The use of polyanions of hydrazines in the synthesis of heterocycles

Article abstract of DOI:10.1016/j.tet.2009.04.040

A novel method for the synthesis of cyclic hydrazine derivatives is reported. The new method for the generation of nitrogen-containing heterocycles is based on a polyanion strategy. The described method provides a convenient access to cyclic hydrazine der

Full text of DOI:10.1016/j.tet.2009.04.040

Tetrahedron 65 (2009) 5438–5442
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
The use of polyanions of hydrazines in the synthesis of heterocycles
*
ˇ
Oleg Lebedev, Aleksei Bredihhin, Svetlana Tsupova, Uno Ma¨eorg
Institute of Chemistry, University of Tartu, Jakobi 2, 51014 Tartu, Estonia
a r t i c l e i n f o
a b s t r a c t
Article history:
A novel method for the synthesis of cyclic hydrazine derivatives is reported. The new method for the
generation of nitrogen-containing heterocycles is based on a polyanion strategy. The described method
provides a convenient access to cyclic hydrazine derivatives, which are extensively used in drug industry
and agriculture. The advantages and limitations of the new method are also demonstrated.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 6 January 2009
Received in revised form 24 March 2009
Accepted 9 April 2009
Available online 17 April 2009
Keywords:
Hydrazines
Heterocysles
Alkylation
Trianion
Dianion
1. Introduction
are sometimes limited by low yields and the availability of starting
materials. A greater success has been achieved in the synthesis of
Heterocyclic compounds are very abundant in nature. Their
structural subunits are found in many natural products such as
antibiotics, hormones, vitamins, etc. Heterocycles are also of sig-
nificant importance in the production of all types of pharmaceuti-
cals, dyes, and agrochemicals.1
The area of application of hydrazine derivatives is very wide.
Many of them show remarkable biological activities and various
similar compounds were discovered to be effective for treatment of
hypertension, tuberculosis, and Parkinson’s disease2 as well to be
active against hepatitis, AIDS, and SARS.3
It is obvious that N-aminopyrrolidines, pyrazolidines, and their
homologs, which are heterocycles containing hydrazine moiety are
of great interest in recent years. These heterocycles are extensively
used as drugs, pesticides, and precursors in organic synthesis.4
These applications have induced great interest in the synthesis of
heterocyclic hydrazine derivatives.
A number of synthetic procedures for obtaining nitrogen-
containing heterocycles have been developed. To construct N-
aminoazacycloalkanes, most often nitrosation followed by LiAlH4
reduction is used.5 However, the area of application of this
method is limited to aromatic substrates, in addition, products of
nitrosation are highly carcinogenic.6 Other methods have utilized
reactions of hydrazines with difunctional substances, such as
dihalides,7 dimesylates8 or dicarbonyl compounds.9 These methods
pyrazolidines and their homologs using reaction of 1,2-di-
substituted hydrazines with dihalides.10 However, the scope of this
strategy is cursorily studied and additional investigations should
be carried out. These heterocycles are also prepared via Diels–
Alder reaction of dienes with azo-compounds11 often requiring the
presence of commercially non-available starting materials, which
should be additionally synthesized. Pyrazolidines can be also
made by the cyclization of homoallylhydrazines,12 however, this
reaction does not proceed selectively tending to low yields.
As we have demonstrated in our previous works, a polyanion
strategy has been successfully employed for alkylation of hydrazine
derivatives.13 In our current work we designed a new method of
construction of N-aminoazacycloalkanes and pyrazolidine-type
ring systems based on this strategy.
2. Results and discussion
The key step of our method is the formation of polyanions,
which are further alkylated with dihalide to yield the correspond-
ing heterocycle.
We have started with commercially available tert-butyl hydra-
zinecarboxylate, which was metalated in THF at ꢀ78 ꢁC with
3 equiv of BuLi to form a trianion. This trianion was stable in the
THF solution at low temperatures, but partial decomposition was
detected at room temperature. We have also noticed that the tri-
anion was unstable in the presence of air, so all reactions must be
carried out in an inert atmosphere. The trianion can be alkylated
* Corresponding author. Tel.: þ372 7 375243; fax: þ372 7 375245.
E-mail address: uno@chem.ut.ee (U. Ma¨eorg).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.04.040

O. Lebedev et al. / Tetrahedron 65 (2009) 5438–5442
5439
with dihalide to form corresponding pyrrolidine, piperidine or
azepane ring systems (Scheme 1). We have also shown that 1,4-
dibromopentane, which contains a secondary reaction center gave
a good yield. Reactions were monitored by TLC, which showed that
generally 4 h was required to obtain the desired product.
Moreover the elevated basicity of phenyl hydrazine trianion pro-
motes transmetallation and elimination reactions.
We have tried to prepare full range of heterocycles from phenyl
hydrazine trianion, but only five and six-membered rings were
obtained. In all other cases a complex mixture of products has
formed. Attempts to optimize the reaction conditions varying
equivalents of BuLi and the temperature of dihalide addition have
given no results.
R2
3 equiv BuLi
- 78 °C, THF
R2
R1
H
R1
H
H
H
Reaction of tert-butyl carbazate trianion with
a,a
0-dibromo-
N
N
N
N
o-xylene in ratio 1:1 has unexpectedly given di-tert-butyl 2,20-[1,2-
phenylenedi(methylene)]dihydrazinecarboxylate (Scheme 2). The
structure of the product shows that one molecule of dibromide
attaches to two trianions. At the next step we carried out the re-
action reducing twice the amount of dibromide, but only traces of
the desired product were found in this experiment. A probable
n
Hal
1a-f
n
Hal
1a-c n = 1-3, R1 = Boc, R2 = H
1d n = 1, R1 = Boc, R2 = Me
1e-f n = 1-2, R1 = Ph, R2 = H
Hal = Cl, Br
mechanism for the reaction of trianion with
is based on transmetallation equilibrium (Scheme 3). We propose
that
0-dibromo-o-xylene interacts with trianion generating
a,a
0-dibromo-o-xylene
Scheme 1. Alkylation of trianion.
We have observed that the yields of heterocycles strongly
depended on the temperature of addition of dihalide (Table 1). The
best yield for tert-butyl pyrrolidine-1-ylcarbamate was achieved
when dihalide was added at ꢀ78 ꢁC. Other heterocycles were
obtained in moderate or good yields with the addition of dihalide at
ꢀ40 ꢁC. We propose that an increase in steric hindrance appears in
the construction of bulkier heterocycles. Therefore, a higher tem-
perature is required to overcome this problem. Further increasing
the temperature of addition of the alkylating agent tended to lower
yields of all heterocycles, probably due to partial decomposition of
the trianion.
The trianion obtained from phenyl hydrazine is a much stronger
base than the trianion obtained from tert-butyl carbazate. The al-
kylation also proceeds much faster even at low temperatures. We
have noticed that the formation of heterocycles from phenyl hydra-
zine trianion was not very selective. For example, in case of 1-bromo-
4-chlorobutane main products were N-phenylpyrrolidin-1-amine
and phenylpiperidazine. We suppose that the difference in the
acidities of PhNH and NH2 groups is not sufficient for ensuring se-
lectivity. In addition, the decrease of selectivity is obviously influ-
enced by the difference of steric hindrances of phenyl and Boc group.
a,a
dianion 4 and ionic intermediate 5, which are stabilized by the
aromatic nucleus and therefore no cyclization is possible. This
intermediate attaches to one molecule of trianion to give in-
termediate 6, which reacts with dianion 4 forming tetraanion 7.
According to this mechanism polyanion strategy is the key step in
the formation of such type products and explains why compound
2a have not been obtained even if the same substrates have been
used in other reports.14
Boc
HN
NH
3 equiv BuLi
- 78 °C, THF
H
H
Boc
H
Boc
NH
N
N
N
H
Br
Br
2a
Scheme 2. Reaction of tert-butyl carbazate trianion with
a,
a
0-dibromo-o-xylene.
Li
Li
Boc
Li
Boc
Li
Br
Li
Br
Br
Li
Br
N
N
N
N
+
+
4
5
Table 1
Synthesis of heterocycles
Li
Boc
- LiBr
N
N
Li
Boc
Li
Boc
HN
NH
Li
Li
Li
N
N
Br
Li
Boc
Li
R
Boc
N
Li
N
N
Boc
NH
Boc
H
R
Boc
Ph
H
Li
N
N
N
N
N
N
N
N
N
N
H
n
n
- LiBr
Boc
Li
1a-d
1e-f
2a
3a-b
Li
6
7
Scheme 3. Proposed mechanism of the reaction of tert-butyl carbazate trianion with
R
n
Conditions
Yield, %
a,
a
0-dibromo-o-xylene.
1a13b
1a
H
H
H
H
H
H
H
H
H
H
Me
Me
1
1
1
2
2
2
2
3
3
3
1
1
1
2
Br(CH2)4Cl, 4 h, ꢀ78 ꢁC to rt
Br(CH2)4Cl, 4 h, ꢀ40 ꢁC to rt
Br(CH2)4Cl, 3 h, rt
Br(CH2)5Br, 4 h, ꢀ78 ꢁC to rt
Br(CH2)5Br, 4 h, ꢀ40 ꢁC to rt
Br(CH2)5Br, 4 h, ꢀ10 ꢁC to rt
Br(CH2)5Br, 3 h, rt
71
54
52
41
73
63
52
24
41
31
48
52
45
34
45
87
64
58
38
To the best of our knowledge it is the first report exploring the
1a
1b9
1b
synthesis of such kind compounds. Our method provides an easy
and convenient access to other new hydrazine derivatives and
heterocycles.
1b
1b
1c
1c
1c
1d
1d
To obtain dianions from PhNHNHBoc and EtNHNHBoc, 2 equiv
of BuLi has been used. These dianions have been alkylated with
dihalides to yield corresponding pyrazolidines (Scheme 4). Re-
actions were normally complete within 3 h. Traces of by-products
of elimination were observed if the dihalide was added to
EtNHNHBoc at room temperature. This problem can be overcome
by addition of the alkylating agent at ꢀ40 ꢁC. Nevertheless, reaction
of PhNHNHBoc with 1,3-dihalides proceeded selectively even if the
addition was made at room temperature. We have also showed that
diiodides exhibit the tendency to give better yields than dibro-
mides. Reaction of dianions with 1,4-dihalides yielded products, in
Br(CH2)6Br, 4 h, ꢀ78 ꢁC to rt
Br(CH2)6Br, 4 h, ꢀ40 ꢁC to rt
Br(CH2)6Br, 4 h, ꢀ10 ꢁC to rt
Br(CH2)3CH(CH3)Br, 4 h, ꢀ78 ꢁC to rt
Br(CH2)3CH(CH3)Br, 4 h, ꢀ40 ꢁC to rt
Br(CH2)4Cl, 2 h, rt
1e15
1f9
2a
Br(CH2)5Br, 2 h, rt
a
,
a
0-Dibromo-o-xylene, 30 min, ꢀ40 ꢁC to rt
3a13c
3a
Ph
Ph
Et
I(CH2)3I, 30 min, rt
Br(CH2)3Br, 1 h, rt
3b
3b
I(CH2)3I, 3 h, ꢀ40 ꢁC to rt
Et
Br(CH2)3Br, 3 h, ꢀ40 ꢁC to rt

5440
O. Lebedev et al. / Tetrahedron 65 (2009) 5438–5442
2 equiv BuLi
- 78 °C, THF
THF (14 mL) was added to dissolve the solid. The reaction mixture
R
H
Boc
H
R
Boc
was cooled down to ꢀ78 ꢁC and 1.6 M BuLi solution in hexane
(6 mmol, 3.75 mL) was added dropwise. The reaction mixture was
allowed to warm up to ꢀ40 ꢁC for another 15 min and 1-bromo-4-
chlorobutane (2 mmol, 0.23 mL) was added. Then the reaction
mixture was allowed to warm up to room temperature. After 4 h
the reaction was mainly complete, but it was allowed to stir over-
night. Then 0.1 mL of H2O was added to the reaction mixture and
the solvent was evaporated under reduced pressure. To the residue
15 mL of chloroform and MgSO4 was added. The mixture was fil-
tered and MgSO4 was washed with chloroform (3ꢂ2 mL). The
volatiles were removed under reduced pressure. The residue was
purified by column chromatography on silica (Hexane/EtOAc 1:1),
resulting title compound 1a (199 mg, 54%) as colorless solid.
Method C. An oven-dried flask was charged with BocNHNH2
(2 mmol, 264 mg), evacuated, and backfilled with argon. There-
after THF (14 mL) was added to dissolve the solid. The reaction
mixture was cooled down to ꢀ78 ꢁC and 1.6 M BuLi solution in
hexane (6 mmol, 3.75 mL) was added dropwise. The reaction
mixture was allowed to warm up to room temperature for another
15 min and 1-bromo-4-chlorobutane (2 mmol, 0.23 mL) was
added. After 3 h the reaction was mainly complete, but it was
allowed to stir overnight. Then 0.1 mL of H2O was added to the
reaction mixture and the solvent was evaporated under reduced
pressure. To the residue 15 mL of chloroform and MgSO4 was
added. The mixture was filtered and MgSO4 was washed with
chloroform (3ꢂ2 mL). The volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica (Hexane/EtOAc 1:1), resulting title compound 1a (195 mg,
52%) as colorless solid.
N N
N
N
Hal
Hal
n
3a-b
3a R = Ph
3b R = Et
Hal = Br, I
Scheme 4. Alkylation of dianion.
which two dianion fragments were connected by the alkyl chain of
dihalide, probably due to steric hindrances.
The dianion of BocNHNHCOOEt has been also obtained using
2 equiv of BuLi. However, it precipitates from the solution and does
not show any reactivity even at 50 ꢁC.
3. Conclusions
In summary, we have demonstrated a new strategy for the
synthesis of nitrogen-containing heterocycles. The scope and lim-
itations of this new method were also described. The formation of
unexpected products was reported. Our method can be easily used
for the construction of many different cyclic hydrazine derivatives.
4. Experimental
4.1. General
All reagents were obtained from commercial sources and used
without further purification. THF was freshly distilled from Na/
benzophenone. NMR spectroscopy was performed on a Bruker
Avance II 200 MHz spectrometer using TMS as an internal standard.
Infrared spectra were measured on a Perkin–Elmer Spectrum BXII
FTIR spectrometer using attenuated total reflectance technique.
HRMS were measured on Thermo Electron LTQ Orbitrap ESI mass-
spectrometer. Melting points were determined on a Gallenkamp
melting point apparatus. Compounds 1a, 1b, 1d, 2a are crystalline
solids, others are oils.
4.2.2. tert-Butyl piperidine-1-ylcarbamate (1b9)
Method A. Compound 1b was prepared as described for 1a using
1,5-dibromopentane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 1:1), resulting title com-
pound 1b (164 mg, 41%) as colorless solid, mp 89–91. Rf (EtOAc/
hexane 1:1) 0.71. 1H NMR (200 MHz, CDCl3, TMS):
d
¼5.50 (br s, 1H,
NH), 2.72 (m, 4H, NCH2), 1.67 (m, 4H, NCH2CH2), 1.47–1.37 (m, 11H,
C(CH3)3, N(CH2)2CH2). 13C NMR (50 MHz, CDCl3, TMS):
¼154.7,
79.9, 57.2, 28.6, 25.8, 23.5. FTIR
(cmꢀ1): 3220, 2978, 2944, 2862,
d
4.2. General procedure for the syntheses of compounds 1a–f
n
1721, 1698, 1548, 1364, 1269, 1251, 1159, 1052, 1037, 856, 643.
Method B. Compound 1b was prepared as described for 1a using
1,5-dibromopentane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 1:1), resulting title com-
pound 1b (293 mg, 73%) as colorless solid.
Method C. Compound 1b was prepared as described for 1a using
1,5-dibromopentane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 1:1), resulting title com-
pound 1b (207 mg, 52%) as colorless solid.
Method D. An oven-dried flask was charged with BocNHNH2
(2 mmol, 264 mg), evacuated, and backfilled with argon. Thereafter
THF (14 mL) was added to dissolve the solid. The reaction mixture
was cooled down to ꢀ78 ꢁC and 1.6 M BuLi solution in hexane
(6 mmol, 3.75 mL) was added dropwise. The reaction mixture was
allowed to warm up to ꢀ10 ꢁC for another 15 min and 1,5-dibromo-
pentane (2 mmol, 0.27 mL) was added. After stirring for another
15 min at ꢀ10 ꢁC the reaction mixture was allowed to warm up to
room temperature. After 4 h the reaction was mainly complete, but
it was allowed to stir overnight. Then 0.1 mL of H2O was added to
the reaction mixture and the solvent was evaporated under re-
duced pressure. To the residue 15 mL of chloroform and MgSO4 was
added. The mixture was filtered and MgSO4 was washed with
chloroform (3ꢂ2 mL). The volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica (Hexane/EtOAc 1:1), resulting title compound 1b (252 mg,
63%) as colorless solid.
4.2.1. tert-Butyl pyrrolidine-1-ylcarbamate (1a13b
)
Method A. An oven-dried flask was charged with BocNHNH2
(2 mmol, 264 mg), evacuated, and backfilled with argon. There-
after THF (14 mL) was added to dissolve the solid. The reaction
mixture was cooled down to ꢀ78 ꢁC and 1.6 M BuLi solution in
hexane (6 mmol, 3.75 mL) was added dropwise. The reaction
mixture was stirred for 15 min and 1-bromo-4-chlorobutane
(2 mmol, 0.23 mL) was added. After stirring for another 1 h at
ꢀ78 ꢁC, the reaction mixture was allowed to warm up to room
temperature. After 4 h the reaction was mainly complete, but it
was allowed to stir overnight. Then 0.1 mL of H2O was added to
the reaction mixture and the solvent was evaporated under re-
duced pressure. To the residue 15 mL of chloroform and MgSO4
was added. The mixture was filtered and MgSO4 was washed with
chloroform (3ꢂ2 mL). The volatiles were removed under reduced
pressure. The residue was purified by column chromatography on
silica (Hexane/EtOAc 1:1), resulting title compound 1a (263 mg,
71%) as colorless solid, mp 107–109 ꢁC. Rf (EtOAc/hexane 1:1) 0.46.
1H NMR (200 MHz, CDCl3, TMS):
4H, NCH2), 1.82 (m, 4H, NCH2CH2), 1.46 (s, 9H, C(CH3)3). 13C NMR
d
¼5.63 (br s, 1H, NH), 2.88 (m,
(50 MHz, CDCl3, TMS):
d
¼155.1, 79.9, 55.0, 28.5, 22.6. FTIR
n
(cmꢀ1): 3225, 2976, 2938, 2842, 1710, 1689, 1542, 1365, 1275, 1253,
1156, 1056, 1017, 862, 632, 624.
Method B. An oven-dried flask was charged with BocNHNH2
(2 mmol, 264 mg), evacuated, and backfilled with argon. Thereafter

O. Lebedev et al. / Tetrahedron 65 (2009) 5438–5442
5441
4.2.3. tert-Butyl azepane-1-ylcarbamate (1c)
4.3. General procedure for the synthesis of compound 2a
Method A. Compound 1c was prepared as described for 1a using
1,6-dibromohexane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 2:1), resulting title com-
pound 1c (103 mg, 24%) as a colorless oil. Rf (EtOAc/hexane 1:2)
4.3.1. Di-tert-butyl 2,20-(1,2-phenylenedi(methylene))-
dihydrazinecarboxylate
An oven-dried flask was charged with BocNHNH2 (11.36 mmol,
1.50 g), evacuated, and backfilled with argon. Thereafter THF
(80 mL) was added to dissolve the solid. The reaction mixture was
cooled down to ꢀ78 ꢁC and 1.6 M BuLi solution in hexane
(34.08 mmol, 21.3 mL) was added dropwise. The reaction mixture
0.57. 1H NMR (200 MHz, CDCl3, TMS):
d
¼5.88 (br s, 1H, NH), 3.00
(m, 4H, NCH2), 1.62–1.45 (m, 17H, C(CH3)3, CH2). 13C NMR (50 MHz,
CDCl3, TMS):
(cmꢀ1):
d
¼155.2, 79.8, 58.6, 28.6, 27.1, 26.9. FTIR
n
3247, 2977, 2913, 2862, 1714, 1499, 1365, 1269, 1252, 1169, 1133,
1095, 1018, 877, 755, 623. HRMS (ESI): m/z calcd for C11H22N2O2
[MH]þ: 215.1754; found: 215.1755.
was allowed to warm up to ꢀ40 ꢁC for another 15 min and
a, -
a0
dibromo-o-xylene (11.17 mmol, 2.95 g) was added. Then the re-
action mixture was allowed to warm up to room temperature. After
30 min the reaction was mainly complete. Then 1 mL of H2O was
added to the reaction mixture and the solvent was evaporated
under reduced pressure. To the residue 75 mL of chloroform and
MgSO4 was added. The mixture was filtered and MgSO4 was
washed with chloroform (3ꢂ2 mL). The volatiles were removed
under reduced pressure. The residue was purified by column
chromatography on silica (Hexane/EtOAc 1:1) resulting title com-
pound 2a (932 mg, 45%) as yellowish solid, mp 120–122. Rf (EtOAc/
Method B. Compound 1c was prepared as described for 1a using
1,6-dibromohexane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 2:1), resulting title com-
pound 1c (174 mg, 41%) as a colorless oil.
Method D. Compound 1c was prepared as described for 1a using
1,6-dibromohexane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 2:1), resulting title com-
pound 1c (137 mg, 32%) as a colorless oil.
4.2.4. tert-Butyl 2-methylpyrrolidine-1-ylcarbamate (1d)
hexane 1:1) 0.48. 1H NMR (200 MHz, CDCl3, TMS):
C6H4), 6.81 (br s, 2H, BocNH), 4.53/4.06 (br s/s, 6H, NHCH2/CH2),
1.46 (s, 18H, C(CH3)3). 13C NMR (50 MHz, CDCl3, TMS):
¼156.9,
137.2, 131.3, 128.0, 80.3, 54.3, 28.6. FTIR
(cmꢀ1): 3336, 3307, 3226,
d
¼7.27 (m, 4H,
Method A. Compound 1d was prepared as described for 1a using
1,4-dibromopentane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 1:1), resulting title com-
pound 1d (193 mg, 48%) as colorless solid, mp 81–83. Rf (EtOAc/
d
n
2977, 2934, 2867, 1698, 1552, 1482, 1454, 1367, 1271, 1251, 1152,
1007, 854, 844, 739, 615. HRMS (ESI): m/z calcd for C18H30N4O4
[MH]þ: 367.2340; found: 367.2340.
hexane 1:1) 0.63. 1H NMR (200 MHz, CDCl3, TMS):
d
¼5.39 (br s, 1H,
NH), 3.29 (m, 1H, NCH), 2.65 (m, 2H, NCH2), 1.98–1.68 (m, 4H, CH2),
1.46 (m, 9H, C(CH3)3), 1.12 (d, J¼6.0 Hz, 3H, CH3). 13C NMR (50 MHz,
CDCl3, TMS):
d
¼155.5, 79.8, 61.0, 55.1, 30.9, 28.6, 20.6, 18.4. FTIR
n
4.4. General procedure for the syntheses of compounds 3a, 3b
(cmꢀ1): 3223, 2970, 2932, 2874, 1693, 1538, 1365, 1273, 1252, 1160,
1051, 1026, 1007, 819, 763, 640. HRMS (ESI): m/z calcd for
C10H20N2O2 [MH]þ: 201.1598; found: 201.1598.
4.4.1. tert-Butyl 2-phenylpyrazolidine-1-carboxylate (3a13c
)
Method E. An oven-dried flask was charged with PhNHNHBoc
(1 mmol, 208 mg), evacuated, and backfilled with argon. Thereafter
THF (5 mL) was added to dissolve the solid. The reaction mixture was
cooled down to ꢀ78 ꢁC and 1.6 M BuLi solution in hexane (2.1 mmol,
1.30 mL) was added dropwise. The reaction mixture was allowed to
warm up to room temperature for another 15 min and 1,3-diiodo-
propane (1 mmol, 0.115 mL) was added. After 30 min the reaction
was mainly complete. Volatiles were removed under reduced pres-
sure. To the residue 7 mL of chloroform and 3 mL of 1 M KOH was
added. KOH solution was separated and extracted with chloroform
(2ꢂ3 mL). The organic fractions were combined and dried over an-
hydrous MgSO4. The mixture was filtered and the volatiles were re-
moved under reduced pressure. The residue was purified by column
chromatography on silica (Hexane/Et2O 1:1), resulting title compound
3a (216 mg, 87%) as colorless oil. Rf (Et2O/hexane 1:1) 0.36. 1H NMR
Method B. Compound 1d was prepared as described for 1a using
1,4-dibromopentane as dihalide. Product was purified by column
chromatography on silica (Hexane/EtOAc 1:1), resulting title com-
pound 1d (207 mg, 52%) as colorless solid.
4.2.5. N-Phenylpyrrolidin-1-amine (1e15
)
An oven-dried flask was charged with PhNHNH2 (2 mmol,
216 mg), evacuated, and backfilled with argon. Thereafter THF
(14 mL) was added. The reaction mixture was cooled down to ꢀ78 ꢁC
and 1.6 M BuLi solution in hexane (6 mmol, 3.75 mL) was added
dropwise. The reaction mixture was allowed to warm up to room
temperature for another 15 min and 1-bromo-4-chlorobutane
(2 mmol, 0.23 mL) was added. After 2 h the reaction was mainly
complete. To the residue 15 mL of chloroform and MgSO4 was added.
The mixture was filtered and MgSO4 was washed with chloroform
(3ꢂ2 mL). The volatiles were removed under reduced pressure. The
residue was purified by column chromatography on silica (Hexane/
EtOAc 4:1), resulting title compound 1e (145 mg, 45%) as colorless oil.
(200 MHz, CDCl3, TMS):
d
¼7.24 (m, 2H, Ph), 6.93 (m, 3H, Ph), 3.57 (m,
4H, NCH2), 1.98 (quin, J¼7.0 Hz, 2H, NCH2CH2), 1.47 (s, 9H, C(CH3)3).
13C NMR (50 MHz, CDCl3, TMS):
80.7, 53.9, 45.0, 28.5, 25.6. FTIR
d
¼156.1, 151.5, 128.9, 121.2, 115.6,
n
(cmꢀ1): 2972, 2933, 2894, 1688,
Rf (EtOAc/hexane 1:4) 0.59. 1H NMR (200 MHz, CDCl3, TMS):
d¼7.20
1598, 1489, 1452, 1390, 1364, 1249, 1161, 1128, 858, 760, 700.
Method F. Compound 3a was prepared as described in method E
using 1,3-dibromopropane as dihalide. Product was purified by
column chromatography on silica (Hexane/Et2O 1:1), resulting title
compound 3a (165 mg, 64%) as colorless oil.
(m, 2H, Ph), 6.89 (m, 2H, Ph), 6.76 (m,1H, Ph), 4.25 (br s,1H, NH), 2.77
(m, 4H, NCH2), 1.83 (m, 4H, NCH2CH2). 13C NMR (50 MHz, CDCl3,
TMS):
d
¼149.0, 129.1, 119.1, 113.4, 55.9, 22.1. FTIR
n
(cmꢀ1): 3239,
3050, 3022, 2963, 2875, 2807, 1602, 1495, 1256, 887, 749, 693.
4.2.6. N-Phenylpiperidin-1-amine (1f 9)
4.4.2. tert-Butyl 2-ethylpyrazolidine-1-carboxylate (3b)
Compound 1f was prepared as described for 1e using 1,5-dibro-
mopentane as dihalide. Product was purified by column chroma-
tography on silica (Hexane/EtOAc 8:1), resulting title compound 1f
(121 mg, 34%) as colorless oil. Rf (EtOAc/hexane 1:4) 0.73. 1H NMR
Method G. An oven-dried flask was charged with EtNHNHBoc
(2 mmol, 320 mg), evacuated, and backfilled with argon. Thereafter
THF (8 mL) was added. The reaction mixture was cooled down to
ꢀ78 ꢁC and 1.6 M BuLi solution in hexane (4.2 mmol, 2.63 mL) was
added dropwise. The reaction mixture was allowed to warm up to
ꢀ40 ꢁC for another 15 min and 1,3-diiodopropane (2 mmol,
0.23 mL) was added. Then the reaction mixture was allowed to
warm up to room temperature. After 3 h the reaction was mainly
complete. The volatiles were removed under reduced pressure. To
(200 MHz, CDCl3, TMS):
1H, Ph), 4.32 (br s,1H, NH), 2.64 (m, 4H, NCH2),1.67 (m, 4H, NCH2CH2),
1.42 (m, 2H, N(CH2)2CH2). 13C NMR (50 MHz, CDCl3, TMS):
¼148.0,
129.1, 119.2, 113.7, 57.8, 26.1, 23.8. FTIR
(cmꢀ1): 3245, 3050, 3021,
2935, 2854, 2784, 1601, 1495, 1253, 1036, 879, 864, 801, 749. 693.
d¼7.18 (m, 2H, Ph), 6.88 (m, 2H, Ph), 6.75 (m,
d
n

5442
O. Lebedev et al. / Tetrahedron 65 (2009) 5438–5442
the residue 14 mL of chloroform and 6 mL of 1 M KOH was added.
KOH solution was separated and extracted with chloroform
(2ꢂ3 mL). The organic fractions were combined and dried over
anhydrous MgSO4. The mixture was filtered and volatiles were
removed under reduced pressure. The residue was purified by
column chromatography on silica (Hexane/EtOAc 1:1) resulting title
compound 3b (234 mg, 58%) as colorless oil. Rf (EtOAc/hexane 1:1)
References and notes
1. (a) Katritzky, A. R.; Pozharskii, A. F. Handbook of Heterocyclic Chemistry: 2000,
2nd ed.; Pergamon: New York, NY, USA, 2000; (b) Padwa, A.; Bur, S. Chem. Rev.
2004, 104, 2401–2432; (c) Sondhi, S. M.; Dinodia, M.; Singh, J.; Rani, R. Curr.
Bioact. Compd. 2007, 3, 91–108.
2. Ragnarsson, U. Chem. Soc. Rev. 2001, 30, 205–220.
3. (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) Ahn, J. H.; Kim, J. A.; Kim, H.-M.; Kwon, H.-M.; Huh, S.-C.; Rhee, S. D.; Kim, K. R.;
Yang, S.-D.; Park, S.-D.; Lee, J. M.; Kim, S. S.; Cheon, H. G. Bioorg. Med. Chem. Lett.
2005, 15, 1337–1340; (b) Paris, D.; Cottin, M.; Demonchaux, P.; Augent, G.; Du-
passieux, P.; Lenoir, P.; Peck, M. J.; Jasserand, D. J. Med. Chem. 1995, 38, 669–685.
5. (a) Smith, A. B., III; Ku¨rtli, L.; Davulcu, A. H. Org. Lett. 2006, 8, 2167–2170; (b)
Winter, A. H.; Gibson, H. H.; Falvey, D. E. J. Org. Chem. 2007, 72, 8186–8195; (c)
Tsotinis, A.; Panoussopoulou, M.; Eleutheriades, A.; Davidson, K.; Sugden, D.
Eur. J. Med. Chem. 2007, 42, 1004–1013.
0.39. 1H NMR (200 MHz, CDCl3, TMS):
d
¼3.51 (m, 2H, BocNCH2),
3.01 (t, J¼6.8 Hz, 2H, EtNCH2), 2.67 (q, J¼7.2 Hz, 2H, NCH2CH3), 2.08
(m, 2H, NCH2CH2), 1.49 (s, 9H, C(CH3)3), 1.11 (t, J¼7.0 Hz, 3H,
NCH2CH3). 13C NMR (50 MHz, CDCl3, TMS):
d
¼156.5, 79.8, 53.0, 51.5,
44.6, 28.6, 24.4, 13.1. FTIR
n
(cmꢀ1): 2976, 2936, 2892, 1714, 1687,
1455, 1390, 1364, 1247, 1170, 1143, 766, 730. HRMS (ESI): m/z calcd
for C10H20N2O2 [MH]þ: 201.1598; found: 201.1598.
6. Eisenbrand, G.; Mueller, N.; Denkel, E.; Sterzel, W. J. Cancer Res. Clin. Oncol. 1986,
112, 196–204.
7. De Jong, J. C.; Sørensen, L. G.; Tornqvist, H.; Jacobsen, P. Bioorg. Med. Chem. Lett.
2004, 14, 1741–1744.
Method H. Compound 3b was prepared as described in method
G using 1,3-dibromopropane as dihalide. Product was purified by
column chromatography on silica (Hexane/EtOAc 1:1), resulting
title compound 3b (154 mg, 38%) as colorless oil.
8. Lassaletta, J. M.; Alcazaro, M.; Fernandez, R. Chem. Commun. 2004, 3, 298–299.
9. Katritzky, R. A.; Fan, W.-Q. J. Org. Chem. 1990, 55, 3205–3209.
10. (a) Ahn, J. H.; Shin, M. S.; Jun, M. A.; Jung, S. H.; Kang, S. K.; Kim, K. R.; Rhee, S.
D.; Kang, N. S.; Kim, S. Y.; Sohn, S.-K.; Kim, S. G.; Jin, M. S.; Lee, J. O.; Cheon, H.
G.; Kim, S. S. Bioorg. Med. Chem. Lett. 2007, 17, 2622–2628; (b) Yuhong, J.;
Varma, R. J. Org. Chem. 2006, 71, 135–141; (c) Melendez, R. E.; Lubell, W. D. J. Am.
Chem. Soc. 2004, 126, 6759–6764.
11. Perez Luna, A.; Ceschi, M.-A.; Bonin, M.; Micouin, L.; Husson, H.-P.; Gougeon, S.;
Estenne-Bouhtou, G.; Marabout, B.; Sevrin, M.; George, P. J. Org. Chem. 2002, 67,
3522–3524.
Acknowledgements
This study was supported by grant No 6706 from the Estonian
Science Foundation and from the project SF0182734s06 of the
Ministry of Education of Estonia.
12. Ternon, M.; Outurquin, F.; Paulmier, C. Tetrahedron 2001, 57, 10259–10270.
13. (a) Bredihhin, A.; Ma¨eorg, U. Tetrahedron 2008, 64, 6788–6793; (b) Bredihhin,
A.; Ma¨eorg, U. Org. Lett. 2007, 9, 4975–4977; (c) Bredihhin, A.; Groth, U. M.;
Ma¨eorg, U. Org. Lett. 2007, 9, 1097–1099.
14. Carpino, L. A. J. Am. Chem. Soc. 1957, 79, 4427–4431.
15. Verardo, G.; Toniutti, N.; Giumanini, A. G. Tetrahedron 1997, 53, 3707–3722.
Supplementary data
Supplementary data associated with this article can be found in
the online version, at doi:10.1016/j.tet.2009.04.040