Chapter 24
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Reactions of Unsaturated Organometallic Reagents on Trifluoroacetaldimines Danièle Bonnet-Delpon, Jean-Pierre Bégué, and Benoit Crousse Centre National de la Recherche Scientifique, Université Paris-Sud, Biocis UPRES A 8076, Rue J.B. Clément, F-92296 Châtenay-Malabry, France
Allyl zinc reagents, vinyl magnesium bromide and lithium acetylides could easily react without any activation on trifluoroacetaldimines to afford homoallyl, allyl and propargyl amines in good yields. From chiral imines, these amines were obtained in excellent diastereoselectivity (>98%). After N-allylation, homoallyl amines could give access to piperidine derivatives by ring closing metathesis. The allyl amine allowed the synthesis of the trifluoromethyl epoxide 24, fluorinated analog of a key precursor of aspartyl proteases inhibitors.
Introduction Amino compounds constitute a large class of naturally occurring and biologically important molecules. One approach to these compounds is the addition of organometallic reagents to imines or imine derivatives. This wellknown reaction allows the preparation of stereochemically defined amines, since the addition of organometallic reagents to the C=N bonds of imines or imine derivatives can be stereocontrolled. Despite the poor reactivity of imines towards nucleophilic reagents, a variety of methods have been developed which broaden the scope of this organometallic reaction. Classically the electrophilicity of the imino function bond can be increased by the addition of external promoters (proton or Lewis acid) to provide a more reactive iminium salt, or by the Nacylation or W-sulfonylation to give more activated imines or iminium salts (/). 412
© 2005 American Chemical Society
Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.
413 N-oxidation is also a good way to increase the reactivity of imines through the formation of nitrones (/). Surprisingly, despite the electronwithdrawing effect of a fluoroalkyl group which can favor to addition of nucleophiles on C=N bond, the addition of an unsaturated organometallic reagent to fluorinated aldimines has not been explored so far. Considering the unique consequences of fluorine substitution for hydrogen in organic molecules, the synthesis of selectively fluorinated and enantiomerically pure unsaturated amino compounds, as biological relevant targets, might be of particular interest (2-4). Consequently our objective was to perform the addition of unsaturated organometallic reagents to trifluoromethyl aldimines, with no particular other type of activation. The success of such method would bring the possibility to prepare, by the easy introduction of a chiral iV-substituent, non racemic amines, as already shown in the case of phenyl lithium addition on chiral fluorinated imine derivatives (4f). We develop in this chapter our studies on these reactions as an access to allyl, homoallyl and propargyl amines, and their use as synthons for the preparation of new biologically relevant fluorinated amino compounds, such as fluorinated peptidomimetic units and heterocyclic compounds (Scheme
1). Scheme 1
All starting trifluoromethyl aldimines were readily synthetized by the condensation between the hydrate or the hemiacetal of fluoral with the appropriate amine, and were always obtained as anti isomers. Trifluoromethyl Homoallylic Amines: Ailylation Reactions. The preparation of homoallyl trifluoromethyl amines had not been intensively explored so far. Few approaches were described: - one synthesis from the N-(p~ toluenesulfonyl)-trifluoromethyl aldimine by an ene reaction (5), - a Lewis acidmediated addition of an allylsilane to aldimines derived from fluoral or related hemiaminals, including non racemic ones (6, 4a). Concerning the organometallic
Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.
414 approach, to our knowledge few examples were reported and they concern imines activated by an electronwithdrawing JV-substituent: the addition of the allylmagnesium on a trifluoromethyl sulfenimine generated by electrooxidation of CF CH NR (7) and on the JV-acyl-l-chloro-2,2,2-trifluoro ethylamine (8), and more recently the addition of allyllithium on oc-trifluoromethyl hydrazones (9). We explored the reaction between the JV-benzyl trifluoroacetaldimine 1 and allyl bromides with different metals under Barbier conditions (10). This approach does not require the isolation of the organometallic reagents allowing thus a great diversity of structures for the allyl moiety. With Mg and In, the reaction was efficient only with, the non substituted allyl bromide. With Zn, conditions were found (1.3 equiy. of allyl bromide, 1.2 equiv. of turnings of Zn activated by TMSC1, at room temperature in DMF) which allowed the complete reaction with allyl bromide and 3,3-dimethyl allyl bromide (table 1). 3
2
2
Table 1. AHylation Reaction under Barbier conditions
+
j|{ 1
X
Allylic bromides
*
a l
»
Homoallylic amines 3a b
Bn
Allyl Br
f
Metal Mg In a
b
Time (h) 0.75 1
product
NHBn
Zn
3
a
b
95 20 Traces
1 24 0.75
Yield (%) 75 96
a
0.75
Mg In" u Zn a
M e
NHBn 3b
97
b
in ether at r.t. in DMF at r.t.
These latter conditions were then successfully applied to the reaction with various patterns of allyl bromides, starting from the N-benzyl aldimine 1 or the N-para-methoxyphenyl aldimine 2 (Table 2). Reactions can be conducted alternatively in DMF at room temperature or in THF at reflux. In all cases reactions were fast and clean, and yields in homoallylic amines 3,4 were good to excellent (75-97%). Similarly imine 1 could react with propargyl bromide to afford the homopropargyl amine 3e in 76% yield.
Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.
415
a
Table 2. Ailylation Reaction with Zinc in D M F and T H F C F
3
Rl
n
il
B
r
+
\ A ^
\R R= Bn R 1 PMP 2
Allyl Br
R
R
C F 3
2
η λ
Time (h) 0.75
Br"
Solvent THF DMF
YV
R= NHR Bn R-i 3 PMP 4
solvent
DMF
R
3/ 2
NHR Ri I f
Zn/cat. TMSCi 3
b
3,4
c p
3>
NHBn 3a CF
Yield (%) 95 85 97
3
1 NHBn
Br
3b
THF 0.75
DMF
0.75
DMF
CF
Br Et OC
82
I NHBn ' 3c
75
NHBnC0 Et
75
3
2
2
3d CF . 3
B r - ^
0.75
1 NHBn
DMF
^
76
3e
0.75
DMF
4
THF
0.75
DMF
0.75
DMF
Br"
3
NHPMP 4a
cf
Br
Br
79
CF .
3 v
NHPMP 4b CF
3
ry
PMP- -NH 8
92
1
82 83
4c
b
At room temperature. At reflux.
Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.
416 The success of this reaction which does not require an activation of the imine group by an JV-acyl substituent, allowed us to envisage a chiral approach using a chiral N-substituent. With the (i?)-JV-phenethyl aldimine 5, the homoallylic amine 6a was obtained in good yield (87%), but with poor diastereoselectivity (60/40) (Scheme 2).
NH
Scheme 2
T
P h ^ 6a
h
DMF/r.t./0.5h
87%, d.e. = 20%
In order to improve diastereoselectivity, other chiral JV-substituents were evaluated. Oxazolidines 7 (62/38) which are prepared from fluoral and phenyl glycinol (4f), were reported to provide a 70/30 mixture of diastereoisomers of chiral homoallyl amine in BF3.Et 0-promoted reaction with an allylsilane (4a). When placed under Barbier conditions in DMF at room temperature, with 1.5 equiv. of zinc, oxazolidines 7 provided amines in very poor yield. An increased amount of Zn (3-4 equiv.) was required to obtain the iV-phenyl glycinol allyl amines 8 in 65%. Compared to reactions from 5, the diastereoisomeric excess was improved (d.e.= 61%). The same reaction performed in THF (reflux) provided 45% of 8 with a very poor d.e. (9%. (Scheme 3). 2
Scheme 3
dmf at r.t. 65%, d.e. = 61% t h f at reflux 45%, d.e. = 9%
The change in ratio of diastereoisomers in starting material and products suggests the intermediate formation of an iminium ion, as already postulated in reaction using Lewis acids (4a). This is probably due to the excess of zinc used in these reactions. These results indicate that chiral oxazolidines are not good substrates for reactions with allyl zinc reagents: they are less reactive than aldimines, and diastereoselectivity is not sufficiently high. In order to prevent the formation of oxazolidines, the (R)-phenylglycinol was converted into the corresponding methyl ether and the allylation reaction was performed with the CF -aldimine 9 in THF and DMF with allyl bromides (Table 3). The high reactivity was recovered : only 1.3 equiv. of Zn were required, and good yields in homoallylic amines 10 were obtained (65-85%). Furthermore diastereoselectivities were excellent. The absolute configuration could not be determined. The stereoselectivity of the addition reaction may be accounted for by a chelation-controlled mechanism (//). From the aldimine 9, the metal coordinates with Ν and Ο atoms of the auxiliary group to produce a rigid five-membered chelate (figure 1). The allyl group attacks the C=N bondfromthe less congested 3
Soloshonok; Fluorine-Containing Synthons ACS Symposium Series; American Chemical Society: Washington, DC, 2005.
417 face (opposite to the phenyl group) to give the amine 10. According to this transition state model, the addition of the allyl moiety occurs with creation of an R chiral center. This has been confirmed with our result obtained in reaction of vinylation (vide infra).
Table 3. Ailylation Reaction with the Aldimine 9. cf . 3
j!] 1.3 eq. Zn /1.3 eq. Allyl Br /off OMe *- Homoallyl amines 10 K
