Facile synthesis of 2-pyrazolines and α,β-diamino ketones via regioselective ring-opening of hydrazone-tethered aziridines

Article abstract of DOI:10.1039/c2cc35135h

A facile strategy to access 2-pyrazolines and α,β-diamino ketones via SN₂-type ring-opening of N-(aziridin-2-ylethylidene) hydrazines or N-(aziridin-2-ylbutylidene)hydrazines in the presence of Lewis acid or trifluoromethanesulfonic acid (TfOH) is described in this context.

Full text of DOI:10.1039/c2cc35135h

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ARTICLE TYPE
Facile Synthesis of 2-Pyrazolines and α,β-Diamino Ketones via
Regioselective Ring-Opening of Hydrazone-tethered Aziridines
Zhen Zhanga, De Wanga, Yin Weib and Min Shia,b*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
shown in Scheme 1b, we assumed the activated aziridine could
undergo intramolecular nucleophilic attack by nitrogen atom of
the hydrazon moiety in an SN2 fashion via path a or path b to
provide 4,5-dihydro-1H-pyrazol-1-ium salt intermediate A or 2,3-
55 dihydroazetium salt intermediate B, respectively.9 In the presence
of water, intermediate A undergoes release of the sulfonyl group
A facile strategy to access 2-pyrazolines and α,β-diamino
ketones via SN2-type ring-opening of N-(aziridin-2-
ylethylidene)hydrazines
or
N-(aziridin-2-
10 ylbutylidene)hydrazines in the presence of Lewis acid or
trifluoromethanesulfonic acid (TfOH) is described in this
context.
(R4) to give 2-pyrazoline and intermediate
B undergoes
hydrolysis to give α,β-diamino ketone. All the reactions proceed
with excellent stereoselectivity with no isomeric products detcted
60 by means of NMR analysis. In addition, the SN2 pathways have
been firmly established by using chiral aziridines to generate
nonracemic products.10
2-Pyrazolines have received considerable attention because of
their potential bioactivities.1 The traditional strategies for the
15 synthesis of racemic and nonracemic 2-pyrazolines basically rely
on the 1,3-dipolar cycloaddition reactions.2 Due to the limited
substrate scope of the cycloaddition reactions,2g the strategy for
the construction of enantioenriched pyrazoline derivatives with
functional diversity is still highly desirable. For instance, amino
20 pyrazolines, exhibiting biological and pharmacological
activities,3 have no efficient strategies for their synthesis until
recently. Only a few examples have been reported by using
functionalized aziridines.4
(a) previous work:
R4 R3
Ns
NHNs
R1
R4
N
N
N
LA
R2
LA
N
N
N
R4
R3
R1
H
H
N
N
N
Ns
R2 R3
R1
Functionalized aziridines have shown a broad utility in organic
25 chemistry due to their highly strained ring and the presence of the
particular substitution which feature noticeable unique
reactivities.5 Recently, we have reported Lewis acid catalyzed
ring-opening of N-(aziridin-2-ylmethylene)hydrazines to provide
enamine derivatives and a mechnism was proposed via azirinium
30 salt intermediate to rationalize the unprecedented 1,2-migration
of the substituent R1 (Scheme 1a).6 During our ongoing
investigation on these functionalized aziridines, we found that N-
R1
N
NHNs
R2
R1
NNs
R2
(b) this work:
R4OH
path a
R3
N
R3
Ns
N
R4
b
LA
or TfOH
N
R4
H2O
A
N
R1
N
H2O
R2
a
R3
R1
NNs
R2
R2
H
NHNs
H
R2
N
R4
N
N
R3
path b
R3
N
R1
O
R4 H2O
B
Scheme 1. Ring-opening reactions of hydrazone-tethered
aziridines .
(aziridin-2-ylethylidene)hydrazines
and
N-(aziridin-2-
65
ylbutylidene)hydrazines failed to give enamines but gave 2-
35 pyrazolines and α,β-diamino ketones as products. It is noteworthy
that α,β-diamino ketones have been found to possess mild avian
antimalarial activity and no examples of synthesis of α,β-diamino
ketones from aziridines have been reported.7,8 The regio- and
stereochemical outcomes of the ring-opening are sigificantly
40 dependent on the nature of the aziridine substitution pattern,5c as
Our studies were initiated by treating aziridine 1a with
various Lewis acids. To our delight, 2-pyrazoline 2a could be
70 obtained in moderate to good yields (68–90%) in
dichloromethane using various metal-containing Lewis acid (5
mol%), such as Sc(OTf)3, Eu(OTf)3, Cu(OTf)2 and Bi(OTf)3,
as catalyst and two equiv water as additive (Table 1, entries
1–5). Only a small amount of 3a was produced along with the
75 formation of 2a. Aziridine 1a was recovered when treating
BF3·Et2O (10 mol%) (Table 1, entry 6). When catalytic
amount of trifluoromethanesulfonic acid (TfOH) (20 mol%)
was used, 2a was formed as the major product (69%) along
with the isolation of product 3a (29%) (Table 1, entry 7).
80 However, 3a was obtained in 76% yield as sole product in the
a Key Laboratory for Advanced Materials and Institute of Fine Chemicals,
East China University of Science and Technology, and 130 MeiLong
Road, Shanghai 200237, P. R. China
45 b State Key Laboratory of Organometallic Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road,
Shanghai 200032, P. R. China. E-mail: mshi@mail.sioc.ac.cn
† Electronic Supplementary Information (ESI) available: Experimental
procedures, characterization data of new compounds, and CCDC 870326,
50 868903 and 892218. See DOI: 10.1039/b000000x/
This journal is © The Royal Society of Chemistry [year]
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Table 2. In(OTf)3-catalyzed ring-opening reaction of aziridine 1.a
presence of 1.2 equiv TfOH (Table 1, entry 7). Further
optimization of solvents revealed that dichloromethane was
the best solvent for the formation of 2a (Table 1, entries 10
and 11). Increasing the amount of water didn’t improve the
yield of 2a (Table 1, entry 12). Thus, the use of In(OTf)3 (5
mol%) as the catalyst in dichloromethane at 20 oC with 2.0
equiv water added was found to be the most efficient
condition for the formation of 2a and the use of 1.2 equiv
TfOH and 2.0 equiv water was the best condition for the
Ns
N
R1
NHNs
NHNs
H
In(OTf)3 (5 mol%)
R2
N
R4
N
R4
+
N
R1
N
H2O (2.0 equiv)
DCM, rt, < 3 h
N
R2
R3
N
O
R1 R3
R2 R3
5
3
2
1
yield (%)b
entry
aziridine 1
2
3
2b
3b
, 0
1
2
3
4
5
6
1b
1c
, R1 = 4-CF3C6H4
, R1 = 4-FC6H4,
, R1 = 2-BrC6H4
, R1 = C6H5
, 81
, 56
Ns
N
2c
3c
, 18
N
Ts
1d
2d
2e
, 88
3d
, 0
R1
N
10 synthesis of 3a.
1e
1f
, 79
3e
, 10
Me Me
1a 1g
, R1 = 3-MeOC6H4
, 74
, 25
2f
3f
Ns
Table 1. Optimization of the Reaction Conditions.
Ns
1
2g
, 85
3g
, 0
1g
1h
1i
n
Bu
, R1 = C6H5
, R1 = 2-BrC6H4
, R1 = 2-BrC6H4,
, R
=
N
Ar
NHNs
NHNs
7
8
2h, trace 3h, 54
N
N
Ts
N
H
R1
catalyst
Me
N
Me
2i
, 92
3i
, 0
, 0
N
Me
+
Me
solvent, rt
H2O (2.0 equiv)
N
N
nPr
Me
Ar
N
1h & 1i
Ns
Me
1j
N
O
Ar Ts
2d
3j
9
10
11
12
, 98
, 69
, 79
Me Ts
R3 = Me
2a
Ar = 4-ClC6H4
1a
, R1 = 2,6-Cl2C6H4,
3a
N
1k
2k
3k
, 0
yield (%)a
R
3 = Me
N
SO2Et
R1
N
entry
solvent
time
catalyst (mol%)
, R1 = 2-BrC6H4,
1l
Me R3
2a
90
3a
10
18
10
2l
3l
, 0
1j 1l
R3 = iPr
1
DCM
DCM
DCM
DCM
2 h
2 h
1 h
3 h
1 h
1 h
Sc(OTf)3 (5)
Eu(OTf)3 (5)
In(OTf)3 (5)
Cu(OTf)2 (5)
, R1 = 4-FC6H4,
2 = R3 = Me, R4 = Ms
1m
c
2c
, trace
2
81
90
76
3m
, 82
R
3
a Reaction conditions: In(OTf)3 (5 mol%), H2O (2.0 equiv), CH2Cl2, room
temperature, < 3 h. b Isolated yield. c Sc(OTf)3 (5 mol%) was used as catalyst.
4
18
32
0
5
6b
DCM
DCM
68
0
Bi(OTf)3 (5)
45
BF3•Et2O (10)
Table 3. TfOH-mediated ring-opening reaction of aziridine 1.a
DCM
DCM
DCM
5 min
5 min
3 h
69
29
7
8
TfOH (20)
TfOH (120)
FeCl3 (20)
trace 76
trace 65
9
10
toluene
CH3CN
DCM
1 h
1 h
2 h
64
59
82
< 10
In(OTf)3 (5)
In(OTf)3 (5)
In(OTf)3 (5)
11
12c
< 10
< 10
a Isolated yield. b No reaction. Ns = 4-NO2PhSO2, c 5.0 equiv H2O was used.
We next examined the substrate scope of this reaction under
15 the optimized conditions and the results are shown in Table 2.
As for aryl-substituted N-(aziridin-2-ylethylidene)hydrazines
(R1 = Ar) 1b–1f, the reactions proceeded smoothly to furnish
the desired 2-pyrazolines 2b–2f in 55–88% yields, along with
the formation of a small amount of products 3 when aromatic
20 rings bearing no groups or bearing fluoride or methoxy group
(Table 2, entries 1–5). Changing the aryl-substitution R1 to
alkyl group (n-Bu), the desired 2-pyrazoline 2g could be
obtained in 85% yield without the detection of 3g (Table 2,
entry 6). Then N-(aziridin-2-ylbutylidene)hydrazines 1h and
25 1i were tested in the optimized conditions. It was found only
trace amount of 2-pyrazoline 2h was formed but 54% yield of
3h was isolated (Table 2, entry 7). However, aziridine 1i
which bearing bromide group on its benzene ring gave 2-
pyrazoline 2i as the sole product in 92% yield, indicating
30 electron-withdrawing groups on the benzene ring (R1)
inhibited the formation of product 3 (Table 2, entry 8). When
an alkylsulfonyl group was introduced to the substrate instead
of the tosyl group, the reactions also proceeded smoothly to
give the corresponding 2-pyrazolines in good yields (Table 2,
35 entries 9 and 10). Introducing an isopropyl group instead of
methyl group (R3), the corresponding product 2l was formed
in 79% yield (Table 2, entry 11). For methanesulfonyl group
substituted substrate 1m, 82% yield of 3m was isolated and
only trace amount of 2c was detected (Table 2, entry 12).
40 Comparing with substrate 1c, it illustrates that the substituent
of hydrazone moiety (R4) also affect the outcome of the ring-
opening.
Furthermore, we investigated TfOH-mediated ring-opening
50 of aziridines 1 and the results are summarized in Table 3. For
aryl-substituted N-(aziridin-2-ylethylidene)hydrazines, the
expected products 3d, 3e and 3f were obtained in 52–64%
yields under the standard conditions no matter electron-
withdrawing or electron-donating groups on the aryl ring (R1)
55 (Table 3, entries 1–3). When R1 was an alkyl group, no
desired product 3g was detected but 2-pyrazoline 2g was
isolated in 72% yield (Table 2, entries 4). For N-(aziridin-2-
ylbutylidene)hydrazines 1h and 1i, the results were similar to
the outcomes of In(OTf)3-catalyzed ring-opening of 1h and 1i
60 (Table 3, entries 5 and 6). These results further imply that the
regiochemical outcomes of the ring-opening of aziridine 1 are
significantly dependent on the aziridine substitution pattern
and the hydrazon substitution pattern.
To make our strategy more attractive as a synthetic
65 methodology, the protocol for the synthesis of chiral 2-
pyrazolines via Lewis-acid catalyzed ring-opening of chrial
aziridines
was
explored.
Chiral
N-(aziridin-2-
ylmethylene)hydrazines could be easily synthesized with good
enantioselectivities by copper bis(oxazoline) complex-
70 catalysed aziridination of N-substituted hydrazones (e.g. (+)-
1j, see: Scheme 2).11 To our delight, aziridine (+)-1j was
converted to 2-pyrazoline (+)-2d in 79% yield with 91% ee
2
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even if the reaction was performed in an enlarged scale (0.4
mmol) (Scheme 2). Its absolute configuration has been
determinde by X-ray diffraction (see Supporting Information).
Other chiral aziridines (+)-1a, (+)-1b and (+)-1f were also
tested in the reaction and the corresponding chiral 2-
pyrazolines were obtained in good stereoselectivity (up to
96% ee) and good yields (up to 81%) (Scheme 3). In addition,
the transformation of chiral aziridine (+)-1f to α,β-diamino
ketone (–)-3f was also examined and the process had no
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45
50
55
60
5
10 variation on ee value (Scheme 4).
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Cromwell, H. Hoeksema, J. Am. Chem. Soc., 1949, 71, 716; (c) N. H.
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H. Cromwell, D. J. Cram, J. Am. Chem. Soc., 1949, 71, 2579; (c) N.
H. Cromwell, D. J. Cram, J. Am. Chem. Soc., 1943, 65, 301.
Scheme 2. Synthesis of chiral pyrazoline (+)-2d.
8 For selected examples on 1,2-diamines synthesis, see: (a) G. Li, H.-X.
70
Wei, S. H. Kim, M. D. Carducci, Angew. Chem. Int. Ed., 2001, 40,
4277; (b) H.-X. Wei, S. H. Kim, G. Li, J. Org. Chem., 2002, 67, 4777;
(c) D. Chen, C. Timmons, H.-X. Wei, G. Li, J. Org. Chem., 2003, 68,
5742; (d) W. Pei, H.-X. Wei, D. Chen, A. D. Headley, G. Li, J. Org.
Chem. 2003, 68, 8404; (e) W. Pei, C. Timmons, X. Xu, H.-X. Wei, G.
Li, Org. Biomol. Chem., 2003, 1, 2919; (f) U. K. Nadir, A. Singh,
Tetrahedron Lett., 2005, 46, 2083; (g) S. Peruncheralathan, H. Teller,
C. Schneider, Angew. Chem. Int. Ed., 2009, 48, 4849; (h) Y. Fukuta,
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51, 1.
75
15
Scheme 3. Synthesis of chiral pyrazolines (+)-2a, (+)-2b and
(+)-2f.
80
9 For reactions via azirinium intermediates, see: (a) R. Aumann, X. Fu, D.
Vogt, R. Fröhlich, O. Kataeva, Organometallics, 2002, 21, 2736; (b)
W. Van Brabandt, Y. Dejaegher, R. Van Landeghem, N. De Kimpe,
Org. Lett., 2006, 8, 1101; (c) J. Barluenga, A. Gómez, J. Santamaría,
M. Tomás, Angew. Chem. Int. Ed., 2010, 49, 1306.
85
10 For ring-opening of chiral aziridines, see: (a) M. K. Ghorai, D. P.
Tiwari, J. Org. Chem., 2010, 75, 6173; (b) M. K. Ghorai, A. Kumar,
D. P. Tiwari, J. Org. Chem., 2010, 75, 137; (c) M. K. Ghorai, D.
Shukla, K. Das, J. Org. Chem., 2009, 74, 7013; (d) M. K.Ghorai, Y.
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Alvaro, R. D. Fabio, A. Gualandi, J. Org. Chem. 2007, 72, 3859; (f)
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Dammacco, L. Degennaro, S. Florio, R. Luisi, B. Musio, A.
Altomare, J. Org. Chem., 2009, 74, 6319.
20 Scheme 4. Synthesis of chiral α,β-diamino ketone (-)-3f.
In conclusion, we have developed a simple protocol for the
synthesis of substituted racemic and nonracemic 2-pyrazolines
and α,β-diamino ketones through a SN2-type ring-opening of N-
90
25 (aziridin-2-ylethylidene)hydrazines
or
N-(aziridin-2-
ylbutylidene)hydrazines. We found the electronic effects of the
substrates govern the reactivity and thus the ring-opening process.
Further applications of this novel type of functionalized aziridines
are under way in our laboratory.
95
11 (a) D. A. Evans, M. M. Faul, M. T. Bilodeau, B. A. Anderson, D. M.
Barnes, J. Am. Chem. Soc., 1993, 115, 5328; (b) H. M. I. Osborn, J.
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L. Ma, P. Jiao, Q. Zhang, J. Xu, Tetrahedron: Asymmetry, 2005, 16,
3718.
30
100
Acknowledgement: We thank the Shanghai Municipal
Committee of Science and Technology (11JC1402600), National
Basic Research Program of China (973)-2009CB825300, and the
National Natural Science Foundation of China for financial
105
35 support (21072206, 20472096, 20872162, 20672127, 20732008
and 21121062).
Notes and references
1 For selected examples, see: (a) M. A. Ali, M. Shaharyar, Bioorg. Med.
Chem., 2007, 15, 1896; (c) A. Sahoo, S. Yabanoglu, B. N. Sinha, G.
40
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Lewis acid-catalyzed or trifluoromethanesulfonic acid-mediated
SN2-type ring-opening of N-(aziridin-2-ylethylidene)hydrazines or
N-(aziridin-2-ylbutylidene)hydrazines forming 2-pyrazolines and
α,β-diamino ketones
Facile Synthesis of 2-Pyrazolines and α,β-Diamino Ketones
via Regioselective Ring-Opening of Hydrazone-tethered
Aziridines
Zhen Zhang, De Wang, Yin Wei and Min Shi*
4
| Journal Name, [year], [vol], 00–00
This journal is © The Royal Society of Chemistry [year]