Synthesis of a new chiral organocatalyst derived from (S)-proline containing a 1,2,4-triazolyl moiety and its application in the asymmetric aldol reaction. Importance of one molecule of water generated in situ

Article abstract of DOI:10.1016/j.tetlet.2019.151128

A simple and efficient preparation of a novel chiral derivative of (S)-proline containing a 1,2,4-triazolyl moiety is described. The high-yielding synthetic protocol includes the use of microwave irradiation to afford new chiral pyrrolidine derivatives in

Full text of DOI:10.1016/j.tetlet.2019.151128

Tetrahedron Letters 60 (2019) 151128
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Tetrahedron Letters
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Synthesis of a new chiral organocatalyst derived from (S)-proline
containing a 1,2,4-triazolyl moiety and its application in the asymmetric
aldol reaction. Importance of one molecule of water generated in situ
Omar Sánchez-Antonio a, Eusebio Juaristi a,b,
⇑
a Departamento de Química, Centro de Investigación y de Estudios Avanzados, Av. IPN 2508, 07360 Ciudad de México, Mexico
b El Colegio Nacional, Luis González Obregón 23, Centro Histórico, 06020 Ciudad de México, Mexico
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 24 July 2019
Revised 6 September 2019
Accepted 8 September 2019
Available online 9 September 2019
A simple and efficient preparation of a novel chiral derivative of (S)-proline containing a 1,2,4-triazolyl
moiety is described. The high-yielding synthetic protocol includes the use of microwave irradiation to
afford new chiral pyrrolidine derivatives in high yield. Our triazolyl-containing heterocycle was evalu-
ated as organocatalyst (10 mol% load, under neat reaction conditions) in the enantioselective aldol reac-
tion between four different types of ketones and a variety of aryl aldehydes. Good results in terms of
enantioselectivity and chemical yield were observed under solvent-free reaction conditions and in the
absence of any additive. Evidence is provided for the involvement of the water molecule generated upon
enamine formation in the transition state of the aldol reaction.
Keywords:
Enantioselective aldol reaction
Proline hydrazides
Thiosemicarbazides
1,2,4-Triazolyl moiety
Asymmetric organocatalysis
Ó 2019 Elsevier Ltd. All rights reserved.
Introduction
synthesis and application of (S)-proline-containing chiral phospho-
ramides for enantiodivergent aldol reactions [5b] and the prepara-
The high efficiency exhibited by (S)-proline, (S)-1, in CAC bond-
forming reactions [1] has attracted the attention of a significant
number of chemists who have demonstrated the enormous poten-
tial of organocatalysis in asymmetric synthesis. Nevertheless, the
low solubility of (S)-proline in most organic solvents is a practical
limitation that has led to the incorporation of diverse functional
groups aimed to improve proline’s solubility while maintaining
high stereoselectivity and catalytic efficacy [2].
The asymmetric aldol reaction is a versatile synthetic tool for
the construction of CAC bonds with the generation of at least
one stereogenic center [3a]. This reaction still proves to be chal-
lenging, particularly because it is of great present interest to per-
form aldol reactions under more sustainable reaction conditions,
such as in water [3b–e], in brine [3f], or in the absence of solvent
[3g]. Furthermore, several research groups have developed useful
aldol methodologies employing supported catalysts or supported
organocatalysts [4].
tion of diamine derivatives of a,a-diphenyl-(S)-prolinol that
proved efficient in asymmetric Michael and Mannich reactions
[5c]. In addition, several pyrrolidinic camphor- and cinchona-based
derivatives have been shown by others groups to be effective in
catalyzing various asymmetric transformations [6].
Relevantly, a significant number of privileged bifunctional
organocatalysts that exhibit excellent performance incorporate
heterocyclic substituents [7]. In a particularly interesting example,
Ley et al., Yamamoto et al., and Arvidsson et al. reported that so-
called (S)-proline-2-tetrazole ((S)-2 in Scheme 1) is rather effective
in the organocatalytic aldol reaction as well as in asymmetric Man-
nich and Michael reactions [8].
The seminar work reported by Yamamoto, Ley and Arvidsson
[8] inspired us to develop the synthesis of a novel organocatalytic
system derived from (S)-proline that incorporates a 1,2,4-triazolyl-
5-benzylthio heterocyclic substituent, (S)-3a (Scheme 1). It is
anticipated that the benzylthio group on the triazole substituent
will increase its lipophilicity, so that organocatalysis should readily
take place both in organic and aqueous media.
The efficiency of our novel organocatalyst was evaluated in
asymmetric aldol reactions. It became apparent that the lipophilic
heterocyclic ring as well as the benzylthio- substituent do help
increase the solubility of (S)-proline-derived organocatalyst in
organic system because the reaction media were notably
Recently, our group has made several contributions in the area
of asymmetric organocatalysis such as in the development of
monoterpene-based (S)-proline derivatives [5a], the design,
⇑
Corresponding author.
E-mail addresses: juaristi@relaq.mx, ejuarist@cinvestav.mx (E. Juaristi).
https://doi.org/10.1016/j.tetlet.2019.151128
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.

2
O. Sánchez-Antonio, E. Juaristi / Tetrahedron Letters 60 (2019) 151128
Ph
O
N
N
N
S
N
Bn
N
H
N
H
N
H
N
H
OH
N
N
(S)-proline (S)-1
This work (S)-3a
(S)-2
Scheme 1. Emblematic organocatalysts (S)-proline, (S)-1, (S)-proline-2-tetrazole,
(S)-2, and novel pyrrolidinic 1,2,4-triazole derivative (S)-3a described in the present
work.
homogenous. Furthermore, theoretical evidence will be provided
below that the triazole ring does indeed participate in the stereoin-
ducing transition state via hydrogen bonding interaction with the
water molecule that is produced during enamine formation. Such
activation by water is in line with the proposal advanced by Naka-
shima and Yamamoto in their study of (2S)-pyrrolidine-tetrazole
(S)-2 as organocatalyst in asymmetric aldol reactions [8e].
Fig. 1. Single crystal X-ray diffraction analysis of N-Boc-(2S)-(5-(benzylthio)-4-
phenyl-(1,2,4-triazol)-3-yl)-pyrrolidine, (S)-9a.
Results and discussion
Ph
Ph
Synthesis of novel organocatalysts (S)-3a-c
S
S
N
R
N
R
N
N
N
N
H
N
N
HCl, rt
The synthesis of the novel 2-(1,2,4-triazol-5-thioeter)-(S)-pro-
line derivatives (S)-3a-c was carried out as described in the ‘refer-
ences and notes’ section [9]. The structure of the pyrrolidinic 1,2,4-
triazol-5-thione (S)-8 precursor was confirmed by single-crystal X-
ray diffraction analysis (Fig. S-85, ESI) [11]. Most relevant is the
distance between carbon and sulfur, 1.66 Å, that fits well with
anticipation for a C@S double bond [12]. In this regard, the length
calculated theoretically at the DFT M06 6-311G* level of theory is
1.65 Å (Fig. S-65, ESI, Section 5.1).
Cl
H
24 h, > 90 %
Boc
(S)-9a-c
(S)-3a-c . HCl
Ph
N
Ph
Ph
Ph
S
S
N
S
N
N
N
N
Cl
N
H
N
H
N
H
N
Cl
N
H
N
Cl
H
(S)-3a . HCl
(S)-3c . HCl
(S)-3b . HCl
In order to obtain the desired alkylthio derivatives (S)-9a-c,
thione (S)-8 was treated with KOH and the resulting thioenolate
was treated with the corresponding halide to yield the five-mem-
bered heterocycles (S)-9a-c in good yields (Table 1).
Compound (S)-9a provided adequate crystals for X-ray diffrac-
tion analysis (Fig. 1) [13]. Most salient, it could be corroborated
that benzylation is highly regioselective and took place at the sul-
fur atom. Furthermore, retention of the (S) configuration of the
proline ring is also confirmed by consideration of the Flack param-
eter, F = 0.061 (Fig. S-89, ESI).
Scheme 2. N-Deprotection of (S)-9a-c under acidic conditions to afford the
hydrochloride salts (S)-3a-cÁHCl.
water as additive was evaluated in the asymmetric aldol reaction
between cyclohexanone and 4-nitrobenzaldehyde. Table 2 summa-
rizes our observations, which indicate that best results in terms of
yield and stereoselectivity are obtained with 10 mol% of the cata-
lyst (S)-3a in its free form, under solvent-free (neat) reaction con-
ditions (entry 1). Quite similar results were obtained with (S)-3b,
anticipated to present similar solubility in organic media (compare
entries 1 and 3).
By contrast, with (S)-3cÁHCl the yield and selectivity were
rather low, probably as consequence of its diminished solubility
(Table 2, entry 4, see also ESI). The use of the protonated form of
organocatalysts (S)-3a and (S)-3b results in decreased yield and
stereoselectivity (entries 2 and 4). On the other hand, while addi-
tion of water to the reaction medium was detrimental (entries 5
to 8), thorough water removal with molecular sieves (entry 9)
led to a drastic decrease in yield and stereoselectivity. This latter
result indicates that water is an essential component for the effi-
cient progress of the aldol reaction [14].
Finally, compounds (S)-9a-c were N-deprotected under acidic
conditions to obtain organocatalysts (S)-3a-c as hydrochloride
salts (Scheme 2).
Evaluation of organocatalysts (S)-3a-c.
The potential efficiency of novel (S)-proline derivatives (S)-3a-c
in organocatalysis, either in free form (after treatment with
NaHCO3) or as hydrochloride salts, and in presence or absence of
Table 1
Preparation of N-Boc-(2S)-(5-(thioalkyl)- and N-Boc-(2S)-(5-(thiobenzyl)-4-phenyl-
(1,2,4-triazol)-3-yl)-pyrrolidines (S)-9a-c.
The reaction’s scope was then examined with a variety of alde-
hydes and under the conditions indicated in entry 1 of Table 2
(Table 3).
Ph
Ph
S
S
N
N
R
Organocatalyst (S)-3a was also evaluated in asymmetric aldol
reactions with acetone, cyclopentanone and cycloheptanone,
maintaining 4-nitrobenzaldehyde as electrophile. Best results were
observed with cyclopentanone (Table 4). As anticipated by the
introduction of the lipophilic triazole substituent in proline (see
Introduction) miscibility of the organocatalyst with organic part-
ners such as the cyclohexanone, acetone, cyclopentanone and
cycloheptanone is remarkably high.
1 equiv. KOH
alkyl/aryl
halide
N
+
N
N
H
N
N
Boc
N
MW
MeCN.
Boc
(S)-9a-c
(S)-8
Product
R-X
Yield (%)
(S)-9a
(S)-9b
(S)-9c
benzyl bromide
2-iodopropane
1-bromo-2-chloroethane
82
85
70
As it was already mentioned, Nakashima and Yamamoto [8e]
reported a study on the asymmetric aldol reaction with acetone,

O. Sánchez-Antonio, E. Juaristi / Tetrahedron Letters 60 (2019) 151128
3
Table 2
Asymmetric aldol reaction between cyclohexanone and 4-nitrobenzaldehyde in the presence of organocatalysts (S)-3a-c, and in the presence or absence of water.
O
O
O
OH
10 mol % (S)-3a-c
H
+
rt, neat, 36 h
NO2
NO2
(2S,1´R)-10
Entry
Organocatalyst
Additive
Yield (%)b
dr (anti/syn)c
erd
1
2
3
4
5
6
7
8
9
(S)-3a
None
None
None
None
96
85
90
22
50
42
35
24
18
85:15
86:14
80:20
80:20
90:10
82:18
75:25
70:30
60:40
96:4
(S)-3aÁHCl
84:16
90:10
60:40
87:13
89:11
80:20
55:45
60:40
(S)-3b
(S)-3cÁHCl
(S)-3a
(S)-3a
(S)-3a
(S)-3a
1 mol % H2O
H2Oa
50 mol % H2O
100 mol % H2O
(S)-3a
MS 3Åe
a
b
c
The value corresponds to 10 mol % of additives.
Determined after column purification Hexane-EtOAc, 9:1.
Determined by 1H NMR spectroscopy.
d
Determined by HPLC analysis with chiral columns (see SI). eMS: Molecular Sieves.
Table 3
Scope of the asymmetric aldol reaction catalyzed with (S)-3a.
O
O
O
OH
10% mol (S)-3ad
H
+
R
R
rt, neat
(2S,1´R)-11-21
Product
R
Time (h)
Yield (%)a
dr (anti/syn)b
er (anti)c
11
12
13
14
15
16
17
18
19
20
21
2-nitro
3-nitro
1-naphth
-H
2-CF3
4-CN
2-Cl
4-Cl
3-Br
4-CF3
4-F
36
36
72
96
48
36
36
36
36
24
48
94
96
68
63
92
94
93
94
92
92
90
80:20
80:20
70:30
75:25
96:4
80:20
60:40
80:20
60:40
70:30
60:40
90:10
91:9
60:40
70:30
60:40
76:24
65:35
75:25
60:40
70:30
65:35
a
b
c
Determined after column purification Hexane-EtOAc, 9:1.
Determined by 1H NMR spectroscopy.
Determined by HPLC analysis. dIn free form.
Table 4
Evaluation of the catalyst (S)-3a with other ketones.
O
O
OH
O
Ph
N
10% mol (S)-3ad
S
+
H
Bn
rt, neat
(CH2)n
N
N
N
(S)-3a
NO2
NO2
(CH2)n
H
n = 0, 1,2
n = 0,1,2
Entry
Ketone
Time (h)
Yield (%)a
dr (anti/syn)b
erc
1
2
3
Acetone
Cyclopentanone
Cycloheptanone
24
36
36
96
92
85
–
83:17
92:08
96:04
93:7
65:35
d
In free form.
a
Determined after column purification hexane-EtOAc, 9:1.
Determined by 1H NMR spectroscopy.
Determined by HPLC analysis.
b
c
catalyzed by so-called (S)-proline tetrazole (S)-2. Comparison with
our catalytic system, indicates comparable yields and stereoselec-
tivities, although reactions catalyzed by (S)-3a seem to proceed in
shorter times. In this context, Nakashima and Yamamoto have pro-
posed activation by a water molecule of the reaction catalyzed by
tetrazole derivative (S)-2 [14]. Suspecting that similar activation is

4
O. Sánchez-Antonio, E. Juaristi / Tetrahedron Letters 60 (2019) 151128
O H
O
Ph
Ph
Ph
N
H
Ph
Ph
Ph
N
Ph
S
S
S
H
S
Ph
N
N
Enamine formation generates H2O
O
N
N
N
N
N
N
N
H
H
Keq
N
N
N
N
N
H
O
H
H
H
H
O
O
H
H
22-C
22-B
22-A
Ph
S
Scheme 3. Calculated equilibrium geometry (DFT M06 6-31G*) for isomeric species
of hydrated (S)-3aÁH2O.
Ph
N
N
N
H
O
Ph
N
O
N
S
Ph
H
N
H
N
N
Re
O
OH
(S)
(R)
NO2
Aldol
Scheme 4. Plausible reaction mechanism proposed with base on both experimental
results and molecular modeling.
Fig. 2. Modeling of the transition state where organocatalyst (S)-3a activates the
electrophilic aldehyde by hydrogen bonding between the catalyst [N(2) at the
triazole ring], water, and the carbonyl substrate.
ical observations suggest that a water molecule is involved in the
transition state.
operative with the triazole analogs (S)-3a and (S)-3b, it was deem
important to carry out a preliminary computational study of the
reaction mechanism involving catalyst (S)-3a. In a first approxima-
tion, the structure of organocatalyst (S)-3a in the presence of one
water molecule was optimized at the Spartan DFT at M06 6-31G*
level of theory. Calculations (cf. Scheme 3) suggest that hydrated
structure 22-A with water hydrogen-bonded to N(2) is more stable
relative to alternative adducts 22-B (water coordinated to N(1) or
22-C (water molecule bound to the exocyclic sulfur).
Acknowledgments
We are indebted to CONACYT-Mexico and Fund SEP-CINVES-
TAV-Mexico for financial support via grants 220945 and 126,
respectively. O. Sánchez-Antonio thanks CONACYT-Mexico for
scholarship number 397321. We are also grateful to T. Cortez-
Picasso and V. M. González-Díaz (CINVESTAV) for their assistance
in the recording of NMR spectra. We also thank to M. A. Leyva-
Ramírez (CINVESTAV) for his support in the acquisition and pro-
cessing of X-ray diffraction data.
The above theoretical evidence, together with Yamamoto’s pro-
posed activation by hydrogen bonding between water and tetra-
zolyl nitrogens of electrophilic aldehydes during the aldol
reaction catalyzed with (S)-2 [8e] support similar activation of
the electrophile by hydrogen bonding between the catalyst (S)-3a
[N(2) at the triazole ring], water, and the carbonyl substrate. Thus,
such proposed transition state was modelled using Spartan 16
(DFT-M06-6-31G*) (Fig. 2) [15]. Indeed, calculations converged to
the energy minimum and reveal a 2.037 Å distance between atom
N(2) of the triazole ring and a hydrogen in the water molecule. The
distance between the second hydrogen of the water molecule with
the oxygen atom of the aldehyde was estimated as 1.449 Å. These
data are in line with the participation of a supramolecular aggre-
gate in the transition state of the asymmetric aldol reaction.
It is then proposed that the equimolar amount of water gener-
ated upon enamine formation gets involved in the suggested tran-
sition state. A plausible reaction mechanism that is in line with the
experimental (Cf. Table 2) and theoretical observations (Cf. Fig. 2)
involves enamine formation in the first step, with the formation
of 1 equivalent of water. Such water molecule is then involved in
the supramolecular complex that leads to the aldol product and
subsequent liberation of the organocatalyst that will enter in a
new cycle (Scheme 4).
Appendix A. Supplementary data
Supplementary data to this article can be found online at
https://doi.org/10.1016/j.tetlet.2019.151128.
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[9] The synthesis of (S)-3a-c was initiated with N-protection of (S)-proline (S)-1
with di t-butoxycarbonyl anhydride (Boc2O) to generate N-Boc protected (S)-4
in 95% yield. Subsequently, hydrazine was incorporated via the formation of a
mixed anhydride with ethyl chloroformate followed by addition of an
ethanolic hydrazine hydrate solution [10a,b], affording hydrazide (S)-5 in 96
% yield. The functionalization of compound (S)-5 was carried out by treatment
with phenyl isothiocyanate 6 under microwave irradiation in ethanol to afford
semi thiocarbazide (S)-7 with high yield [10c]. Intramolecular cyclization of
semi thiocarbazide (S)-7 was accomplished by means of dehydration in basic
media [10d,e], giving pyrrolidinic 1,2,4-triazol-5-thione derivative (S)-8 as a
white solid in 85% yield.
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0502;
(n) O. Illa, O. Porcar-Tost, C. Robledillo, C. Elvira, P. Nolis, O. Reiser, V.
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