Expeditious and practical synthesis of tertiary alcohols from esters enabled by highly polarized organometallic compounds under aerobic conditions in Deep Eutectic Solvents or bulk water

Article abstract of DOI:10.1016/j.tet.2020.131898

An efficient protocol was developed for the synthesis of tertiary alcohols via nucleophilic addition of organometallic compounds of s-block elements (Grignard and organolithium reagents) to esters performed in the biodegradable choline chloride/urea eutectic mixture or in water. This approach displays a broad substrate scope, with the addition reaction proceeding quickly (20 s reaction time) and cleanly, at ambient temperature and under air, straightforwardly furnishing the expected tertiary alcohols in yields of up to 98%. The practicability of the method is exemplified by the sustainable synthesis of some representative S-trityl-L-cysteine derivatives, which are a potent class of Eg5 inhibitors, also via telescoped one-pot processes.

Full text of DOI:10.1016/j.tet.2020.131898

Tetrahedron 81 (2021) 131898
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Expeditious and practical synthesis of tertiary alcohols from esters
enabled by highly polarized organometallic compounds under aerobic
conditions in Deep Eutectic Solvents or bulk water
a
a
a
b, **
ꢀ
Andrea F. Quivelli , Giovanna D’Addato , Paola Vitale , Joaquín García-Alvarez
,
Filippo M. Perna a ***, Vito Capriati a
Dipartimento di FarmaciaeScienze del Farmaco, Universita di Bari “Aldo Moro”, Consorzio C.I.N.M.P.I.S., Via E. Orabona 4, I-70125, Bari, Italy
,
, *
a
ꢁ
b
ꢀ
ꢀ
ꢀ
ꢀ
Laboratorio de Compuestos Organometalicos y Catalisis (Unidad Asociada Al CSIC), Departamento de Química Organica e Inorganica (IUQOEM), Centro de
ꢀ
Innovacion en Química Avanzada (ORFEO-CINQA), Facultad de Química, Universidad de Oviedo, E-33071, Oviedo, Spain
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient protocol was developed for the synthesis of tertiary alcohols via nucleophilic addition of
organometallic compounds of s-block elements (Grignard and organolithium reagents) to esters per-
formed in the biodegradable choline chloride/urea eutectic mixture or in water. This approach displays a
broad substrate scope, with the addition reaction proceeding quickly (20 s reaction time) and cleanly, at
ambient temperature and under air, straightforwardly furnishing the expected tertiary alcohols in yields
of up to 98%. The practicability of the method is exemplified by the sustainable synthesis of some
Received 20 November 2020
Received in revised form
18 December 2020
Accepted 19 December 2020
Available online 25 December 2020
representative S-trityl-
scoped one-pot processes.
L-cysteine derivatives, which are a potent class of Eg5 inhibitors, also via tele-
Keywords:
Tertiary alcohols
Esters
© 2020 Elsevier Ltd. All rights reserved.
Deep Eutectic Solvents
Organolithium compounds
Water chemistry
1. Introduction
the production of reduced secondary alcohols, and mixtures of
ketones and carbinols can also be obtained, depending on the
conditions employed (Scheme 1a) [3]. The increasing awareness
towards environmental pollution and climate changes has impelled
research in organic synthesis to search for more environmentally
responsible and less impactful solvents in place of toxic and often
hazardous volatile organic compounds (VOCs), which are known to
account for about 80e90% of the total mass used in any organic
reaction [4], thereby reshaping long-established paradigms [5]. In
this vein, the past decade witnessed an explosive growth of ap-
plications of bio-based solvents [e.g., glycerol, ethyl lactate, 2-
Tertiary alcohols are important structural subunits in chemical
building blocks and common amongst biologically active com-
pounds [1]. The additions of organometallic compounds of s-block
elements (typically organolithium and Grignard reagents) to ke-
tones or esters are among the most efficient and direct routes to
accessing tertiary alcohols. At about this point, teaching textbooks
are clear: highly polarized organometallic reagents need to be
reacted at low temperature (often ꢀ78 ꢁC), in aprotic solvents such
as Et2O or THF, under a dry, inert atmosphere of argon or nitrogen,
with the corresponding reactions usually coming to an end within a
few hours [2]. As for the addition to esters, these reactions, once run
under the aforementioned conditions, are sometimes plagued by
methyltetrahydrofuran,
g-valerolactone] [6] and aqueous media
[7] in several fields of chemistry. Deep Eutectic Solvents (DESs) are
among an emerging class of neoteric, nature-inspired designer
solvents comprising at least one hydrogen bond donor and one
hydrogen bond acceptor that, when mixed in a proper molar ratio,
strongly associate with each other via hydrogen bond interactions,
thereby forming an eutectic mixture with a melting point much
lower than those of the individual components, and that of an ideal
liquid mixture [8]. In addition, they are non-flammable, highly
thermally stable, and characterized by low volatility. Recent
* Corresponding author. CNReIstituto di Chimica dei Composti Organometallici
(ICCOM), Bari section, Via E. Orabona 4, I-70125, Bari, Italy.
** Corresponding author.
*** Corresponding author.
E-mail addresses: garciajoaquin@uniovi.es (J. García-Alvarez), filippo.perna@
uniba.it (F.M. Perna), vito.capriati@uniba.it (V. Capriati).
ꢀ
https://doi.org/10.1016/j.tet.2020.131898
0040-4020/© 2020 Elsevier Ltd. All rights reserved.

A.F. Quivelli, G. D’Addato, P. Vitale et al.
Tetrahedron 81 (2021) 131898
Table 1
Addition reaction of n-BuLi to methyl benzoate (1a) under air, at room temperature
and in various green protic solvents to obtain tertiary alcohol 3a via ketone 2a.
Entry
Solvent
n-BuLi (equiv)
3a yield (%)
1
2
3
4
5
6
H2Oa
1
2
2.5
2.5
2.5
2.5
30b
90c
98c
96c
98c
95c
H2Oa
H2Oa
ChCl/Glyd
ChCl/ureae
Gly
Scheme 1. Synthesis of tertiary alcohols employing esters and highly polarized
organometallic compounds (Grignard and organolithium reagents) using: (a) a tradi-
tional approach with VOCs (Volatile Organic Compounds), and (b) non-conventional,
environmentally friendly solvents like DESs (Deep Eutectic Solvents) or H2O
(RT ¼ room temperature).
a
H2O: 1 mL per 0.5 mmol of 1a.
b
Calculated by 1H NMR analysis of the crude reaction mixture by using an in-
ternal standard technique (NMR internal standard: CH2Br2).
c
The yields reported are for products isolated and purified by column
chromatography.
d
ChCl (choline chloride)/Gly (glycerol) (1:2 molar ratio): 1 g per 0.5 mmol of 1a.
ChCl (choline chloride)/urea (1:2 molar ratio): 1 g per 0.5 mmol of 1a.
independent ground-breaking studies by the groups of Hevia,
e
ꢀ
García-Alvarez and Capriati have shown that s-block organome-
tallic compounds are truly compatible with bio-inspired protic
solvents like DESs, glycerol and even water [9]. Indeed, they have
been successfully used to promote either the nucleophilic addition
to carbonyl compounds [10], imines [11], styrene derivatives [12],
amides [13], and nitriles [11b,14] or cross-coupling reactions with
aryl halides under “on water” conditions [15]. On the basis of these
precedents, our main aim was to investigate the addition of highly
polarized organometallic compounds to esters in protic environ-
mentally friendly reaction media to prepare valuable tertiary al-
cohols. Herein, we report that this nucleophilic addition takes place
smoothly and cleanly working at room temperature (RT, 25 ꢁC) and
under air, thereby granting access to tertiary alcohols in up to 98%
yield, with a broad substrate scope, and within 20 s reaction time
(Scheme 1b).
The chemistry of highly polar organometallic compounds in
protic media has been recently discussed in a Concept article [9a].
Various studies have assessed the unusual kinetic stability exhibi-
ted by these reagents in the unique tridimensional hydrogen-
bonding structure, which is common to both DESs and water. It is
thought that this network can contribute in shielding the organo-
metallic reagent from competitive protonolysis processes.
The substrate scope of the reaction was evaluated next, by
treating several functionalized esters with some typical, commer-
cially available organolithium compounds either in water or in
ChCl/urea as the representative eutectic mixture at RTand under air
(Scheme 2). With regard to unsubstituted benzoate 1a, excellent
yields (86e98%) of the desired alcohols (3ae3d) were obtained
both in water and in ChCl/urea when it was reacted with either
aliphatic or aromatic organolithium reagents (i-PrLi, n-BuLi, PhLi
and 2-thienylLi). At this point, it is important to note that in all
cases the formation of 3a-3d occurs chemoselectively with no side
products observed in the crude reaction mixture. Substituted
benzoates bearing electron-donating (Me, MeO, OH, Me2N) or
electron-withdrawing (CN) groups at the ortho-, meta-, and para-
positions (1be1g) effectively participated as electrophilic partners
as well, thereby providing in the reaction with both aliphatic (MeLi,
EtLi, n-BuLi) and aromatic (PhLi) organolithium reagents the ex-
pected adducts 3ee3n in comparable range yields [water: 60e90%;
ChCl/urea: 60e95%]. Again, it is important to highlight the high
chemoselectivity of the studied process as we do not observe: i)
metalation of activated benzylic position in benzoate 1d or ortho-
lithiation processes in vicinal position to the methoxy group in
benzoates 1b, 1c and 1f; or ii) competitive addition to nitrile group
in benzoate 1g. An aliphatic ester like ethyl acetate (1h) also served
as competent reaction partner, delivering alcohols 3o and 3p in
80e90% yield in the reaction with PhLi and n-hexylLi, respectively,
in water or in DES.
Comparison between water and DESs as reaction media as well
as between organolithium and Grignard reagents in terms of
reactivity have been provided and discussed. Additionally, this
work also represented an opportunity for targeting a sustainable
synthesis of S-trityl-L-cysteine (STLC) and three of its derivatives,
which are potent and selective inhibitors of the human kinesin Eg5,
that has proven antitumor activity by preventing mitotic progres-
sion [16].
2. Results and discussion
We initiated our investigation using methyl benzoate (1a,
0.5 mmol) as the model substrate: 1 equivalent of n-BuLi (2.0 M in
cyclohexane) was quickly spread throughout a suspension of 1a in
water (1 mL) at RT under air, with vigorous stirring to generate an
emulsion (vortex). After 20 s reaction time, the mixture was diluted
with the environmentally friendly cyclopentyl methyl ether (CPME)
[17] (1 mL). An analysis of the crude mixture by GC-MS and 1H NMR
revealed the formation of the desired tertiary alcohol 3a in 30%
yield only. The precursor ketone 2a was still detected, but formed in
less than 5% yield (Table 1, entry 1). Pleasingly, alcohol 3a could be
isolated in 98% yield as the sole product just by increasing the
amount of n-BuLi up to 2.5 equivalents (Table 1, entries 2,3). Of
note, upon replacing water with some prototypical choline chloride
(ChCl)-based eutectic mixtures, namely ChCl/glycerol (Gly) (1:2 M
ratio) and ChCl/urea (1:2), the effectiveness of this transformation
was still maintained as 3a was isolated in 96e98% yield (Table 1,
entries 4,5). A reaction yield of 95% was instead achieved in Gly
when using it as the reaction medium (Table 1, entry 6).
Encouraged by these initial findings, which glimpse the poten-
tial that water or ChCl/urea eutectic mixture have as green solvents
for the chemoselective addition of organolithium reagents to esters
under standard bench experimental techniques, we then assessed
the scope of this methodology by extending our studies to a range
of Grignard reagents. Under the best experimental conditions, upon
switching organolithiums for organomagnesium reagents (e.g.,
MeMgCl, PhMgCl) as the nucleophilic partners, lower yields (75%)
2

A.F. Quivelli, G. D’Addato, P. Vitale et al.
Tetrahedron 81 (2021) 131898
Scheme 2. Synthesis of alcohols 3 by addition of organolithium or Grignard reagents to esters 1 in H2O or in ChCl/urea, at ambient temperature (RT) under air (reaction conditions:
ester: 0.5 mmol; organometallic reagent: 1.25 mmol; H2O: 1 mL; ChCl/urea: 1 g). The yields reported are for products isolated and purified by column chromatography.
were observed in ChCl/urea in the synthesis of some representative
alcohols like 3c, 3k and 3o. The latter, indeed, had been previously
prepared in 85e98% yields when using the corresponding orga-
nolithium reagents (MeLi, PhLi) in DES. Benzoates 1a and 1b also
underwent nucleophilic addition of MeMgCl and EtMgBr in ChCl/
urea to afford tertiary alcohols 3qe3s in 75e95% yield. On the other
hand, the reaction of Grignard reagents with esters in water proved
to be ineffective. We propose that the large decrease in the polarity
of the metal-carbon bonds in these commodity reagents (RMgX),
when compared with organolithium compounds, may be the key to
explain the experimentally observed decrease of activity when
Grignard reagents are alternatively employed in water or in protic
eutectic mixtures.
inhibitor of human mitotic kinesin Eg5, that represents a novel
mitotic spindle target for cancer chemotherapy (Scheme 3) [16a].
The above STLC derivatives are currently prepared in two steps
including the synthesis of the intermediate trityl alcohols 3, and the
reaction with -cysteine (5ae5c) or cysteamine hydrochloride (5d),
L
the latter performed in trifluoroacetic acid (TFA) as the sole solvent.
Tertiary aromatic alcohols 3, in turn, were furnished by exploiting a
preliminary regioselective bromine-lithium exchange reaction with
n-BuLi at ꢀ78 ꢁC in THF for 1 h on the selected aryl bromide 4,
followed by a nucleophilic addition to benzophenone. The reaction
was then stirred for 4e6 h at ꢀ78 ꢁC, then RT overnight (Scheme
3a). According to our protocol, by reacting benzoates 1a, 1d and
1f (0.5 mmol each) with PhLi (1.25 mmol) in ChCl/urea, at RT under
air, the corresponding alcohols 3c, 3e and 3i were isolated in
75e98% yield, the reaction time being 20 s only. The isolated al-
cohols were finally suspended in ChCl/urea (1 g) in the presence of
The application of this method was then highlighted by the
sustainable synthesis of S-trityl-
L-cysteine (STLC) (5a) and related
analogues 5be5d, which have been proven potent and selective
3

A.F. Quivelli, G. D’Addato, P. Vitale et al.
Tetrahedron 81 (2021) 131898
[9a,10d,11b]. Grignard reagents proved to be effective nucleophilic
partners as well in ChCl/urea, though providing the desired alco-
hols in lower yields in comparison with organolithiums. The
practicability of this methodology was demonstrated by the sus-
tainable preparation of some S-trityl-L-cysteine derivatives, which
are pharmaceutically relevant molecules. The latter could also be
straightforwardly obtained via telescoped, one pot nucleophilic
addition/thioetherification processes run in water starting from
esters, through the tertiary alcohol intermediates, which allowed
the isolation of the target molecule by filtration only. These results,
which are in the footsteps of others [9e15], attest to the synthetic
power, versatility and excellent performance of main group
organometallic compounds when used in protic bio-based solvents
under aerobic conditions. The adoption of these conditions is thus
expected to have practical implications for synthetic organic
chemistry, when reshaping other classical main-group-mediated
transformations, which are traditionally carried out in VOC media.
Scheme 3. (a) General route for the synthesis of thiothers; reagents and conditions: (i)
n-BuLi, ꢀ78 ꢁC, 1 h; (ii) Ph2CO, THF, ꢀ78 ꢁC, 4e6 h, then RT overnight; (iii) cysteamine
hydrochloride or L-cysteine, TFA, RT, 3 h. (b) This work: reagents and conditions: (iv) 1
(0.5 mmol), PhLi (1.25 mmol), ChCl/urea (1 g), RT, under air, 20 s; (v) 3 (0.5 mmol),
ChCl/urea (1 g), TFA (0.2 mL), cysteamine hydrochloride (0.5 mmol) or L-cysteine hy-
drochloride (0.5 mmol), 2 h.
4. Experimental section
0.2 mL TFA, and reacted with L-cysteine or cysteamine hydrochlo-
1H NMR,13C NMR were recorded on a Varian-Mercury 300 MHz
or a Bruker 400 MHz spectrometers and chemical shifts are re-
ported in parts per million (d). FT-IR spectra were recorded on a
ride. After 2 h reaction time, the desired targets 5ae5d were iso-
lated in 95e98% yield (overall yields for the two steps: 71e95%)
(Scheme 3b).
PerkinElmer 681 spectrometer. GC analyses were performed on a
HP 6890 model, Series II by using a HP1 column (methyl siloxane;
Finally, we decided to investigate a telescoped, one-pot tandem
process for the preparation of STLC derivatives using water as the
sole reaction medium, under aerobic conditions. These one-pot
tandem protocols are attractive processes in the toolbox of syn-
thetic chemistry for improving the economic efficiency of chemical
reactions as they allow: i) the drastic reduction of isolation and
purification steps of intermediates of reaction (thus minimizing
both the generation of chemical waste and the required time and
energy); and ii) the possibility to work with unstable reaction in-
termediates as no isolation of highly reactive and transitory species
is needed [18]. To this end, benzoate 1a (0.5 mmol) was suspended
in water (1.0 mL) and treated, at RT under air, with PhLi (2.5 equiv)
under vigorous stirring. After 1 min, cysteamine hydrochloride
30 m ꢂ 0.32 mm ꢂ 0.25
mm film thickness). Analytical thin-layer
chromatography (TLC) was carried out on pre-coated 0.25 mm
thick plates of Kieselgel 60 F254; visualization was accomplished by
UV light (254 nm) or by spraying a solution of 5% (w/v) ammonium
molybdate and 0.2% (w/v) cerium (III) sulfate in 100 mL 17.6% (w/v)
aq. sulphuric acid and heating to 473 K until blue spots appeared.
Chromatography was run by using silica gel 60 with a particle size
distribution 40e63 mm and 230e400 ASTM. GC-MS analyses were
performed on HP 5995C model. Cyclopentyl methyl ether (CPME)
or ethyl acetate (EtOAc) were used as the solvents in the work-up
procedures. High-resolution mass spectrometry (HRMS) analyses
were performed using a Bruker microTOF QII mass spectrometer
equipped with an electrospray ion source (ESI). Reagents and sol-
vents, unless otherwise specified, were purchased from Sigma-
Aldrich (Sigma-Aldrich, St. Louis, MO, USA) and used without any
further purification. Methyl 2,5-dimethoxybenzoate (1b) and
methyl 2-hydroxy-5-methoxybenzoate (1c) were prepared ac-
cording to the reported procedure [19].
(0.5 mmol) or L-cysteine hydrochloride (0.5 mmol) and TFA (0.2 mL)
were sequentially added. After 2 h stirring at RT, the dropwise
addition of an aqueous solution of NaOH (4 N) favored the pre-
cipitation of 5a (pH ¼ 5e6) or 5d (pH ¼ 9). The latter were isolated
by filtration in both good yield (80e84%) and purity, with no need
of column chromatography (Scheme 4) (see experimental part for
details).
Reactions were carried out in deionized water (pH ¼ 6.1,
determined by pH meter 507 Crison). The following solutions of
organolithium reagents were furnished by Albemarle (Germany)
and were used with the following concentrations: n-BuLi, 2.0 M in
cyclohexane; EtLi, 0.5 M in hexane; i-PrLi, 0.7 M in pentane; 2-
thienylLi, 1.0 M in THF/hexane; MeLi, 1.6 M in Et2O; PhLi, 1.9 M in
Bu2O. The following solutions of Grignard or organolithium re-
agents were purchased from Sigma-Aldrich (Sigma-Aldrich, St.
Louis, MO, USA) and were used with the following concentrations:
MeMgCl, 3.0 M in THF; EtMgBr, 3.0 M in Et2O; PhMgCl, 2.0 M in
THF; n-hexylLi, 2.3 M in hexane.
3. Conclusion
In summary, we have shown that the nucleophilic addition of
organolithium reagents to esters can be conveniently carried out
using bulk water or ChCl/urea, working under air and at RT. These
reactions proceeded smoothly in such strongly hydrogen-bonded
associated media, under heterogeneous conditions, and also very
quickly (20 s reaction time), straightforwardly delivering tertiary
alcohols in very good yields (60e98%). Similarly to other cases, they
are thought to occur at the oil/water (or DES) phase boundary
Full characterization data, including copies of 1H and 13C NMR
spectra (see Supplementary Material), have been reported for both
the newly synthesized (3d, 3f, 3g, 3h, 3j, 3m, 3n) and the known
(3a, 3b, 3c, 3e, 3i, 3k, 3l, 3o, 3p, 3q, 3r, 3s, 5a, 5b, 5c, 5d) com-
pounds. The following abbreviations have been used to explain the
multiplicities: s ¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet,
m ¼ multiplet, quin ¼ quintuplet, sext ¼ sextet, sep ¼ septet, br
s ¼ broad singlet. Deep Eutectic Solvents [urea/choline chloride
(ChCl) (2:1 mol/mol); glycerol (Gly)/ChCl (2:1 mol/mol)] were
prepared by heating under stirring at 60e80 ꢁC for 10e30 min the
corresponding individual components until a clear solution was
Scheme 4. Telescoped, one pot nucleophilic addition/thioetherification reactions from
benzoate 1a in a water mixture, leading to STLC derivatives 5a and 5d, via tertiary
alcohol 3a.
4

A.F. Quivelli, G. D’Addato, P. Vitale et al.
Tetrahedron 81 (2021) 131898
obtained.
4.2.4. Phenylbis(thiophen-2-yl)methanol (3d)
SAFETY NOTE: Organolithiums were handled under an inert
atmosphere until they were mixed with a suspension of the sub-
strate in water (or DES), under an air atmosphere and with vigorous
magnetic stirring, whereupon they react quickly. No particular
problems were experienced during the addition. Organolithiums,
however, are notoriously prone to ignition in air, and caution
should be exercised in adopting the recommended procedure,
especially on a larger scale.
2-ThienylLi, water: 98%, DES: 86%; white solid, m.p. 165e167 ꢁC;
Rf 0.3; ymax (KBr) 3650, 3066, 2930, 1490, 1445, 1228, 1157, 1067,
1012, 945, 824, 697 cmꢀ1
; dH (300 MHz, CDCl3) 7.56e7.51 (2H, m)
7.42e7.29 (5H, m), 7.01e6.98 (2H, m), 6.92e6.91 (2H, m), 3.29 (1H,
br s); dC (75 MHz, CDCl3) 151.9, 146.0, 128.04, 128.02, 127.9, 126.7,
126.5, 125.9, 125.8, 65.9; m/z (70 eV) 272 (44, Mþ), 255 (35), 239
(80), 221 (14), 195 (78), 171 (20), 161 (43), 134 (8), 111 (100), 77 (30),
51 (7); HRMS (ESI): [MþNa]þ, found 295.0193. C15H12S2ONa re-
quires 295.0222.
4.1. Synthesis of aryl esters 1b, 1c. Typical procedure
4.2.5. Diphenyl(p-tolyl)methanol (3e) [23]
According to the procedure reported by Paquette [20], HCl 37%
(1 mL) was carefully added to a solution of the corresponding
benzoic acid derivative (15.6 mmol) in MeOH (20 mL). The reaction
mixture was refluxed for 2 h. MeOH was removed under reduced
pressure, and the reaction mixture was extracted with CPME
(3.0 mL ꢂ 3). The volatiles were removed under reduced pressure to
give the methyl ester 1b or 1c without further purification.
PhLi, water: 90%, DES: 80%; colourless solid, m.p. 65e66 ꢁC [24];
Rf 0.45; ymax (KBr) 3466, 3058, 3028, 2920, 1957, 1914, 1599, 1510,
1488, 1446, 1407, 1329, 1276, 1207, 1184, 1155, 1117, 1080, 1009, 922,
894, 842, 814, 755, 722, 699 cmꢀ1
; dH (300 MHz, CDCl3) 7.33e7.10
(14H, m), 2.34 (1H, s); dC (75 MHz, CDCl3) 147.0, 144.0, 139.9, 128.6,
127.92, 127.95, 127.1, 81.9, 21.0; m/z (70 eV) 274 (28, Mþ), 257 (39),
197 (100), 183 (19), 168 (22), 165 (12), 119 (34), 105 (70), 91 (17), 77
(35), 65 (3); HRMS (ESI): [M ꢀ H]-, found 273.1284. C20H17O re-
quires 273.1285.
4.2. Synthesis of alcohols 3 by addition of organolithium or
Grignard reagents to esters 1 in water or DES. General procedure
4.2.6. 5-(p-Tolyl)nonan-5-ol (3f)
In a 10 mL Schlenk-like flask, aryl or alkyl ester 1 (0.5 mmol) was
added to 1.0 mL of water or 1.0 g of DES, at room temperature in air,
and the resulting mixture was vigorously stirred. A solution of the
corresponding organolithium or Grignard reagent (2.5 equiv),
handled under argon using conventional Schlenk techniques, was
rapidly spread over the mixture under air and with vigorous stir-
ring at room temperature to generate an emulsion. After 20 s, the
reaction mixture was diluted with 2 mL of water, and then
extracted with CPME (3.0 mL ꢂ 3). The volatiles were removed
under reduced pressure, and the residue was purified by column
chromatography on silica gel (hexane/EtOAc, 8/2) to provide the
desired product 3.
n-BuLi, water: 60%, DES: 92%; colourless oil. Rf 0.35; ymax (liquid
film) 3469, 3052, 2956,1677,1611,1512,1466,1405,1378,1231,1181,
1112, 975, 819, 726 cmꢀ1
; dH (300 MHz, CDCl3) 7.24 (2H, d, J 8.5 Hz),
7.13 (2H, d, J 8.5 Hz), 2.33 (3H, s), 1.81e1.70 (4H, m), 1.66 (1H, br s),
1.29e1.10 (6H, m), 1.09e0.86 (2H, m), 0.83 (6H, t, J 6.0 Hz); dC
(75 MHz, CDCl3) 143.5,135.6,128.6,125.1, 76.6, 42.7, 25.6, 23.0, 20.9,
14.0; m/z (70 eV) 234 (10, Mþ), 177 (100), 159 (5), 132 (9), 105 (7), 91
(8), 77 (6), 57 (11). HRMS (ESI): [M ꢀ H]-, found 233.1910. C16H25
O
requires 233.1911.
4.2.7. 5-(2,5-Dimethoxyphenyl)nonan-5-ol (3g)
n-BuLi, water: 60%, DES: 65%; colourless oil. Rf 0.43; ymax (liquid
film) 3503, 2955, 1737, 1586, 1492, 1465, 1378, 1277, 1260, 1219,
4.2.1. 5-Phenylnonan-5-ol (3a) [19]
1178, 1094, 876, 803 cmꢀ1
; dH (300 MHz, CDCl3) 6.87 (1H, d, J
n-BuLi, water: 98%, DES: 98%; colorless oil; Rf 0.43; ymax (liquid
film) 3609, 3419, 3399, 2957, 2934, 2861, 1654, 1648, 1508, 1494,
3.0 Hz), 6.82 (1H, d, J 6.0 Hz), 6.72 (1H, dd, J 3.0 Hz, J 6.0 Hz), 3.81
(3H, s), 3.77 (3H, s), 2.00e1.92 (2H, m), 1.79e1.72 (2H, m), 1.29e1.09
(9H, m), 0.85 (6H, t, J 6 Hz); dC (75 MHz, CDCl3) 153.4, 151.2, 135.0,
117.0, 114.6, 112.3, 77.5, 56.0, 55.5, 40.4, 26.0, 23.1, 14.0; m/z (70 eV)
280 (5, Mþ), 223 (100), 205 (25), 190 (8), 174 (3), 151 (18), 121 (5), 91
(3), 57 (5); HRMS (ESI): [M ꢀ H]-, found 279.1967. C17H28O3 requires
279.1966.
1458, 1379, 1113, 1078, 764, 700 cmꢀ1
; dH (300 MHz, CDCl3)
7.39e7.30 (4H, m), 7.25e7.19 (1H, m),1.89e1.68 (4H, m),1.68 (1H, br
s), 1.32e1.17 (6H, m), 1.08e0.99 (2H, m), 0.83 (6H, t, J 7.0 Hz); dC
(75 MHz, CDCl3) 146.5, 128.1, 126.2, 125.2, 77.2, 42.7, 25.6, 23.1, 14.0;
m/z (70 eV) 220 (11, Mþ), 202 (35), 163 (100), 145 (10), 138 (10), 117
(3), 105 (5), 91 (7), 77 (9), 51 (8); HRMS (ESI): [M ꢀ H]-, found
219.1750. C15H23O requires 219.1754.
4.2.8. 5-(2-Hydroxy-5-methoxyphenyl)nonan-5-ol (3h)
n-BuLi, water: 70%, DES: 60%; colourless oil; Rf 0.35; ymax (liquid
film) 3502, 2957, 1747, 1588, 1468, 1428, 1376, 1220, 1179, 1029, 876,
4.2.2. 2,4-Dimethyl-3-phenylpentan-3-ol (3b) [21]
i-PrLi, water: 98%, DES: 96%; viscous oil; Rf 0.40; ymax (liquid
film) 3605, 3088, 2966, 2876, 1634, 1468, 1384, 1318, 1156, 980, 759,
803,750 cmꢀ1
; dH (300 MHz, CDCl3) 6.77 (1H, d, J 6.0 Hz), 6.70 (1H,
dd, J 6.0, 3.0 Hz), 6.48 (1H, d, J 3.0 Hz), 3.75 (3H, s), 1.94e1.88 (2H,
m),1.82e1.76 (2H, m),1.34e1.26 (8H, m),1.25 (1H, br s), 0.87 (6H, t, J
6.0, 3 Hz); dC (75 MHz, CDCl3) 153.4, 149.6, 130, 118.3, 114.6, 112.0,
77.5, 55.6, 40.4, 25.9, 23.1, 14.0; m/z (70 eV) 266 (Mþ, 7), 248 (80),
206 (11), 191 (100), 177 (13), 163 (28), 151 (18), 137 (50), 121 (23), 91
(11) 77 (11), 57 (13); HRMS (ESI): [MþH]þ, found 267.1956.
705 cmꢀ1
; dH (300 MHz, CDCl3) 7.42e7.23 (5H, m), 2.38e2.29 (2H,
m), 1.58 (1H, s), 0.88 (6H, d, J 6.6 Hz), 0.79 (6H, d, J 6.6 Hz); dC
(75 MHz, CDCl3) 142.9, 127.3, 126.7, 126.2, 81.0, 33.8, 17.5, 16.5; m/z
(70 eV) 192 (23, Mþ), 149 (100), 131 (10), 105 (52), 91 (14), 77 (23),
71 (20), 51 (7), 43 (11). HRMS (ESI): [MþH]þ, found 193.1582.
C
13H21O requires 193.1587.
C16H27O3 requires 267.1955.
4.2.3. Triphenylmethanol (3c) [22]
4.2.9. 1-(4-Methoxyphenyl)diphenylmethanol (3i) [24]
PhLi, water: 98%, DES: 98%; PhMgCl, DES: 75%; white solid, m.p.
PhLi, water: 80%, DES: 75%; colourless oil; Rf 0.40; ymax (liquid
film) 3565, 3055, 2932, 1606, 1488, 1296, 1116, 1081, 1005, 896, 795,
161e163 ꢁC; Rf 0.30; ymax (KBr) 3584, 3467, 3063, 2924, 1597, 1489,
1444, 1329, 1156, 1030, 1010, 888, 756, 696 cmꢀ1
;
dH (300 MHz,
754, 701 cmꢀ1
; dH (300 MHz, CDCl3) 7.35e7.25 (10H, m), 7.17 (2H, d,
CDCl3) 7.37e7.27 (15H, m), 2.82 (1H, br s); dC (75 MHz, CDCl3) 146.8,
127.9, 127.3, 82.0; m/z (70 eV) 260 (37, Mþ), 239 (6), 183 (100), 165
(14), 154 (30), 165 (16), 154 (30), 105 (76), 77 (56), 51 (94). HRMS
(ESI): [M ꢀ H]-, found 259.1126. C19H15O requires 259.1128.
J 8.7 Hz),6.84 (2H, d, J 8.7 Hz), 3.80 (3H, s), 2.80 (1H, s); dC (75 MHz,
CDCl3) 159.1, 147.5, 139.6, 129.6, 128.3, 128.2, 127.6, 113.6, 82.1, 55.7;
m/z (70 eV) 290 (37, Mþ), 273 (8), 213 (100), 185 (11), 165 (8), 135
(30),105 (39), 77 (24), 51 (3); HRMS (ESI): [M ꢀ H]-, found 289.1231.
5

A.F. Quivelli, G. D’Addato, P. Vitale et al.
Tetrahedron 81 (2021) 131898
C20H17O2 requires 289.1234.
4.2.16. 7-Methyltridecan-7-ol (3p) [28]
HexylLi, water: 85%, DES: 80%; colorless oil. Rf 0.40; ymax (liquid
film) 3309, 2957, 2931, 1464, 1376, 1143, 925, 880 cmꢀ1
dH
4.2.10. 5-(4-Methoxyphenyl)nonan-5-ol (3j)
;
n-BuLi, water: 80%, DES: 85%; colourless oil. Rf 0.48; ymax (liquid
film) 3478, 3037, 2932,1613,1583,1513,1463,1412,1378,1337,1247,
(500 MHz, CDCl3) 1.43e1.41 (4H, m),1.31e1.25 (16H, m),1.14 (3H, s),
0.89e0.87 (6H, m); dC (125 MHz, CDCl3) 72.7, 41.8, 31.8, 29.9, 26.9,
23.8, 22.6, 14.0; m/z (70 eV) 213 (2), 129 (100), 111 (8), 69 (25), 43
(14); HRMS (ESI): [M ꢀ H]-, found 213.2215. C14H29O requires
213.2224.
1178, 975, 898, 831, 801, 752, 702 cmꢀ1
; dH (300 MHz, CDCl3) 7.28
(2H, d, J 8.7 Hz), 6.86 (2H, d, J 8.7 Hz), 3.80 (3H, s),1.80e1.73 (4H, m),
1.68 (1H br s), 1.31e1.17 (6H, m), 1.10e0.99 (2H, m), 0.83 (6H, t, J
6.1 Hz); dC (75 MHz, CDCl3) 157.9, 138.7, 126.3, 113.3, 76.6, 55.1, 42.7,
25.6, 23.1, 14.0; m/z (70 eV) 250 (Mþ, 10), 232 (6), 193 (100), 175
(88), 148 (20), 135 (8), 121 (8), 103 (6), 91 (8), 77 (9), 57 (10). HRMS
(ESI): [M ꢀ H], found 249.1861. C16H25O2 requires 249.1860.
4.2.17. 2-Phenylpropan-2-ol (3q) [29]
MeMgCl, DES: 90%; colourless oil; Rf 0.30; ymax (liquid film)
3393, 3087, 3026, 2976, 2871, 1950, 1808, 1602, 1494, 1446, 1364,
1290, 1173, 1101, 1073, 1029, 954, 764, 697 cmꢀ1
; dH (300 MHz,
4.2.11. 2-(4-Methoxyphenyl)propan-2-ol (3k) [25]
CDCl3) 7.54e7.51 (2H, m), 7.39e7.26 (3H, m), 1.97 (1H, br s), 1.62
(6H, s); dC (75 MHz, CDCl3) 149.1, 128.2, 126.7, 124.4, 72.5, 31.7; m/z
(70 eV) 136 (34, Mþ),121 (100),105 (6), 91 (9), 77 (20), 51 (9); HRMS
(ESI): [MþNa]þ, found 159.0789. C9H12ONa requires 159.0786.
MeLi, water: 60%, DES: 95%; MeMgCl, DES: 75%; colourless oil. Rf
0.33; ymax (liquid film) 3774, 3418, 3039, 2973, 2933, 2837, 1701,
1668, 1614, 1583, 1514, 1415, 1361, 1300, 1247, 1179, 1097, 1034, 954,
864, 832, 797 cmꢀ1
; dH (300 MHz, CDCl3) 7.41 (2H, d, J 6.0 Hz), 6.87
(2H, d, J 6.0 Hz), 3.80 (3H, s), 1.56 (6H, s); dC (75 MHz, CDCl3) 154.3,
137.4, 121.7, 109.5, 68.2, 51.3, 27.9, 27.8; m/z (70 eV) 166 (Mþ, 20),
151 (100), 148 (33), 133 (23), 109 (9), 77 (20), 65 (6), 43 (10). HRMS
(ESI): [MþH]þ, found 165.0922. C10H15O2 requires 165.0921.
4.2.18. 3-phenylpentan-3-ol (3r) [30]
EtMgBr, DES: 75%; colourless oil; Rf 0.45; ymax (liquid film) 3472,
3435, 2968, 2936, 1645, 1493, 1460, 1377, 1162, 1031, 961, 894, 757,
701 cmꢀ1
; dH (300 MHz, CDCl3) 7.42e7.22 (5H, m), 1.96e1.77 (4H,
m), 1.68 (1H, br s), 0.78 (6H, t, J 7.4 Hz); dC (75 MHz, CDCl3) 145.7,
128.0, 126.3, 125.5, 65.9, 35.0, 7.8; m/z (70 eV) 164 (34, Mþ), 135
(100), 117 (6), 105 (8), 91 (8), 77 (13), 57 (41), 51 (10); HRMS (ESI):
[MþNa]þ, found 187.1085. C11H16ONa requires 187.1093.
4.2.12. [4-(Dimethylamino)phenyl]diphenylmethanol (3l) [26]
PhLi, water: 86%, DES: 80%; colourless oil; Rf 0.45; ymax (liquid
film) 3586, 3467, 3063, 2924, 1598, 1489, 1444, 1329, 1124, 1156,
1030, 1016, 888, 756, 696 cmꢀ1
; dH (300 MHz, CDCl3) 7.34e7.27
(10H, m), 7.12 (2H, d, J 8.6 Hz), 6.69 (2H, d, J 8.6 Hz), 2.97 (6H, s), 2.77
(1H, br s); dC (75 MHz, CDCl3) 149.6, 147.3, 128.9, 127.9, 127.8, 126.9,
111.8, 81.8, 40.5; m/z (70 eV) 303 (37, Mþ), 226 (14), 183 (100), 154
(36),120 (8),105 (11), 91 (16), 77 (55), 51 (94). HRMS (ESI): [MþH]þ,
found 304.1695. C21H22ON requires 304.1696.
4.2.19. 2-(2,5-Dimethoxyphenyl)propan-2-ol (3s) [31]
MeMgCl, DES: 95%; colourless oil; Rf 0.35; ymax (liquid film)
3300, 2954, 2923, 2853, 1514, 1463, 1456, 1377, 1302, 1248, 1169,
954, 829 cmꢀ1
; dH (300 MHz, CDCl3) 6.87 (1H, d, J 3.0 Hz), 6.83 (1H,
d, J 8.8 Hz), 6.72 (1H, dd, J 3.0 Hz, J 8.8 Hz), 3.87 (3H, s), 3.77 (3H, s),
1.25 (1H, br s); dC (75 MHz, CDCl3) 153.3, 150.9, 143.8, 115.7, 115.1,
112.3, 77.1, 55.9, 55.5, 30.0; m/z (70 eV) 196 (Mþ, 91), 181 (100), 163
(19), 151 (20), 135 (12), 124 (13), 105 (11), 91 (10), 77 (14), 43 (5);
HRMS (ESI): [M ꢀ H]-, found 195.1027. C11H15O3 requires 195.1026.
4.2.13. 5-[4-(Dimethylamino)phenyl]nonan-5-ol (3m)
n-BuLi, water: 75%, DES: 70%; m.p. 170e172 ꢁC; Rf 0.40; ymax
(KBr) 3584, 3411, 2956, 1611, 1519, 1463, 1348, 1224, 1196, 1124,
1016, 947, 815 cmꢀ1
; dH (300 MHz, CDCl3) 7.25 (2H, d, J 8.5 Hz), 6.73
(2H, d, J 8.5 Hz), 2.95 (6H, s), 1.81e1.74 (4H, m), 1.64 (1H, br s),
1.31e1.02 (8H, m), 0.83 (6H, t, J 6.0 Hz); dC (75 MHz, CDCl3) 148.9,
139.6, 126.8, 126.0, 112.5, 112.2, 76.0, 42.5, 40.8, 40.7, 31.1, 30.6,
23.24, 23.21, 14.1, 14.0; m/z (70 eV) 263 (15, Mþ), 230 (6), 190 (10),
176 (100), 146 (15), 134 (42), 120 (46), 105 (20), 91 (16), 77 (21), 51
(15); HRMS (ESI): [M ꢀ H]-, found 262.2175. C17H28NO requires
262.2176.
4.3. Synthesis of S-trityl-
procedure in DES
L
-cysteine thioethers 5aec. General
L-Cysteine hydrochloride (0.5 mmol), alcohol 3c or 3e or 3i
(0.5 mmol) and 0.2 mL of trifluoroacetic acid (TFA) were sequen-
tially added to the eutectic mixture ChCl/urea (1.0 g) at room
temperature under air. After stirring for 2 h at room temperature,
2 mL of water were added. An aqueous NaOH solution (4 N) was
then added dropwise in water up to a pH of about 5e6. The reaction
mixture was extracted three times with EtOAc (5 mL ꢂ 3). The
resulting organic phase was dried (Na2SO4), filtered, and the vola-
tiles were removed under reduced pressure. The residue was pu-
rified by flash chromatography (CH2Cl2/CH3OH 9:1) to provide the
desired product 5aec.
4.2.14. 4-(5-Hydroxynonan-5-yl)benzonitrile (3n)
n-BuLi, water: 75%, DES: 70%; m.p. 160e162 ꢁC; Rf 0.30; ymax
(KBr) 3610, 3399, 2958, 2934, 2861, 2315, 1654, 1649, 1508, 1494,
1458, 1379, 1113, 1078, 754, 700 cmꢀ1
; dH (300 MHz, CDCl3) 7.93
(2H, d, J 8.5 Hz), 6.46 (2H, d, J 8.5 Hz), 1.89e1.68 (4H, m), 1.60 (1H, br
s), 1.49e1.39 (6H, m), 1.26e1.19 (2H, m), 0.83 (6H, t, J 6.0 Hz); dC
(75 MHz, CDCl3) 151.8, 127.9, 125.5, 118.3, 109.3, 79.4, 42.8, 25.5,
23.0, 14.0; m/z (70 eV) 245 (34, Mþ), 228 (10), 189 (100), 173 (6), 145
(15), 105 (20), 91 (16), 77 (21), 51 (15); HRMS (ESI): [MþH]þ, found
246.1851. C16H24NO requires 246.1852.
4.3.1. S-Trityl-
White solid, 95% yield. Rf 0.33; m.p. 190e192 ꢁC; ymax (KBr)
3028, 2974, 1732, 1651, 1598, 1556, 1490, 1442, 1395 cmꢀ1
dH
L
-cysteine (5a) [32]
;
(300 MHz, CD3OD) 7.47e7.44 (6H, m), 7.35e7.22 (9H, m), 3.09 (1H,
dd, J 4.1, 9.1 Hz), 2.80 (1H, dd, J 13.3, 4.1 Hz), 2.70 (1H, dd, J 13.3,
9.1 Hz); dC (75 MHz, CD3OD) 176.6, 145.7, 130.5, 129.1, 128.1, 68.2,
54.6, 34.6; HRMS (ESI): [MþNa]þ, found 386.1186. C22H21NO2SNa
requires 386.1185.
4.2.15. 1,1-Diphenylethanol (3o) [27]
PhLi, water: 90%, DES: 85%; PhMgCl, DES: 75%; colourless oil. Rf
0.40; ymax (liquid film) 3418, 3059, 3020, 2977, 1682, 1594, 1547,
1493, 1446, 1372, 1220, 1192, 1176, 926, 903, 830, 749, 696 cmꢀ1
; dH
(300 MHz, CDCl3) 7.44e7.40 (4H, m), 7.35e7.21 (6H, m),1.96 (3H, s);
dC (75 MHz, CDCl3) 148.0, 128.1, 126.9, 125.8, 76.0, 30.8; m/z (70 eV)
198 (Mþ,10),183 (100),178 (5),165 (8),155 (6),121 (10),105 (50), 77
4.3.2. S-4-Methyltrityl-
White solid, 95% yield. Rf 0.43; m.p. 198e200 ꢁC; ymax (KBr)
3032, 2970, 1724, 1650, 1600, 1554, 1495, 1440, 1385 cmꢀ1
dH
(300 MHz, CD3OD) 7.42 (4H, d, J 6.5 Hz), 7.30e7.18 (8H, m), 7.11 (2H,
L
-cysteine (5b)
(26), 51 (7), 43 (20); HRMS (ESI): [M ꢀ H]-, found 179.0972. C14H13
O
;
requires 179.0972.
6

A.F. Quivelli, G. D’Addato, P. Vitale et al.
Tetrahedron 81 (2021) 131898
d, J 8.2 Hz), 3.20e3.16 (1H, m), 2.70 (2H, d, J 6.0 Hz) 2.28 (3H, s); dC
(75 MHz, CD3OD) 173.0, 144.14, 144.09, 141.0, 136.7, 129.2, 129.1,
128.4, 127.7, 126.7; HRMS (ESI): [MþNa]þ, found 400.1343.
Declaration of competing interest
The authors declare that they have no known competing
financial interests or personal relationships that could have
appeared to influence the work reported in this paper.
C
23H23NO2SNa requires 400.1342.
4.3.3. S-4-Methoxytrityl-
White solid, 95% yield. Rf 0.40; m.p. 178e180 ꢁC; ymax (KBr)
3029, 2978, 1730, 1658, 1597, 1550, 1495, 1442, 1395 cmꢀ1
dH
(300 MHz, CD3OD) 7.43 (2H, d, J 8.2 Hz), 7.33e7.18 (10H, m), 6.83
(2H, d, J 8.2 Hz), 3.74 (3H, s), 3.14e3.08 (1H, m), 2.83e2.67 (2H, m);
dC (75 MHz, CD3OD) 171.1, 158.4, 144.5, 136.0, 130.5, 129.1, 127.7,
126.5, 112.9, 66.2, 54.3, 53.5, 32.7; HRMS (ESI): [MþNa]þ, found
416.1290. C23H23NO3SNa requires 416.1291.
L
-cysteine (5c)
Acknowledgments
;
This work was carried out under the frameworks of the Pro-
gramma Operativo Nazionale Ricerca e Innovazione (PON RI 2014/
2020), Axis I Investments in Human Capital, Action I.1.eInnovative
Ph.D.s with industrial characterization, funding FSE-FESR (D.D. n.
1377 on 5/6/2017), and the national PRIN project “Unlocking Sus-
tainable Technologies Through Nature-inspired Solvents”
(NATUREChem) (grant number: 2017A5HXFC_002), financially
supported by the University of Bari “Aldo Moro”, the Interuniversity
4.4. Synthesis of 2-(tritylthio)ethan-1-amine 5d. Typical procedure
in DES
ꢁ
Consortium C.I.N.M.P.I.S., and the Ministero dell'Universita e della
Ricerca (MUR-PRIN). J.G.-A. also thanks: i) the Spanish MINECO
(Projects CTQ2016-75986-P and CTQ2016-81797-REDC); and ii)
PhosAgro/UNESCO/IUPAC for the award of a “Green Chemistry for
Life Grant”. University of Salento is also gratefully acknowledged for
NMR facilities. We are also indebted to Albemarle for the generous
gift of organolithium reagents.
Cysteamine hydrochloride (0.5 mmol), alcohol 3c (0.5 mmol)
and 0.2 mL of TFA were sequentially added to the eutectic mixture
ChCl/urea (1.0 g) at RT under air. After stirring for 2 h at RT, 2 mL of
water were added. An aqueous NaOH solution was added dropwise
in water up to a pH of about 9. The reaction mixture was then
extracted three times with EtOAc (5 mL ꢂ 3), dried (Na2SO4) and
filtered, and the volatiles were removed under reduced pressure.
The residue was purified by flash chromatography (AcOEt/hexane
1:1) to provide the desired product 5d.
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tet.2020.131898.
4.4.1. 2-(Tritylthio)ethan-1-amine (5d) [16a]
Supplementary Material
White solid, 98% yield. Rf 0.33; m.p. 146e148 ꢁC; ymax (KBr)
3379, 3057, 2932, 1680, 1484, 1439, 1206, 1130, 698 cmꢀ1
; dH
Supplementary Material to this article, which contains 1H and
13C NMR spectra of all synthesized compounds, can be found in a
separate electronic file.
(300 MHz, CDCl3) 7.39 (6H, d, J 6 Hz), 7.27 (6H, t, J 6 Hz), 7.20 (3H, t, J
6 Hz), 2.57 (2H, m), 2.33 (2H, m); dC (75 MHz, CDCl3) 146.7, 130.1,
129.1, 127.7, 67.6, 41.6, 36.2; HRMS (ESI): [MþH]þ, found 320.1466.
C
21H22NS requires 320.1467.
References
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4.5. One-pot synthesis of 5a or 5d. Typical procedure in water
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In a 10 mL Schlenk-like flask, methyl benzoate 1a (68 mg,
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a 2 M solution), handled under argon using conventional Schlenk
techniques, was rapidly spread over the mixture under air and with
vigorous stirring at room temperature to generate an emulsion.
2
3
After 1 min, cysteamine hydrochloride (56.5 mg, 0.5 mmol) or L-
cysteine hydrochloride (78.81 mg, 0.5 mmol) and 0.2 mL of TFA
were sequentially added to the reaction mixture, at room temper-
ature under air. After additional stirring for 2 h at room tempera-
ture, an aqueous NaOH solution (4 N) was added dropwise in water
up to pH of about 9 (for the synthesis of 5d) or pH of about 5e6 (for
the synthesis of 5a). The resulting white precipitate was collected
by filtration. The crude product was further washed with water
4
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(a) T. Laird, Org. Process Res. Dev. 16 (2012) 1e2;
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ꢀ
(1.0 mL) and hexane (2.0 mL), and then dried to obtain 5a (from L-
7
8
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cysteine hydrochloride) as a white solid in 80% yield or 5d (from
cysteamine hydrochloride) as a white solid in 84% yield [33].
Alternative work-up procedure for 5d: After stirring the whole
mixture for 2 h at room temperature, an aqueous NaOH solution
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action mixture was then extracted three times with EtOAc
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