Synthesis of functionalized α-trifluoroethyl amine scaffolds via Grignard addition to N-aryl hemiaminal ethers

Article abstract of DOI:10.1039/c3ra47708h

The synthesis of a variety of α-branched trifluoroethyl amines was achieved by reaction of N-aryl hemiaminal ethers with organomagnesium reagents.

Full text of DOI:10.1039/c3ra47708h

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Synthesis of functionalized a-trifluoroethyl amine
scaffolds via Grignard addition to N-aryl
hemiaminal ethers†
Cite this: RSC Adv., 2014, 4, 9288
a
b
a
b
Received 17th December 2013
Accepted 22nd January 2014
*
*
Amrei Deutsch, Herbert Glas, Anja Hoffmann-Roder and Carl Deutsch
¨
DOI: 10.1039/c3ra47708h
www.rsc.org/advances
The synthesis of a variety of a-branched trifluoroethyl amines was catalyzed asymmetric isomerization reactions of ketoimines.10
achieved by reaction of N-aryl hemiaminal ethers with organo- Furthermore, nucleophilic addition reactions of various organo-
magnesium reagents.
metallics to triuoromethylated imines11 and hydrazones12 have
been reported. In this context, Lauzon and Charette have shown
that triuoromethyl amine derivatives can be prepared by
copper-catalyzed nucleophilic addition of diorganozinc reagents
to N-phosphinoylimines, using an excess of organozinc reagent.13
Similarly, triuoromethylated a,a-dibranched carbinamines can
be obtained from N-tert-butylsulnyl hemiaminals with organo-
magnesium or organolithium reagents.14 However, most of these
approaches are either hampered by the high tendency of a,a,a-
triuorethylimines to form hydrates or by the need of additional
deprotection steps for further functionalization of the nitrogen
atom. In a seminal paper, Mikami and coworkers showed
that an excess of Grignard reagents can be used to prepare a-
triuoromethylated amines from stable N,O-acetals of tri-
uoroacetaldehyd.15,16 This work was recently extended to the use
of arylboroxines for palladium(II)-catalyzed synthesis of a-(tri-
uoromethyl)arylmethyl amines.17
Herein, we report a systematic study on the synthesis of
functionalized a-substituted triuoromethyl amines using
Grignard reagents and readily available triuoromethylated
hemiaminal ethers.18 The latter are shelf-stable compounds
derived from 1-ethoxy-2,2,2-triuoroethanol and aromatic
amines and can be converted into triuoromethylated aldi-
mines in situ. Thus, upon treatment with Grignard reagent
deprotonation should provide the corresponding imine which
would then undergo nucleophilic attack by excess Grignard
reagent to furnish the desired triuoromethyl amine
(Scheme 1). Formation of the transient imine species was
conrmed by observing the corresponding imine hydrate via
HPLC-MS aer addition of MeMgBr to the reaction mixture.
The design of compounds suitable for drug development is a
multi-dimensional process that requires the ne tuning of
molecular properties beyond potency. For instance, physical–
chemical properties that directly affect hydrolytic stability and
bioavailability of the compound must be addressed to avoid
side effects in vivo. Due to the excellent pharmacological prole
of uorinated drugs, the strategic incorporation of uorine
atoms has nowadays become routine in medicinal chemistry
development programs.1 For instance, incorporation of a tri-
uoromethyl substituent adjacent to an amine is a means to
improve the metabolic stability and to attenuate the basicity of
the compound by shiing its pKa value more towards those of
amides.2 Furthermore the C–CF3 bond is substantially isopolar
with the C]O bond and the triuoroethyl amine moiety has a
structural similarity to the tetrahedral proteolytic transition state.3
As a consequence, triuoroethyl amines can be used as versatile
hydrolysis-resistant bioisosteres of amides4 which retain the
geometry of the amide bond and, in contrast to other mimetics5,
also preserve the donating properties of the N–H bond. An illus-
trative example for the successful replacement of the amide
functionality by a triuoroethyl amine is given by Odanacatib, a
highly potent drug candidate for the inhibition of Cathepsin K.6
Various methods for the synthesis of a-triuoromethylated
amines have been described so far,7 including hydrogenation8
and aromatic substitution9 of activated imines, as well as base-
aCenter For Integrated Protein Science Munich (CIPSM
) at the Department of
Chemistry, Ludwig-Maximilians-Universitaet, Butenandtstr. 5–13, 81377 Munich,
Germany. E-mail: Anja.Hoffmann-Roeder@cup.lmu.de; Fax: +49 89 2180 77914;
Tel: +49 89 2180 77913
bMedicinal Chemistry, Merck, Frankfurter Strasse 250, 64293 Darmstadt, Germany.
E-mail: Carl.Deutsch@merckgroup.com; Tel: +49 6151 72 2500
† Electronic supplementary information (ESI) available: See DOI:
10.1039/c3ra47708h
Scheme 1
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Table 1 Optimization studies
To determine the optimal conditions, 3-chloro-N-(1-ethoxy-
2,2,2-triuoroethyl)aniline 1a was treated with MeMgBr in dry
THF under argon at different reaction temperatures (Table 1).
Thus, the addition proceeded smoothly at ꢀ78 ꢁC furnishing
the desired triuoroethyl amine 2a in 74% yield aer one hour.
Whereas higher temperatures above 0 ꢁC led to signicant
formation of side and decompositiꢁon products, best yields were
obtained at a temperature of ꢀ15 C (Table 1, entries 1–5). For
complete conversion of the triuoromethyl N,O-acetals at least
2 eq. MeMgBr are required. However, larger excess of the
nucleophile did not improve the yield signicantly. Similar
results were obtained with N-(1-ethoxy-2,2,2-triuoroethyl)-
aniline 1b bearing a neutral aryl ring (Table 1, entries 7–9).
With the optimized reaction conditions in hands, the
substrate scope of the nucleophilic addition was tested using
various functionalized aryl N,O-acetals 1 and MeMgBr (Table 2).
We were pleased to nd that besides halides also ester, triazole,
triuoromethyl groups and morpholino substituents are well
tolerated to provide the desired triuoroethyl amines 2 in fair to
excellent yields (Table 2, entries 1, 5, 6 and 8). However, elec-
tron-rich aniline derivatives proceeded more sluggishly and led
to formation of the desired product with only diminished yields
(Table 2, entry 4). In contrast, both electron-decient and
moderately electron-rich heteroaromatic N,O-acetals 1c and
1g–j were readily converted to the corresponding amines 2c,
2g–j (Table 2, entries 3, 7–10), thus giving access to compounds
with potential applications in drug design.
Entry
Ar
Eq. [MeMgBr]
T [ꢁC]
Yield (%)a
Product
1
2
3
4
5
6
7
8
9
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
3-ClC6H4
C6H5
2
2
2
2
2
3
1
2
3
40
25
0
ꢀ15
ꢀ78
ꢀ15
ꢀ15
ꢀ15
ꢀ15
65
70
84
87
74
75
34b
63
65
2a
2a
2a
2a
2a
2a
2b
2b
2b
C6H5
C6H5
a
Yield of isolated product aer ash chromatography. b Reaction time
of 2 h.
Table 2 Addition of MeMgBr to (hetero)aromatic N,O-acetalsa
Next, we turned our attention to other Grignard reagents for
nucleophilic addition to triuoromethylated N,O-acetals. Thus,
Entry
Ar
Yield (%)b
Product
1
2
3
4
5
3-ClC6H4
C6H5
4-pyridyl
4-OMeC6H4
4-COOEtC6H4
87
63
81
40
94c
2a
2b
2c
2d
2e
Table 3 Addition of Grignard reagents to 3-chlorophenyl N,O-acetala
6
7
57
69
2f
Entry
RMgX
i-PrMgCl
i-PrMgCl$LiCl
n-BuMgBr
Yield of 3 (%)b
Yield of 4 (%)b
1
2
3
4
3a, 70
3a, 67
3b, 94
3c, 57
16
30
2g
ndc
nd
t-BuMgCl
96d
80
2h
2i
5
3d, 78
nd
8
9
6
3e, 26
19
7
8
3f, 62
3g, 84
nd
nd
10
74
2j
9
3h, 85
nd
a
All reactions were performed according to the optimized procedure.
Aer ash chromatography. Use of 3 eq. MeMgBr. Without
a
b
c
d
All reactions were performed according to the optimized procedure.
b
Aer ash chromatography. c nd ¼ not detected.
further purication.
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von der Heyden and Mr Markus Knoth (Merck) for NMR support
and fruitful discussions.
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This work was supported by the Excellence Cluster CIPSM and
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9290 | RSC Adv., 2014, 4, 9288–9291
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