Synthesis of chiral sulfoximine-based thioureas and their application in asymmetric organocatalysis

Article abstract of DOI:10.3762/bjoc.8.164

For the first time, chiral sulfoximine derivatives have been applied as asymmetric organocatalysts. In combination with a thioureatype backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic routes provide the newly designed thiourea-sulfoximine catalysts in high overall yields without affecting the stereohomogeneity of the sulfur-containing core fragment.

Full text of DOI:10.3762/bjoc.8.164

Synthesis of chiral sulfoximine-based thioureas and
their application in asymmetric organocatalysis
Marcus Frings, Isabelle Thomé and Carsten Bolm*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 1443–1451.
Institut für Organische Chemie, Landoltweg 1, RWTH Aachen
University, 52074 Aachen, Germany
doi:10.3762/bjoc.8.164
Received: 24 May 2012
Accepted: 30 July 2012
Email:
Carsten Bolm* - carsten.bolm@oc.rwth-aachen.de
Published: 03 September 2012
* Corresponding author
This article is part of the Thematic Series "Organocatalysis".
Guest Editor: B. List
Keywords:
anhydride opening; catalytic asymmetric Biginelli reaction;
organocatalysis; sulfoximines; thioureas
© 2012 Frings et al; licensee Beilstein-Institut.
License and terms: see end of document.
Abstract
For the first time, chiral sulfoximine derivatives have been applied as asymmetric organocatalysts. In combination with a thiourea-
type backbone the sulfonimidoyl moiety leads to organocatalysts showing good reactivity in the catalytic desymmetrization of a
cyclic meso-anhydride and moderate enantioselectivity in the catalytic asymmetric Biginelli reaction. Straightforward synthetic
routes provide the newly designed thiourea-sulfoximine catalysts in high overall yields without affecting the stereohomogeneity of
the sulfur-containing core fragment.
Introduction
Since their discovery in the middle of the last century, sulfox- Being monoaza analogs of sulfones, sulfoximines have fasci-
imines 1 (Figure 1) represent an important compound class nated researchers from both academia and industry. Because of
among the comprehensive group of organosulfur reagents [1-4]. their interesting chemical properties and the biological activi-
ties found for several derivatives, the use of sulfoximines has
been explored in numerous applications. For instance, in agri-
cultural chemistry it was discovered that sulfoximines can
improve plant growth or act as insecticides in crop protection
[5-9]. Further exemplary contributions come from medicinal
chemistry where sulfoximines show potential as enzyme inhibi-
tors [10-14], and from materials science where they were evalu-
Figure 1: General structure of sulfoximines 1 and one of the enan-
tiomers of S-methyl-S-phenylsulfoximine ((S)-2) used in this study.
ated as functional building blocks [15]. In addition, sulfox-
imines are most present in synthetic organic chemistry for
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Beilstein J. Org. Chem. 2012, 8, 1443–1451.
various reasons and recent findings include their use as fluoro- Recently, we reported the enantioselective ring opening of
methylation reagents, as fluorophores or as directing groups cyclic meso-anhydrides and asymmetric Michael additions of
[16-19]. Two quality characteristics make them particularly 1,3-dicarbonyl compounds to nitroalkenes with thiourea-based
attractive for asymmetric synthesis: 1) The stereogenic sulfur organocatalysts [48,49]. Based on those studies and in the light
atom which is stable towards many reaction conditions, and 2) of our long-standing interest in utilizing chiral sulfoximines in
the ease of functionalization at the adjacent nitrogen and carbon stereoselective catalytic reactions, we wondered about a molec-
atoms which allows a great structural diversity of the sulfox- ular combination of the two successfully applied entities,
imine motif. Hence, optically active compounds based on 2 thioureas and sulfoximines. To the best of our knowledge, such
have been utilized in the synthesis of pseudopeptides [20-24], compounds have never been reported and thiourea(-like)
and they have found widespread application in auxiliary- catalysts with S-stereogenic sulfonimidoyl substituents are
assisted diastereoselective transformations or as chiral ligands unknown. Herein, we present our first results concerning syn-
in enantioselective metal catalysis [25-33]. With respect to the thetic approaches towards such molecules and describe prelimi-
latter field we have recently demonstrated that various ligands nary studies of two applications in asymmetric organocatalysis.
bearing a sulfonimidoyl moiety lead to excellent stereo-
selectivities in transition metal-catalyzed hydrogenations and Results and Discussion
carbon–carbon bond formations [34-36].
Our investigations began with a very straightforward approach:
Enantiopure (S)-S-methyl-S-phenylsulfoximine [(S)-2] was
During the past decade, asymmetric organocatalysis had a added to 3,5-bis(trifluoromethyl)phenyl isothiocyanate to
tremendous impact on synthetic organic chemistry [37-41]. Yet, provide product (S)-3 (Scheme 1).
this field of research continues to grow, and the quest for new
organic molecules which efficiently catalyze reactions in a
highly enantioselective manner has no end in sight. In this
context, thiourea-based organocatalysts have caught significant
attention due to their ability to activate substrates through
hydrogen-bonding [42-47]. Usually, these chiral thioureas are
classified into several categories, for example, being mono- or
bis-thioureas. Furthermore, they can be mono- or bifunctional
with variably weak amine (primary, secondary, tertiary) or
amide groups attached. Figure 2 illustrates a few selected exam-
ples of the aforementioned chiral thioureas which have success-
fully been applied in organic transformations with hydrogen
Scheme 1: Synthesis of compound (S)-3.
bond accepting substrates.
Figure 2: Structures of chiral mono- and bifunctional (bis-)thioureas that have been used as organocatalysts.
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Beilstein J. Org. Chem. 2012, 8, 1443–1451.
This kind of addition was first described by Wehr in 1965 who An organocatalytic activity of thiourea(-like) (S)-3, however,
allowed a number of isothiocyanates to react with dimethylsulf- was clearly demonstrated.
oximine [50]. The chemistry of the resulting thiourea-like com-
pounds, however, has remained rather unexplored until now. Next, our attention was focused on sulfoximine-based thioureas
Only two patents from Dow Agrosciences report syntheses of with the potential of double hydrogen bond donation. Two
related structures, their use as intermediate products, and their structural alternatives were envisaged as represented by com-
insecticidal activity [51,52]. Furthermore, only achiral or pounds (R)-9 and (S)-12. In the first, the stereogenic sulfur of
racemic sulfoximines have been applied, and the reactions were the sulfonimidoyl moiety was linked to the thiourea core by a
performed at elevated temperatures, such as 80 °C, or in a steam methylene group, which originated from the methyl substituent
bath. The protocol introduced here is most simple: After addi- of (S)-2. In the second, a linker connected the thiourea back-
tion of the isothiocyanate to a solution of sulfoximine (S)-2 in bone with the sulfonimidoyl nitrogen. Preference was given to
dichloromomethane (DCM) the mixture was stirred at room the first strategy, because in structures such as (R)-9 the stereo-
temperature, and after a few hours, (S)-3 started to precipitate. genic center was rather close to the thiourea hydrogen bridge
Removal of the solvent and washing of the product with binding site. Scheme 3 summarizes our intended preparative ap-
n-pentane gave analytically pure (S)-3 in 91% yield.
proach towards (R)-9 via N-methyl-α-aminosulfoximine (R)-8,
which unfortunately, remained unsuccessful.
Although not capable of double hydrogen bonding [53], we
wondered about the possible catalytic activity of (S)-3. Because Heating of (S)-2 with 2 equiv of formaldehyde in formic acid
it was known for chiral bifunctional amine-based sulfonamides under Eschweiler–Clarke conditions led to N-methylated
that two hydrogen bond donors were not strictly required in the sulfoximine (S)-6 in 91% yield [55,56]. The α-nitro group was
enantioselective organocatalytic ring opening of meso-anhy- introduced under conditions reported by Wade [57]. Thus,
drides [48,54], this particular transformation was chosen as deprotonation of (S)-6 in tetrahydrofuran (THF) with potassium
initial test reaction. Cyclic anhydride 4 served as starting ma- bis(trimethylsilyl)amide (KHMDS) at −78 °C and trapping the
terial for a methanolysis in the presence of a catalytic amount of resulting carbanion with isobutyl nitrate at −40 °C afforded
enantiopure (S)-3 (Scheme 2). To our delight, the use of a nitrosulfoximine (R)-7 in 81% yield. The product proved rather
combination of 10 equiv of methanol and 10 mol % of (S)-3 in stable at low temperature and could be stored in the fridge
methyl tert-butyl ether (MTBE) at room temperature furnished without decomposition for several months. All attempts,
the desired products, hemiesters 5 and ent-5, in good yield however, to reduce the α-nitro group of (R)-7 to the corres-
(66%) within 24 h. Disappointingly, however, the product was ponding amino substituent (as in (R)-8) failed [58]. None of the
racemic.
reductive conditions, which included (1) hydrogenation over
palladium/charcoal, (2) applying samarium diiodide with
In general, two concomitant events are discussed for bifunc- methanol as proton source, and (3) using a combination of zinc
tional organocatalysts such as amino group-containing sulfon- powder with hydrochloric acid or calcium chloride in aqueous
amides or thioureas: One is the activation of the anhydride car- ethanol allowed the isolation of α-aminosulfoximine (R)-8. In
bonyl group by hydrogen bonding to the thiourea or sulfon- all cases the starting material was fully consumed and degraded.
amide unit, and the second relates to the activation of the As decomposition products N-methylbenzenesulfinamide and
alcohol by the basic nitrogen of the amine. Which effect domi- diphenyl disulfide were identified and isolated. Hence,
nates in the case of (S)-3 – a carbonyl activation by a single α-aminosulfoximine (R)-8 could not be obtained, and the syn-
hydrogen bond or an enhancement of the alcohol activity by the thesis of the sulfoximine-based thiourea (R)-9 had to remain
weakly basic sulfoximine nitrogen – remains to be elucidated. uncompleted.
Scheme 2: Organocatalytic desymmetrization of the cyclic anhydride 4 with (S)-3.
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Beilstein J. Org. Chem. 2012, 8, 1443–1451.
Scheme 3: Attempted synthesis of sulfonimidoyl-substituted thiourea (R)-9.
Next, the second strategy was approached, and thiourea/sulfox- In (S)-12 and (S)-13 the 1,2-benzene linker connects both func-
imine derivatives (S)-9 and (S)-13 became synthetic targets tional groups – the stereogenic sulfonimidoyl group and the
(Scheme 4). In both the stereogenic fragments are linked to the thiourea core – in a rather rigid manner. In order to allow a
thiourea core via the sulfonimidoyl nitrogen. They differ in their higher degree of conformational flexibility and with the goal to
aryl substitution pattern.
determine the effects of structural rigidity and the presence of
additional stereogenic centers, alternative molecules with
substituted ethylene linkers ((SS,SC)-18 and (RS,SC)-19) were
designed. Their syntheses are outlined in Scheme 5, which also
underlines the value of the highly modular preparative ap-
proach towards such compounds leading to a variety of mole-
cules by using closely related synthetic protocols.
Copper-catalyzed arylation of (S)-2 with 2-iodonitrobenzene
gave rise to coupling product (S)-10 in excellent yield (98%).
After subsequent reduction of the aromatic nitro group to give
aniline (S)-11 in 83% yield [35,59,60], two isothiocyanates,
namely phenyl isothiocyanate and 3,5-bis(trifluoromethyl)phe-
nyl isothiocyanate, were added. Both thiourea formations went
very well, and the desired products (S)-12 and (S)-13 were In the syntheses of (SS,SC)-18 and (RS,SC)-19 we benefited
obtained in almost quantitative yields (98% and 99%, respec- from our expertise in preparing sulfoximine-based pseudopep-
tively).
tides [20,21]. Hence, the reaction of (S)-2 with N-Boc protected
Scheme 4: Synthesis of the sulfonimidoyl-containing thioureas (S)-12 and (S)-13.
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Beilstein J. Org. Chem. 2012, 8, 1443–1451.
Scheme 5: Syntheses of ethylene-linked sulfonimidoyl-containing thioureas (SS,SC)-18 and (RS,SC)-19.
L-valine, N,N'-dicyclohexylcarbodiimide (DCC) and hydroxy- proved inappropriate for this reaction, and no further efforts
benzotriazole (HOBt) provided (homochiral) (SS,SC)-14 in good were made to improve the anhydride desymmetrization with
yield (74%). Already at this early stage we wondered, which of these types of organocatalysts.
the two stereogenic centers in the resulting thioureas – the one
at the sulfur atom or the one stemming from the amino acid – Next, the catalysis screening was focused on Biginelli reactions,
would determine the absolute configuration of the catalysis which provide access to dihydropyrimidines by three-compo-
products. For this reason, a heterochiral product was prepared nent condensations of aldehydes, urea-type substrates and
by coupling (R)-2 (the mirror image of the previously applied enolisable carbonyl compounds. Because of the pharmacologi-
sulfoximine) with N-Boc protected L-leucine to give (RS,SC)-15 cal relevance of the products, considerable research has been
(84% yield). Reduction of the two N-acylated sulfoxmines directed towards asymmetric approaches of these inherently
(SS,SC)-14 and (RS,SC)-15 with borane-THF complex led to chiral heterocycles [61-63]. Until recently, enantioenriched
removal of the carbonyl groups and established the desired dihydropyrimidines could only be obtained by special resolu-
substituted ethylene bridges in (SS,SC)-16 and (RS,SC)-17 (71% tion methods which were not generally applicable. The search
and 45% yield, respectively). Subsequently, the N-Boc groups for a truly catalytic asymmetric Biginelli reaction with high
were smoothly cleaved upon treatment with trifluoroacetic acid enantiocontrol has proven very challenging for a long time and
(TFA), and for both substrates full conversion was observed useful protocols have just recently been developed. They
after 2.5 h. An aqueous work-up followed by the addition of involve both metal catalysis [64,65] as well as organocatalysis.
3,5-bis(trifluoromethyl)phenyl isothiocyanate to each crude pri- In the latter field, chiral phosphoric acids [66,67], bicyclic di-
mary amine completed the syntheses of ethylene-linked sulfon- amines [68], bifunctional thioureas [69], proline ester salts [70],
imidoyl-containing thioureas (SS,SC)-18 and (RS,SC)-19 pyrrolidinyl tetrazoles [71], and a quinine-derived amine [72]
providing them in very good yields (98% and 87%, respective- were reported to catalyze the condensation reaction in an asym-
ly) over two steps.
metric fashion.
One representative of each class was briefly tested in the Using a slightly modified procedure of the thiourea-catalyzed
desymmetrization of anhydride 4. Under the conditions Biginelli reaction developed by Miao and Chen [69], we chose
described above for organocatalyst (S)-3 two catalyses were the condensation between urea, benzaldehyde (1.5 equiv), and
performed with (S)-12 (10 mol %) and (RS,SC)-19 (5 mol %). ethyl acetoacetate (3 equiv) to give dihydropyrimidine 20
Whereas benzene-bridged sulfonimidoyl-containing thiourea (Table 1) as test reaction. As catalysts, substoichiometric quan-
(S)-12 provided the product (5/ent-5) in a comparable yield tities of the sulfonimidoyl-containing thioureas in combination
(67%) as (S)-3, the reactivity of (RS,SC)-19 was remarkably with 10 mol % of trifluoroacetic acid (TFA) were applied. The
higher. Even though in the reaction with (RS,SC)-19 the catalyst results are summarized in Table 1.
loading was lower, the product was isolated in a better yield
(81%) under identical conditions. Unfortunately, both catalyses The experiment with 10 mol % of chiral organocatalyst (S)-3
led to racemic hemiesters (5/ent-5). Apparently, both thioureas served as starting point (Table 1, entry 1). The low product
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Table 1: Evaluation of the sulfonimidoyl-containing thiourea organocatalysts in the asymmetric Biginelli reaction to afford scalemic dihydropyrimidi-
none (S)-20.
entry
chiral
thiourea
catalyst loading (mol %)/
concentration (mol/L)
time (d)
substrate concentration
(mol/L)a
yield (%)
er (%)b
1
(S)-3
10/0.025
10/0.025
10/0.025
10/0.025
10/0.025
10/0.025
10/0.025
20/0.05
3
3
3
3
3
5
5
5
5
5
5
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.025
0.25
28
32
30
42
21
89
40
90
42
92
53
50:50
50:50
50:50
58:42
57:43
58:42
57:43
59:41
57:43
72:28
51:49
2
(SS,SC)-18
(RS,SC)-19
(S)-12
3
4
5
(S)-13
6
(S)-12
7
(S)-13
8
(S)-12
9
(S)-13
20/0.05
10
11
(S)-12
10/0.0025
1/0.0025
(S)-12
aWith respect to urea. bDetermined by HPLC analysis with a chiral stationary phase.
yield (28%) even after a long reaction time (3 days) revealed raised the yields (Table 1, entries 6 and 7), and now, for
the insufficient catalytic activity of this thiourea derivative. example, the catalysis with (S)-12 gave the product in 89%
Furthermore, product 20 was racemic. Analogous results were yield (Table 1, entry 6). The enantiomer ratios remained unaf-
observed with the two ethylene-bridged sulfonimidoyl- fected. Increasing the catalyst loading from 10 to 20 mol % had
containing thioureas (SS,SC)-18 and (RS,SC)-19 when the cataly- essentially no effect on both yield and enantioselectivity
ses were conducted under identical conditions (Table 1, entries (Table 1, entries 8 and 9).
2 and 3). Racemic dihydropyrimidinone 20 was obtained in
32% and 30% yields, respectively. Next, we focused on the In previous studies it was found that the enantioselectivity in
application of thioureas (S)-12 and (S)-13 having a more rigid some thiourea-catalyzed reactions was dependent on the
benzene linker (Table 1, entries 4 and 5). Although the yields concentration of the substrates and that in several cases the
were only moderate (42% and 21%, respectively), we delight- enantiomeric excess could significantly be improved by dilu-
fully noted that product 20 was enantioenriched for the first tion [48,74-76]. This effect was attributed to the formation of
time (with the S-enantiomer being formed in preference). With less active aggregates by thioureas self-association at high
enantiomer ratios of 58:42 and 57:43 the enantioselectivities concentrations resulting in lower enantioselectivities [77]. Inter-
were still low, but we envisaged that improvements were estingly, a dilution effect was also observed in our study. Thus,
possible by catalyst structure optimizations and reaction condi- changing the molar substrate (urea) concentration from
tion adjustments. Apparently, the substituents at the 3,5-posi- 0.25 mol/L to 0.025 mol/L caused a distinct improvement of the
tions of the phenyl rings at the thiourea moieties (CF3 versus H) enantiomeric excess and the enantiomer ratio of the product 20
had only a marginal effect on the stereoselectivity of the raised from 58:42 to 72:28 (Table 1, entry 6 vs entry 10). In
Biginelli reaction. However, they affected the catalyst activity addition, product 20 was isolated in a slightly better yield
as indicated by the doubled yield in the catalysis with (S)-12 (92%). The attempt to reduce the catalyst loading from
compared to the one with (S)-13 (42% versus 21%). This 10 mol % to 1 mol % (while retaining its concentration at
increase in yield might have been because of a higher acidity of 0.0025 mol/L; Table 1, entry 10 vs entry 11) remained unsuc-
(S)-12 due to the presence of the two CF3 substituents on the cessful resulting in 53% of 20 with an er of only 51:49. Prob-
thiourea aryl [73]. Prolonging the reaction time from 3 to 5 days ably, the reaction path was affected by the 10-fold higher sub-
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Beilstein J. Org. Chem. 2012, 8, 1443–1451.
strate concentration, which led to this unsatisfying enantio- addition of phenyl isothiocyanates to suitable amino-functional-
selectivity.
ized sulfoximines or to the sulfoximine nitrogen itself proceeds
in high yields to give sulfonimidoyl-containing thiourea-type
These results allow drawing a few preliminary conclusions structures. While these compounds show good catalytic activity
related to the structural requirements of the chiral sulfonimi- but no enantiocontrol in the ring opening of a cyclic meso-anhy-
doyl-containing thioureas for achieving enantiocontrol in subse- dride, low to moderate enantioselectivities have been achieved
quent asymmetric catalysis studies. For example, it is note- in the catalytic asymmetric Biginelli reaction leading to a dihy-
worthy that compared to most other organocatalysts of the dropyrimidinone. In the future we aim to expand the scope of
thiourea-type, which commonly have the stereogenic center the chiral sulfonimidoyl-containing thiourea framework and
directly attached to one of the NH groups of the thiourea moiety hope to find more applications of these interesting molecules in
(Figure 2), the nearest stereogenic center in (S)-12, (S)-13, asymmetric organocatalysis.
(SS,SC)-18 and (RS,SC)-19 is relatively remote from the thiourea
core, which most likely serves as binding site for the substrate.
Supporting Information
Nevertheless, a remarkable enantiomeric ratio of 78:22 has
already been achieved in the Biginelli reaction, which is known
Supporting Information File 1
to be difficult to control. Thus, bringing the sulfonimidoyl
group into closer proximity to the thiourea core might be bene-
ficial for achieving a higher enantiocontrol, but it does not
appear to be essential. Another point should be emphasized here
as well. Compounds such as (S)-12 and (S)-13 are some of the
very rare examples of chiral organocatalysts, whose only stereo-
controlling element is not an asymmetrically substituted carbon
but rather a stereogenic sulfur center [78-80].
Experimental section and full characterization data of all
new compounds.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-8-164-S1.pdf]
Acknowledgements
This study was supported by Fonds der Chemischen Industrie
and the Deutsche Forschungsgemeinschaft (DFG) within the
SPP 1179 (“Organocatalysis”). The authors thank Dr. Ingo
Schiffers and Dr. Iuliana Atodiresei (both RWTH Aachen
University) for stimulating discussions. Dr. Ingo Schiffers is
also kindly acknowledged for providing a sample of cyclic
anhydride 4.
With respect to the properties of the linker between the sulfon-
imidoyl group bearing the stereogenic sulfur atom and the
thiourea unit (aryl vs substituted ethylene as is 12 and 13 vs 18
and 19) it became clear that conformational rigidity is benefi-
cially leading to higher enantioselectivities. Perhaps, substi-
tuted arene backbones could be used for inducing enhanced
positive effects on both units through electronic fine-tuning.
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