Organocatalytic enantioselective Strecker reaction of cyclic trifluoromethyl-ketoimines

Article abstract of DOI:10.1016/j.tetlet.2012.12.119

A quinine thiourea promoted enantioselective Strecker reaction of cyclic ketoimines with TMSCN has been developed. The process affords new enantioenriched trifluoromethyl dihydroquinazolinones in high yields and with high enantioselectivities. Copyright

Full text of DOI:10.1016/j.tetlet.2012.12.119

Tetrahedron Letters 54 (2013) 1409–1411
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Organocatalytic enantioselective Strecker reaction of cyclic
trifluoromethyl-ketoimines
Hexin Xie a,b, Aiguo Song a, Xixi Song a, Xinshuai Zhang a, Wei Wang a,b,
⇑
a Department of Chemistry and Chemical Biology, University of New Mexico, Albuqueruqe, NM 87131-0001, USA
b School of Pharmacy, East China University of Science & Technology, Shanghai 200237, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
A quinine thiourea promoted enantioselective Strecker reaction of cyclic ketoimines with TMSCN has
been developed. The process affords new enantioenriched trifluoromethyl dihydroquinazolinones in high
yields and with high enantioselectivities.
Received 10 November 2012
Revised 26 December 2012
Accepted 28 December 2012
Available online 5 January 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Amine thiourea
Ketoimines
Organocatalysis
Strecker reaction
The Strecker reaction is a powerful tool for C–C bond forma-
tion.1,2 Furthermore, the versatile nitrile groups can be conve-
niently transformed into a variety of new functionalities, which
are highly valuable for the diversity oriented synthesis. Inspired
by Harada’s pioneering work,3 asymmetric Strecker reactions have
been realized in a catalytic fashion.1,2 Recently, impressive organ-
ocatalytic enantioselective processes have been made.1,4 However,
the substrates of the electrophiles have been largely restricted to
aldimines.1,4 Limited success on enantioselective Strecker
reactions with ketoimines5 has been observed because of their
lower reactivity and difficulty in control of enantiofacial selectivity.
Furthermore, even for ketoimines, intensive studies have been
focused on the methyl ketoimines.4i,5a–g Only two cases using
trifluoromethyl ketoimines are reported by Enders and Zhou recen-
tly.5h,i However, to our knowledge, cyclic trifluoromethyl ketoi-
mines have not been explored for organocatalytic asymmetric
Strecker reactions so far.6
Recently we have developed a chiral quinine derived thiourea I
catalyzed highly enantioselective aza-Henry reaction of trifluoro-
methyl 2(1H)-quinazolinones with nitroalkanes (Scheme 1,
Eq. 1).7 In addition, the reaction has been successfully applied as
a key step in the efficient synthesis of anti-HIV drug DPC 083. In
our continuing effort on the exploration of the medicinally
valuable molecular architectures for the synthesis of structurally
diverse, biologically interesting chiral trifluoromethyl dihydroqui-
nazolinones,8 we conceived that the use of TMSCN as nucleophiles
could produce new functionalized compounds, which may be use-
ful for biological studies. Herein we wish to report the study out-
comes. Notably, highly enantioselective addition of TMSCN to
cyclic trifluoromethyl quinazolinone ketoimines has been achieved
under mild reaction conditions in high yields and with high
enantioselectivities.
A model reaction between trifluoromethylquinazolin-2(1H)-
one (1a) (1.0 equiv) and TMSCN (2.0 equiv) in the presence of
I,9,10 a catalyst used in our aza-Henry reaction, in CH2Cl2 at rt
Previous work: aza-Henry reaction (eq. 1)7
R
F3C
NO2
NH
CF3
1 mol % I
N
RCH2NO2
+
toluene, rt
N
O
N
O
X
PMB
X
PMB
up to 97% yield
up to 98% ee
This work: Strecker reaction (eq. 2)
CF3
F3C CN
NH
10 mol % III
EtOH (2.0 equiv.)
CH2Cl2, - 78 oC
N
+
TMSCN
N
O
N
O
X
PMB
X
PMB
up to 98% yield
up to 97% ee
⇑
Corresponding author. Tel.: +1 505 277 0756; fax: +1 505 277 2609.
E-mail address: wwang@unm.edu (W. Wang).
Scheme 1. Organocatalytic enantioselective aza-Henry and Strecker reactions.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.119

1410
H. Xie et al. / Tetrahedron Letters 54 (2013) 1409–1411
Table 1
Table 2
Exploration of organocatalytic enantioselective Strecker reaction with 2(1H)-quinaz-
Scope of III-catalyzed Strecker reactions of 2(1H)-quinazolinone (1) with TMSCNa
olinone (1a)a
10 mol % III
EtOH
R
R
CN
NH
5
F3C CN
4
CF3
(2.0 equiv.)
N
Cl
TMSCN
10 mol% cat.
+
X
*
X
Cl
NH
CH2Cl2, - 78 oC
1
N
7
+
TMSCN
2 equiv.
N
O
N
O
EtOH (2 equiv.)
Solvent, -78 oC
PMB
PMB
N
O
N
O
PMB
1
2
PMB
2a
Yieldb (%)
Eec (%)
1a
Entry
1
X, R, 2
t (d)
cat.
CF3
F3C CN
NH
Cl
OMe
N
S
1.5
92
97
OH
N
O
HN
N
H
CF3
PMB
2a
N
OBn
F3C CN
H
Br
I
N
NH
2
3
4
2
2
2
88
96
95
96
97
94
quinine (II)
H
N
I
N
O
PMB
2b
F3C CN
NH
F3C
CF3
NMe
2H
H
N
N
CF3
OMe
HN
HN
N
O
PMB
S
S
2c
F3C CN
CF3
F
N
IV
NH
H
N
III
N
O
PMB
2d
F3C CN
NH
Entry
Cat
Solvent
t (h)
Yieldb (%)
Eec (%)
PMB
MeO
1d
2
3
4
5
I
I
II
III
III
IV
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
CH2Cl2
36
36
36
36
36
36
87
95
83
92
91
91
30 (R)
53 (R)
42 (S)
97 (R)
95 (R)
96 (S)
5
6
7
2
2
2
98
95
70
95
95
92
N
O
PMB
2e
F3C CN
6
NH
a
Unless otherwise specified, a mixture of quinazolin-2(1H)-one 1 (0.07 mmol),
N
O
EtOH (0.14 mmol) and catalyst (0.007 mmol) in CH2Cl2 or toluene (1 mL) in dry
ice—acetone bath (À78 °C) was added TMSCN (0.14 mmol) slowly (the CH2Cl2
solution needs to be sufficiently cooled before TMSCN is added, otherwise, lower ee
might be observed). The resulting mixture was then stirred in dry ice—acetone bath
for a specific amount of time, then the reaction was allowed to raise to room
temperature slowly. The pure product was obtained after purification by column
chromatography on silica gel.
PMB
2f
F3C CN
NH
N
O
PMB
2g
b
Isolated yields.
Ph CN
NH
c
Enantiomeric excess (ee) determined by chiral HPLC analysis (Chiralcel OD-H).
Without MeOH.
Cl
Br
Cl
d
8d
9d
10
6
3
3
69
59
52
—
N
O
PMB
2h
was carried out (Table 1, entry 1). Disappointingly, despite high
yield, poor enantioselectivity (30% ee) was obtained. We envi-
sioned that the use of HCN might deliver the product with improv-
ing enantioselectivity since the amine functionality in the catalysts
affords stronger interaction with HCN instead with TMSCN.
Accordingly, 2.0 equiv of EtOH was used in situ to generate HCN
from TMSCN. Indeed, an enhanced enantioselectivity was observed
(53% ee, entry 2). Screening of other organocatalysts11–13 revealed
that quinine gave rise to an unsatisfactory outcome (entry 3). Nev-
ertheless, Soós’s catalyst III11 and Takemoto’s IV12 afforded prod-
uct 2a in high yields (92% and 91% respectively, entries 4 and 6)
and with high enantioselectivities (97% and 96%, respectively).
Change of CH2Cl2 to toluene, a medium used in our early aza-Henry
process,7 did not give a more encouraging result. Therefore, we
decided to use Soós’s catalyst III to probe the scope of the process
in CH2Cl2.
4-CF3C6H4 CN
NH
77
N
O
PMB
2i
Me CN
NH
No reaction
N
O
PMB
2j
a
b
c
See footnote in Table 1 and Supplementary data.
Isolated yield after chromatographic purification.
Determined by chiral HPLC analysis (Chiralpak AS-H, or Chiralcel OD-H).
At room temperature.
d
broad substrate tolerance and a quaternary stereogenic center is
generated highly enantioselectively in all cases (entries 1–7). A full
range of cyclic ketoimine 1, including electron-withdrawing (en-
tries 1–4), -donating (entries 5 and 6), and -neutral substituents
With the optimal conditions in hand, the generality of the
Strecker reaction was investigated accordingly. Notably, as shown
in Table 2, the III-promoted Strecker process exhibits a relatively

H. Xie et al. / Tetrahedron Letters 54 (2013) 1409–1411
1411
Acknowledgements
Financial support of this research is provided by the National
Science foundation (CHE-1057569), the China 111 Project (Grant
B07023) and East China University of Science & Technology. We
also acknowledge the NSF for providing support of NMR facilities
at UNM (NSF grants 0840523 and 0946690).
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.
2012.12.119.
Figure 1. Single X-ray crystallographic structure of 2b.
References and notes
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MeO
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TS
Figure 2. Proposed transition state (TS) model.
(entry 7) can engage in the reactions in good to excellent yields (70–
98%) and with excellent enantioselectivities (92–97%). A similar
trend observed in the aza-Henry reactions is also obeyed in the
Strecker reactions that the CF3 moiety in the cyclic ketoimines 1 is
important for reactivity and enantioselectivity. As shown, moderate
ee values but good yields are obtained when Ph and 4-CF3Ph instead
of CF3 group are employed (Table 2, entries 8 and 9), while no reac-
tion occurs in the aza-Henry reaction. No reaction is also seen with
less reactive methyl group (entry 10). The absolute configuration of
2b was determined by X-ray crystallographic analysis (Fig. 1).14
A transition state (TS) model is proposed to rationalize the out-
come of high enantioselectivity and absolute (R) configuration of
the asymmetric Strecker reaction (Fig. 2). The amine and thiourea
moieties in the rigid catalyst III gauche each other as well so that
they can simultaneously activate nucleophile HCN through base-
acid interaction and electrophile carbonyl imine through two
stronger H-bond interactions of the thiourea moiety. More impor-
tantly, the resulting rigid TS can provide products in high levels of
enantioselectivity, as observed from the investigation. Further-
more, the TS model also explains the stereochemistry outcome of
the addition adduct with R configuration. The base–acid interac-
tion directs the nucleophile CNÀ to attack substrates 1 from the
Re face.
In conclusion, we have developed a highly enantioselective
Strecker reaction of cyclic ketoimines using a simple bifunctional
thiourea as catalyst under mild reaction conditions. The process
expands the scope of organocatalyzed asymmetric reactions of
synthetically challenging cyclic ketoimines for the construction
of quaternary carbon stereocenters from the Henry7 to the Strecker
reactions. The process affords an alternative access to structurally
diverse, biologically interesting optically active 4-trifluoro-
methyl-dihydroquinazolinones. The investigation on the biological
properties of these products and their application in diversity-ori-
ented synthesis is currently being pursued.
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14. CCDC-907158 contains the supplementary crystallographic data for this paper.
These data can be obtained free of charge via www.ccdc.cam.ac.uk and see
Supplementary data.