Chiral Bronsted acid-catalyzed diastereo- and enantioselective synthesis of CF3-substituted aziridines

Article abstract of DOI:10.1039/c2cc35246j

A multicomponent organocatalyzed highly diastereo- and enantioselective synthesis of CF₃-substituted aziridines is described. This reaction of in situ generated CF₃CHN₂ and aldimines was realized by chiral Bronsted acid catalysis. The utility of the products is illustrated by easy access to β-CF₃ isocysteine and aziridine-containing dipeptides.

Full text of DOI:10.1039/c2cc35246j

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Chiral Brønsted Acid-Catalyzed Diastereo- and Enantioselective
Synthesis of CF3-Substituted Aziridines†‡
Zhuo Chai, Jean-Philippe Bouillon and Dominique Cahard*
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
5
DOI: 10.1039/b000000x
reactivity with an imine in situ generated from phenyl glyoxal
monohydrate 2a and p-anisidine in the presence of Brønsted
50 acid catalysts (Table 1). The privileged chiral phosphoric acid
A multicomponent organocatalyzed highly diastereo- and
enantioselective synthesis of CF3-substituted aziridines is
described. This reaction of in situ generated CF3CHN2 and
aldimines was realized by chiral Brønsted acid catalysis. The
Table 1 Screening of reaction conditionsa
10 utility of the products is illustrated in easy access to β-CF3
CF3CH2NH2•HCl + NaNO2
isocysteine and aziridine-containing dipeptides.
PhCH3/H2O
(30:1)
0 °C, 1h
PMP
N
NH2
N
O
PMP
O
N
N
OH
1 (x mol%)
Enantiopure aziridines are versatile chiral building blocks that
have high potential for further elaboration to a wide range of
chiral nitrogen-containing derivatives.1 Aziridines are not
15 only important reactive intermediates but also this three-
membered ring motif is present in many biologically active
compounds.2 In the context of an explosion of research in
organofluorine chemistry due to the matchless properties of
fluorinated molecules, trifluoromethylated building blocks are
20 privileged scaffolds for library design and drug discovery.3
Including a CF3 unit in potential medicines have positive
effects that substantially improve catabolic stability,
lipophilicity, and transport rate.4 Established methods for the
synthesis of CF3-substituted aziridines require the use of
[CF3CHN2]
RT
O
Ph
+
CF3
+
CF3
PhCH3, MgSO4
RT, 1h
OH
Ph
Ph
3a
2a
6
OMe
R
O
1a: R = 2,4,6-(i-Pr)3-C6H2, X = OH
1b: R = SiPh3, X = OH
1c: R = 3,5-(CF3)2C6H3, X = OH
O
X
P
O
4: R = 2,4,6-(i-Pr)3-C6H2, X = OCH2CF3
5: (PhO)2PO2H
R
Entry Catalyst (mol %) Time (h) Yieldb (%) Product ratioc eed (%)
cis-3a:trans-3a:6
1
2e
1a (10)
1a (10)
1a (10)
1a (5)
1a (5)
1a (5)
3 h
3 h
6 h
82
81
78
91
82
<10i
79
48i
5i
18:1:2
23:1:2
13:1:5
39:1:2
45:1:2
n.d.
78:1:3
263:1:4
43:1:8
17:1:2
n.d.
97
98
95
97
98
n.d.
99
99
n.d.
55
n.d.
98
3f
4
8 h
5g
12 h
24 h
24 h
24 h
12 h
48 h
16 h
24 h
24 h
32 h
6h
25 fluoral
hemiacetals,5a,b
trifluoromethylated
imines,5c,d
(CF3)vinyl derivatives,5e-g α-CF3-β-chloroamines,5h,i or α-
CF3-β-amino alcohols.5j,k So far, stereocontrolled accesses to
chiral CF3-substituted aziridines rely on enzymatic
resolution,5l chiral auxiliaries5a,g as well as stereospecific ring
30 closure reactions involving non-racemic precursors.5f,j,k Very
recently, Carreira and co-workers obtained racemic CF3-
substituted aziridines from the aza-Darzens reaction of
preformed imines and in situ generated trifluoromethyl
diazomethane (CF3CHN2) in the presence of excess BF3•OEt2
35 at –78 °C.6 The method of generating this simple and readily
available diazo reagent by diazotization of trifluoroethylamine
hydrochloride in the presence of sodium nitrite appeared as
early as in 1960s.7 However, in contrast to the many
successful examples of utilizing other diazo alkanes in the
40 asymmetric catalytic aza-Darzens reaction to prepare chiral
aziridines,8 the compatibility of CF3CHN2 with these chiral
catalytic systems remains to be explored. Herein, we report
the first catalytic asymmetric synthesis of CF3-substituted
aziridines that is remarkable for its simplicity, a low catalyst
45 loading, and a very high enantioselectivity.
7
8
9
1a (4)
1a (2.5)
1b (5)
10
11
12j,k
13j,k
14j,k
1c (5)
5 (10)
10i
0
83
65
75
1a (3+2)
1a (2.5+2)
1a (2.5+2)
185:1:2
431:1:4
417:1:4
99
99
aUnless noted otherwise, 2a/p-anisidine/CF3CHN2 is 1:1:2; [imine]0
=
0.05 M. bYield of isolated pure cis-3a product. cDetermined by 19F NMR
d
55 analysis of the crude reaction mixture. Ee of the cis-3a was determined
by chiral HPLC using OD-H column. ePreformed imine (0.1 M) was used.
fCH2Cl2 was used as solvent and the yield refers to a mixture of three
g
h
compounds. 1.5 eq of in situ generated CF3CHN2 was used. [imine]0 =
i
0.025 M. Unreacted imine accounts for most of the material balance.
60 j[imine]0 = 0.1 M. kThe catalyst was added in two batches at a time
interval of 12 h (entries 12 and 13) or 16 h (entry 14). n.d. : not
determined.
1a ((S)-TRIP) was found to be an efficient catalyst for this
reaction in toluene to give the desired aziridine product 3a in
65 high yield and ee value at a catalyst loading of 10 mol %
(Table 1, entry 1). Notably, 19F- and 1H NMR analysis
revealed three products: the desired cis/trans-aziridines and
cis-triazoline by-product 6. The use of preformed imine gave
Using in situ generated CF3CHN2, and inspired by
Akiyama’s related work with N2HCCO2Et,8h we tested its
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similar results (Table 1, entry 2). Replacing the solvent 45 donating groups (Table 2, entries 6–7). In addition,
a
toluene by CH2Cl2 led to much poorer product ratio and a
slight drop in both yield and ee value (Table 1, entry 3).
Decreasing the amount of CF3CHN2 or reducing the
concentration of the imine were detrimental to the overall
reaction results (Table 1, entries 5–6). While lowering the
catalyst loading amount to 2.5 mol % could improve the
product selectivity remarkably with enhanced ee, the
conversion of the imine and yield of the product dropped
heteroaromatic substrate 2h also participated in the reaction
well (Table 2, entry 8). The absolute configuration of the
aziridine cis-3b was determined by X-ray crystallographic
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5
analysis and the others were assigned by analogy.
50
The scope of this reaction was further explored by using
preformed α-imino glyoxalate 7 and α-imino glyoxylic amide
8 (Table 3). In contrast to the cis-aziridines obtained as the
major products for the above aryl glyoxal monohydrates, the
use of 7 led to cis-triazoline 6i as the major product (entries
10 significantly even with a greatly prolonged reaction time
(Table 1, entry 8). Monitoring the reaction mixture by 1H 55 1–3). Excellent ee value of 6i could still be obtained, albeit a
NMR revealed the reaction proceeded with little further
conversion after 12 h from the starting point, although 19F
co-solvent of PhCH3/CH3CH2CN (2/1) and a larger catalyst
loading were required to achieve full conversion and good
yields. It is also notable that in Carreira’s system using excess
Lewis acidic BF3•OEt2, the cis-aziridine 3i remained the
NMR analysis indicated
a considerable concentration of
15 CF3CHN2 remained in the system. Such a phenomenon could
be explained by the isolation of compound 4 from the reaction 60 major product while 6i was presumed to be the minor
system, which was formed by the trifluoroethylation of 1a by
CF3CHN2.9 This deactivation of the catalyst was assumed to
be at least partly responsible for the inefficiency of other
20 phosphoric acids for this reaction (Table 1, entries 9–11);
product.13 Our first use of imine 8 bearing a glyoxylic amide
structure in the aza-Darzens reaction with a diazo compound
led to some more interesting observations (Table 3, entries 4–
7). In this case, the cis-aziridine 3j and triazoline 6j were
indeed, 19F NMR analysis suggested the formation of similar 65 isolated in a 1:1 ratio. The ees of the cis-aziridine 3j remained
species in these cases.10 Notably, this type of undesired
reaction has not been mentioned in previous studies with other
diazo compounds using Brønsted acid catalysis,11 and our
25 finding should be useful in future design of catalytic systems
excellent (97–99%). Interestingly, the high ee values (82–
89%) of the triazoline product poses a sharp contrast to the
moderate ones of the trans-aziridine product 3j (7–49% ee).
Moreover, compared to other imine substrates, 8 displayed
using CF3CHN2 as reagent. After some experimentation, we 70 exceptionally high reactivity in that the reaction proceeded to
found that adding 1a in two batches at a time interval of 12 or
16 h led to the optimum overall results, which provide an
extremely high 431:1 dr ratio for the diastereomeric aziridines
30 and 99% ee for the cis-3a (Table 1, entries 12–14).
completion within 1 h (Table 3, entries 4-7). The reaction
could be run on a 1 mmol scale using as low as 0.5 mol% of
the catalyst while maintaining the excellent enantioselectivity
of the cis-aziridine product, which adds to the practicality of
75 this reaction (Table 3, entry 7). This phenomenon might be
ascribed to the free amide NH bond in 8, which may provide
an additional H-bond interaction with the phosphoric acid
catalyst leading to a more stable transition state.14
Table 2 Scope study with aryl glyoxal monohydrates a
CF3CH2NH2•HCl + NaNO2
3b
PhCH3/H2O
(30:1)
0 °C, 1h
PMP
N
NH2
O
Table 3 Scope study with 7 and 8a
OH
1a (2.5 + 2 mol%)
[CF3CHN2]
Ar
O
CF3
+
RT
PhCH3, MgSO4
RT, 1h
OH
O
Ar
3
2
OMe
R
N
PMP
N
PMP
O
N
R
N
N
7 or 8
PMP
0 °C, 1h
Yieldb (%)
Product ratioc eed (%)
CF3CH2NH2•HCl
+
NaNO2
[CF3CHN2]
+
O
Entry
2 (Ar)
3
CF3
1a (x mol %)
PhCH3, MgSO4
RT
CF3
PhCH3/H2O
(30:1)
cis-3:trans-3:6
R
3i: R = OEt
3j: R = NHBn
6i: R = OEt
6j: R = NHBn
1
2
3
4
5
6
7
8
2a (Ph)
3a
3b
3c
3d
65
82
78
75
71
80
85
79
431:1:4
69:1:2
95:1:3
140:1:2
59:1:2
227:1:2
60:1:2
131:1:3
99
>99
98
>99
96
>99
97
99
80
2b (4-BrC6H4)
2c (3-BrC6H4)
2d (4-ClC6H4)
2e (3,4-Cl2C6H3) 3e
2f (4-MeC6H4) 3f
Entry 7 or 8 (R)
1ab cis-3:trans-3:6c Yieldd (%)
eee (%)
–/–/95
–/20/92
–/–/96
98/46/88
99/42/89
98/49/88
98/7/82
1f
2f,g
3h
4i
7 (OEt)
7 (OEt)
7 (OEt)
10
10
5
5
3
1.4:1:26
1.1:1:14
1.2:1:29
7:1:6
6:1:6
6:1:6
82
87
42
45/7/41
46/8/45
43/8/46
46/6/47
2g (4-MeOC6H4) 3g
2h (2-benzofuryl) 3h
8 (NHBn)
8 (NHBn)
8 (NHBn)
8 (NHBn)
5i
6i
1
0.5
aReactions were conducted with [imine]0 = 0.1 M; for entries 1-5: 2.5+2
mol% of 1a at a time interval of 12 h and for entries 6-8: 3+2 mol% of 1a
35 at a time interval of 16 h were used respectively. bYields of isolated pure
cis-3 products. cEstimated by 19F NMR analysis of crude reaction mixture.
dEes of cis-3 were determined by chiral HPLC using OD-H column.
7j
8:1:8
a
CF3CHN2 used for entries 1–3 and entries 4–8 was 2.0 eq and 1.5 eq
respectively; for entries 1–3, a co-solvent of PhCH3/CH3CH2CN (2/1)
b
c
was used, see ESI for details. Catalyst loading (mol %). Estimated by
d
19F NMR analysis of the crude reaction mixture. Entries 1–3, the yield
Next, a series of aryl glyoxal monohydrates12 were tested in
this reaction by adding the catalyst 1a in two batches (Table
40 2). For substrates 2a-2g, high yields, excellent product ratios
and ee values were obtained, irrespective of the electronic
nature and position of the substituents on the benzene ring
(Table 2, entries 1–7), although a slightly larger catalyst
loading amount was necessary for substrates with electron-
85 refers to an inseparable mixture of cis-3i and 6i; entries 4–7, isolated
yields for cis-3:trans-3:6, respectively. eEes for cis-3:trans-3:6,
respectively. Reaction time: 2 h. gReaction was run at 0 °C. hReaction
f
time: 24 h. Reaction time:1 h; [imine]0 = 0.05 M. j1.0 mmol scale,
i
[imine]0 = 0.2 M, reaction time: 3 h.
90
As an illustration of the utility of these chiral CF3-
substituted aziridines, cis-3j derived from the highly reactive
2
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This journal is © The Royal Society of Chemistry [year]

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substrate 8 was readily converted to the chiral free aziridine 9.
Notably, the CH3-counterpart of 9 and its analogs have been
shown as highly useful building block in the modifications of
unprotected peptides.15 Following
a
similar literature
Azema, T. Hanamoto, Org. Lett., 2010, 12, 2548; (h) S. Kenis, M.
View Online
5
method,15b 9 was easily converted to CF3-substituted dipeptide
10 in a diastereomerically pure form in an unoptimized yield
of 78% (Scheme 1). The high dr value indicated that the
integrity of the stereochemistry was almost completely
maintained during this two-step process. In addition, the ring-
60
65
70
75
80
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10 opening of cis-3j with a nucleophile like phenylmethanethiol
was achieved to give the β-CF3 isocysteine derivative 11 as a
single diastereomer in excellent yield with 97% ee.5c, 16
6
7
NHBn
NHBn
CAN (2.5 eq)
CH3CN-H2O (3:1)
0 °C, 45 min
SBn
CF3SO3H (1.1 eq)
BnSH, RT, 24 h
8
For selected recent examples of asymmetric catalytic aza-Darzens
reactions with diazos: (a) Y. Zhang, Z. Lu, W. D. Wulff, Synlett,
2009, 2715 (review); (b) J. N. Johnston, H. Muchalski, T. L. Troyer,
Angew. Chem. Int. Ed., 2010, 49, 2290 (review); (c) L. Huang, Y.
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Mukherjee, W. D. Wulff, J. Am. Chem. Soc., 2010, 132, 14669; (f)
T. Hashimoto, H. Nakatsu. K. Yamamoto, K. Maruoka, J. Am.
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Suzuki, K. Mori, Org. Lett., 2009, 11, 2445.
O
BnHN
CF3
O
PMP
NH
N
90% yield
82% yield
O
HN
F3C
F3C
PMP
cis-3j
97% ee
9
11
DIPEA (2.0 eq)
BOP (1.5 eq)
CHCl3, RT, 1.5 h
NHBn
O
HO2C
Bn
O
Bn
NHBoc
N
9
+
10
78% yield
dr > 18:1
NHBoc
F3C
Scheme 1 Examples of utility of cis-3j
15
In summary, we have described the first catalytic diastereo-
and enantioselective synthesis of CF3-substituted aziridines
and related compounds. Besides establishing a facile way to
this kind of very useful chiral CF3-containing structures, the
identification of several competitive processes in this study
20 such as the deactivation of the Brønsted acid catalyst by
CF3CHN2 and the competitive formation of the aziridine and
triazoline products would also be useful in future related
studies. Efforts towards a deeper mechanistic understanding
of the current reactions as well as further applications to
25 related reaction systems are underway in our laboratory.
9
For acid-catalyzed trifluoroethylation of related compounds with
CF3CHN2: K. L. Koller, H. C. Dorn, Anal. Chem., 1982, 54, 529.
85 10 The inefficiency of other phosphoric acid catalysts for this reaction
was also mentioned by Carreira and co-workers (ref. 6). For the
preparation of most of the racemic aziridines for HPLC assay in this
study, a procedure using 10 mol% of Yb(OTf)3 was developed, see
the ESI† for details.
90 11 For a review and discussion on the use of Brønsted acid catalysis in
the reactions of diazos, see ref 8b. For a pioneering use of Brønsted
acid catalysis in the reaction between ethyl diazoacetate and imines:
A. L. Williams, J. N. Johnston, J. Am. Chem. Soc., 2004, 126, 1612.
12 Imines derived from simple aryl aldehydes like benzaldehyde, 2-
95
pyridyl carboxaldehyde did not undergo the reaction under the
current reaction conditions.
Notes and references
13 Triazoline 6i was proposed as an inseparable side product for imine 7
by Carreira et al. (see ESI of ref. 6). The assignment of other
triazolines (Tables 1 and 2) was based on the similarity of 19F- and
1H NMR signals observed in the crude mixture to the fully
characterized 6i and 6j. Throughout this study, no signal assignable
to the corresponding trans-triazoline structure was identified. See
the ESI† for a preliminary study on the formation of triazoline
products in this system.
UMR CNRS 6014 C.O.B.R.A., Université et INSA de Rouen, 1 rue
Tesnière, 76821 Mont Saint Aignan, France.; Tel: 33 235522466; E-mail:
dominique.cahard@univ-rouen.fr
30 † Electronic Supplementary Information (ESI) available: Experimental
procedures and spectral data, X-ray data of compound 3b. See
DOI: 10.1039/b000000x/
100
‡ FEDER funds BIOFLUORG is acknowledged for financial support.
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