Asymmetric synthesis of 4-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides via Pd-catalyzed hydrogenation of cyclic ketimines

Article abstract of DOI:10.1039/c6ob02655a

An efficient access to optically active sulfahydantoins, 4-aryl-1,2,5-thiadiazolidin-3-one 1,1-dioxides, was developed through palladium-catalyzed asymmetric hydrogenation of the corresponding cyclic N-sulfonylketimines with up to 98% ee.

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Asymmetric synthesis of 4-aryl-1,2,5-thiadiazolidin-3-one 1,1-
dioxides via Pd-catalyzed hydrogenation of cyclic ketimines
Received 00th January 20xx,
Accepted 00th January 20xx
Zhou-Hao Zhu, Meng-Lin Chen and Guo-Fang Jiang*
DOI: 10.1039/x0xx00000x
www.rsc.org/
An efficient access to optically active sulfahydantoins, 4-aryl-1,2,5- was provided by Montero’s group through alkaline cyclization
thiadiazolidin-3-one 1,1-dioxides, was developed through starting from chiral N-sulfamylamino acid alkyl esters and a
palladium-catalyzed asymmetric hydrogenation of the corres- series of improvements have been developed by other groups,
ponding cyclic N-sulfonylketimines with up to 98% ee.
but access to chiral N-sulfamylamino acid alkyl esters has
strictly limited the application of this strategy (eq 1, Scheme
2).5 Recently, Nishimura’s and Xu’s groups separately
Sulfahydantoins, 1,2,5-thiadiazolidin-3-one 1,1-dioxides, are
valuable substructures with the potentially pharmacological
properties and industrial utility.1 They are structural analogues
of hydantoins, 2,4-imidazolidinediones, which are found in
several medicinally important compounds and well known as
anticon-vulsant drugs for the management of epilepsy.2
Notably, the heterocyclic ring in sulfahydantoins is a highly
effective peptide-mimetic scaffold and their sulfone
derivatives are found to be efficient inhibitors of serine
proteinases.3 What’s more, sulfahydantoins are functionally
related to herbicides (bentazon) and sweeteners (sodium
saccharin) ascribing to their common sulfonamide functional
group (Scheme 1).4
documented
enantioselective
synthesis
of
diaryl
sulfahydantoins through Rh-catalyzed arylation of cyclic
ketimines and moderate to high enantioselectivities could be
obtained (eq 2, Scheme 2).6 To satisfy the increasing demand
for diverse chiral sulfahydantoins, developing facile and
efficient strategies is still highly desirable.
According to retrosynthetic analysis of chiral 4-aryl sulfahy-
dantoins, asymmetric hydrogenation of the corresponding
cyclic N-sulfonylketimines is one of the most efficient and
atom economic approaches. In the search for an effective way
to the asymmetric hydrogenation of imines, various catalytic
systems such as organocatalysts and a number of transition-
metal-based catalysts have made
a
great achievement.7
Specially, over the last few decades, palladium has gradually
grown up as an efficient and popular metal catalyst in
asymmetric hydrogenation and much progress has been
made,7h including functional olefins,8 enamines,9 ketones,10 as
well as aromatic compounds.7f,11 Notably, palladium catalyst
has shown its powerful ability in the hydrogenation of
activated imines.12-14 Pioneering work by Amii and co-workers
established the use of Pd(OCOCF3)2/BINAP as a catalyst for
asymmetric hydrogenation of α-fluorinated iminoesters with
up to 91% ee.12 In 2006, Zhang’s group documented a
palladium-catalyzed asymmetric hydrogenation of N-
tosylimines with up to 99% ee.13 Subsequently, using
palladium catalytic systems, a series of cyclic sulfonamides and
sulfamidates substrates have been successfully hydrogenated
in Zhou’s group with excellent yields and enantioselectivities.14
Considering the similar N-sulfonylketimine structure and the
practicability of palladium catalysts, we became interested in
exploring the synthesis of chiral sulfahydantoins via palladium-
catalyzed hydrogenation strategy. Herein, we present an
efficient method for the enantioselective synthesis of 4-aryl
O
O
S
O O
S
H
N
O
O
S
O
HN
NH
HN
O
NH
R'
NNa
N
R'
O
R
R
O
O
Sulfahydantoins
Hydantoins
Bentazon
Sodium saccharin
Scheme 1. Analogues of sulfahydantoins
The diverse biological and chemical properties of sulfahy-
dantoins have commanded the interest of organic chemists.
Consequently, various synthetic methods have been
developed for the construction of sulfahydantoins.1,5
Noteworthily, some special biological properties are closely
linked with the absolute configuration of compounds, but the
preparation of optically pure sulfahydantoins has been
explored scarcely. A general access to chiral sulfahydantoins
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sulfahydantoins by asymmetric hydrogenation of the
corresponding cyclic ketimines using the chiral palladium
complex as catalyst, and up to 98% ee was obtained (eq 3,
Scheme 2).
a
Conditions: 1a (0.1 mmol), Pd(OCOCF3)2 (2.0 mol%), L (2.4 mol%), Solvent
(1.5 mL), H2 (600 psi), 40 oC, 12 h. b Isolated yields. c Determined by HPLC.
With the optimal reaction conditions in hand, a range of 4-
aryl substituted cyclic N-sulfonylketimines
1 were investigated
and the results are shown in Table 2. For different N-protected
groups, the methyl group afforded the highest 98% ee value,
which was better than that of ethyl group or benzyl group
(Table 2, entries 1-3). Notably, the steric effect of the aryl
substituents of substrate
1 obviously influenced the reaction
(Table 2, entries 4-6), when a methyl group was introduced to
the ortho-position of the phenyl ring, the transformation
displayed poor reactivity and moderate 80% ee of
enantioselectivity. To improve the reactivity, acid additives
were screened and when 10 mol% L-CSA was added without
affecting the enantioselectivity, the reaction proceeded
smoothly with 99% yield in 12 h (Table 2, entry 4). With the
help of acid additive, substrates with different electron-
withdrawing groups such as fluorine, chlorine and bromine
also proceeded smoothly, giving the desired products in high
yields and ee values (Table 2, entries 8-10). Additionally,
naphthyl group was also tolerated in the reaction (Table 2,
entry 11).
Scheme 2. Synthesis of chiral sulfahydantoins
At the outset, using cyclic N-sulfonylketimines 1a as model
substrates, reaction conditions for the palladium-catalyzed
asymmetric hydrogenation of 1a were investigated. Initial
examinations began with the solvents. The reaction proceeded
smoothly in TFE (2,2,2-trifluoroethanol) with 89% yield and 16%
ee (Table 1, entry 1). However, racemic product was obtained
when the reaction was conducted in methanol and poor
reactivity was obtained in dichloromethane or toluene (Table 1,
entries 2-4). To further improve the reaction efficiency, we
investigated different chiral ligands’ influence on the reactivity
and enantioselectivity. Fortunately, when we chose ferrocene-
derived bisphosphine L4 as ligand, both excellent reactivity
and 98% of enantioselectivity were obtained (Table 1, entry 7).
Therefore, the optimal reaction conditions were established:
Pd(OCOCF3)2/L4 as the catalyst, TFE as the solvent and reaction
temperature was 40 oC.
Table 2. Asymmetric hydrogenation of cyclic N-sulfonylketimines 1 a
Entry
1
R
Ar
Yield (%)b
>99 (2a)
98 (2b)
94 (2c)
99 (2d)
98 (2e)
>99 (2f)
98 (2g)
99 (2h)
99 (2i)
Ee (%)c
98
Me
Et
C6H5
2
C6H5
96
Table 1. Evaluation of the reaction parameters a
3
4d
Bn
C6H5
94
Me
Me
Me
Me
Me
Me
Me
Me
2-CH3C6H4
3-CH3C6H4
4-CH3C6H4
4-CH3OC6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
2-Naphthyl
80
5
98
6
97
7d
8d
9d
10d
11
97
Entry
Solvent
TFE
L
Yield (%)b
Ee (%)c
16
97
96
1
2
3
4
5
6
7
L1
L1
L1
L1
L2
L3
L4
89
35
96 (2j)
94
CH2Cl2
Toluene
MeOH
TFE
17
95 (2k)
93
18
10
a Conditions: 1 (0.2 mmol), Pd(OCOCF3)2 (2.0 mol%), L4 (2.4 mol%),
TFE (3.0 mL), H2 (600 psi), 40 oC, 12 h. b Isolated yields. c Determined
by HPLC. d 10 mol% L-CSA (L-camphorsulfonic acid) was added.
80
0
84
36
Moreover, to further demonstrate the practicality of the
above hydrogenation strategy, 0.5 mol% palladium catalyst
was used in the hydrogenation of model substrate 1a on a
TFE
89
71
TFE
>99
98
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hydrogenation product, 2a was transformed into the known
compound 3a by a simple transformation of reduction with
lithium aluminium hydride in THF (Scheme 4). Compared with
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Scheme 4. Determination of the absolute configuration of 2a
8
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In summary, we have reported a highly efficient access to a series
of optically active 4-aryl sulfahydantoin derivatives via palladium-
catalyzed asymmetric hydrogenation of the corresponding cyclic N-
sulfonylketimines with up to 98% ee. Further efforts to achieve the
asymmetric hydrogenation of some other functionalized imines are
ongoing in our laboratory.
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