Tertiary Amine-Catalyzed Difluoromethylthiolation of Morita–Baylis–Hillman Carbonates of Isatins with Zard's Trifluoromethylthiolation Reagent

Article abstract of DOI:10.1002/adsc.201600954

In this paper, we report that a novel tertiary amine-catalyzed [3+2] annulation between Morita–Baylis–Hillman (MBH) carbonates derived from isatins with thiocarbonyl fluoride (F₂C=S) in situ generated from Zard's reagent proceeds smoothly under mild conditions, affording difluoromethylthiolated spirocyclic oxindoles in good to excellent yields. Moreover, the asymmetric variant could be realized with a modified Cinchona alkaloid, giving the desired cyclic adducts in good to excellent yields with good enantioselectivities. (Figure presented.).

Full text of DOI:10.1002/adsc.201600954

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DOI: 10.1002/adsc.201600954
Tertiary Amine-Catalyzed Difluoromethylthiolation of Morita–
Baylis–Hillman Carbonates of Isatins with Zardꢀs Trifluorome-
thylthiolation Reagent
Xing Fan,a Haibin Yang,a and Min Shia,*
a
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, University of Chinese Academy of Science, 354 Fenglin Lu, Shanghai 200032, Peopleꢀs Republic of China
Fax : (+86)-21-6416-6128; e-mail: mshi@mail.sioc.ac.cn
Received: August 26, 2016; Revised: October 19, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600954.
Abstract: In this paper, we report that a novel terti-
ary amine-catalyzed [3+2] annulation between
Morita–Baylis–Hillman (MBH) carbonates derived
from isatins with thiocarbonyl fluoride (F2C=S) in
situ generated from Zardꢀs reagent proceeds
smoothly under mild conditions, affording difluoro-
methylthiolated spirocyclic oxindoles in good to ex-
cellent yields. Moreover, the asymmetric variant
could be realized with a modified Cinchona alka-
loid, giving the desired cyclic adducts in good to ex-
cellent yields with good enantioselectivities.
in the in situ generation of a strong Brønsted base,
the tert-butoxy anion, which can facilitate the depro-
tonation of MBH carbonates, producing the corre-
sponding allylic ylide. This in situ generated ylide can
undergo an annulation with a suitable electrophilic
partner, such as electron-deficient olefins,[4] imines[5]
or diazo compounds[6] to enable the rapid construc-
tion of densely functionalized spirocyclic scaffolds.[7]
Recently, organofluorine chemistry has become
a hot field in synthetic organic chemistry.[8] This is not
only because fluorinated compounds play a key role
in pharmaceutical, agrochemical, and material scien-
ces, but also due to that fluorine is a fascinating atom
revealing subtle effects.[9] In this field, trifluorome-
thylthio (CF3S) and difluoromethylthio (CF2S) groups
have also gained great attention. The difluorome-
thylthio group (Hansch parameter pR =0.68)[10b] is
slightly more lipophilic than the methyl group (pR =
0.56),[10a] but much less lipophilic than the trifluoro-
Keywords: [3+2] annulation.; difluoromethylthiola-
tion; Morita–Baylis–Hillman (MBH) carbonates;
organocatalysis; spirocyclic oxindoles
Spiro-fused cyclic frameworks have drawn tremen- methylthio group (CF3S, pR =1.44),[10b] providing the
dous interest of researchers in the area of synthetic opportunity for fine tuning of the drug moleculeꢀs
organic chemistry and medicinal chemistry worldwide
because they often occur in many natural products
and have significant bioactivities. Thus far, much
effort has been devoted to the exploration of the
novel and efficient synthetic methods to the rapid
construction of spirocyclic oxindole structures since
they often have very interesting biological activities
(Figure 1).[1]
In this aspect, the Morita–Baylis–Hillman (MBH)
adduct of isatin has proved to be a versatile precursor
for the synthesis of spiro-fused products,[2] since Lu
and co-workers first reported that tert-butoxycarbonyl
(Boc) as a much superior decorating group can
endow electrophilic character at the allylic position
for MBH adducts.[3] The basic strategy is that, using
tertiary amine or phosphine as nucleophilic catalyst,
the displacement and subsequent decarboxylation of
the Boc group on a MBH carbonate of isatin results with spirocyclic skeletons.
Figure 1. Selected examples of biologically active molecules
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lipoACHTUNGTRENNUNGphilicity, which might be able to bring about desir-
able changes in the physical and biological properties
of drug molecules.[10] Therefore, the development of
new and efficient methods for the synthesis of
difluoroACHTUNGTRENNUNGmethylthiolated compounds is of great inter-
est.[11] The trifluoromethylthiolate anion can act as
the precursor of thiocarbonyl fluoride (F2C=S) be-
cause there is an equilibrium between the trifluoro-
methylthiolate anion and thiocarbonyl fluoride
Figure 2. The equilibrium between trifluoromethylthiolate
anion and thiocarbonyl fluoride.
(Figure 2).[12] Nevertheless, gaseous thiocarbonyl fluo-
ride (F2C=S) is not commercially available and is
labile, limiting its wide application in organic synthe-
sis. On the basis of above information, we anticipated
that a new strategy to produce difluoromethylthiolat-
ed spirocyclic oxindole could be feasible through the
[3+2] annulation between thiocarbonyl fluoride
(F2C=S) in situ generated from trifluoromethylthio-
late anion and the allylic ylide derived from isatinꢀs
MBH carbonate.
Scheme 1. Spirocyclic oxindole skeletons constructed by
[3+2] annulation.
Thus far, several nucleophilic trifluoromethylthiola-
tion reagents have been reported such as, e.g.,
[15]
(bpy)CuSCF3, CuSCF3,[13] AgSCF3,[14] Hg(SCF3)2 or porting Information). Further optimization of the re-
[16]
CsSCF3 as well as some organic SCF3 reagents such action conditions was performed by changing the cat-
as Me4NSCF3 and (CF3S)2(TDAE).[17] Among of alyst, the additive and the solvent and the results are
them, CF3SCO2C18H37 (O-octadecyl-S-trifluorothiol- summarized in Table 1. When other types of nucleo-
carbonate) is a cheap and storable crystalline source philic catalysts were used, the yield of 3a decreased
of SCF3 anion, reported by Li and Zard.[18] We envis- significantly (Table 1, entries 2–5). However, 3a could
aged that Zardꢀs reagent could be used as a suitable be obtained in 61% yield when 20 mol% of DABCO
thiocarbonyl fluoride (F2C=S) precursor and that the was used (Table 1, entry 6). Other additives were then
in situ generated F2C=S species could go through examined and the results indicated that a base is es-
a [3+2] annulation with the MBH carbonate of isatin sential for this reaction (Table 1, entries 7 and 8). The
catalyzed by a tertiary amine. Herein, we wish to inorganic base KOH is better than organic base
report the first successful implementation of a tertiary DIPEA in this annulation (Table 1, entries 9 and 10).
amine-catalyzed [3+2] annulation between MBH car- When the employed amount of base was increased
bonates 1 derived from isatins with the in situ F2C=S from 5.0 to 10 equiv., the yield of 3a could be im-
species generated from Zardꢀs reagent 2, affording di- proved from 76% to 88% (Table 1, entries 10 and 11).
fluormethylthiolated spirocyclic oxindoles in good Consequently, a few of the other inorganic bases were
yields along with the asymmetric variant in the pres- also tested, and K2CO3 gave the best result (Table 1,
ence of a modified Cinchona alkaloid under mild con- entries 12–17). Subsequently, we screened solvents
ditions (Scheme 1).
such as DCM, MeCN, toluene, EtOAc and DCE, and
We initiated our investigation by examining the re- found that EtOAc was the best choice (Table 1, en-
action outcomes of compound 1a (0.2 mmol) and tries 18–22). We finally identified that the optimized
Zardꢀs reagent 2 (1.0 equiv.) in THF using DABCO reaction conditions were to carry out the reaction in
(0.5 equiv.) as the catalyst. The reaction proceeded EtOAc at room temperature with 10 equivalents
smoothly after 2.0 h at room temperature, affording K2CO3 and loading 20 mol% of DABCO as the cata-
the desired [3+2] annulation product 3a in 58% yield lyst.
(Table 1, entry 1). The structure of 3a has been con-
Having established the optimal reaction conditions,
firmed by X-ray diffraction data of 3b, an analogue of we next turned our attention to explore the substrate
3a (Figure 3; the CIF data of 3b are shown in the Sup- scope and the results are summarized in Table 2,
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Table 1. Optimization of the reaction conditions of 1a with Zardꢀs reagent 2.[a,b]
[a]
Reaction conditions: 1a (0.1 mmol), 2 (0.1 mmol), at room temperature.
Yield of isolated product purified by column chromatography on silica gel.
[b]
Table 3 and Scheme 2, respectively. Overall, we found
that various MBH carbonate performed very well in
this reaction under optimal conditions regardless of
whether electron-donating or electron-withdrawing
substituents were introduced on the aromatic rings
and different N-protecting groups were utilized,
giving the desired products in good to excellent
yields.
As shown in Table 2, when R1 is an electron-donat-
ing substituent such as a methyl or isopropyl group,
the reaction proceeded smoothly to give the desired
products 3c and 3d in 82% and 87% yields, respec-
tively. When R1 is a halogen atom such as F, Cl, Br or
I at C-5 or C-7 of aromatic ring, the reactions ran effi-
ciently, affording the desired products in good to ex-
cellent yields (84–93%). As for substrates 1g and 1k
bearing strongly electron-withdrawing groups such as
CF3 and OCF3, the reactions also worked very well to
give the desired products 3g and 3k in 84% and 70%
yields, respectively.
As indicated in Table 3, when using an allyl group
as the N-protecting group, the reactions could pro-
ceed smoothly for a variety of substrates bearing dif-
Figure 3. X-ray crystal structure of product 3b.
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Table 2. Reaction scope toward the synthesis of 3.[a,b]
Table 3. Reaction scope toward the synthesis of 3.[a,b]
[a]
[b]
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol) and
EtOAc (2.0 mL) were used.
Yield of isolated product purified by column chromatog-
raphy on silica gel.
[a]
Reaction conditions: 1 (0.2 mmol), 2 (0.2 mmol) and
EtOAc (2.0 mL) were used.
Yield of isolated product purified by column chromatog-
[b]
raphy on silica gel.
take place to give the desired product 3x in 47%
yield.
ferent substituents at the aromatic rings, affording the
To investigate the asymmetric variant for this reac-
desired products in moderate to excellent yields rang- tion, we screened a variety of chiral tertiary amines
ing from 58% to 99% with no significant impact on under the optimized reaction conditions (for the de-
the reaction outcomes. In the cases of substrates 1s, tailed screening process, see the Supporting Informa-
1t, and 1u, in which the N-protecting group was a Bn, tion). The selected chiral tertiary amines are shown in
2-naphthylmethyl, or 9-anthracenylmethyl group, the Figure 4 and the related optimization results are indi-
reactions took place very well to afford the desired cated in Table 4 using 1g as the model substrate. For
products 3s, 3t, and 3u in high yields.
catalyst a-IC, the annulation product 3g was obtained
As shown in Scheme 2, we also examined the sub- in 85% yield with 3% ee (Table 4, entry 1). When b-
strate scope of this [3+2] annulation reaction for ICD was used as the catalyst, the yield of 3g de-
MBH carbonates having different functional groups. creased to 54% while the ee value increased to À37%
In the case of substrate 1v, in which the CO2Me has (Table 4, entry 2). To our delight, when b-IQD was
been replaced by a CN group, the desired product 3v used as the catalyst, the annulation product 3g was
was obtained in 28% yield, suggesting that the CN obtained in 94% yield along with 64% ee (Table 4,
was not a suitable group for this reaction. On chang- entry 3). However, when using b-isocinchonine as the
ing the leaving group BocO (t-BuOCO2) to EtOCOO, catalyst, the yield of 3g decreased to 84% along with
the reaction occurred smoothly to give the desired À38% ee (Table 4, entry 4). On the basis of above cat-
product 3w in 91% yield. As for substrate 1x having alyst results, we assumed that the substituent at the
two linked MBH carbonates, the reaction could also C-6 position in these Cinchona alkaloid catalysts
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Figure 4. Selected chiral tertiary amine catalysts.
firmed as S by X-ray diffraction (Figure 5) (for de-
tails, see the Supporting Information).
With these optimal reaction conditions in hand, we
next examined the substrate scope of this asymmetric
annulation reaction and the results are summarized in
Scheme 2. Reaction scope toward the synthesis of 3. Reac-
tion conditions: 1 (0.2 mmol), 2 (0.2 mmol) and EtOAc
(2.0 mL) were used. Yields of isolated products purified by
column chromatography on silica gel are reported.
plays a very important role in this reaction. Thus, we
focused our attention on modification of the Cincho-
na alkaloid b-IQD by introducing different substitu-
ents at the C-6 position. Aromatic group, sulfide
group, alkoxy group, amide and amine groups have
been introduced at the C-6 position of the corre-
sponding Cinchona alkaloid and the reaction out-
comes have been examined (Table 4, entries 5–9) (for
more details, see Tables S1, S2 and Figure S1 in the
Supporting Information). We found that C-16 gave
a superb outcome in this reaction, giving 3g in 99%
yield along with À81% ee in EtOAc (Table 4,
entry 8). The examination of solvent effects revealed
that toluene was the optimal solvent, affording 3g in
96% yield along with À83% ee at 208C (Table 4, en-
tries 10–15). After recrystallization from hexane/
DCM=50:1, a single crystal of 3g (93% ee) has been
obtained and its absolute configuration has been con- Figure 5. The absolute configuration of product 3g.
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Table 4. Optimization of the reaction conditions for the
asymmetric synthesis of 3g.[a,b]
Table 5. Substrate scope for the asymmetric synthesis of
3.[a,b,c]
[a]
Reaction conditions: 1g (0.1 mmol), 2 (0.1 mmol), at
room temperature (26–328C).
Yield of isolated product purified by column chromatog-
[b]
raphy on silica gel.
Determined by chiral HPLC, and the absolute configura-
tion was determined by X-ray diffraction.
[a]
Reaction conditions: 1 (0.1 mmol), 2 (0.1 mmol), at room
temperature.
Yield of isolated product purified by column chromatog-
[c]
[b]
raphy on silica gel.
Determined by chiral HPLC, and the absolute configura-
[c]
Table 5. All these reactions proceeded smoothly to
give the desired products in 57–99% yields along with
80–88% ee values, respectively.
tion of 3g has been determined by X-ray diffraction and
others are also assigned as the S-configuration.
To demonstrate the synthetic utility of the obtained
product, we further explored the transformation of which produces the corresponding allylic ylide
product 3 (Scheme 3). We found that upon oxidation through depotonation with tert-butoxy anion. The nu-
of 3g with mCPBA (1.2 equiv.) at 08C in DCM for cleophilic addition of B to the in situ generated CF2=
18 h, the desired sulfoxide product 4g was formed in S species gives intermediates C and D, which under-
59% yield as a single diastereomer. Use of 3.0 equiv. goe elimination of DABCO to afford the desired
of mCPBA produced the corresponding sulfone prod- product 3b.
ucts 5g and 5s in 92% and 77% yields, respectively at
With regard to the generation of CF2=S species, we
508C. The structure of 5g has been unambiguously have performed a detailed mechanistic exploration on
confirmed by X-ray diffraction and its CIF data are the interaction of Zardꢀs reagent with DABCO in our
presented in the Supporting Information.
previous work.[19,20] The intermediates X and Y can be
On the basis of previous literature and our own re- generated on the basis of the nucleophilic addition of
sults, a plausible mechanism has been proposed as DABCO to 2. The counter anion C18H37OÀ in inter-
shown in Scheme 4.[19,20] We supposed that DABCO mediate X can also attack intermediate Y to generate
played dual roles in activating Zardꢀs trifluorome- DABCO and product 6, which has been confirmed
thylthiolation reagent and the MBH carbonate. The before.[19] The corresponding CF2=S species can be
reaction is initiated by the formation of zwitterionic produced from CF3SÀ in the presence of a large
intermediate A upon addition of DABCO to 1b, amount of base.[12]
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Scheme 4. Proposed mechanism for the reactions.
reagent activated by a tertiary amine, affording the
corresponding difluoromethylthiolated spirocyclic ox-
indoles in good to excellent yields under mild condi-
tions. Furthermore, the enantioselective annulation
catalyzed by modified Cinchona alkaloids has been
also achieved, giving the desired spirocyclic adducts
in good to excellent yields along with good enantiose-
lectivities. Efforts are in progress towards the applica-
tion of this new methodology to synthesize interesting
biologically active compounds in our laboratory.
Scheme 3. Transformations of 3g and 3s. Reaction condi-
tions: 3 (0.2 mmol), mCPBA (x equiv.) and DCM (2.0 mL)
were used. The isolated yields after column chromatography
on silica gel are reported.
Experimental Section
General Procedure for Synthesis of 1
In summary, we have developed the first example
of the amine-catalyzed [3+2] annulation between
MBH carbonates derived from isatins and the in situ
Under an argon atmosphere, S3a was added slowly to a sus-
pension of sodium hydride in dry DCM at room tempera-
generated thiocarbonyl fluoride (F2C=S) from Zardꢀs ture, and the mixture was stirred for 30 min. Then the solu-
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tion was added slowly to a solution of Boc2O in 2.0 mL dry
DCM at room temperature and the mixture was stirred at
room temperature for overnight. The mixture was filtered
and the filtrate was concentrated under vacuum. The residue
was purified by a flash chromatograph on silica gel using
PE/EtOAc (5:1) as the eluent to afford the desired product
1a as a yellow solid.
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General Procedure for Synthesis of 3
Under an argon atmosphere, DABCO (4.5 mg, 0.2 mmol)
was added to a solution of compound 1 (0.2 mmol), Zardꢀs
reagent (79.8 mg, 0.2 mmol) and K2CO3 (276.4 mg,
2.0 mmol) in EtOAc (2.0 mL) in a Schlenk tube. The mix-
ture was stirred at room temperature until compound 1 was
consumed completely. The reaction mixture was quenched
with water (10 mL) and extracted with EtOAc (3ꢂ10 mL).
The combined organic layers were dried over MgSO4 and
concentrated under reduced pressure. The residue was puri-
fied by a silica gel column flash chromatography (eluent: pe-
troleum ether/ethyl acetate=10/1) to afford the product 3.
[4] For some selected examples with regard to the annula-
tion of allylic ylide and olefins, see: a) J. Peng, X.
Huang, L. Jiang, H.-L. Cui, Y.-C. Chen, Org. Lett.
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[5] For some selected examples on the annulation of allylic
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[6] For some selected examples with respect to the annula-
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Crystal Structures
CCDC 1059847 (3b), CCDC 1509487 (3g) and CCDC
1501068 (5g) contain the supplementary crystallographic
data for this paper. These data can be obtained free of
charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
Supporting Information
Detailed descriptions of experimental procedures and the
spectroscopic data of the products as well as their crystal
structures are presented in the Supporting Information.
[7] For other recent reports on the formation of spirocyclic
compounds, see: a) B. M. Trost, N. Cramer, S. M. Silver-
man, J. Am. Chem. Soc. 2007, 129, 12396–12397; b) X.-
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Am. Chem. Soc. 2009, 131, 13819–13825; c) G. Benci-
venni, L.-Y. Wu, A. Mazzanti, B. Giannichi, F. Pesciaio-
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Acknowledgements
We are grateful for the financial support from the National
Basic Research Program of China [(973)-2015CB856603],
and the National Natural Science Foundation of China
(20472096, 21372241, 21361140350, 20672127, 21421091,
21372250, 21121062, 21302203, 20732008 and 21572052).
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10 Tertiary Amine-Catalyzed Difluoromethylthiolation of
Morita–Baylis–Hillman Carbonates of Isatins with Zardꢀs
Trifluoromethylthiolation Reagent
Adv. Synth. Catal. 2016, 358, 1 – 10
Xing Fan, Haibin Yang, Min Shi*
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