Enantioselective organocatalytic substitution of α-cyanoacetates on imidoyl chlorides - Synthesis of optically active ketimines

Article abstract of DOI:10.1039/b715810f

The enantioselective substitution of α-cyanoacetates on imidoyl chlorides under phase-transfer catalytic conditions is presented; a simple quinidine-derived phase-transfer catalyst gives access to the products, highly substituted ketimines, in generally g

Full text of DOI:10.1039/b715810f

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Enantioselective organocatalytic substitution of a-cyanoacetates on
imidoyl chlorides – synthesis of optically active ketimines{
Stefano Santoro, Thomas B. Poulsen and Karl Anker Jørgensen*
Received (in Cambridge, UK) 12th October 2007, Accepted 7th November 2007
First published as an Advance Article on the web 16th November 2007
DOI: 10.1039/b715810f
o-nitrophenyl was found to be optimal with respect to enantio-
selectivity. Furthermore, the screening also revealed that bulky
ester groups, such as tert-butyl, in the a-substituted-a-cyanoacet-
ates gave higher enantioselectivities compared to smaller groups.
On the basis of these results, we decided to perform a catalyst
and conditions screening using 2,2,2-trifluoro-N-(2-nitrophenyl)
acetimidoyl chloride 2a and tert-butyl 2-cyanopentanoate 3a as the
nucleophile. Several phase-transfer catalysts derived from cinchona
alkaloids were tested (Fig. 1 and Table 1).
The enantioselective substitution of a-cyanoacetates on imidoyl
chlorides under phase-transfer catalytic conditions is presented;
a simple quinidine-derived phase-transfer catalyst gives access
to the products, highly substituted ketimines, in generally good
yields and up to 90% ee.
Imidoyl halides are reactive and versatile chemical compounds
which have found wide application in organic synthesis and in the
study of chemical reactivity.1 The halide in these compounds can
be replaced by various nucleophiles for functionalization, in which
process the imidoyl halide acts as an electrophile equivalent to the
imidoyl carbocation. Furthermore, the CLN bond can be used for
other processes, e.g. alkylation, cyclization and reduction to
amines. Among imidoyl halides, trifluoroacetimidoyl chlorides are
probably the most interesting as they are important building
blocks for the synthesis of functionalized fluorine-containing
compounds.2 Trifluoroacetimidoyl chlorides are easily accessible
and can be prepared in a one-step synthesis starting from cheap
and commercially available materials.3
Up to now, no asymmetric reactions involving these compounds
are known, although the optically active products might have
considerable synthetic applicability. In this communication, we
wish to present our initial investigations towards this goal by
performing a substitution at the carbon atom in the imidoyl
chlorides using asymmetric phase transfer catalysis.4 Regarding the
choice of a model system for studying this reaction, our interest
focused on the use of a-substituted-a-cyanoacetates as the
nucleophilic component, considering the synthetic possibilities
associated with having both an ester and nitrile functionality
attached to the same chiral carbon atom.5 This reaction leads
to the formation of an all-carbon quaternary stereocenter,6 and
furthermore, the products – optically active ketimines – contain
functional groups that may be used for successive modifications.
We started our investigation with a preliminary screening of the
substituent at the nitrogen atom of the imidoyl chloride and the
alcoholic moiety of the ester group of the a-substituted-a-
cyanoacetate. This screening (see ESI{) clearly demonstrated that
electron-deficient aryl substituents on the imidoyl chloride were a
necessity for sufficient reactivity and in particular that mono-nitro
substituted aryl groups seemed to afford a good compromise
between reactivity and stability. Of the substrates tested,
Fig. 1 Catalysts.
Generally, the reaction occurred with excellent conversion after
stirring overnight. Commercially available N-benzylcinchoninium
chloride 1a and the quasienantiomer N-benzylcinchonidinium
bromide 19a catalyzed the reaction with moderate enantioselec-
tivity (Table 1, entries 1 and 2). Derivatisation of the catalyst motif
revealed that the 9-OH functionality had to be unprotected to
maintain these levels of enantioinduction (entry 3). Additionally,
increasing the size of the substituent R at the nitrogen atom led to
a significant improvement in the enantioselectivity (entry 5). An
equivalent or even larger increase in the enantioselectivity could
also be realized by introducing two or three methoxy groups on
the benzyl ring (catalysts 1e and 1f, entries 6 and 7). Unfortunately,
changing the ether substituents from methyl to benzyl (catalyst 1g)
was unproductive.7 Finally, we prepared a new catalyst, changing
the alkaloid moiety from cinchonine to quinidine (R0 = OMe),
and obtained a further increase in the enantiomeric excess of 4a to
86% ee (catalyst 1h, entry 11). Temperatures higher or lower than
220 uC afforded decreased enantioinduction and slight changes in
the solvent had no significant effect.
Danish National Research Foundation: Center for Catalysis,
Department of Chemistry, Aarhus University, Aarhus C, DK-8000,
Denmark. E-mail: kaj@chem.au.dk; Fax: +45 8619 6199;
Tel: +45 8942 3910
{ Electronic supplementary information (ESI) available: Full experimental
details. See DOI: 10.1039/b715810f
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Chem. Commun., 2007, 5155–5157 | 5155

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Table 1 Catalyst and conditions screeninga
an a-aryl-a-cyanoacetate was employed, the reaction occurred with
low enantioselectivity (entry 9). All reactions afforded the products
4 in good yields, with the exception of those performed with a-(sec-
alkyl)-a-cyanoacetates (entries 4 and 5). In these cases the reaction
was slower and probably the hydrolysis of the imidoyl chloride
became competitive with the substitution reaction. The best result
was obtained using tert-butyl 2-cyano-5-phenylpentanoate 3h as
the nucleophile. The reaction afforded the corresponding ketimine
4h in 98% yield and 90% ee.
Conv.
T/uC (%)b
Entry Catalyst Solvent
ee (%)c
It was possible to obtain compound 4c as a single enantiomer by
recrystallization from EtOAc–hexane. An X-ray crystal structure
(Fig. 2) revealed that the absolute configuration of the reaction
products was (S) and that the imine was formed as the sterically
less encumbered (Z)-isomer.8
1
2
3
4
5
6
7
1a
19a
1b
1c
1d
1e
1f
o-Xylene–CHCl3 7 : 1 220 95
o-Xylene–CHCl3 7 : 1 220 95
o-Xylene–CHCl3 7 : 1 220 97
o-Xylene–CHCl3 7 : 1 220 80
o-Xylene–CHCl3 7 : 1 220 96
o-Xylene–CHCl3 7 : 1 220 84
o-Xylene–CHCl3 7 : 1 220 92
o-Xylene–CHCl3 7 : 1 230 72
30
242
16
36
72
76
81
73
73
71
86
279
85
8d
9e
10
11
12
13
14
a
1f
1f
o-Xylene–CHCl3 7 : 1
0
39
1g
1h
19h
1h
1h
o-Xylene–CHCl3 7 : 1 220 95
o-Xylene–CHCl3 7 : 1 220 89
o-Xylene–CHCl3 7 : 1 220 n. d.
m-Xylene–CHCl3 7 : 1 220 n. d.
o-Xylene–DCM 7 : 1
220 n. d.
86
Reaction performed with 3a (0.1 mmol), 2a (1.3 equiv.) and
catalyst (6 mol%) in 0.66 mL of solvent and 0.33 mL of 20% KOH
b
aqueous solution.
Determined from HPLC. 50% KOH aqueous solution was used
Determined from NMR spectroscopy.
d
c
e
as the base. 40% K3PO4 aqueous solution was used as the base.
Fig. 2 X-Ray structure of (S)-4c (ellipsoids drawn at 50% probability).
Using the optimized conditions we studied the generality of
the asymmetric substitution on trifluoroacetimidoyl chloride 2a
using a variety of tert-butyl a-substituted-a-cyanoacetates as the
nucleophile (Table 2). Among these substituents, both simple
a-(primary-alkyl)- and a-(sec-alkyl)-a-cyanoacetates exhibited high
enantioselection (entries 1 and 4–8).
Several synthetic manipulations of the products can be
envisioned. For instance, ketimine 4a was stereoselectively
reduced in a substrate-controlled process in high yield and good
diastereoselectivity (7 : 1). Subsequent reduction of the nitro-group
and treatment with NaNO2 in acidic media led to the formation of
the corresponding 1-substituted benzotriazole 7 in good yield (70%
over two steps, Scheme 1).
Spatial proximity of an aryl-group to the a-carbon atom had a
negative effect on the enantioselectivity (entries 2 and 3), and when
The asymmetric substitution reaction presented here is not
limited to the use of trifluoroacetimidoyl chlorides as the
electrophilic reaction partner. Preliminary results obtained from
the reaction between 3a and carbethoxyacetimidoyl chloride 2b in
the presence of phase-transfer catalyst 1i have showed that this
methodology can also be used for the synthesis of optically active
a-imino esters, such as 8, with promising selectivities (eqn (1)).
Table 2 Scope of the reactiona
(1)
Reaction
Substrate time
Entry
R
Yield (%)b ee (%)c
1
2
3
CH3CH2CH2
PhCH2
(2-Furanyl)CH2 3c
Cyclohexyl
(CH3)2CH
CH3
TBSO(CH2)5
PhCH2CH2CH2 3h
Ph 3i
3a
3b
18 h
17 h
17 h
7 d
4a - 76
4b - 99
4c - 70
4d - 30
4e - 27
4f - 90
4g - 95
4h - 98
4i - 78
86
62
ðÞ
65 (S)d
86
90
4e
5e
6
3d
3e
3f
7 d
12 h
16 h
16 h
5 d
84
88
90
34
7
3g
8
9f
a
Reaction performed with 3 (0.2 mmol), 2a (1.3 equiv.) and 1h
(6 mol%) in 1.33 mL of o-xylene–CHCl3 7 : 1 and 0.66 mL of 20%
KOH aqueous solution. Isolated yield. Determined from HPLC.
b
c
In summary, we have presented the first example of an
asymmetric reaction involving the use of imidoyl halides as the
electrophile. The substitution reaction is an effective and practical
method for preparing optically active ketimines a-functionalized
d
e
Configuration assigned from X-ray crystallography. Reaction
performed with 3 equiv. of 2a. 40% K3PO4 aqueous solution used
as base.
f
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4 For recent reviews on asymmetric phase transfer catalysis, see: (a) T. Ooi
and K. Maruoka, Angew. Chem., Int. Ed., 2007, 46, 4222; (b) J. Vachon
and J. Lacour, Chimia, 2006, 60, 266; (c) K. Maruoka and T. Ooi, Chem.
Rev., 2003, 103, 3013; (d) M. J. O’Donnell, Acc. Chem. Res., 2004, 37,
506; (e) B. Lygo and B. I. Andrews, Acc. Chem. Res., 2004, 37, 518; for
recent examples of enantioselective substitution at unsaturated carbon,
see: (f) T. B. Poulsen, L. Bernardi, J. Alema´n, J. Overgaard and
K. A. Jørgensen, J. Am. Chem. Soc., 2007, 129, 441; (g) M. Bell,
T. B. Poulsen and K. A. Jørgensen, J. Org. Chem., 2007, 72, 3053; (h)
T. B. Poulsen, L. Bernardi, M. Bell and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2006, 45, 6551; (i) M. Bella, S. Kobbelgaard and K. A. Jørgensen,
J. Am. Chem. Soc., 2005, 127, 3670.
Scheme 1 Diastereoselective reduction of the ketimine and benzotriazole
formation.
5 For recent examples of the application of a-substituted-a-cyanoacetates
in asymmetric synthesis, see: (a) X. Wang, M. Kitamura and
K. Maruoka, J. Am. Chem. Soc., 2007, 129, 1038; (b) M. S. Taylor
and E. N. Jacobsen, J. Am. Chem. Soc., 2003, 125, 11204; (c) M. S. Taylor,
D. N. Zalatan, A. M. Lerchner and E. N. Jacobsen, J. Am. Chem. Soc.,
2005, 127, 1313; (d) H. Li, J. Song, X. Liu and L. Deng, J. Am. Chem.
Soc., 2005, 127, 8948; (e) Y. Wang, X. Liu and L. Deng, J. Am. Chem.
Soc., 2006, 128, 3928; (f) F. Wu, R. Hong, J. Khan, X. Liu and L. Deng,
Angew. Chem., Int. Ed., 2006, 45, 4301. See also ref. 4g.
with a quaternary stereocenter. The reaction is catalyzed by a
simple and readily accessible catalyst prepared from commercially
available and cheap starting materials. The process occurs with
generally high yields and with up to 90% ee.
This work was made possible by a grant from The Danish
National Research Foundation and OChemSchool. Thanks are
expressed to Jacob Overgaard for X-ray analysis.
6 For a recent review on the construction of quaternary stereocenters, see
e.g.: B. M. Trost and C. Jiang, Synthesis, 2006, 369.
7 R. Ceccarelli, S. Insogna and M. Bella, Org. Biomol. Chem., 2006, 4,
4281.
Notes and references
8 Crystal data for [4c]: C20H18F3N3O5, M = 437.37, orthorhombic, space
group P212121 (no. 14), a = 8.2352(4), b = 14.0673(5), c = 17.2845(8) s,
1 (a) T. D. Petrova and V. E. Platonov, Russ. Chem. Rev., 1988, 57, 234,
(Usp. Khim., 1988, 57, 405); (b) T. Ulrich, The Chemistry of Imidoyl
Halides, Plenum Press, New York, 1968; (c) R. Bonnet, in The Chemistry
of the Carbon-Nitrogen Double Bond, ed. S. L. Patai, John Wiley & Sons,
New York, 1970.
2 K. Uneyama, J. Fluorine Chem., 1999, 97, 11.
3 K. Tamura, H. Mizukami, K. Maeda, H. Watanabe and K. Uneyama,
J. Org. Chem., 1993, 58, 32.
V = 2002.36(15) s3, T = 100 K, Z = 4, m(Cu-Ka) = 1.067 mm21
,
8608 reflections collected, 2538 unique (Rint = 0.0336) which were
used in all calculations. Refinement on F2, final R(F) = 0.0331,
wR(F2) = 0.0778. Flack parameter is 0.08(14). CCDC 663280. For
crystallographic data in CIF or other electronic format, see DOI: 10.1039/
b715810f.
This journal is ß The Royal Society of Chemistry 2007
Chem. Commun., 2007, 5155–5157 | 5157