Efficient methodology for selective alkylation of hydrazine derivatives

Article abstract of DOI:10.1021/ol070026w

(Chemical Equation Presented) Formation and use of a nitrogen dianion for selective hydrazine alkylation is reported. The scope and limitations of a new method were demonstrated. The novel method provides fast and easy access to substituted hydrazines, wh

Full text of DOI:10.1021/ol070026w

ORGANIC
LETTERS
2007
Vol. 9, No. 6
1097-1099
Efficient Methodology for Selective
Alkylation of Hydrazine Derivatives
Aleksei Bredihhin,† Ulrich M. Groth,‡ and Uno Maeorg*,†
1
Institute of Organic and Bioorganic Chemistry, UniVersity of Tartu,
Jakobi 2, 51014 Tartu, Estonia, and Department of Chemistry,
UniVersity of Konstanz, Konstanz D-78464, Germany
uno@chem.ut.ee
Received January 5, 2007
ABSTRACT
Formation and use of a nitrogen dianion for selective hydrazine alkylation is reported. The scope and limitations of a new method were
demonstrated. The novel method provides fast and easy access to substituted hydrazines, which are widely used as drugs, pesticides, and
precursors for a variety of compounds in organic synthesis.
Many hydrazine derivatives show remarkable biological
activities. Hydrazine derivatives are well-known among
pesticides, drugs, amino acid precursors, and synthetic
building blocks for heterocycle synthesis. Several similar
compounds were shown to be effective for treatment of
tuberculosis, Parkinson’s disease, and hypertension.1 Also,
hydrazine-based peptidomimetics (azapeptides) are found to
be potent agents against diseases such as hepatitis, AIDS,
and SARS.2 Therefore, it can be easily seen that synthesis
of substituted hydrazines is a matter of great interest.
A number of systematic synthetic methods using orthogo-
nal protective group methodology were recently developed.3
These methods have their specific advantages but demand
many steps (protection and deprotection) for obtaining the
end product. Very recently, several methods using only two
protective groups have been reported.4 Our method we wish
to report here provides hydrazine derivatives with a minimum
number of steps and protective groups.
Metalation of the NH group followed by addition of an
electrophile is widely used in amine alkylation. However,
in hydrazine alkylation, there are several problems such as
(3) (a) Ma¨eorg, U.; Grehn, L.; Ragnarsson, U. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2626-2627. (b) Ma¨eorg, U.; Ragnarsson, U. Tetrahedron
Lett. 1998, 39, 681-684. (c) Ma¨eorg, U.; Pehk, T.; Ragnarsson, U. Acta
Chem. Scand. 1999, 53, 1127-1133. (d) Grehn, L.; Lo¨hn, H.; Ragnarsson,
U. Chem. Commun. 1997, 1-2. (e) Brosse, N.; Pinto, M.-F.; Jamart-
Gregoire, B. J. Org. Chem. 2000, 65, 4370-4374. (f) Brosse, N.; Pinto,
M.-F.; Bodiguel, J.; Jamart-Gregoire, B. J. Org. Chem. 2001, 66, 2869-
2873.
† University of Tartu.
‡ University of Konstanz.
(1) For a review, see: Ragnarsson, U. Chem. Soc. ReV. 2001, 30, 205-
220.
(2) (a) Zhang, R.; Durkin, J. P.; Windsor, W. T. Bioorg. Med. Chem.
Lett. 2002, 12, 1005-1008. (b) Lee, T.-W.; Cherney, M. M.; Huitema, C.;
Liu, J.; James, K. E.; Powers, J. C.; Eltis, L. D.; James, M. N. G. J. Mol.
Biol. 2005, 354, 1137-1151.
(4) (a) Tsubrik, O.; Ma¨eorg, U. Org. Lett. 2001, 3, 2297-2299. (b)
Tsubrik, O.; Ma¨eorg, U.; Ragnarsson, U. Tetrahedron Lett. 2002, 43, 6213-
6215. (c) Tsubrik, O.; Ma¨eorg, U.; Sillard, R.; Ragnarsson, U. Tetrahedron
2004, 60, 8363-8373.
10.1021/ol070026w CCC: $37.00
© 2007 American Chemical Society
Published on Web 02/20/2007

selectivity, lability of protective groups, etc.5 Despite all
aforementioned concerns about stability of such kinds of
compounds, a dianion, formed by metalation of PhNHNH-
Boc, was very stable in solution even at room temperature.
Also, one might expect problems with solubility; how-
ever, this dianion is very soluble in THF. In strong contrast
to the THF solution of the monoanion, which is mostly of
red color, the THF solution of the dianion exhibits a clear
bright yellow color. Therefore, this can be used for titration
of strong bases.
Familiarity with the acidity of NH groups is of vital interest
for the preparative chemist. Knowledge of corresponding pKa
values can be useful in the prediction of reactivity of
compounds, thus providing the way to selective reactions.
Recent reports show great advances in structure-property
relationship development using NH group acidity. pKa values
of corresponding NH groups can be estimated as 28
(PhNHNH2) and 17 (PhNHNHCbz).6 This huge difference
provides an opportunity for selective alkylation of either the
PhNH or the BocNH group.
proceeded without the formation of byproducts. It was not
possible to obtain dialkylated product from sterically more
hindered electrophiles (Pr, i-Pr, etc.) even using a great
excess of alkylating agent.
An attempt to utilize dielectrophiles was successful (2h).
Therefore, this method opens the access to many heterocycles
(pyrazolidine, piperazine, etc.) in a simple and convenient
one-pot fashion.
Because the first alkylation of the dianion proceeded much
faster, selective monoalkylation at the more reactive phenyl
nitrogen (Scheme 2) was conducted under conditions similar
Scheme 2. Selective Alkylation of Phenyl Nitrogen
Our method can be used in several different ways. It is
possible to perform double (symmetrical) alkylation, selective
monoalkylation of either of the nitrogens, or one-pot selective
alkylation of both nitrogens with different substituents.
There are very few reports utilizing a similar methodology
for the preparation of pyrazolidine ring systems, but there
are no reports about selective alkylation.7 Furthermore, our
method provides the possibility to carry out reactions under
milder conditions, more safely and with simpler separation
of products with an excellent yield.
to those for the dialkylation, with the only exception being
the addition of only 1 equiv of alkyl halide. Reactions were
normally complete within 2 h. For the reactive electrophiles
(methyl, allyl, etc.), traces of unselective alkylation products
were observed. This problem could be overcome by addition
of the alkylating agent at lower temperature.
Monoalkylation of the Boc nitrogen (Scheme 3) was more
complicated. Alkylation was carried out at -20 °C because
We have started with symmetrical alkylation (Scheme 1).
PhNHNHBoc can be easily prepared from phenyl hydrazine
Scheme 3. Selective Alkylation of Boc Nitrogen
Scheme 1. Symmetrical Alkylation
at higher temperatures alkylation proceeded unselectively,
probably due to some kind of equilibrium between mono-
metallated intermediates. This type of reaction is much
slower than those described above.
Successful consecutive monoalkylation of both nitrogens
with diverse electrophiles in a one-pot fashion could also
be achieved (Scheme 4). Probably this method is the most
and Boc2O.3 Metalation was conducted in THF at -78 °C
with 2 equiv of n-BuLi. Dianion formation was detected via
color change of the solution. The alkylating agent was then
added at room temperature. Alkylation took from 3 h to 4
days depending on the bulkiness of the employed electrophile
and its reactivity. The reaction rate increases in the following
order of leaving groups: chloride, bromide, and iodide.
Bulkier alkyl halogenides also exhibit a lower rate of
reaction. Reactions were monitored by TLC, and the stepwise
character of reactions could easily be observed; i.e., monoalky-
lated products were formed quickly (2 h), and dialkylated
products were formed very slowly (1-4 days). The reaction
Scheme 4. Selective One-Pot Alkylation of Both Nitrogens
(5) (a) Brown, B. R. The Organic Chemistry of Aliphatic Nitrogen
Compounds; Clarendon: Oxford, United Kingdom, 1994; pp 588. (b)
Greene, T. W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthe-
sis, 3rd ed.; John Wiley & Sons, Inc.: New York, 1999; Chapter 10,
pp 737.
interesting of the methods described here from the practical
point of view.
1098
Org. Lett., Vol. 9, No. 6, 2007

cause of the insolubility of this intermediate, a second
alkylation was carried out with the aid of slight heating
(Table 1). Nevertheless, reactions took more time than in
the case of 4b or 4d to complete. We have never noticed
similar sedimentation in the course of the other reactions,
despite the formation of PhNMeNLiBoc in two of them (once
as product (2a) and once as an intermediate (1a)).
Table 1. Alkylation Products
R1
R2
conditions
yield, %
Several new methods for the selective hydrazine alkylation
were developed. Use of a dianion for this purpose is reported
for the first time. Also, the scope and limitations of
applicability of this new method were demonstrated (Table
1). In summary, this new method can be easily applied in
the systematic synthesis of hydrazine derivatives, in the
synthesis of heterocycles, and even for analytical purposes
(titration of BuLi).
1a
1b
1c
Me
Et
All
Me
Et
All
Bz
H
H
H
H
H
H
H
H
Me
Et
i-Pr
All
Bz
Et
2 equiv of MeI, 3 h, rt
2 equiv of EtBr, 4 days, rt
2 equiv of AllBr, 1 day, rt
2 equiv of BzBr, 1 day, rt
MeI, 2 h, rt
EtBr, 2 h, rt
PrBr, 2 h, rt
i-PrI, 2 h, rt
AllBr, 2 h, rt
89
87
85
92
86
82
80
76
90
76
78
72
80
45
41
60
62
84
1d Bz
2a
2b
2c
2d i-Pr
2e
2f
Me
Et
n-Pr
All
Bz
C7H13
BzBr, 2 h, rt
C7H13Br, 2 h, rt
IPrI, 1 h, rt
Acknowledgment. This study was supported by grant No.
6706 from the Estonian Science Foundation. A. Bredihhin
thanks the Herberdt Quandt foundationsAltana AGsfor the
fellowship.
a
2g
2h -(CH2)3-
3a
3b
3c
3d
3e
4a
H
H
H
H
H
Me
MeI, 3 h, -20 °Cb
EtBr, 3 days, -20 °Cb
i-PrI, 3 days, -20 °Cb
AllBr, 1 day, -20 °Cb
BzBr, 1 day, -20 °Cb
MeI, -78 °C, 2 h;
EtBr, 1 day, 40 °C
EtBr, -78 °C, 2 h;
MeI 12 h, rt
Supporting Information Available: Experimental pro-
cedures and full spectroscopic data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
4b
4c
Et
Me
91
76
89
Me
n-Pr MeI, -78 °C, 2 h;
OL070026W
PrBr, 1 day, 40 °C
PrBr, -78 °C, 2 h;
4d n-Pr
Me
(6) (a) Ragnarsson, U.; Grehn, L.; Koppel, J.; Loog, O.; Tsubrik, O.;
Bredikhin, A.; Ma¨eorg, U.; Koppel, I. J. Org. Chem. 2005, 70, 5916-
5921. (b) Bredikhin, A.; Tsubrik, O.; Sillard, R.; Ma¨eorg, U. Synlett 2005,
1939-1941.
MeI, 12 h, rt
b
a C7H13 ) cyclohexylmethyl. Addition was made at -78 °C.
(7) (a) Wilkinson, D. E.; Thomas, B. E., IV; Limburg, D. C.; Holmes,
A.; Sauer, H.; Ross, D. T.; Soni, R.; Chen, Y.; Guo, H.; Howorth, P.;
Valentine, H.; Spicer, D.; Fuller, M.; Steiner, J. P.; Hamilton, G. S.; Wu,
Y.-Q. Bioorg. Med. Chem. 2003, 11, 4815-4825. (b) Hemmerlin, C.; Cung,
M. T.; Boussard, G. Tetrahedron Lett. 2001, 42, 5009-5012.
Some very interesting details have to be mentioned. In
both experiments where MeI was added first (4a, 4c), a
precipitate (presumably PhNMeNLiBoc) was formed. Be-
Org. Lett., Vol. 9, No. 6, 2007
1099