNH2 × HCl
5a
4a, R1 = Boc,
R2 = CF3CO
R22O
R1NHNH2
R1NHNHR2
CF3CONHNH2 × TFA
CF3CONHNH2
5b
5c
4
4b, R1 = Z,
R2 = CF3CO
H2, Pd/C
MeOH
Scheme 1 Synthesis of trifluoroacetyl-substituted hydrazines
corresponding salts 5a and 5b are perfectly stable on In conclusion, this work reports novel systematic study of
storage at room temperature and the disproportionation the preparation of multisubstituted hydrazines with sever-
was observed only when compounds were refluxed in al electronegative groups using trifluoroacetyl moiety as
acetonitrile (CF3CONHNHCOCF3 was formed). In anal- an example. All procedures reported here are character-
ogy with typical amine salts, 5a and 5b can be employed ized by easy reproducible techniques, mild reaction con-
in the synthesis or pKa measurements.
ditions, fast reactions and good yields. Neither extremely
toxic compounds nor explosives have been used. From the
strategical point of view, one does not have to use protect-
ing groups for the directly accomplishable di-, tri- and
tetrasubstituted derivatives, although activation of NH by
metallation is absolutely essential. However, the protect-
ing groups like Z and Boc are useful in the convenient
preparation of monosubstituted derivative.
An attempt to introduce more trifluoroacetyl groups into
the compound 4a under typical acylating conditions
[(CF3CO)2O/Et3N/DMAP] has failed. Instead of the de-
sired compounds we have isolated CF3COCH=CHNEt2
1
(structure confirmed by H NMR and 13C NMR) as the
only product due to the oxidation of triethylamine with
(CF3CO)2O.15 Attempted direct triacylation of
BocNHNH2 under the same conditions also has failed due
to the same oxidation process [(CF3CO)2C=CHNEt2
isolated and characterized by NMR].
Acknowledgment
This work was financially supported by the Estonian Science
Foundation (No. 5255).
Similarly with the compounds 4a and 4b, other combina-
tions of different electron-withdrawing groups should be
considered as derivatives with remarkable acidic proper-
ties. The disubstituted substances 4, prepared in the
current study, are demonstrated in Table 1 below.16
References
(1) For a review see: Ragnarsson, U. Chem. Soc. Rev. 2001, 30,
205; and references therein.
The obtained compounds are now being employed in the
pKa measurements. As it could be anticipated from high
electron-withdrawing effect, pKa of 1, 4a and 4c reached
values of 7–10 units (DMSO).8
(2) (a) Mäeorg, U.; Grehn, L.; Ragnarsson, U. Angew. Chem.,
Int. Ed. Engl. 1996, 35, 2626. (b) Brosse, N.; Jamart-
Gregoire, B. Tetrahedron Lett. 2002, 43, 249. (c) Tšubrik,
O.; Mäeorg, U. Org. Lett. 2001, 3, 2297. (d) Tšubrik, O.;
Mäeorg, U.; Sillard, R.; Ragnarsson, U. Tetrahedron 2004,
60, 8363.
Table 1 Disubstituted Hydrazines
(3) (a) Brosse, N.; Pinto, M.-F.; Jamart-Gregoire, B. J. Org.
Chem. 2000, 65, 4370. (b) Brosse, N.; Pinto, M.-F.; Jamart-
Gregoire, B. J. Chem. Soc., Perkin Trans. 1 1998, 3685.
(c) Young, J. A.; Durrell, W. S.; Dresdner, R. D. J. Am.
Chem. Soc. 1962, 84, 2105.
(4) (a) Ye, F.; Noftle, R. E. J. Fluorine Chem. 1997, 81, 193.
(b) Narula, P. M.; Day, C. S.; Powers, B. A.; Odian, M. A.;
Lachgar, A.; Pennington, W. T.; Noftle, R. E. Polyhedron
1999, 18, 1751.
(5) (a) Mattioni, B. E.; Jurs, P. C. J. Chem. Inf. Comput. Sci.
2002, 42, 94. (b) Scozzafava, A.; Menabuoni, L.; Mincione,
F.; Briganti, F.; Mincione, G.; Supuran, C. T. J. Med. Chem.
2000, 43, 4542. (c) Mcmahon, E. G.; Olins, G. M.; Schuh, J.
R. PCT Int. Appl. WO 9640256, 1996.
(6) Ding, H.; Friestad, G. Org. Lett. 2004, 6, 637.
(7) Koppel, I.; Koppel, J.; Degerbeck, F.; Grehn, L.;
Ragnarsson, U. J. Org. Chem. 1991, 56, 7172.
Number R1
R2
Conditions
Yield
(%)
4a
4b
4c
4d
4e
Boc
COCF3
COCF3
SO2CF3
SO2CF3
COCF3
0 °C, TEA, MeCN
0 °C, CH2Cl2
96
100
63
Z
Boca
Z
–80 °C, TEA, CH2Cl2
–80 °C to r.t., TEA, CH2Cl2
0 °C, TEA, CH2Cl2/ACN
68
DNPb
98
a Previously prepared by Hendrickson.17
b 2,4-Dinitrophenyl.
Synlett 2005, No. 12, 1939–1941 © Thieme Stuttgart · New York

LETTER
Introduction of Highly Electronegative Groups into the Hydrazine Molecule
1941
(8) Ragnarsson, U.; Grehn, L.; Koppel, J.; Loog, O.; Tšubrik,
O.; Bredikhin, A.; Mäeorg, U.; Koppel, I. J. Org. Chem.
2005, in press.
(9) (a) Groth, R. H. J. Org. Chem. 1959, 25, 102. (b)Brown,H.
C.; Cheng, M. T.; Parcell, L. J.; Pilipovich, D. J. Org. Chem.
1961, 26, 4407.
(12) Ried, W.; Franz, G. Liebigs Ann. Chem. 1961, 644, 141.
(13) Fritz, H.; Kristinsson, H.; Mollenkopf, M.; Winkler, T.
Magn. Res. Chem. 1990, 28, 331.
(14) Compound 4a: mp 130–132 °C. 1H NMR (DMSO-d6):
d = 1.42 (s, 9 H, Boc), 9.31 (s, 1 H, NH), 11.27 (s, 1 H, NH).
13C NMR (DMSO-d6): d = 27.9 (Me, Boc), 80.1 (Cq, Boc),
115.9 (q, CF3, JCF = 287 Hz), 154.4 (CO, Boc), 156.2 (q,
CF3CO, JCF = 36 Hz). IR: 3294, 3192 (NH), 1740, 1696
(C = O) cm–1. Anal. Calcd for C7H11F3N2O3: C, 36.85; H,
4.86; N, 12.28. Found: C, 37.14; H, 4.77; N, 12.03.
Compound 4b: mp 106–108 °C. 1H NMR (CDCl3):
d = 5.150 (s, 2 H, PhCH2), 4.341 (s, 5 H, CHarom), 9.096 (s, 1
H, NH-Z), 10.926 (s, 1 H, NHCOCF3). 13C NMR (CDCl3):
d = 67.4 (PhCH2), 116.0 (q, JCF = 286 Hz, CF3), 128.1,
128.3, 128.5, 136.0 (Carom), 155.8 (CO, Z), 157.1 (q, JCF = 38
Hz, CF3CO). ESI-MS: m/z calcd for C10H8F3N2O3: 261.049;
found: 261.096 [M–].
(10) Braun, M. W.; Rudolph, W. H.; Palsherm, S. B.; Eichholz,
K. L. US Patent 5532411, 1996.
(11) An oven-dried flask was charged with 224 mg of the
compound 1 (1 mmol), then evacuated and backfilled with
argon. Then, 8 mL of Et2O was added to dissolve the solid
and the solution was cooled down to –80 °C. A 1.6 M
solution of n-BuLi in hexane (2 equiv, 1.26 mL) was added
dropwise and the obtained mixture stirred for 30 min. In the
other flask, 6 mL of trifluoroacetylanhydride was added to
the solution of pyridinium chloride (10 equiv) in minimum
quantity of TFA. The emerging gaseous CF3COCl was
passed into the solution of metallated compound 1. The
mixture was stirred for 30 min at –80 °C and then let to warm
up to r.t. LiCl was filtered off and solvents were evaporated
in vacuo, yielding 271 mg of 2 (mp 148–150 °C). The ESI
molecular ion does not exist due to the rapid decomposition
to 1. 13C NMR (DMSO-d6): d = 116.1 (q, JCF = 286 Hz,
CF3CONH), 117.1 [q, JCF = 294 Hz, (CF3CO)2N], 155.8 (q,
JCF = 37 Hz, CF3CONH), 159.2 [q, JCF = 33, (CF3CO)2N].
Compound 3 was obtained in the same way in THF using 1
equiv n-BuLi for the first deprotonation of 1. After the
reaction with CF3COCl the addition of 1 equiv n-BuLi and
CF3COCl was repeated. THF was removed using rectifi-
cation, furnishing 3 as a colorless oil. ESI-HRMS: m/z calcd
for C8HF12N2O4: 416.9739; found: 416.9745 [MH]+.
13C NMR (DMSO-d6): d = 116.9 [q, JCF = 293 Hz,
(CF3CO)2N], 160.2 [q, JCF = 34, (CF3CO)2N].
(15) Schreiber, S. L. Tetrahedron Lett. 1980, 21, 1027.
(16) Compound 4d: mp 140–141 °C. 1H NMR (DMSO-d6):
d = 5.15 (s, 2 H, PhCH2), 7.38 (s, 5 H, Ph), 10.12 (s, 1 H,
NH-Z), 11.66 (s, 1 H, NHSO2CF3). 13C NMR (DMSO-d6):
d = 66.9 (s, PhCH2), 119.2 (q, JCF = 321 Hz, CF3SO2), 127.9,
128.2, 128.4, 136.0 (Carom), 156.1 (CO). ESI-MS: m/z calcd
for C9H8F3N2O4S: 297.016; found: 297.083 [M–].
Compound 4e: mp 161–163 °C. 1H NMR (DMSO-d6):
d = 7.29 (d, JCH = 9.6 Hz, 1 H, Ar), 8.39 (m, 1 H, Ar), 8.90
(d, JCH = 2.6 Hz, 1 H, Ar), 10.41 (s, 1 H, NH). 13C NMR
(DMSO-d6): d = 115.1 (Carom), 115.9 (JCF = 286 Hz,
COCF3), 123.1, 130.5, 137.6, 147.1 (Carom), 156.4 (JCF = 36
Hz, CO). ESI-MS: m/z calcd for C8H4F3N4O5: 293.013;
found: 293.071 [M–].
(17) Hendrickson, J. B.; Sternbach, D. D. J. Org. Chem. 1975, 40,
3450.
Synlett 2005, No. 12, 1939–1941 © Thieme Stuttgart · New York