Addition of Highly Polarized Organometallic Compounds to N-tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air: Preparation of Chiral Amines of Pharmaceutical Interest

Article abstract of DOI:10.1002/cssc.202001142

Highly polarized organometallic compounds of s-block elements are added smoothly to chiral N-tert-butanesulfinyl imines in the biodegradable d-sorbitol/choline chloride eutectic mixture, thereby granting access to enantioenriched primary amines after quantitatively removing the sulfinyl group. The practicality of the method is further highlighted by proceeding at ambient temperature and under air, with very short reaction times (2 min), enabling the preparation of diastereoisomeric sulfinamides in very good yields (74–98 %) and with a broad substrate scope, and the possibility of scaling up the process. The method is demonstrated in the asymmetric syntheses of both the chiral amine side-chain of (R,R)-Formoterol (96 % ee) and the pharmaceutically relevant (R)-Cinacalcet (98 % ee).

Full text of DOI:10.1002/cssc.202001142

Chemistry–Sustainability–Energy–Materials
Accepted Article
Title: Addition of Highly Polarized Organometallic Compounds to N-
tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air:
Preparation of Chiral Amines of Pharmaceutical Interest
Authors: Luciana Cicco, Antonio Salomone, Paola Vitale, Nicolás Ríos-
Lombardía, Javier González-Sabín, Joaquín García-Álvarez,
Filippo Maria Perna, and Vito Capriati
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
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to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: ChemSusChem 10.1002/cssc.202001142
Link to VoR: https://doi.org/10.1002/cssc.202001142
01/2020

10.1002/cssc.202001142
ChemSusChem
COMMUNICATION
Addition of Highly Polarized Organometallic Compounds to N-
tert-Butanesulfinyl Imines in Deep Eutectic Solvents under Air:
Preparation of Chiral Amines of Pharmaceutical Interest
Luciana Cicco,[a] Antonio Salomone,[b] Paola Vitale,[a] Nicolás Ríos-Lombardía,[c] Javier González-Sabín,[c]
Joaquín García-Álvarez,*[d] Filippo M. Perna,*[a] and Vito Capriati*[a,e]
In memory of Professor Hans J. Reich, a pioneer of organolithium chemistry, who has left an indelible mark in this field.
[a]
[b]
Dr. L. Cicco, Dr. P. Vitale, Dr. F. M. Perna, Prof. V. Capriati
Dipartimento di Farmacia–Scienze del Farmaco
Università di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S.
Via E. Orabona 4, I-70125, Bari, Italy
E-mail: filippo.perna@uniba.it
vito.capriati@uniba.it
Prof. A. Salomone
Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali
Università del Salento
Prov.le Lecce-Monteroni, I-73100, Lecce, Italy
[c]
[d]
Dr. N. Ríos-Lombardía, Dr. J. González-Sabín
EntreChem SL
Vivero Ciencias de la Salud, Colegio Santo Domingo de Guzmán, s/n 33011 Oviedo, Spain
Prof. J. García-Álvarez
Laboratorio de Compuestos Organometálicos y Catálisis (Unidad Asociada al CSIC), Departamento de Química Orgánica e Inorgánica (IUQOEM), Centro
de Innovación en Química Avanzada (ORFEO-CINQA)
Universidad de Oviedo, E-33071 Oviedo, Spain
E-mail: garciajoaquin@uniovi.es
[e]
Prof. Vito Capriati
Dipartimento di Chimica, Istituto di Chimica dei Composti Organometallici (ICCOM) – CNR
Università di Bari “Aldo Moro”
Via E. Orabona 4, I-70125 Bari, Italy
Supporting information for this article is given via a link at the end of the document.
Abstract: We first report that highly polarized organometallic
compounds of s-block elements add smoothly to chiral N-tert-
butanesulfinyl imines in the biodegradable D-sorbitol/choline chloride
eutectic mixture, thereby granting access to enantioenriched primary
amines after quantitatively deblocking the sulfinyl group. The
practicability of the methodology was further highlighted by (a)
working at ambient temperature and under air, (b) very short reaction
times (2 min), (c) the preparation of diastereomeric sulfinamides in
very good yields (74–98%) and with a broad substrate scope, (d) the
possibility of scaling up the process, and (e) the asymmetric synthesis
of both the chiral amine side-chain of (R,R)-Formoterol (96% ee) and
the pharmaceutically relevant (R)-Cinacalcet (98% ee).
amine auxiliaries (e.g., phenylethylamine).[5] Within this context,
the nucleophilic addition of highly polarized organometallic
reagents to chiral N-tert-butanesulfinyl imines, pioneered by
Ellman and co-workers, followed by the removal of the N-tert-
butanesulfinyl auxiliary group, represents a versatile approach to
forge new C-C bonds en route to chiral α-branched amines.[6]
These reactions, however, are typically carried out in toxic,
anhydrous and aprotic volatile organic compounds (VOCs) (e.g.,
THF, CH2Cl2, toluene), at low temperature (up to -78 °C), under
inert atmospheres, and for reaction times of a few hours (Scheme
1a).
Recent, independent ground-breaking studies by Hevia,
García-Álvarez and our group has led to a profound paradigm
shift in the way s-block organometallic compounds can be used
in organic synthesis.[7] It was indeed shown that these commodity
reagents are truly compatible with environmentally responsible,
bio-inspired protic solvents like the so-called deep eutectic
Chiral nonracemic primary amines are well-established and
flexible building blocks for the synthesis of valuable active
pharmaceutical ingredients (APIs) and intermediates thereof,
agrochemicals, fragrances, and are also key players in
organocatalysis and in catalytic asymmetric synthesis.[1] The
asymmetric reduction of a prochiral precursor containing the C=N
moiety represents among one of the most pursued approaches to
synthesize chiral amines. Enantioselective methodologies include
transition metal-catalyzed amination reactions in the presence of
amine sources and reductants,[2] organocatalyzed strategies,[3]
solvents (DESs).[8] As
a consequence, they have been
successfully employed as nucleophilic partners either to promote
addition reactions to unsaturated functional groups such as
carbonyl derivatives,[9] imines,[10] styrene derivatives,[11]
amides,[12] and nitriles[10b,13] in DESs, glycerol and even water or
to trigger fast, direct Pd-catalyzed cross-coupling reactions under
“on water” conditions.[14] Building upon these findings, we were
eager to investigate the usefulness of sustainable,
unconventional reaction media to prepare enantiomerically
enriched primary amines. Here we first show that the nucleophilic
and
biotechnological
processes.[4]
Diastereoselective
methodologies usually encompass reduction of Schiff bases
derived from carbonyl compounds containing removable chiral
1
This article is protected by copyright. All rights reserved.

10.1002/cssc.202001142
ChemSusChem
COMMUNICATION
addition of both organolithium and Grignard reagents to N-tert-
butanesulfinyl imines are feasible in DESs, working at room
temperature (RT, 25 °C) and under air, thereby granting access
to both enantiomers of chiral α,α-disubstituted primary amines in
overall yields up to 98% and within 2 min reaction time (Scheme
1b). Comparison of DESs with water and other solvents as
reaction media have been provided and discussed. The
application and the utility of the described protocol was
additionally demonstrated by the whole synthesis of (R)-
Cinacalcet and of the chiral amine side chain of (R,R)-Formoterol
in a choline chloride (ChCl)-based eutectic mixture.
1, entry 12). The effectiveness of this transformation was still
maintained when n-BuMgCl was alternatively used (2a: 91%
yield), but no reaction occurred when n-BuMgCl was reacted with
2a in water (Table 1, entries 13,14). The addition of n-BuLi or n-
BuMgCl in the presence of a Lewis acid additive like LiCl (2 equiv)
gave no improvement on the yield and stereoselectivity of the
transformation (Table 1, entries 15,16). Scaling up the process
was also successful. Indeed, the reaction of (SS)-1a (5 mmol, 1.05
g) with n-BuLi (1.4 equiv) in 5.0 g of D-sorbitol/ChCl resulted In
the formation of (SS,R)-2a in 96% (1.28 g) isolated yield (Table 1,
entry 11).
Conventional approach:
Ellman (Ref. 6)
Table 1. Synthesis of sulfinamide 2a from n-BuLi or n-BuMgCl and sulfinyl imine
1a in different solvents: reaction condition optimization.[a]
VOCs
(toluene, CH2Cl2, THF)
S
S
NH2
N
O
HN
O
(a)
+ R2M
S
S
S
Solvent
HN
Ph
O
N
O
N2, low temperature
a few hours
R1 R2
*
HN
O
R1
*
R1 R2
R or S
+ BuM
+
R or S
RT, 2 min
under air
M = Li, MgX (X = Br, Cl)
Bu
Ph
Ph
Bu
(SS)-1a
(SS,R)-2a
(SS,S)-2a
This work:
Entry
1
BuM
Solvent
2a yield (%)
87[d]
dr[b]
S
S
DES
NH2
HN
O
N
O
(b)
+ R2M
H2O[c]
65:35
65:35
58:42
61:39
50:50
–
R1 R2
R1 R2
*
R or S
n-BuLi
R1
RT, under air
*
2 min
R or S
2
n-BuLi
–
72[d]
M = Li, MgX (X = Br, Cl)
up to 98% yield
20 examples
up to >98% ee
3
n-BuLi
Gly[c]
17[b]
4
n-BuLi
ChCl/Gly[c]
31[b]
Scheme 1. Organometallic nucleophilic addition to sulfinyl imines using (a)
VOCs under inert atmospheres and at low temperature (up to -78 °C) or (b) DES
at room temperature (RT, 25 °C) and under air (ee = enantiomeric excess).
5
n-BuLi
ChCl/urea[c]
ChCl/LA[e]
28[b]
6
n-BuLi
NR[f]
32[b]
7
n-BuLi
ChCl/H2O[c]
ChCl/EG[e]
58:42
60:40
64:36
65:35
65:35
65:35
53:47
–
We elected to study the reaction between SS-sulfinyl imine 1a (0.5
mmol) and commercially available n-BuLi as a model system for
the preparation of sulfinamide 2a in various protic solvents and
mixtures. We first investigated the reaction in water. When 1.4
equiv of n-BuLi (2.0 M in cyclohexane) were quickly spread over
a suspension of 2a in water (1 mL), at RT and under air and
vigorous stirring to generate an emulsion, followed after 2 min
reaction time by dilution with the environmentally friendly
cyclopentyl methyl ether (CPME)[15] (5 mL), adduct 2a was
isolated in 87% yield as a separable mixture of two diastereomers
[diastereomeric ratio (dr) 65:35 in favor of (SS,R)-2a]. The
absolute configuration of the two diastereomers was secured by
comparing their NMR spectroscopic data with those reported in
the literature (Table 1, entry 1) (ESI). By carrying out the reaction
in the absence of any solvent, the yield of 2a was 72% only (dr:
65:35), whereas by changing water to pure glycerol (Gly) the yield
of 2a dropped down to 17% (dr: 58:42) (Table 1, entries 2,3). We
then screened this transformation in some prototypical choline
chloride (ChCl)-based eutectic mixtures, namely ChCl/Gly (1:2
mol mol–1), ChCl/urea (1:2 mol mol–1), ChCl/L-lactic acid (LA) (1:2
mol mol–1), ChCl/H2O (1:2 mol mol–1), ChCl/ethylene glycol (EG)
(1:2 mol mol–1), D-isosorbide/ChCl (2:1 mol mol–1), ChCl/D-
fructose (1:2 mol mol–1) and D-sorbitol/ChCl (1:1 mol mol–1)
(Table 1, entries 4–11). Sugar-based eutectic mixtures emerged
among as optimal regarding the yield of 2a, and in D-sorbitol/ChCl
adduct 2a formed in 98% yield as the sole product (dr: 65:35)
(Table 1, entry 11). A lower yield (66%) was instead achieved by
decreasing the number of equiv of n-BuLi from 1.4 to 1.1 (Table
8
n-BuLi
48[b]
9
n-BuLi
D-isosorbide/ChCl[e]
D-fructose/ChCl[c]
D-sorbitol/ChCl[e]
D-sorbitol/ChCl[e]
D-sorbitol/ChCl[e]
H2O[c]
49[b]
10
11
12
13
14
15
16
n-BuLi
85[d]
n-BuLi
n-BuLi[h]
n-BuMgCl
n-BuMgCl[i]
n-BuLi[j]
n-BuMgCl[j]
98[d,g]
66[d]
91[d]
NR[f]
93[d]
D-sorbitol/ChCl
D-sorbitol/ChCl
62:38
52:50
90[d]
[a] Reaction conditions: 1.0 g DES or 1 mL H2O or 1 mL Gly per 0.5 mmol of
(SS)-1a and 1.4 equiv BuM; DES: ChCl/Gly (1:2 mol mol–1); ChCl/urea (1:2 mol
mol–1); ChCl/L-lactic acid (LA) (1:2 mol mol–1); ChCl/H2O (1:2 mol mol–1);
ChCl/ethylene glycol (EG) (1:2 mol mol–1); D-isosorbide/ChCl (2:1 mol mol–1);
ChCl/D-fructose (1:2 mol mol–1); D-sorbitol/ChCl (1:1 mol mol–1). [b] Calculated
by 1H-NMR analysis of the crude reaction mixture using an internal standard
technique (NMR internal standard: CH2Br2). [c] Heterogeneous conditions:
suspension of 1a in water, in Gly or in DES. [d] The yields reported are for
products isolated and purified by column chromatography. [e] Homogeneous
conditions: solution of 1a in DES. [f] NR = no reaction; substrate 1a was
quantitatively recovered. [g] 96% isolated yield by carrying out the reaction
between (SS)-1a (5 mmol) and n-BuLi (1.4 equiv) in 5.0 g DES. [h] 1.1 equiv of
n-BuLi. [i] 3.0 equiv of n-BuMgCl. [j] In the presence of 2.0 equiv of LiCl.
2
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10.1002/cssc.202001142
ChemSusChem
COMMUNICATION
The formation of the SS,R-diastereomer as the major
stereoisomer is consistent with the intervention of a chelated
transition state (A, Scheme 2), which is known to be typically
favored in conventional non-coordinating reaction solvents such
as toluene or CH2Cl2, where steric hindrance factors are mainly
responsible for the selectivity. Water and DESs, however, are
both characterized by strong and extended H-bond networks,
where (i) protonolysis processes are disfavored compared to
organolithium-promoted nucleophilic additions, and (ii) alkali
metal ion-chelated supramolecular heteroaggregates are highly
privileged.[7b] Overall, the poor-to-moderate diastereoselectivity
observed with Grignard and organolithium reagents may likely be
due to a competition between the proposed chelated and open (B,
Scheme 2) transition states for such nucleophilic additions, the
latter being favored in conventional coordinating solvents (e.g.,
THF).[16] It is also particularly interesting to note that despite S–N
bonds have been recognized to be quite polar in nature by the
topological analysis of the experimental electron density,[17] the
integrity of N-tert-butanesulfinyl imine (SS)-1a remains well
preserved in the aforementioned DES media in the presence of
organolithium/Grignard reagents.
organolithium reagents in a D-sorbitol/ChCl mixture at RT and
under air (Table 2). The reaction is amenable to both electron-
withdrawing and electron-donating groups. Indeed, either the
unsubstituted arylsulfinyl imine 1a or aryl-substituted sulfinyl
imines 1b,c effectively participated as electrophilic partners,
thereby providing in the reaction with both aliphatic and aromatic
organomagnesium chlorides (n-BuMgCl, MeMgCl, EtMgCl, i-
PrMgCl, allylMgCl) and organolithiums (n-BuLi, MeLi, EtLi, t-BuLi,
PhLi) the expected adducts 2a–q in very good yields (RLi: 87–
98%; RMgCl: 74–98%).‡
‡
H
S
S
M
O
HN
Ph
O
N
Bu
‡
Ph
Bu
(R)
A
S
(SS,R)-2a
N
O
BuM
Ph
+ BuM
H
Ph
(SS)-1a
M = Li, MgCl
O
S
HN
O
N
Ph (S) Bu
(SS,S)-2a
B
We then evaluated the scope of the reaction by reacting
several α-functionalized N-tert-butanesulfinyl imines (SS)-1 with
Scheme 2. Competition between chelating six-membered (A) and open (B)
transition states in the nucleophilic addition of Grignard and organolithium
reagents to N-tert-butanesulfinyl imines in nonconventional solvents (water and
DES).
representative,
commercially
available
Grignard
and
Table 2. Synthesis of sulfinamides 2a–r by addition of organolithium and Grignard reagents to sulfinyl imines 1a–d.[a]
S
S
D-sorbitol/ChCl
S
HN
R1
O
HN
R1
O
N
O
+ R2M
+
RT, 2 min, under air
M = Li, MgCl
R2
major
R2
R1
(SS)-1
minor
2a–s
1a: R1 = Ph; 1b: R1 = 4-CH3OC6H4, 1c: R1 = 4-CF3C6H4; 1d: R1 = t-Bu
S
S
S
S
S
HN
Ph
O
HN
Ph
O
HN
Ph
O
HN
Ph
O
HN
Ph
O
t-Bu
Bu
Et
Me
Ph
2a: M = Li, 98%; dr 65/35
M = MgCl, 91%; dr 53/47
2c: M = Li, 98%; dr 64/36
M = MgCl, 96%; dr 51/49
2b: M = Li, 98%; dr 50/50
M = MgCl, 94%; dr 54/46
2d: M = Li, 98%; dr 53/47
2e: M = Li, 96%
S
S
S
HN
O
HN
O
HN
O
S
S
Me
Et
Bu
HN
Ph
O
HN
Ph
O
H3CO
H3CO
H3CO
i-Pr
2h: M = Li, 88%; dr 66/34 2i: M = Li, 87%; dr 52/48 2j: M = Li, 97%; dr 64/36
M = MgCl, 87%; dr 64/36 M = MgCl, 85%; dr 87/13 M = MgCl, 98%; dr 53/47
2g: M = MgCl, 91%; dr 75/25
2f: M = MgCl, 83%; dr 63/37
S
S
S
S
HN
O
HN
O
HN
O
HN
O
Ph
t-Bu
i-Pr
H3CO
H3CO
H3CO
H3CO
2l: M = Li, 92%; dr 66/34
M = MgCl, 74%; dr 65/35
2m: M = MgCl, 81%; dr 54/46
2n: M = MgCl, 98%; dr 76/24
2k: M = Li, 96%; dr 51/49
S
S
S
HN
O
HN
O
HN
O
S
S
HN
O
HN
O
Ph
Me
Et
Me
Ph
F3C
F3C
F3C
2r: M = Li, 98%; dr 60/40 2d: M = Li, 62%; dr 60/40
2p: M = Li, 90%; dr 55/45
2q: M = Li, 96%; dr 56/44
2o: M = Li, 98%; dr 68/32
M = MgCl, 95%; dr 65/35 M = MgCl, 60%; dr 55/45
M = MgCl, 88%; dr 60/40
M = MgCl, 98%; dr 63/37
M = MgCl, 95%; dr 55/45
[a] Reaction conditions: 1.0 g DES per 0.5 mmol of (SS)-1 and 1.4 equiv RM. The yields reported are for products isolated and purified by column chromatography.
3
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10.1002/cssc.202001142
ChemSusChem
COMMUNICATION
Notably, the presence of a considerably sterically hindered t-butyl
group at the iminic carbon atom (1d) was equally tolerated, and
the nucleophilic addition promoted by MeLi and PhLi or MeMgCl
and PhMgCl delivered adducts 2r and 2d in overall 60–98% yield
(Table 2). A secondary organolithium like s-BuLi, because of the
presence of an additional stereogenic center, gave complex
mixtures of three diastereomers, and thus its reactions were not
further investigated. In all cases studied, sulfinamides 2 formed
with poor-to-moderate (up to 87:13) diastereoselectivity, as
assessed by 1H NMR analysis of the crude reaction mixture. It is
worth noting, however, that, under the best conditions, each
reaction proceeded fast (2 min) at RT and under air, with high
yield and high chemoselectivity. When using conventional VOCs,
a higher stereoselectivity is usually offset by a low reactivity and
longer reaction times (a few hours) at low temperature (up to –
78 °C). Competitive imine reduction has also been observed.[6]
The two diastereomers obtained using DES as solvent could
always be easily separated by column chromatography on silica
gel. The absolute configuration of each sulfinamide at the newly
formed stereogenic center was established either by matching its
1H NMR data with those of known compounds (adducts 2a–g, 2i–
o, 2q,r) or, in the case of unknown adducts (2h and 2p), by DFT
computations (ESI). It was also ascertained that the major
stereoisomer isolated in each reaction was always the one formed
via the chelating six-membered transition state (A, Scheme 2).
Cleavage of the sulfinyl group was easily achieved under
acidic conditions (HCl 2 M) directly in a D-sorbitol/ChCl eutectic
mixture at RT and under air, followed by extraction with CPME
and basification with NaHCO3 (ESI). The practicability of this
procedure was demonstrated by the preparation of chiral
nonracemic primary amines (R)- and (S)-3a,b (98% yield, up to
99% ee) from the corresponding sulfinamides (SSR)- and (SSS)-
2a,b (Scheme 3), and of (R)-3s (60% yield, 96% ee) from
sulfinamide (SSR)-2s. The latter, in turn, was obtained by reacting
sulfinyl imine (SS)-1e with MeMgCl (85% yield; dr 85/15) or with
MeLi (87% yield; dr 55/45) in D-sorbitol/ChCl and separating the
two diastereomers via column chromatography (Scheme 4) (ESI).
so far via chemoenzymatic[19] or transition-metal-catalyzed[20]
approaches using either free or protected amine (R)-3s.
H3CO
S
H3CO
S
N
O
HN
O
MeMgCl or MeLi
Me
(SS,R)-2s + (SS,S)-2s
D-sorbitol/ChCl
RT, under air, 2 min
(SS)-1e
MeMgCl: 85% yield; dr 85:15; MeLi: 87% yield; dr: 55:45
1) HCl (2.0 M)
H3CO
D-sorbitol/ChCl
NH2
Me
RT, under air, 3 h
(SS,R)-2s
2) NaHCO3 aq.
(R)-3s: 60% yield; 96% ee
OH
H
H
O
N
N
ref.
HO
OCH3
(R,R)-Formoterol (4)
Scheme 4. Synthesis of enantioenriched amine side-chain (R)-3s of (R,R)-
Formoterol (4) (ee: enantiomeric excess).
Finally, we embarked on the asymmetric synthesis of (R)-
Cinacalcet (6) (Scheme 5), which is a blockbuster drug acting as
calcimimetic, and used to treat secondary hyperparathyroidism. It
is sold under the brand name Sensipar in USA and Australia, as
Mimpara in Europe, and as Regpara in Asia.[21] (R)-(+)-1-(1-
Naphthyl)ethylamine (3t) is the key intermediate towards the
preparation of this drug. Synthetic methodologies to access this
enantiopure amine include (a) classical or enzymatic resolution of
the racemic amine,[22] and (b) transition-metal-catalyzed
asymmetric hydrogenation or hydrogen-transfer reductive
amination of the corresponding sulfinyl imine or ketone,
respectively.[23] Several strategies have then been developed to
couple (R)-3t to the remaining skeleton of the molecule. Among
these, for example, are amide reduction and reductive amination
or substitution reactions.[24] All the described procedures, however,
typically rely on several steps using toxic VOCs. Recent
chemoenzymatic routes employing transaminases and
ketoreductases as effective biocatalysts have also been
explored.[25] Following the aforementioned approach, we
succeeded in synthesising (R)-6 in only three steps making use
of D-sorbitol/ChCl as a sustainable reaction mixture. As depicted
in Scheme 5, first, sulfinyl imine (SS)-1f was treated with MeMgCl
(1.4 equiv), at RT and under air, thereby providing sulfinamide 2t
in overall 86% yield as a mixture of two diastereomers (dr 1:1),
1) HCl (2.0 M)
D-sorbitol/ChCl
RT, under air, 3 h
(R)-3a: R = Bu
98% yield; 92% ee
S
R
HN
Ph
O
NH2
R
Ph
(R)-3b: R = Me
(R)-3a,b 98% yield; 97% ee
2) NaHCO3 aq.
(SS,R)-2a,b
1) HCl (2.0 M)
D-sorbitol/ChCl
RT, under air, 3 h
S
(S)-3a: R = Bu
NH2
HN
O
98% yield; 92% ee
Ph
R
Ph
R
which
were
separated
by
column
chromatography.
(S)-3b: R = Me
98% yield; 99% ee
2) NaHCO3 aq.
(S)-3a,b
Diastereoisomer (SS,R)-2t was then dissolved in the above
eutectic mixture and treated with a solution of HCl (2.0 M) to afford
free amine (R)-3t (88% yield; >98% ee). Finally, (R)-3t was
directly N-alkylated in DES with alcohol 5 in a process mediated
by the Iridum catalyst [Cp*IrCl2]2 (1 mol%)[26] to give the desired
target drug (R)-6 in 98% yield and 98% ee (HPLC analysis) after
12 h reaction time at 60 °C, and working under air (Scheme 5). It
is worth noting that by performing this same alkylation in toluene,
at 110 °C for 17 h in a sealed reactor and under an Argon
atmosphere, enantiopure (R)-6 could be isolated in an overall
yield of only 50%.[25]
(SS,S)-2a,b
Scheme 3. Synthesis of enantioenriched amines (R)- and (S)-3a and (R)- and
(S)-3b (ee: enantiomeric excess).
Enantioenriched amine (R)-3s is an important chiral intermediate
for the synthesis of (R,R)-Formoterol (4), which is known to be a
long-acting β2-agonist used as
management of asthma and chronic obstructive pulmonary
disease. Formoterol is commercialized in its racemic form, but the
(R,R)-isomer was found to be 1000-fold more potent than the
(S,S)-isomer.[18] The preparation of eutomer 4 has been realized
a
bronchodilator in the
4
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10.1002/cssc.202001142
ChemSusChem
COMMUNICATION
J.G.-Á. thanks PhosAgro/UNESCO/IUPAC for the award of a
Green Chemistry for Life Grant and Spanish MINECO (Project
CTQ2016-81797-REDC and CTQ2016-75986-P).
O
S
O
S
N
Me
NH
MeMgCl
D-sorbitol/ChCl
RT, under air, 2 min
Keywords: deep eutectic solvents • organolithiums • Grignard
(SS,R)-2t + (SS,S)-2t
(86% overall yield; dr 50:50)
reagents • imines • amines
(SS)-1f
Me
NH2
1) HCl (2.0 M)
D-sorbitol/ChCl
RT, under air, 3 h
(SS,R)-2t
‡ SAFETY NOTE: No particular problems were experienced during these
additions. t-BuLi, however, is known to be prone to ignition in air and caution
should be exercised in adopting the recommended procedure, especially on a
larger scale.
2) NaHCO3 aq.
(R)-3t: 88% yield; >98% ee
[1]
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H
N
HO
CF3
Me
3
5
CF3
D-sorbitol/ChCl
[Cp*IrCl2]2 (1 mol%)
60 °C, under air, 12 h
(R)-Cinacalcet (6)
98% yield; 98% ee
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synthesis of chiral primary amines in DESs using D-sorbitol/ChCl
as a sustainable and biodegradable unconventional reaction
mixture. The nucleophilic addition promoted by both Grignard and
organolithium reagents to chiral nonracemic aromatic and
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min reaction time) in the above eutectic mixture, at RT and under
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synthesize libraries of chiral nonracemic primary amines, which
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and several commodity chemicals, but also to set up other
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Acknowledgements
This work was carried out under the framework of the Project
"Development of Sustainable Synthetic Processes in
Unconventional Solvents for the Preparation of Molecules of
Pharmaceutical Interest” realized with the contribution of
Fondazione Puglia. It was also financially supported by
Ministero dell’Università e della Ricerca (MIUR-PRIN) (grant
number: 2017A5HXFC_002), by Interuniversity Consortium
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6
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COMMUNICATION
Entry for the Table of Contents
Polar organometallic chemistry embraced by nature: Highly enantioenriched amines, en ruote to valuable APIs, are obtained via a
fast and chemoselective addition of organolithium and Grignard reagents to chiral sulfinyl imines, under hydrous conditions and at
ambient temperature, in the biodegradable D-sorbitol/choline chloride eutectic mixture.
7
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