Facile preparation of allyl amines and pyrazoles by hydrazinolysis of 2-ketoaziridines

Article abstract of DOI:10.1016/j.tetlet.2005.11.039

Allyl amines and pyrazoles can be obtained by hydrazinolysis of 2-ketoaziridines. A variety of aziridines, including N-unprotected, N-substituted, as well as bicyclic enamine and aminal type, can be transformed into diversely substituted linear or cyclic products. The hydrazinolysis of homochiral aziridines proceeds without racemization.

Full text of DOI:10.1016/j.tetlet.2005.11.039

Tetrahedron
Letters
Tetrahedron Letters 47 (2006) 255–259
Facile preparation of allyl amines and pyrazoles by
hydrazinolysis of 2-ketoaziridines
Gang Chen, Mikio Sasaki and Andrei K. Yudin*
Davenport Research Laboratories, Department of Chemistry, University of Toronto, 80 St. George Street, Toronto,
Ontario, Canada M5S 3H6
Received 7 October 2005; revised 4 November 2005; accepted 8 November 2005
Abstract—Allyl amines and pyrazoles can be obtained by hydrazinolysis of 2-ketoaziridines. A variety of aziridines, including
N-unprotected, N-substituted, as well as bicyclic enamine and aminal type, can be transformed into diversely substituted linear
or cyclic products. The hydrazinolysis of homochiral aziridines proceeds without racemization.
Ó 2005 Published by Elsevier Ltd.
Allyl amines are often found in the structures of natural
products and pharmaceuticals. Specific examples of the
allyl amine-containing drugs are flunarizine,1 naftifine,2
and terbinafine,3 to name a few. In addition, allyl amines
are useful synthetic intermediates for the preparation of
other value-added molecules. One of the well known
examples of allyl amine involvement in synthesis is the
catalytic asymmetric hydrogen migration during the
syntheses of (À)-menthol, a-tocopherol, and metho-
prene.4 Traditional synthetic routes to allyl amines have
been based on (a) Gabriel synthesis, (b) reaction
between lithium amides and substituted alkynes in the
presence of zirconocene complexes, (c) allylic amination
catalyzed by the transition metal complexes, (d) azida-
tion of allyl halides followed by azide reduction, (e)
reduction of a,b-unsaturated imines or oximes, (f) reac-
tion between nitrobenzenes and allylmagnesium halides
followed by reduction, and (g) sigmatropic rearrange-
ment of allyl ether derivatives.5
1. NH2OMe
EtOH, 70 oC
R1
Ar
R1
Ar
N
H
2. NaOMe, DMF, r.t.
O
O
1a-1i
Scheme 1. Synthesis of 2-ketoaziridines.
When we applied the hydrazinolysis conditions to 1a–i,
the 2-alkylaziridines were transformed into the corre-
sponding allyl amine derivatives and 3,5-disubstituted
pyrazoles (Scheme 2).10 The reaction proceeded equally
well in ethylene glycol at 100 °C with potassium hydrox-
ide as base or in tert-butanol at the same temperature
with sodium methoxide as base. Product purification
and isolation was facilitated using tert-butanol. The
scope of base-mediated hydrazine reduction of 2-keto-
aziridines was investigated (Table 1). The selectivity
between allyl amine and pyrazole formation is moderate
to high. The reactions are clean and the separation of
pyrazoles from allyl amines can be easily performed
on silica gel.11,12
Our interest in synthetic applications of functionalized
aziridines6 has led us to investigate their use in the syn-
thesis of other nitrogen-containing molecules such as
allyl amines.7 In the present study, 2-ketoaziridine start-
ing materials were prepared using 1,4-addition of
methoxyamine to a,b-unsaturated ketones followed by
base-promoted ring closure (1a–i)8 (Scheme 1), electro-
chemical olefin aziridination (1l),6a or by further deriva-
tization of unprotected aziridines (1k,m,n).9
The unsubstituted aziridines are within the scope of the
process. The aziridines which contain sterically demand-
ing R1 substituents also afford good yields of allyl
amines, indicating that the reaction is not sensitive to
substitution at this position (Table 1, entries 1–2). Chal-
cone-derived aziridines (Table 1, entries 3–9) afford
lower selectivity for allyl amine formation if the aryl
group distal to the carbonyl functionality contains an
electron-donating substituent or if the proximal aryl
Keywords: Allyl amine; Pyrazole; 2-Ketoaziridine; Hydrazinolysis.
*
Corresponding author. E-mail: ayudin@chem.utoronto.ca
0040-4039/$ - see front matter Ó 2005 Published by Elsevier Ltd.
doi:10.1016/j.tetlet.2005.11.039

256
G. Chen et al. / Tetrahedron Letters 47 (2006) 255–259
.
H2NNH2 H2O 10 eq
O
N
KOH
3 eq
HN
R1
NHR2
R3
+
R1
R3
ethylene glycol, 100 oC
N
R1
R3
R2
Scheme 2. Hydrazinolysis of 2-ketoaziridines.
Table 1. Hydrazine reduction of 2-ketoaziridines under alkaline conditions
Entry
Starting material
Yielda
Amine product
Pyrazole product
O
1
N
H
HN
N
NH2
(3a)
30%
(2a)
(1a)
60%
O
HN
N
N
H
NH2
2
3
4
(2b)
67%b
(3b)
(1b)
22%
NH2
O
N
H
HN
N
(2c)
(3c)
(1c)
46%
14%
NH2
Cl
O
Cl
HN
N
N
Cl
H
(3d)
(2d)
(1d)
23%
65%
Cl
Cl
NH2
Cl
O
N
H
HN
5
N
(2e)
60%
(3e)
14%
(1e)
MeO
NH2
O
HN
N
H
N
6
7
MeO
MeO
(2f)
11%
(3f)
(1f)
8%
O
NH
Cl
2
N
H
Cl
Cl
HN
N
(2g)
(1g)
(3e)
33%
18%

G. Chen et al. / Tetrahedron Letters 47 (2006) 255–259
257
Table 1 (continued)
Entry
Starting material
Yielda
Amine product
Pyrazole product
O
NH2
MeO
N
H
8
OMe
OMe
HN
(3f)
N
(1h)
(2h)
69%
13%
NH2
O
N
9
0%
Cl
Cl
Cl
H
Cl
(2i)
(1i)
62%
O
Me
Me
HN
N
H
N
10
0%
(3j)
58%
(1j)
O
HN
N
N
NH2
11
Boc
(3a)
(2a)
(1k)
34%
50%
O
O
Ph
Ph
N
N
HN N
(3c)
12
0%
O
45%
(1l)
O
Me
N
Ph
Ph
N
13
0%
(2m)
65%c
(1m)
O
Ph
N
Ph
N
14
0%
(2n)
OH
(1n)
40%d
NH2
O
N
H
HN
N
15
(3c)
[(2S,3R)-1c]
[(1S)-2c]
14%
ee > 99%
46%, > 99%eee
a Isolated yield.
b Based on 95% conversion.
c The initial enamine product was tautomerized to cyclic imine.
d Dehydrated product observed.
e Enantiomeric excess was determined by the Mosher acid method.

258
G. Chen et al. / Tetrahedron Letters 47 (2006) 255–259
ring contains an electron-withdrawing substituent.
Overall, the distal electron-withdrawing substituents
and the proximal electron-donating substituents led to
enhanced reactivity. These reactions result in moderate
to good yields. However, if methyl ketone is used instead
of phenyl ketone, none of the allyl amine is formed and
the pyrazole is the only product observed (Table 1, entry
10). The activated aziridine which contains amide nitro-
gen also afford higher yield of pyrazole (Table 1, entry
11). N-Aminophthalimide containing aziridine does
not result in any allyl amine formation (Table 1, entry
12). The strained bicyclic enamine gives clean formation
of allyl amine which tautomerizes to imine under the
reaction conditions (Table 1, entry 13). The compounds
of this type can be readily and stereoselectively reduced
to the corresponding pyrrolidine derivatives using DI-
BAL-H.9 The aldehyde derived aziridine 1n leads to
cyclic imine 2n after dehydration of the allyl amine
product (entry 14). Finally, if one of the enantiomers
of 1c is used as the starting material, the reaction only
affords corresponding homochiral allyl amine (Table 1,
entry 15), indicating that the reaction process is
stereospecific.
stabilize the negative charge which later opens the aziri-
dine ring in the process of allyl amine formation. Anion
stabilizing substituents should facilitate allyl amine
formation relative to pyrazole formation, which is
reflected in entry 10.
In conclusion, simple hydrazinolysis of 2-ketoaziridines
affords allyl amines in good yields and moderate selec-
tivities. Electronic and steric effects from the substitu-
ents influence the reactivity of the substrates and
selectivity between allyl amine and pyrazole product.
In the cases of bicyclic aziridines, cyclic imines are the
only products. Enantiomerically pure allyl amine can
be synthesized if the homochiral aziridine is used as
the starting material.
Acknowledgements
We thank the Natural Sciences and Engineering
Research Council (NSERC), Canada Foundation for
Innovation, ORDCF, and University of Toronto for
financial support. Sumitomo Chemical Co, Ltd is grate-
fully acknowledged for a fellowship (M.S.). Andrei
Yudin is a Cottrell Scholar of Research Corporation.
Ms. Lily Yu is acknowledged for preparation of
compound 1j.
In a typical Wolff–Kishner reduction, the anionic por-
tion of intermediate B is protonated followed by further
deprotonation of the N@N–H fragment and subsequent
elimination of nitrogen to give the methylene group. In
the case of 2-ketoaziridines, intermediate B reacts with
the adjacent aziridine ring at the alpha position and
opens it up to give the allyl amine product (Fig. 1, path
a). Alternatively, the anionic nitrogen center in inter-
mediate A can attack the aziridine ring at the beta
position to form the pyrazole ring (Fig. 1, path b). This
result suggests that the phenyl substituent is necessary to
Supplementary data
NMR spectra of compound 1a–n, 2a–i,m,n, 3a–f, and 3j.
Text describing the general procedure for the prepara-
tion of 1b–1i, procedure for preparation of 1k,n, HPLC
condition for separation of (2S,3R)-1c and procedure
for ee determination of (1S)-2c. Supplementary data
associated with this article can be found, in the online
version at doi:10.1016/j.tetlet.2005.11.039.
H2N
O
N
NH2NH2
R
Ph
R
Ph
N
N
References and notes
R'
R'
-OH
1. Holmes, B.; Brogden, R. N.; Heel, R. C. Drugs 1984, 27,
6.
-
2. Monk, J. P.; Brogden, R. N. Drugs 1991, 42, 659.
3. Balfour, J. A.; Faulds, D. Drugs 1992, 43, 259.
4. For review, see: Otsuka, S.; Tani, K. Synthesis 1991, 665.
5. Marson, C. M.; Hobson, A. D. In Comprehensive Organic
Functional Group Transformations; Katritzky, A. R.,
Meth-Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford,
1995; Vol. 2, p 297.
path a
path b
HN
N
R
Ph
N
R'
A
a
b
HN
N
-
6. (a) Siu, T.; Yudin, A. K. J. Am. Chem. Soc. 2002, 124, 530;
(b) Caiazzo, A.; Dalili, S.; Yudin, A. K. Org. Lett. 2002, 4,
2597; (c) Sasaki, M.; Dalili, S.; Yudin, A. K. J. Org. Chem.
2003, 68, 2045; (d) Krasnova, L. B.; Hili, R. M.;
Chernoloz, O. V.; Yudin, A. K. Arkivoc 2005, IV, 26.
7. For conversion of 2-ketoepoxides into allyl alcohols with
hydrazine, see: Wharton, P. S.; Bohlen, D. H. J. Org.
Chem. 1961, 26, 3615.
8. Seko, S.; Tani, N. Tetrahedron Lett. 1998, 39, 8117.
9. Sasaki, M.; Yudin, A. K. J .Am. Chem. Soc. 2003, 125,
14242.
10. Interestingly, the reactions between 2-ketoaziridines and
hydrazine in the presence of acids proceed to give
HN
N
R
Ph
N
R
Ph
H
R'
B
NHR'
HO-
HO-
H
N
N
HN
NHR'
R'HN
R
N
Ph
R
R
Ph
Ph
Figure 1. Base-mediated hydrazinolysis of 2-ketoaziridines.

G. Chen et al. / Tetrahedron Letters 47 (2006) 255–259
259
pyrazoles: Cromwell, N. H.; Barker, N. G.; Wankel, R.
A.; Vanderhorst, P. J.; Olson, F. W.; Anglin, J. H. J. Am.
Chem. Soc. 1951, 73, 1044.
was removed in vacuum. The residue was purified on a
silica gel column (hexane/ethyl acetate = 6/4, followed by
methanol/dichloromethane/triethyl amine = 10/89/1), to
afford 1-styrylpent-4-enylamine (2a) as colorless oil
(56 mg, 60%) 1H NMR (CDCl3, 400 MHz): d 7.25–7.37
(m, 5H), 6.50 (d, J = 11.6 Hz, 1H), 5.79–5.86 (m, 1H), 5.57
(dd, J = 11.6, 6.0 Hz, 1H), 4.94–5.04 (m, 1H), 3.89–3.91
(m, 1H), 2.11–2.17 (m, 2H), 1.58–1.66 (m, 2H); 13C NMR
(CDCl3, 100 MHz): d 138.3, 137.3, 129.1, 128.6, 128.3,
128.2, 126.9, 114.7, 48.2, 37.3, 30.4; HR-MS (EI) m/z:
calcd for C13H16N 186.1283, found 186.1278. 5-But-3-
enyl-3-phenyl-1H-pyrazole (3a) (29 mg, 30%).1H NMR
(CDCl3, 400 MHz): d 7.75–7.77 (m, 2H), 7.40–7.44 (m,
1H), 7.30–7.36 (m, 2H), 6.42 (s, 1H), 5.84–05.94 (m, 1H),
5.04–5.14 (m, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.43–2.49 (m,
2H); 13C NMR (CDCl3, 100 MHz): d 137.4, 128.7, 127.9,
125.7, 115.7, 101.2, 33.2, 25.9; HR-MS (EI) m/z: calcd for
C13H14N2 198.1157, found 198.1154.
11. For conventional pyrazole synthesis, see: The Chemistry of
Heterocycles: Structure, Reactions, Syntheses and Applica-
tions; Eicher, T., Hauptmann, S., Eds.; Georg. Thieme
Verlag Stuttgart: New York, 1995.
12. Typical procedure for the synthesis of allyl amine. A
mixture of (3-but-3-enyl-trans-aziridin-2-yl)-phenylmetha-
none (1a, 100 mg, 0.5 mmol), hydrazine monohydrate
(250 mg, 5.0 mmol), potassium hydroxide (84 mg,
1.5 mmol), and ethylene glycol (2 mL) was stirred at
100 °C for 1 h. After no starting material detected by
TLC, dichloromethane (10 mL), and water (10 mL) were
added and separated. Water layer was extracted with
another portion of dichloromethane (5 mL). The com-
bined organic layers were washed with water (10 mL)
followed by drying over magnesium sulfate. The solvent