Synthesis of enantiomerically-enriched N-aryl amino-amides via a Jocic-type reaction

Article abstract of DOI:10.1016/j.tetlet.2018.09.046

Enantiomerically-enriched secondary trichloromethyl-alcohols react with aryl amines to give enantiomerically-enriched α-N-arylamino-acid derivatives. The intermediate acid chlorides can react in situ with aryl or, regioselectively, with alkyl amines to gi

Full text of DOI:10.1016/j.tetlet.2018.09.046

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of enantiomerically-enriched N-aryl amino-amides via a Jocic-
type reaction
⇑
Christian Hobson, Michael S. Perryman, Gavin Kirby, Guy J. Clarkson, David J. Fox
Department of Chemistry, University of Warwick, Gibbet Hill Road, Coventry CV4 7AL, UK
a r t i c l e i n f o
a b s t r a c t
Article history:
Enantiomerically-enriched secondary trichloromethyl-alcohols react with aryl amines to give enan-
Received 22 August 2018
Revised 14 September 2018
Accepted 18 September 2018
Available online xxxx
tiomerically-enriched
with aryl or, regioselectively, with alkyl amines to give aryl or alkyl
a
-N-arylamino-acid derivatives. The intermediate acid chlorides can react in situ
-N-arylamino amides.
Ó 2018 Published by Elsevier Ltd.
a
Keywords:
Jocic reaction
N-Aryl amino-amides
Enantiomerically-enriched
Introduction
N-Aryl amino acids, amides and other derivatives are common
features in biologically active molecules (Fig. 1). The majority of
syntheses of these molecules involve the N-arylation of an amino
acid or a derivative. Aryl halides with electron withdrawing groups
react directly with amino acids, for instance during the synthesis of
fibrinogen receptor antagonist SB 214857 1 and NNRTIs talviraline
(HBY097) 4 [1–5]. Copper-catalysed coupling of aryl halides [6–11]
has also been used in the synthesis of SB-214857 1 [12] as well as
for (ꢀ)-indolactam V 2 [13,14], benzolactam-V8 3 [15], and
GW420867X 5 [16]. Catalysis can also occur in mixed copper/ pal-
ladium systems [17,18], or with palladium-only catalysts [19–23]
sometimes with noticeable racemization. Copper can also mediate
arylation with boronic acids [24–28]. Arylation can also be effected
with arynes [29–32], or by condensation with carbonyls [33,34].
Control of stereochemistry nucleophilic substitution of aryl
amines onto chiral electrophiles has been reported in an alterna-
tive synthesis of (ꢀ)-by the direct indolactam V by SN2 reaction
of a chiral triflate [35–37]. Jocic [38] and Bargellini [39] reactions
that occur via /-trichloromethylalcohols and dichloroepoxides
are also very useful methods for the introduction of nucleophiles
at the /-carbon of acid derivatives, often with excellent stereocon-
trol [40–53]. Previously, we reported the enantioselective reduc-
tion of trichloromethyl ketones using ruthenium asymmetric
transfer hydrogenation (ATH) catalysts [54–59] and the subse-
Fig. 1. N-Aryl amino amide derivatised drugs.
quent Jocic-type reactions of the products to give enantiomerically
enriched amino-amides (Scheme 1) [60,61]. In these reactions we
noted that the primary alkyl amine component of a diamine gener-
ally reacts with the epoxide intermediate preferentially, before
subsequent intra- or inter molecular amidation of the intermediate
acid chloride. The Bargellini-type reaction of primary aryl amines
with achiral tertiary alcohol derived dichloroepoxides has previ-
ously been reported by Lai [62]. These results raised the question
of whether primary aryl amines can open the dichloroepoxide
⇑
Corresponding author.
E-mail address: d.j.fox@warwick.ac.uk (D.J. Fox).
https://doi.org/10.1016/j.tetlet.2018.09.046
0040-4039/Ó 2018 Published by Elsevier Ltd.
Please cite this article in press as: C. Hobson et al., Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.09.046

2
C. Hobson et al. / Tetrahedron Letters xxx (2018) xxx–xxx
Fig. 2. Crystal structure of (S)-10.
enantiomerically enriched secondary alcohols. Conversions were
however very low (results not shown) and changing the solvent
to acetone improved the yields (Table 2). The importance of the
original biphasic reaction medium (Table 1) on maintaining the
stereospecificity of the reaction, presumably separating the organ-
ically soluble product from the aqueous base, was demonstrated as
the products, isolated as their methyl esters, had lost stereochem-
ical integrity during the Jocic process (Table 2). We have previously
shown that stereochemical integrity can be lost in the Jocic reac-
tions of amines with trichloromethyl secondary alcohols when
using methanol as a single phase solvent [61]. By analogy with
the formation of compound (S)-10 we have assigned the major
enantiomer of the ester products to have the (S)-configuration
(See Table 3).
Chiral N-alkyl-N-aryl-aminoamides are fragments of drug com-
pounds 1–3. Direct Jocic-type synthesis of amino amides with dif-
ferent nitrogen substituents requires the selective in situ reaction
of two different amines, an aryl amine to open the intermediate
epoxide, and an alkyl amine to capture the acid chloride. Such a
strategy is known [62] but again only on achiral tertiary alcohol-
derived epoxides. Table 3 shows the results of the reaction of 10
equivalents of an aryl amine and two of an alkyl secondary amine
with chiral alcohol (R)-8 in biphasic conditions. In most cases the
major product is the /-N-aryl tertiary amide, but with the most
nucleophilic aniline (4-methoxyaniline) the secondary aryl amide
19 was the major product. Stereochemical integrity was
Scheme 1. Previous work. Reagents and conditions: (i) PhNHCH2CH2NH2, NaOH,
BnNEt3Cl, CH2Cl2, H2O; (ii) PhNHCH2CH2CH2NH2, NaOH, BnNEt3Cl, CH2Cl2, H2O.
intermediates, derived from enantiomerically-enriched secondary
trichloromethyl alcohols, with control of stereochemistry.
Results and Discussion
The synthesis of known alcohol (R)-6 (95% e.e.) [60] as well as
new enantiomerically enriched alcohols (R)-7 (95% e.e.) and (R)-8
(95% e.e.) was followed by their reactions with an excess amount
of four para-substituted anilines (Table 1). The stereochemical pur-
ity of the starting material is maintained during the Jocic-type
reactions. The formation of the (S)-N-aryl amide (X-ray crystallog-
raphy) from the (R)-alcohol demonstrates the inversion of stereo-
chemistry typical for such reactions (Fig. 2). We assume that all
of the reactions in Table 1 occur via the same inversion of
stereochemistry.
Jocic-type reactions can also be performed in alcohol solvents
instead of chlorinated solvents [46,47,52,63,64]. The related forma-
tion of N-aryl amino acids from achiral trichloromethyl-alcohols
using a single equivalent of aniline in methanol has been reported
[65], and we wished to test these reaction conditions with the
Table 1
Formation of N-aryl amino-amides.
Entry
S. M.
R
X
Yield %a
e.e. %b
Product
1
2
3
4
5
6
7
8
(R)-6
(R)-6
(R)-6
(R)-6
(R)-7
(R)-7
(R)-7
(R)-7
(R)-8
(R)-8
(R)-8
(R)-8
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH3
CH2CH3
CH2CH3
CH2CH3
(CH2)6CH3
(CH2)6CH3
(CH2)6CH3
(CH2)6CH3
H
Cl
OCH3
CH3
H
82
61
78
74
73
61
69
62
73
56
63
61
98
97
97
96
96
97
97
95
96
95
95
96
9
10
11
12
13
14
15
16
17
18
19
20
Cl
OCH3
CH3
H
Cl
OCH3
CH3
9
10
11
12
a
Isolated yield.
By chiral HPLC analysis.
b
Please cite this article in press as: C. Hobson et al., Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.09.046

C. Hobson et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
Jocic-type reactions with arylamines.
Entry
S. M.
R
X
Yield %a
e.e. %b
Product
1
2
3
4
5
6
7
8
(R)-6
(R)-6
(R)-6
(R)-6
(R)-8
(R)-8
(R)-8
(R)-8
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
CH2CH(CH3)2
(CH2)6CH3
(CH2)6CH3
(CH2)6CH3
(CH2)6CH3
H
Cl
OCH3
CH3
H
Cl
OCH3
CH3
65
65
53
59
69
58
61
64
76
73
82
79
33
49
52
65
21
22
23
24
25
26
27
28
a
Isolated yield.
By chiral HPLC analysis.
b
Acknowledgements
Table 3
Formation of N-aryl amino-amides.
We wish to thank University of Warwick (studentship for MSP,
URSS funding for GK) for funding, Johnson Matthey Plc for the kind
donation of transfer hydrogenation catalyst, and Prof. Martin Wills
for use of, and help with, chiral GC analysis. The Oxford Diffraction
Gemini XRD system was obtained with support from Advantage
West Midlands and part funded by the European Regional
Development Fund. Data are available at http://wrap.warwick.ac.
uk/101137.
Appendix A. Supplementary data
Supplementary data (Synthesis details, NMR spectra, chiral
HPLC chromatograms and crystallographic details. The crystal
structure has been deposited at the Cambridge Crystallographic
Data Centre and assigned the deposition number CCDC 1568159)
to this article can be found online at https://doi.org/10.1016/j.tet-
let.2018.09.046.
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