Enantioselective synthesis of pyrazolone α-aminonitrile derivatives: Via an organocatalytic Strecker reaction

Article abstract of DOI:10.1039/c7cc02874a

A new organocatalytic enantioselective Strecker reaction of pyrazolone-derived ketimine electrophiles has been developed. Using pseudo-enantiomeric squaramide catalysts the nucleophilic 1,2-addition of trimethylsilyl cyanide to the ketimines efficiently provides a direct entry to both enantiomers of pyrazolone α-aminonitrile derivatives at will in good yields and high enantioselectivities for a wide variety of substrates.

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Marilyn M. Olmstead, Alan L. Balch, Josep M. Poblet, Luis Echegoyenet al.
Reactivity differences of Sc
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Enantioselective synthesis of pyrazolone α-aminonitrile
derivatives via an organocatalytic Strecker reaction
†
a
† a
a
a
b
Received 00th January 20xx,
Accepted 00th January 20xx
Suruchi Mahajan, Pankaj Chauhan, Uğur Kaya, Kristina Deckers, Kari Rissanen and Dieter
Enders*
a
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new organocatalytic enantioselective Strecker reaction of
pyrazolone-derived ketimine electrophiles has been developed.
Using pseudo-enantiomeric squaramide catalysts the nucleophilic
Like oxindoles, the pyrazolones are very important and
interesting heterocyclic scaffolds for chemical modifications and
biological evaluations. These 1,2-azoles have been known for more
than a century and possess a broad spectrum of applications in
1,2-addition of trimethylsilyl cyanide to the ketimines efficiently
8
dyes, analytical and pharmaceutical chemistry. Due to the
provides a direct entry to both enantiomers of pyrazolone α-
aminonitrile derivatives at will in good yields and high
enantioselectivities for a wide variety of substrates.
synthetic and biological significance of pyrazolones, a rapid
progress has been noticed in the last few years, especially in
catalytic asymmetric synthesis to obtain new potentially bioactive
9
and virtually enantiopure pyrazolone derivatives. Most of these
The Strecker reaction is the oldest known method for the synthesis
of α-amino nitriles, which are eventually utilized for the synthesis of
natural and synthetic α-amino acids as well as other bioactive
methods utilized the known reactivity of pyrazolin-5-one
9 10
derivatives, especially the C-4 nucleophilicity. , In this context, the
11
12
groups of Feng and Rios reported the enantioselective α-
amination of 4-substituted pyrazolones to afford the amino-
pyrazolone derivatives using a chiral transition metal complex and
an organocatalyst. To the best of our knowledge, the
enantioselective nucleophilic addition to the C-4 position of
pyrazolones is not known, hence we envisaged that the imines
derived from the pyrazolin-5-ones can undergo a 1,2-addition
1
compounds including natural products. The first example of a
catalytic asymmetric Strecker reaction was published around two
2
decades ago in 1996, and since then a number of enantioselective
methods employing chiral transition metal and organo-catalysts
have been developed. Due to their high reactivity, a special
emphasis was laid on the nucleophilic cyanation of aldimines to
3
afford highly enantiomerically enriched α-amino nitriles. Despite
reaction to afford the amino-pyrazolones bearing
substituted stereocenter.
a tetra-
the significant progress in catalytic asymmetric Strecker reactions,
the corresponding processes that utilize the ketimines as substrates
are considered comparably more difficult and hence are less
Owing to the wide array of applications of pyrazolones and in
view of the synthetic importance of the asymmetric Strecker
4
explored. Therefore, the design and development of more reactive
ketimines is of high interest. In this context, the ketimines derived
from fluoromethylated ketones and isatin derivatives have been
recently developed and also utilized in the catalytic asymmetric
Strecker reaction (Scheme 1). These transformations lead to the
Previous work:
TMSCN
R2
R2
ref.5
HN
R1
N
+
CN
R1
X
X
X = CF3, CHF2
5
formation of tetrasubstituted fluorinated and oxindole-based
H
CN
N
6
R1
N
R1
N
R3
amino nitriles . In general, the ketimines derived from oxindoles
R3
ref.6
7
have been widely explored in various asymmetric transformations.
TMSCN
+
O
O
Hence, we anticipated that the design of new ketimine substrates
with a heterocyclic core will open new possibilities in asymmetric
synthesis.
N
2
R2
R
R2
N
N
Ph
nucleophilic
R2
R1
R O2C R1
3
4
ref.11,12
3
N
CO2R3
R O2C
N
N
Ph
N
N
H
3
+
R O2C
N
O
N
O
a.
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074
Aachen, Germany E-mail: enders@rwth-aachen.de
Department of Chemistry, Nanoscience Center, University of Jyvaskyla, 40014 JYU,
Finland
This work:
electrophilic
TMSCN
b.
R3
R3
NC
O
†
S.M. and P.C. contributed equally.
organocatalyst
HN
N
4
N
R1
+
R1
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
N
N
O
R2
R2
Scheme 1 Organocatalytic enantioselective Strecker reactions with ketimines
and the synthesis of tetrasubstituted αꢀamino pyrazolone derivatives.
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reaction, we herein report a new organocatalytic enantioselective screening revealed that the dichloroethane provided the best yield
Strecker synthesis of pyrazolone α-amino nitrile derivatives of 83% with an er-value of 96:4 (entry 2). It is well established in the
employing pyrazolone derived ketimines as electrophiles.
literature that protic solvents as an additive lead to the
In order to achieve this goal, we started the optimization improvement of the yield and enantioselectivity in the
6
b,7a-b,14
studies by screening various bifunctional organocatalysts for the enantioselective Strecker reaction.
reaction of TMSCN (1a) with a pyrazolone-derived ketimine 2a in solvents such as isopropanol,
dichloromethane as solvent at room temperature. Initially the hexafluoroisopropanol and water were tested as additives (entries
Hence, different protic
trifluoroethanol,
1
3
reactions were carried out with 5 mol% of squarmides (C-1 to C- 10-13), however, no improvement in enantioselectivity was
) derived from cinchona alkaloids. The squaramides C-1 and C-2 observed. Furthermore, varying the catalyst loading did not lead to
5
where the squaramide unit is directly attached to an aryl group any improvement of yield and er-value of 3a (entries 14-15).
provided better yields and enantioselectivities of the desired However, a lowering of the reaction concentration gave a better
product 3a than the catalyst C-3 bearing a benzylic group. The yield of 88% without affecting the enantioselectivity of 3a (entry
squaramide catalysts derived from the quinine C-2 and quinidine C- 16).
5
resulted in good yields and best er-values of 3a and its
a
Table 2. Optimization of the reaction conditions.
enantiomer ent-3a, respectively. The other bifunctional hydrogen
bonding catalysts, such as thiourea C-6 and cupreine derivatives C-7
and C-8, failed to provide better yields and enantioselectivities of 3a
than the squaramide catalysts. The cinchona alkaloid dimers C-9
and C-10 were also tested, but these catalysts only provide
moderate yields and lower er-values.
Table 1. Catalyst screening.
b
c
Entry
1
Solvent
CH Cl
Yield (%)
77
er
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1c
1d
1a
2
2
95.4.5
96:4
ClCH
CHCl
2
CH
2
Cl
83
3
71
96:4
.
Toluene
Xylene
59
90.5:9.5
90:10
76:24
84.5:15.5
64.5:35.5
69:31
95.5:4.5
96:4
60
X
2
Et O
46
H
N
OH
THF
55
CF3
NH
H
N
EtOH
i-PrOH
40
N
n
O
NH
OX
28
CF3
N
d
O
10
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
ClCH
2
CH
CH
CH
CH
CH
CH
CH
CH
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
2
Cl
77
e
C-1. X = H, n = 0, 67%, 92.5:7.5 er
C-2. X = OMe, n = 0, 77%, 95.5:4.5 er
C-3. X = OMe, n = 1, 41%, 81:19% er
C-7. X = H, 36%, 51.5:48.5 er
C-8. X = Bn, 36%, 52.5:47.5 er
11
2
79
f
1
1
1
2
3
4
2
83
96:4
g
h
i
2
69
95.4.5
93.5:6.5
90.5:9.5
95.4.5
93:7
X
Me
Me
84
N
H
2
N
N
N
N
O
O
15
2
88
HN
H
H
j
1
1
1
6
7
8
2
88
N
MeO
OMe
HN
O
2
60
N
N
F3C
O
2
CH
traces
traces
83
ND
C-9. 46%, 10:90 er
CF3
19
20
ClCH CH Cl
ND
2
2
C-4. X = H, 71%, 7.5:92.5 er
C-5. X = OMe, 64%, 4.5:95:5 er
k
Me
Me
ClCH
2
CH
2
Cl
55:45
N
N
a
Reaction conditions: 0.3 mmol of 1, 0.2 mmol 2a, 5 mol% of C-2 in 1.0 mL of
O
O
CF3
b
c
H
H
solvent. Yield of isolated product 3a after column chromatography. The
MeO
N
N
OMe
enantioselectivity was determined by HPLC analysis on a chiral stationary
S
d
e
f
phase. 0.2 mmol of iꢀPrOH was used. 0.2 mmol of trifluoroethanol was used.
N
N
CF3
g
h
N
N
0.2 mmol of hexafluoroisopropanol was used. 0.2 mmol of water was used.
H
H
N
i
j
2
.5 mol% of catalyst was used. 10 mol% of catalyst was used. 3 mL of solvent
k
Me
Me
was used. An N-Boc ketimine 2b was used and the reaction was carried out
C-6. 24%, 16.5:83.5% er
C-10. 60%, 30.5:69.5 er
for 3 days.
Other nitrile donors were also tested for the organocatalytic
Strecker reaction of pyrazolone imines (entries 17-19). It turned
out that ethyl cyanoformate (1b) resulted in the formation of 60%
of α-amino nitrile 3a with 93:7 er-value (entry 17), however, acetyl
cyanide (1c) and diethyl cyanophosphonate (1d) turned out to be
Reaction conditions: 0.3 mmol of 1a, 0.2 mmol 2a, 5 mol% of C-1 to C-10 in 1.0
mL of dichloromethane.
In order to further improve the yield and enantioselectivity of
α-amino nitrile 3a, further optimizations were carried out by
screening different solvents (Table 2, entries 1-9). The solvent
2
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unreactive under the standard reaction conditions (entries 18-19). incoming cyanide nucleophile. The ketimines with different N-aryl
2
Under the optimized reaction conditions an N-Boc ketimine 2b groups (R ) on the pyrazolone nitrogen were also well tolerated to
resulted in very good yield of 3b with a faster reaction rate, albeit provide very good yields and enantioselectivities of the pyrazolone
with a poor er-value (entry 20).
products 3h-j. An N-alkyl pyrazolone imine was also used under the
In the next stage, the substrate scope and limitations of the standard reaction conditions and it was found out that the reaction
optimized Strecker reaction have been evaluated at 0.3 mmol scale was faster than the imines bearing aryl substituents, thus leading to
1
(
Table 3). Initially, the effect of the N-aryl groups (R ) was tested. It the formation of amino nitrile 3k in good yield after 3 days with
3
was observed that the aryl groups bearing electron-withdrawing high enantioselectivity. At last, the variation of the substituents (R )
and electron-donating substituents at different positions led to the at the C-3 position of the pyrazolone imines has been evaluated. It
formation of the desired products 3c-g with high er-values, except turned out that with an increase in the steric bulk of the R alkyl
3
in the case of 4-CF substituent, where only a moderate er was group, an improvement in the enantioselectivity of 3l-n was
3
observed. The electron-donating aryl groups showed lower observed with a gradual decline in the product yield. A t-Bu at this
reactivity, and hence gave a lower yield of the corresponding position, however didn't provide any product whereas a phenyl
products. A reason of the lower yield of 3g as compared to 3f may group was found to be less reactive to give 3p in good
be steric hindrance caused by the ortho-methyl substituent to the
enantioselectivity, albeit in a poor yield.
a
The substrate scope and the limitation were also evaluated with
the pseudo-enantiomeric squaramide catalyst C-5 (Table 3). The
enantiomeric products ent-3 were synthesized without much effect
on the yield and stereochemical outcome of the transformation.
Table 3. Substrate scope with catalyst C-2 and C-5.
6 4
Deprotection of the N-aryl group (4-MeOC H ) was also carried
with periodic acid and sulfuric acid to afford free amino nitrile
product 4 without affecting the er-value (Scheme 2).
c
3
2
Yield
er
b
(%)
1
1
1
1
1
2
3
a
R
= Ph, R = Ph, R = Me (2a)
90
86
75
69
80
79
82
80
60
59
38
37
78
78
87
87
79
75
92
92
81
79
75
74
56
54
ꢀ
95.5:4.5
94:4
ent-a
c
2
3
R
R
R
R
= 4ꢀFC
6
H
4
, R = Ph, R = Me (2c)
97:3
ent-c
d
97:3
2
3
= 4ꢀClC
6
H
4
, R = Ph, R = Me (2d)
94.5:5.5
94.5:5.5
84.5:15.5
89:11
ent-d
e
2
3
= 4ꢀCF
3
C
6
H
4
, R = Ph, R = Me (2e)
ent-e
f
Scheme 2. Synthesis of αꢀamino nitrile product 4.
2
3
= 4ꢀMeOC
6
H
4
, R = Ph, R = Me
97.5:2.5
96.5:3.5
93.5:6.5
92:8
The absolute configuration of the products 3a-p synthesized
with catalyst C-2 could be assigned to be (R) in analogy with the X-
ray crystal structure of the product 3h (Figure 1).
(
2f)
ent-f
g
1
1
1
1
1
1
1
1
1
1
2
3
R
R
R
R
R
R
R
R
R
R
= 2ꢀMeC
6
H
4
, R = Ph, R = Me (2g)
15
ent-g
h
2
3
= Ph, R = 4ꢀClC
6
H
H
4
4
, R = Me (2h)
95.7:2.5
97:3
ent-h
i
2
3
= Ph, R = 2ꢀClC
6
, R = Me (2i)
97:3
ent-i
j
95.5:4.5
97:3
2
3
= Ph, R = 4ꢀMeC
6
H
4
, R = Me (2j)
ent-j
k
96:4
2
3
d
d
= Ph, R = Me, R = Me (2k)
96.5:3.5
97.5:2.5
96.5:3.5
95.5:4.5
98:2
ent-k
l
2
3
= Ph, R = Ph, R = Et (2l)
ent-l
m
2
3
= Ph, R = Ph, R = nꢀPr (2m)
Fig. 1 Determination of the absolute configuration by Xꢀray crystal structure
analysis of 3h.
ent-m
n
98:2
2
3
= Ph, R = Ph, R = iꢀPr (2n)
98.5:1.5
98.5:1.5
ꢀ
ent-n
o
By knowing the absolute configuration, we could also propose
the possible transition state for the enantioselective Strecker
reaction of the pyrazolone ketimine (Scheme 3). It is postulated that
HCN (generated from TMSCN and traces of water present in the
2
3
= Ph, R = Ph, R = tꢀBu (2o)
ent-o
p
ꢀ
ꢀ
2
3
= Ph, R = Ph, R = Ph (2p)
14
13
95.5:4.5
95.5:4.5
5c
solvent), gets deprotonated by the tertiary amine of the catalyst.
ent-p
Simultaneously, the imine is activated by H-bonding with the
squaramide moiety to undergo a Re-face attack of the cyanide
anion to afford the (R)-enantiomer of the product.
a
Reaction conditions: 0.3 mmol of 1a, 0.45 mmol of pyrazolone imines 2, 5
mol% of catalyst C-2 or C-5 in 4.5 mL of dichloroethane. Yield of isolated
products 3 after column chromatography. Enantioselectivity was determined by
HPLC analysis on a chiral stationary phase. Yield after 3 days.
b
c
d
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N
Synth. Catal., 2013, 355, 548; (d) H. Wang, K. Wang, Y. Ren, N. Li,
B. Tang, G. Zhao, Adv. Synth. Catal., 2017, DOI:
O
CF
3
O
1
0.1002/adsc.201700029.
MeO
R
1
HN
7
For recent reviews on the asymmetric reactions involving
oxindole based ketimines, see: (a) P. Chauhan and S. S. Chimni,
Tetrahedron: Asymmetry, 2013, 24, 343; (b) J. Kaur, S. S. Chimni,
N
3NC
N
O
H
R
N
H
CF
3
H
N
N
R1
R2
S.; Mahajan and A. Kumar, RSC Adv., 2015, 5, 52481.
N
NC
3
O
8
For a book on pyrazolone chemistry, see: (a) G. Varvounis,
Pyrazol-3-ones. Part IV: Synthesis and Applications in Advances
in Heterocyclic Chemistry; A. R. Katritzky, Ed.; Academic Press:
New York, 2009; Vol. 98, p 143. For reviews, see: (b) H.; Yoshida,
H. Yanai, Y. Namiki, K. Fukatsu-Sasaki, N. Furutani and N. Tada,
CNS Drug Rev., 2006, 12, 9; (c) S. Fustero, M. Sánchez-Roselló, P.
Barrio and A. Simón-Fuentes, Chem. Rev., 2011, 111, 6984; (e) A.
Schmidt and A. Dreger, Curr. Org. Chem., 2011, 15, 1423; (f) P.
R
N
N
R2
Scheme 3 Proposed transition state for the enantioselective Strecker reaction of
pyrazoloneꢀderived ketimines.
In summary, we have developed an organocatalytic
enantioselective Strecker reaction employing a series of new
pyrazolone ketimines as substrates. In the presence of pseudo-
enantiomeric squaramide organocatalysts, both enantiomers of the
corresponding α-amino nitrile pyrazolone derivatives bearing a
tetrasubstituted stereocenter have been synthesized in moderate
to good yields and good to excellent level of enantioselectivities.
Further applications of pyrazolone ketimines in asymmetric
transformation are currently under investigation in our laboratory.
Gupta, J. K. Gupta and A. K. Halve, Int. J. Pharm. Sci. Res., 2015
6, 2291.
,
9
1
For a review, see: P. Chauhan, S. Mahajan and D. Enders, Chem.
Commun., 2015, 12890-12907.
0 For selected examples, see: (a) Y.-H. Liao, W.-B. Chen, Z.-J. Wu,
X.-L. Du, L.-F. Cun, X.-M. Zhang and W.-C. Yuan, Adv. Synth.
Catal., 2010, 352, 827; (b) X. Companyó, A. Zea, A.-N. R. Alba, A.
Mazzanti, A. Moyano and R. Rios, Chem. Commun., 2010, 6953;.
(
c) A.-N. R. Alba, A. Zea, G. Valero, T. Calbet, M. Font-Bardía, A.
Mazzanti, A. Moyano and R. Rios, Eur. J. Org. Chem., 2011, 1318;
d) P. Chauhan, S. Mahajan, C. C. J. Loh, G. Raabe and D. Enders,
(
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