Organocatalytic, asymmetric synthesis of 3-sulfenylated N-Boc-protected oxindoles

Article abstract of DOI:10.1002/chem.201201262

Sulfenylated oxindoles: The first asymmetric sulfenylation of N-Boc-protected oxindoles has been developed to provide products containing a tetrasubstituted stereogenic center in high to excellent yields (86-98 %) and, in most cases, excellent enantioselectivities (up to 96 % ee; see scheme). Copyright

Full text of DOI:10.1002/chem.201201262

COMMUNICATION
DOI: 10.1002/chem.201201262
Organocatalytic, Asymmetric Synthesis of 3-Sulfenylated N-Boc-Protected
Oxindoles
Chuan Wang, Xuena Yang, Charles C. J. Loh, Gerhard Raabe, and Dieter Enders*[a]
Dedicated to Professor Heribert Offermanns on the occasion of his 75th birthday
The oxindole core is present as a characteristic structural
motif in numerous alkaloids that exhibit diverse biological
and pharmaceutical activities.[1] In particular, 3,3-disub-
stitued oxindoles are important precursors for the synthesis
forward route for the construction of a sulfur-containing,
stereogenic center from achiral precursors, but these enan-
tioselective protocols are often restricted to aldehydes and
ß-keto esters.[10] Herein, we report the first asymmetric sul-
fenylation of N-Boc-protected oxindoles by using N-(sulfa-
nyl)phthalimides as the sulfenylating agent (Scheme 1).
of hexahydropyrroloACTHNUTRGNEUNG[2,3-b]indoles, which exist in a series of
biologically active natural products.[2] Therefore, the asym-
metric synthesis of 3,3-disubstituted oxindoles has been in-
vestigated intensively and many excellent results have been
achieved by the use of both organo- and transition-metal
catalysis.[3] Oxindoles with a heteroatom at the C-3 position
have received considerable attention owing to their poten-
tial applications in medicinal chemistry.[1g–m] Recently, vari-
ous methods for the asymmetric synthesis of 3-fluorooxin-
doles,[4] 3-chlorooxindoles,[5] 3-aminooxindoles,[6] and 3-hy-
droxyoxindoles[7] have been reported. Many oxindoles with
a thio group at the carbon stereocenter have been found to
have anticancer, antifungal, or antitubercular activities.[1k–m]
Therefore, the synthesis of 3-sulfanyloxindoles has been
widely explored and many approaches have been devel-
oped.[8] For example, Procter et al. successfully used the
Pummer reaction for the efficient synthesis of 3-sulfanylox-
indoles by employing various thiols and glyoxamides as pre-
cursors.[8d–g] Recently, Wang, Zhang et al. developed a Rh-
ACHTUNGTRENNUNG(OAc)2-catalyzed thia-Sommelet–Hauser rearrangement
that led to the formation of 3-arylthiooxindoles in moderate
to good yields.[8h] However, the direct, asymmetric construc-
tion of oxindoles that have a sulfur-containing tetrasubstitut-
ed stereocenter remains elusive.
The asymmetric, eletrophilic sulfenylation of oxindoles
can be achieved through a variety of strategies. Sulfenyla-
tions employing either stoichiometric amounts of chiral
agents or chiral auxiliaries have been used since 1979, and
have proven to be a useful method for the preparation of
sulfenylated compounds in an enantioselective manner.[9]
Moreover, catalytic, asymmetric sulfenylation is a straight-
[a] Dr. C. Wang, Dipl.-Chem. X. Yang, C. C. J. Loh, Prof. Dr. G. Raabe,
Prof. Dr. D. Enders
Institute of Organic Chemistry
RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
Fax : ( +49)241-809-2127
E-mail: enders@rwth-aachen.de
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201201262.
Scheme 1. Asymmetric sulfenylation of 1a by using different types of
organocatalyst (4–11). Boc=tert-butoxycarbonyl.
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Initially, we studied the cinchona alkaloid dimer
(DHQD)2PHAL (4) and (S)-diarylprolinols 5 as catalysts
for the sulfenylation reaction between the N-Boc-protected
oxindole 1a and N-(phenylsulfanyl)phthalimide (2a) in
chloroform to give product 3a (Table 1) because these cata-
improving on their corresponding thiourea analogues in
both catalytic activity and selectivity.[11–13] Therefore, we in-
vestigated two squaramides, 10 and 11, for this sulfenylation
reaction. To our delight, the squaramide 10, which possesses
an (R,R)-diaminocyclohexane subunit, was able to efficient-
ly promote the sulfenylation to furnish the product in excel-
lent yield (98%) and enantioselectivity (96% ee; Table 1,
entry 10). In contrast, a reaction catalyzed by the squar-
amide 11, which is derived from quinidine, gave the product
only in very low enantioselectivity (21% ee) (Table 1,
entry 11).
Because a catalyst loading of 20 mol% resulted in a com-
plete reaction within just 1 h, we repeated the reaction with
a 5 mol% loading of catalyst 10 and a full conversion of the
oxindole 1a was achieved within 12 h. The product was ob-
tained in excellent yield (98%) without a decrease in enan-
tioselectivity (96% ee; Table 1, entry 12). Next, a number of
solvents were screened at room temperature by using squar-
amide 10 (5 mol%) as the catalyst; however, no improve-
ment in enantioselectivity was obtained (Table 1, entries 13–
15). In an attempt to increase the enantioselectivity, we low-
ered the reaction temperature to 08C. Surprisingly, the reac-
tion gave the product in a lower enantiomeric excess
(78% ee) (Table 1, entry 16). When the reaction was con-
ducted at 508C, the reaction rate was increased, but no im-
provement in the enantioselectivity was obtained (Table 1,
entry 17).
Table 1. Optimization of the reaction conditions for the sulfenylation.[a]
Entry
Cat.
Loading
[mol%]
T
[8C]
Solvent
t
Yield[b]
[%]
ee[c]
[%]
G
[h]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
4
5a
5b
5b
5c
6
7
8
9
10
11
10
10
10
10
10
10
20
20
20
20
20
20
20
20
20
20
20
5
À30
RT
RT
À30
À30
À30
RT
RT
RT
RT
RT
RT
RT
RT
RT
0
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
MeOH
MeCN
THF
48
36
48
48
48
48
24
48
72
1
1
12
1
24
12
48
6
79
89
84
86
81
46
98
73
35
98
98
98
96
93
97
91
98
35
50
59
73
55
À3
75
À11
0
96
21
96
52
75
82
78
96
5
5
5
5
CHCl3
CHCl3
5
50
[a] The reactions were performed by using N-Boc-protected oxindole 1a
(0.5 mmol), N-(pheylsulfanyl)phthalimide (2a; 1.2 equiv), and a catalyst
(4–11) in a solvent (10 mL). [b] Yields of isolated product. [c] The ee
values were determined by HPLC analysis on a chiral stationary phase.
Cat.=catalyst.
After optimizing the reaction conditions, we started to
evaluate the substrate scope of this reaction by varying the
structure of both N-Boc-protected oxindoles 1 and N-(sulfa-
nyl)phthalimides 2. First, we reacted different N-Boc-oxin-
doles 1a–i with N-(phenysulfanyl)phthalimide (2a). In the
cases of 3-benzyloxindoles 1a–d and 3-methyloxindole 1i,
the reactions were complete within 12 h at room tempera-
ture under the catalysis of the squaramide 10, furnishing the
products 3a–d and 3i in high to excellent yields (86–98%)
and excellent enantiomeric excess (92–96% ee; Table 2, en-
tries 1–4 and 9). In contrast, 3-aryloxindoles 1e–h were
found to be more reactive precursors for the sulfenylation
reaction. The corresponding reactions were completed
within a shorter time (6 h) giving the products 3e–h in ex-
cellent yields (91–98%) and high enantioselectivities (85–
87% ee; Table 2, entries 5–8).
Subsequently, we treated various N-Boc-oxindoles, 1a–c,
1e, and 1i, with several N-(sulfanyl)phthalimides 2b–g
which contained electron-withdrawing or -donating substitu-
ents at different positions. When the chloro-, methyl-, and
methoxy-substituted N-(arylsulfanyl)phthalimides 2b, c, and
e were used as precursors, the reactions were conducted at
room temperature providing the products 3j, k, m, o, and q
in high to excellent yields (88–98%) and excellent enantio-
meric excesses (90–95% ee; Table 2, entries 10,11,13,16,
and 17 respectively). In the cases of nitro-substituted N-(ar-
ylsulfanyl)phthalimides 2d and f, the reactions had to be
carried out at 508C to give the products 3l and 3n in excel-
lent yields (97–98%) and enantioselectivities (90% ee;
Table 2, entries 12 and 14). When N-(benzylsulfanyl)phthal-
lysts showed good activity and a high level of asymmetric in-
duction in the a-sulfenylation of ß-keto esters.[10e,j,k] Un-
fortunately, these catalysts turned out to be unsuitable for
our thiolation reaction with regard to the enantioselectivity.
When the catalyst (DHQD)2PHAL (4) was used, the reac-
tion was complete within 48 h at À308C and gave the prod-
uct in good yield (79%), albeit with low enantiomeric
excess (35% ee; Table 1, entry 1). Three different (S)-diaryl-
prolinols 5a–c were also evaluated for the sulfenylation re-
action at both room temperature and À308C; however, only
a moderate level of asymmetric induction (50–73% ee) was
achieved (Table 1, entries 2–5). Next, we employed the qui-
nine derivative 6 as a catalyst, which showed lower catalytic
activity and almost no enantioselectivity (À3% ee; Table 1,
entry 6). Three enantiopure thioureas 7–9 were also tested
for this reaction. In the case of thiourea 7, the reaction pro-
ceeded smoothly at room temperature with excellent yield
(98%); however, the enantioselectivity obtained (75% ee)
was not satisfactory (Table 1, entry 7). When thiourea 8,
which has a quinine scaffold, was employed as a catalyst,
the reaction took longer to complete (72 h), providing the
product in moderate yield (73%) and very low enantioselec-
tivity (À11% ee; Table 1, entry 8). In the case of thiourea 9,
which contains a secondary alcohol group, the reaction gave
only a racemic mixture of products (Table 1, entry 9).
Recently, squaramides have been found to be more pow-
erful hydrogen-bonding catalysts in many transformations,
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Organocatalytic, Asymmetric Synthesis of Oxindoles
COMMUNICATION
Table 2. Yields and enantioselectivities of the sulfenylation of N-Boc-oxindoles 1 with
N-(sulfanyl)phthalimides 2 as the sulfenylating agent.[a]
yield (96%). The thioether moiety in 3b was also
successfully converted into the corresponding sul-
fone 13 in good yield (82%) by using meta-chloro-
perbenzoic acid (mCPBA) as the oxidizing agent
(Scheme 2). Notably, the enantiomeric excess re-
mained at an excellent level for both of these reac-
tions.
Entry
R1
R2
R3
T
t
Yield[b] ee[c]
The absolute configuration of 12 was unambigu-
ously determined to be the R-configuration by
X-ray crystal-structure analysis (Figure 1).[14] The
N-Boc-protected products 3 were assumed to have
the same configuration as 12.
In summary, we have developed an organocata-
lytic, asymmetric sulfenylation of N-Boc-protected
oxindoles by using N-(sulfanyl)phthalimides as the
sulfenylating agents. This process was efficiently
promoted by the use of a low catalyst loading of a
squaramide, with a hydrogen-bonding activation
mode furnishing the products, which contain a tet-
rasubstituted stereocenter, in high to excellent
yields (86–98%) and, in most cases, excellent enan-
tioselectivities (up to 96% ee).
[8C] [h] [%]
[%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
3a (piperonyl)methyl
3b Bn
3c pCH3C6H4CH2
3d mFC6H4CH2
3e Ph
H
H
H
H
H
2a Ph
2a Ph
2a Ph
2a Ph
2a Ph
RT 12 98
RT 12 96
RT 12 95
RT 12 90
96
96
95
96
85
86
87
86
92
95
93
90
95
90
95
55
94
RT
RT
RT
RT
6
6
6
6
96
95
98
91
3 f
Ph
CH3 2a Ph
3g pMeOC6H4
3h pFC6H4
H
H
H
H
H
H
H
H
H
2a Ph
2a Ph
2a Ph
2b p-ClC6H4
2c p-CH3C6H4
3i
3j
Me
RT 12 86
RT 12 98
RT 12 94
(piperonyl)methyl
3k (piperonyl)methyl
3l (piperonyl)methyl
3m pCH3C6H4CH2
3n (piperonyl)methyl
3o Bn
2d p-NO2C6H4 50
2e p-MeOC6H4 RT 12 98
2 f m-NO2C6H4 50 97
2c p-CH3C6H4 RT 12 88
6
98
6
3p Ph
3q Me
CH3 2g Bn
2b p-ClC6H4
50
RT
24 86
92
H
6
[a] The reactions were performed by using N-Boc-protected oxindoles 1 (0.5 mmol),
N-(sulfanyl)phthalimides (1.2 equiv), and catalyst 10 (5 mol%) in chloroform
2
(10 mL). [b] Yields of isolated product. [c] The ee values were determined by HPLC
analysis on a chiral stationary phase.
imide (2g) was used as the electrophile in a reaction with
the N-Boc-protected oxindole 1 f, the product 3p was ob-
tained after 24 h at 508C in high yield (86%), although the
level of asymmetric induction was only moderate (55% ee;
Table 2, entry 16).
Furthermore, the Boc group can be readily removed from
the oxindole product, as demonstrated in Scheme 2. The N-
Boc-protected oxindole 3j was successfully deprotected by
treatment with trifluoroacetic acid (TFA) at room tempera-
ture in dichloromethane to give the product 12 in excellent
Figure 1. X-ray crystal structure of 12. This compound crystallizes with
two symmetrically independent species in the asymmetric unit, one of
which is heavily disordered. Only the nondisordered molecule is shown.
The Flack parameter for the refined structure is 0.027(17).
Experimental Section
General procedure: The (sulfanyl)phthalimide 2 (0.60 mmol) was added
to a solution of 3-substituted N-Boc-protected oxindole 1 (0.50 mmol)
and squaramide 10 (5 mol%) in chloroform (10 mL) at either room tem-
perature or 508C. After stirring for the time shown in Table 2, the solvent
was removed under vacuum and the residue was purified by flash column
chromatography on silica gel (pentane/ether) to give the corresponding
3-sulfanyl-N-Boc-oxindole 3.
Acknowledgements
We thank the BASF SE and the former Degussa AG for the donation of
chemicals.
Keywords: asymmetric synthesis
oxindoles · squaramides · sulfenylation
·
organocatalysis
·
Scheme 2. Deprotection of the N-Boc-oxindole 3j, and the oxidation of
the N-Boc-oxindole 3b.
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Organocatalytic, Asymmetric Synthesis of Oxindoles
COMMUNICATION
[14] CCDC-875714 (12) contains the supplementary crystallographic
The Cambridge Crystallographic Data Centre via www.ccdc.cam.a-
c.uk/data_request/cif.
data for this paper. These data can be obtained free of charge from
Received: April 13, 2012
Published online: && &&, 0000
Chem. Eur. J. 2012, 00, 0 – 0
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www.chemeurj.org
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D. Enders et al.
Organocatalysis
C. Wang, X. Yang, C. C. J. Loh,
G. Raabe, D. Enders* ....... &&&& — &&&&
Organocatalytic, Asymmetric Synthesis
of 3-Sulfenylated N-Boc-Protected
Oxindoles
Sulfenylated oxindoles: The first asym-
metric sulfenylation of N-Boc-pro-
tected oxindoles has been developed
to provide products containing a tetra-
substituted stereogenic center in high
to excellent yields (86–98%) and, in
most cases, excellent enantioselectivi-
ties (up to 96% ee; see scheme).
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 0000, 00, 0 – 0
ÝÝ
These are not the final page numbers!