Thioamide-substituted cinchona alkaloids as efficient organocatalysts for asymmetric decarboxylative reactions of MAHOs

Article abstract of DOI:10.1002/ejoc.201700870

A new class of thioamide-substituted cinchona derivatives is reported. A convergent and practical approach was developed to insert the thioamide functional group onto the cinchonidine from readily available dithioesters. These organocatalysts were effective in asymmetric decarboxylative Mannich and protonation reactions of α-amido-substituted malonic acid half oxyesters (MAHOs), affording α,β- and α-amino acid derivatives, respectively, in good yields and stereoselectivities.

Full text of DOI:10.1002/ejoc.201700870

A Journal of
Accepted Article
Title: Thioamide-substituted cinchona alkaloids as efficient
organocatalysts for asymmetric decarboxylative reactions of
MAHOs
Authors: Yuttapong Singjunla, Morgane Pigeaux, Romain Laporte,
Jérôme Baudoux, and Jacques Rouden
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201700870
Link to VoR: http://dx.doi.org/10.1002/ejoc.201700870
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10.1002/ejoc.201700870
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Organocatalysis
Thioamide-substituted cinchona alkaloids as efficient organocatalysts
for asymmetric decarboxylative reactions of MAHOs
Yuttapong Singjunla, Morgane Pigeaux, Romain Laporte, Jérôme Baudoux* and Jacques Rouden*
nitroalkenes using
a
quinolinium thioamide has been
Abstract: A new class of thioamide-substituted cinchona
derivatives is reported. A convergent and practical approach
was developed to insert the thioamide functional group onto the
cinchonidine from readily available dithioesters. These
organocatalysts were effective in asymmetric decarboxylative
Mannich and protonation reactions of -amido-substituted
Malonic Acid Half Oxyesters (MAHOs) affording ,- and -
amino acid derivatives in good yields and stereoselectivities
respectively.
described.[12] The fundamental role of the thioamide conformation
into an organocatalyst was confirmed for a kinetic resolution of
monoprotected diols.[13]
Although catalysts derived from cinchona alkaloids bearing an
amide group instead of an alcohol group were synthesized and
tested in several organocatalyzed reactions[ 14 ] their thioamide
analogs were not described yet. In our attempts to confirm the
important association of a basic quinuclidine nitrogen atom with
the acidity/NH-bond donor ability at the C-9 stereocenter of the
cinchona, we investigated the thioamide-based catalysts.[4c] Thus,
the objective of this work was to develop an effective synthesis of
these novel alkaloids bearing a thioamide functional group, and
then to show their potential compared to other cinchona
organocatalysts including their amide analogues.
Over the last decade, natural cinchona alkaloids and their
derivatives have emerged as efficient organocatalysts in several
asymmetric reactions.[1] Among them, cinchona-based ureas or
thioureas represented a significant improvement with excellent
catalytic activity and selectivity. This high level of performance is
due to a substantial rigidity of the asymmetric structure around a
Brønsted base associated to a hydrogen-bond donor group.[2] To
date, various alkaloid analogs containing a thiourea moiety were
synthetized and compared to their urea oxygen analogs.[3] Indeed,
the presence of sulfur induces fundamental modifications of the
catalyst properties in terms of electronegativity, covalent radius,
and C=X bond length translating in a higher charge density from
the nitrogen to the sulfur and an increased hydrogen-bond
donating ability.[4] All these properties regularly lead to a better
turnover frequency (TOF) for the sulfur incorporating cinchona
catalysts.[5] In this research area, thioamide is another example of
a sulfur-based functional group which shows different properties
compared to amide. Especially for secondary thioamides, the
conformation switches depending on the N-substituent whereas
amides favor cis conformation predominantly.[6] The thioamide
moiety is a strong hydrogen bond donor[ 7 ] and shows higher
acidity than its oxygen analogue.[8] Despite these properties, there
are only very few examples of thioamides synthesized and tested
as organocatalysts. Some aldol reactions catalyzed by proline
thioamide derivatives have been reported in high yields. In all
cases, the crucial role of the acidic N-H proton for the
enantioselectivity was confirmed during the process when
switching from a prolinamide catalyst to a thioamide analogue[9]
and a catalytic improvement was also observed[10] which confirms
the potential of the proline thioamide skeleton in aldol reactions.[11]
Apart from proline derivatives, the efficient addition of indoles on
Cinchonidine
1) PPh3, DIAD, DPPA, THF
2) PPh3, H2O
thioacylation
N
N
N
PhCOCl
thionation
C9
NH2 DMAP, Et3N
NH
NH
H
H
H
DCM, rt
N
Ph
N
Ph
N
S
O
R
3a
4
1
2
R = H
R = Ph
Scheme 1. Strategies for the Preparation of Thioamide Cinchona Catalysts
Initially, thionation was attempted from the amide[15] 2 of epi-
cinchonidine and Lawesson's reagent[16] or alternatively by using
molecular sulfur and hydrochlorosilanes,[ 17 a] or phosphorus
thiochloride[17b] but all these methods were unsuccessful.
Additional method described by Charette’s group[18] gave a very
low yield of the desired product 3a (Scheme 1, R = H). To
overcome the poor reactivity issue of the benzamide alkaloid 2, a
convergent thionation strategy was investigated from the amine
analog of epi-cinchonidine 1. Firstly, amine 1 was transformed
into its isothiocyanate analogue and then subjected to
phenyllithium (or Grignard reagent) to yield a product 4 resulting
from the addition of the organometallic reagent to the quinoline
ring.[19] From these results, access to thioamide 3 from amine 1
using a thioacylation appeared more efficient and flexible. In
presence of S8, the Willgerodt-Kindler reaction[20] afforded 20%
yield of product 3a. Finally, we studied a synthetic sequence using
dithioesters that are known to react with various amines, although
their reactivity with cinchona alkaloids was unknown so far.
[a]
Normandie Univ., LCMT, ENSICAEN, UNICAEN, CNRS,
6 Boulevard du Maréchal Juin, 14000-France
E-mail: jerome.baudoux@ensicaen.fr
jacques.rouden@ensicaen.fr
https://www.lcmt.ensicaen.fr/
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700870
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Organocatalysis
represented the best solvent in terms of yield and selectivity
among all solvents screened (THF, toluene, chloroform,
dichloromethane and carbon tetrachloride, data not shown). With
these optimized conditions in hands, thioamide 3a-f were tested
for this Mannich reaction and compared to other cinchona
alkaloids such as alcohol 11, thiourea[23] 12, squaramide[24] 13 and
the amide counterpart 2 (Table 1). Worth of note, all catalysts
were tested as 9-epimers including 9-epi-cinchonidine 11, in order
to evaluate organocatalysts having the same configuration.
Table 1. Asymmetric Decarboxylative Mannich Reaction Catalyzed by
Cinchona Derivatives[a]
Scheme 2. Preparation of Thioamides 3a-f from Dithioesters 7a-f
Firstly, all dithioesters 7a-f were synthesized in excellent
yields according to an efficient two-step procedure starting from
their corresponding chloride derivatives 5a-f.[21] In presence of
amine 1, the unpurified PhCS2Me 7a afforded thioamide 3a in
71% yield after isolation. Under these same conditions, 2-pyridyl
dithioester 7b provided thioamide 3b in 71% yield while bulkiest
entry
catalyst
yield (%)[b] dr (anti:syn)[c] er (anti)[c]
er (syn)[c]
1
2
alcohol 11
thiourea 12
62 (48 h)
66 (48 h)
71 (48 h)
79 (48 h)
78 (48 h)
70 (48 h)
29 (72 h)
76 (48 h)
50 (72 h)
74 (72 h)
81:19
64:36
50:50
66:34
66:34
66:34
67:33
67:33
72:28
53:47
56:44
53:47
53:47
60:40
68:32
58:42
56:44
78:22
52:48
57:43
66:34
65:35
84:16
72:28
88:12
78:22
54:46
87:13
68:32
89:11
3
squaramide 13
amide 2
4
5
thioamide 3a
thioamide 3b
thioamide 3c
thioamide 3d
thioamide 3e
thioamide 3f
dithioesters 7c-f reacted with the amine
1 to form the
6
corresponding thioamide in moderate to good yields (scheme 2).
In some cases, unreacted amine 1 was easily recovered and
subjected again to the thionation.
7
8
These thioamide incorporated cinchona alkaloids 3a-f were
then tested in specific asymmetric reactions developed in our
9
10
22
]
laboratory,[
namely the decarboxylative Mannich and
[a] Reaction was conducted on a 0.2 mmol scale at 0.3 M concentration. [b]
Isolated yield. [c] Determined by HPLC analysis.
protonation reactions of -amido-Malonic Acid Half Oxyesters 8
(MAHOs). These two reactions would lead to ,-diamino and -
amino acids derivatives 9 and 10 respectively (scheme 3).
The decarboxylative Mannich reaction of MAHO 8a
catalyzed by 9-epi-cinchonidine 11 afforded product 9 in good
diastereoselectivity
(anti-Mannich)
but
moderate
Mannich
NHTs
MAHOs
Protonation
enantioselectivities were observed (entry 1). By using thiourea 12,
Mannich product 9 was obtained in a 64/36 diastereomeric ratio
without improvement in terms of enantioselectivity compared to
alcohol 11 (entry 2). The same trend was observed with
squaramide 13, although a good enantioselectivity was noticeable
for the minor diastereoisomer syn-9 (entry 3). The Mannich
reaction with amide 2 was similar to the one obtained with
thiourea 12 despite a better yield (entry 4). Thereafter, the newly
synthesized thioamide catalysts 3a-f were evaluated under the
conditions described above. In presence of catalyst 3a, the
reaction afforded 9 in good yield (78%) with a diastereomeric ratio
similar to the amide 2 but accompanied by a significant rise of
enantioselectivities for both diastereomers, anti-9 (er 68/32) and
syn-9 adducts (er 88/12, entry 5). Changing the phenyl moiety of
the catalyst by a 2-pyridyl led to a slight drop of performances
(entry 6). An electron withdrawing group (2-NO2) on the aromatic
NTs
Ph
O
O
O
O
catalysts 3
catalysts 3
EtO
OH
O
EtO
O
EtO
O
- CO2
- CO2
NH
Me
NH
Me
9 (from 8a)
HN
R
Me
, R = H
8b, R = Bn
8a
10 (from 8b)
Scheme 3. Evaluation of Catalysts 3 in Asymmetric Decarboxylative reactions.
Initial experiments of the decarboxylative Mannich reaction
between MAHO 8a and N-tosyl phenylimine catalyzed by Et3N
were necessary to optimize the main reaction parameters, i.e.
solvent, reaction time and temperature. We concluded that room
temperature was the minimum temperature allowed to ensure
complete conversion in a reasonable time (15 h) and THF
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10.1002/ejoc.201700870
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Organocatalysis
ring of catalyst 3c inhibited the reaction which afforded Mannich-
product 9 in only 29% yield and poor stereoselectivity (entry 7).
On the opposite, the presence of an electron donating group (2-
OEt) had a positive impact on the reaction and catalyst 3d gave
76% yield with good enantioselective ratios for both
diastereomers, similar to those afforded by catalyst 3a (entry 8).
Catalysts 3e and 3f presenting respectively two CF3 or bulky t-
Butyl groups did not provide better results for this asymmetric
decarboxylative Mannich reaction, lower conversions and mixed
results for the selectivity (entries 9 and 10).
Overall, the best compromise in terms of yield (reaction rate)
and selectivity was achieved by thioamides 3a and 3d. At this
point, comparison of performances (yield, dr, er) between amide
2 and thioamide 3a revealed a slight advantage for the latter on
the enantioselectivity. Interestingly, the minor syn-9 product was
always obtained with a better enantioselectivity than its anti-
isomer, especially for squaramide 13, thioamides 3a and 3d.
Thus, thioamide 3a was selected in the following part to catalyse
the asymmetric decarboxylative protonation.
(entries 6 and 7). Thus, the thioamide catalyst 3a afforded better
yield and er compared to the other cinchona-based catalysts used
in this study.
As anticipated by previous studies involving amide versus
thioamide organocatalysts,[9-13] the comparison between amide
epi-cinchonidine 2 and its thioamide analogue 3a confirmed the
efficiency of the sulfur-based functional group. Moreover, for both
reactions tested, thioamide 3a was a better catalyst than other
well-known organocatalysts such as thiourea 12 or squaramide
13. Although it was too early to draw any conclusions on the origin
of the thioamide efficiency, we suggested that the increased NH-
bond donor ability or acidity of the thioamide functional group
compared to amide (or the other catalysts) played a decisive role.
These properties provided by the sulfur could lead to a better
interaction of the catalyst with the substrate(s). From
a
mechanistic point of view, the high enantioselectivities of the
decarboxylative protonation might be related to the higher acidity
of the thioamide moiety to facilitate the ion-pairing with enolate[28]
whereas the decarboxylative Mannich reaction could be achieved
by a strong H-bond[29] with the nitrogen of the N-tosyl phenylimine.
Deeper mechanistic studies are necessary to clarify these
interactions and to develop better cinchona catalysts based on
this thioamide cinchona scaffold.
MAHO 8b having an N-acetyl protecting group was chosen
according to our previous knowledge of this reaction. The reaction
was carried out using 20 mol% of catalyst in various solvents at
30 °C (table 2).[25]
In conclusion, we have developed a convenient synthesis of
thioamide-substituted cinchona alkaloids which effectively
catalyzed two decarboxylative C-C and C-H bond forming
reactions involving MAHO substrates. For such reactions,
thioamides proved to be more efficient than their amide analogues
or other well-known organocatalysts like thioureas or
squaramides derivatives. Overall, this study disclosed a new
class of bifunctional thioamide-based organocatalysts that
combines the chiral cinchona scaffold with a basic quinuclidine
and the acidity or H-bonding ability of the N-H thioamide. No doubt
that these structures will promote efficiently other reactions in high
selectivity under environmentally friendly conditions and will be of
interest to many organic chemists. Further assessments of these
thioamide organocatalysts are under investigation in our
laboratory to unveil their full potential.
Table 2. Asymmetric Decarboxylative Protonation Catalyzed by Cinchona
Derivatives[a]
entry
catalyst
thioamide 3a
thioamide 3a
thioamide 3a
thioamide 3a
thiourea 12
squaramide 13
amide 2
solvent
toluene
EtOAc
acetone
THF
yield (%)[b]
er (R:S)[c]
88:12
81:19
82:18
92:8
1
2
3
4
5
6
7
74
44
23
84
85
35
22
THF
77:23
83:17
83:17
THF
Experimental Section
toluene[d]
Procedure for the synthesis of thioamide cinchona alkaloid
derivatives. To a solution of the cinchonidine amine 1 (2.0 g, 6.8
mmol, 1 equiv) in dichloromethane (5 ml), was added the
dithioester 7 (8.9 mmol, 1.5 equiv) and triethylamine (6.8 eq., 1
equiv). The mixture was stirred for 4 days and concentrated under
vacuum. The residue was purified by column chromatography on
silica gel (Dichloromethane/MeOH: 99/1) to afford pure
compounds 3a-f.
[a] Reaction was conducted on a 0.5 mmol scale at 0.09 M concentration.
[b] Isolated yield. [c] Determined by HPLC analysis. [d] Reaction was
conducted at 20 °C.
Since the nature of the solvent has a decisive impact on the
catalyst performances, we screened the commonly used solvents
for this reaction.[ 26 ] Starting in toluene, the decarboxylative
protonation of MAHO 8b catalyzed by 20 mol% of thioamide 3a
afforded the product 10 in 74% yield and an encouraging 88:12 er
in favor of the R product (entry 1).[27] In EtOAc or Acetone, the
reaction rate decreased sharply and the enantioselectivity slightly
as well (entries 2 and 3). The best result was obtained using
catalyst 3a in THF which gave 10 in 84% yield with 92:8 er (entry
4). On the other hand, we tested organocatalysts 12, 13 and 2 for
the decarboxylative protonation. Thiourea 12 was an effective
catalyst affording compound 10 in 85% yield but with a clear drop
of the enantioselectivity (entry 5). Squaramide 13 and amide 2
proved to be inefficient with a very poor yield despite a good er
Procedure for Asymmetric Decarboxylative Mannich
Reaction. Under inert atmosphere, catalyst (0.04 mmol) was
added to a solution of MAHO 8a (38 mg, 0.2 mmol) and N-tosyl
phenylimine (62 mg, 0.24 mmol) in dry THF (0.6 ml) in the
presence of molecular sieve 4 Å (50 mg). The mixture was stirred
at 20 °C for a given time (see table 1). The solution was
concentrated under reduced pressure and the residue was
purified by flash chromatography (cyclohexane/EtOAc, 60/40) to
afford pure product 9 as a mixture of 4 stereoisomers. Dr and er
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10.1002/ejoc.201700870
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Organocatalysis
Keywords: Thioamides • Cinchona Alkaloids • Organocatalysis •
Malonic Acid Half Oxyester • Mannich reaction
were determined by chiral HPLC analysis using a ChiralPak IC
column (n-heptane/i-PrOH, 50/50 at 1.0 mL/min), anti-isomers: tr
= 12.8 and 16.3 min, syn-isomers: tr = 8.4 and 10.6 min.
Procedure for Asymmetric Decarboxylative Protonation
Reaction. To a solution of MAHO 8b (140 mg, 0,5 mmol) in dry
THF (5.5 ml) under inert atmosphere, catalyst (0.1 mmol) was
added and the mixture was stirred at 30 °C for 72 h. The solution
was concentrated under reduced pressure at room temperature.
The residue was purified by flash chromatography
(cyclohexane/EtOAc, 60/40) to afford pure product 10 as a
mixture of 2 enantiomers. Er was determined by chiral HPLC
analysis using a ChiralPak IA column (n-heptane/i-PrOH, 80/20 at
1.0 mL/min): (R)-10 tr = 5.2 min, (S)-10 tr = 6.7 min.
Acknowledgements
The Ministry of Higher Education and Research, the “Region
Basse-Normandie” (fellowships to Y.S.), CNRS, and the
European Union (FEDER) are gratefully acknowledged for
funding this work. We also thank LABEX SynOrg (ANR-11-
LABX-0029) for additional financial support.
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10.1002/ejoc.201700870
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Organocatalysis
Entry for the Table of Contents (Please choose one layout)
SHORT COMMUNICATION
Key Topic*
Yuttapong Singjunla, Romain Laporte,
Morgane Pigeaux, Jérôme Baudoux*
and Jacques Rouden*
Page No. – Page No.
Thioamide-substituted cinchona
alkaloids as efficient organocatalysts
for asymmetric decarboxylative
reactions of MAHOs
A new class of thioamide-substituted cinchona alkaloid derivatives has been successfully synthesized by a convenient and efficient
approach from easily accessible dithioesters. These organocatalysts were effective in asymmetric Mannich reaction and
enantioselective protonation reactions of -amido-Malonic acid Half Oxyester as cheap glycine equivalents affording ,- and -amino
acid derivatives respectively in good yields and stereoselectivities.
This article is protected by copyright. All rights reserved.