Zinc triflate-mediated cyclopropanation of oxindoles with vinyl diphenyl sulfonium triflate: a mild reaction with broad functional group compatibility

Article abstract of DOI:10.1039/C6RA24985J

The first use of zinc triflate for the cyclopropanation of unprotected oxindoles with vinyl diphenyl sulfonium triflate salt is reported. The reaction proceeded under ambient conditions and consistently provided high yields with broad functional group tolerability. The utility for the late-stage functionalization (LSF) of complex molecules is demonstrated.

Full text of DOI:10.1039/C6RA24985J

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Zinc triflate-mediated cyclopropanation of
oxindoles with vinyl diphenyl sulfonium triflate:
a mild reaction with broad functional group
compatibility†
Cite this: RSC Adv., 2017, 7, 3741
Received 10th October 2016
Accepted 6th November 2016
a
b
a
b
a
Mingwei Zhou,ab Ke En, Yimin Hu, Yufang Xu, Hong C. Shen and Xuhong Qian
*
*
DOI: 10.1039/c6ra24985j
www.rsc.org/advances
The first use of zinc triflate for the cyclopropanation of unprotected literature, different cyclopropanation strategies can provide
oxindoles with vinyl diphenyl sulfonium triflate salt is reported. The access to spirocyclopropyl oxindoles.2 However, the potential of
reaction proceeded under ambient conditions and consistently applying such strategies in the context of the late-stage func-
provided high yields with broad functional group tolerability. The tionalization3 (LSF) remains to be fully explored. There are
utility for the late-stage functionalization (LSF) of complex molecules limited choices of mild and selective conditions to tolerate
is demonstrated.
aqueous environment, to be compatible with unprotected and
sensitive functional groups such as amines, hydroxyl and
carboxyl groups, and boronic acids, and to be suitable for
functionalization of complex structures.4
Oxindole is a common motif in numerous molecules of great
biological and medicinal interest (Fig. 1). Functionalization at
the 3-position of oxindoles is a key lead derivatization strategy
in medicinal chemistry. In particular, spirooxindoles have
demonstrated many applications in drug discovery.1 Speci-
cally, spirocyclopropyl oxindoles (Fig. 1: compound 4, 5, and 6)
are important because such designs in drug discovery could
introduce potentially favorable conformational restraint with
marginal addition of molecular weight and lipophilicity. In the
One common cyclopropanation method involves the use of
1,2-dibromoethane. In general, a strong base, such as NaH or
LiHMDS, is needed for this transformation.5 Application of
such method oen requires protection on oxindole nitrogen as
well as other acidic functional groups. With unprotected oxin-
doles, over-alkylation on the nitrogen is a common side reac-
tion. Over-alkylation can be used as a protection strategy. With
unprotected oxindole 7a, Robertson obtained over-alkylated
product 8a with excess reagents rst.6 Subsequent treatment
with magnesium achieved debromoethylation to afford cyclo-
propyl oxindole 9a, with an overall poor yield (Scheme 1).
Recently, Marini reported a vinyl selenone-based approach for
the synthesis of spirocyclopropyl oxindoles in aqueous sodium
hydroxide solution.2e Limited choices of substitutions on the
oxindole were reported. A strong base (NaOH) along with
surfactants is necessary for optimal yields.
On the other hand, vinyl sulfonium salts can be easily
prepared with robust and safe protocols, and have demon-
strated diverse applications in the construction of different
carbo- and hetero-cycles.7 In 2012, Lin reported the use of vinyl
sulfonium salts, with DBU as the base in dichloromethane, for
the cyclopropanation of a-amino aryl ketones.8 In the case of
unprotected oxindoles, due to the similar pKa of C3–H and N–H
(ꢀ18.2),9 selective C-3 functionalization could be more chal-
lenging than the case of a-amino aryl ketones. Indeed simple
application of Lin's conditions with oxindole 7a did not produce
satisfactory results. An incomplete conversion and more than
50% of over-alkylated product 10a were observed. During our
optimization, we found that addition of Zn(OTf)2 promoted C-3
Fig.
interests.
1 Oxindoles and spirocyclopropyl oxindoles of medicinal
aShanghai Key Laboratory of Chemical Biology, East China University of Science and
Technology, Shanghai 200237, China. E-mail: xhqian@ecust.edu.cn
bRoche Pharmaceutical Research and Early Development, Roche Innovation Center
Shanghai, Shanghai 201203, China. E-mail: yimin.hu@roche.com
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c6ra24985j
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Table 1 Optimization with oxindole 7aa
Entry
Base (equiv.)
Additive (equiv.)
Solvent
Yield (%)
1
2
3
4
5
6
7
8
DBU (3.0)
TEA (3.0)
—
—
—
—
—
—
DCM
DCM
DCM
DCM
DCM
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
32
30
27
0
DIPEA (3.0)
Pyridine (3.0)
Cs2CO3 (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (2.0)
DBU (4.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
<5
38
56
68
<5
<5
55
70
78
90
91
68
46
50
Mg(OTf)2 (2.0)
Ca(OTf)2 (2.0)
Cu(OTf)2 (2.0.)
Ag(OTf) (2.0)
CuCl2 (2.0)
Zn(OTf)2 (2.0)
Zn(OTf)2 (1.0)
Zn(OTf)2 (2.0)
Zn(OTf)2 (1.0)
Zn(OTf)2 (0.5)
Zn(OAc)2 (1.0)
Ca(OTf)2 (1.0)
9
10
11
12
13
14
15
16
17
18
Scheme 1 Cyclopropanation of unprotected oxindoles.
a
alkylation over N-alkylation. Herein, we report an efficient
cyclopropanation for both N-nonsubstituted and N-substituted
oxindoles with vinyl diphenylsulfonium triate salt mediated by
zinc triate. The ambient reaction conditions are simple, mild,
and devoid of alkali bases. We were pleased to nd that this
cyclopropanation could proceed efficiently with high yields,
Reaction conditions: 7a (0.2 mmol), vinyl diphenyl sulfonium triate
(0.24 mmol), with indicated amount of base and additive, 1 mL
solvent, at room temperature (ca. 21 ꢁC), under air, stirring for 4 h.
Isolated yields are shown.
tolerating a variety of functional groups such as carboxylic acid, withdrawing substituents afforded high yields of desired prod-
hydroxyl, amine, boronic acid, etc. The utility in LSF has also ucts. The substitution position of the oxindole had minimal
been demonstrated with three examples.
inuence on the reaction yields either, with the exception of 7m
Optimization efforts with unprotected indole 7a are summa- and 7n. 1.5 equivalents of Zn(OTf)2 were necessary to obtain full
rized in Table 1. As stated above, partial conversion and a 32% conversion and high yields of 9m and 9n. A broader substrate
isolated yield of product 9a could be obtained by applying scope was demonstrated in Table 2B. Both electron decient
previously reported conditions, with DBU as the base and DCM pyridine 9o and electron rich thiophene 9p were obtained in high
as the solvent (entry 1). Screening of different bases and solvents yields. Remarkably, phenol 7q, boronic ester 7r, and even pyridyl
did not produce any improvement on regioselectivity over N- boronic acid 7s, all underwent cyclopropanation to give the cor-
alkylation (entries 2–5). A marginally improved yield of 38% was responding products 9q–s in good yields. Cyclopropanation on
observed with a polar solvent such as DMF (entry 6). To our medicinally relevant and complex compounds was also performed
delight, addition of 2 equivalents of Mg(OTf)2 promoted the C-3 to demonstrate the utility in LSF (Table 2C). For example, cyclo-
alkylation with a 56% yield of 9a (entry 7). Encouraged by this propanation of Ropinirole (1a), a dopamine agonist used in the
nding, various metal salts were screened. Zn(OTf)2 and Ca(OTf)2 treatment of Parkinson's disease and restless legs syndrome
gave the best yields (entry 8–12). Further renement of condi- (RLS), and bearing a basic tertiary amine, proceeded under our
tions focused on adjusting the amounts and ratio of DBU and standard conditions to form 1b in 85% yield. Ziprasidone (2a), an
Zn(OTf)2 (entries 13–16). We found that reducing the amount of atypical antipsychotic containing a benzisothiazole found in many
Zn(OTf)2 from 2 to 1 equivalent (entry 15 vs. 12) gave a clean signal transduction modulators, also underwent a smooth cyclo-
reaction with full conversion. Over 90% of the desired product 9a propanation to give 2b in 95% yield. Finally, cyclopropanation of
was isolated with almost no N-alkylation product observed by LC/ PF562271 (3a), a focal adhesion kinase inhibitor once in early
MS. The use of Zn(OAc)2 resulted in poorer yields of 9a. Different clinical trials for treatment of cancer, with 1 active methylene
from Zn(OTf)2, reducing the equivalents of Ca(OTf)2 from 2 to 1 group and 2 more unprotected NHs in addition to oxindole NH,
gave only a 50% isolated yield (entry 18 vs. 8).
reacted well to afford 3b in 92% yield. The above results, partic-
With the optimized conditions in hand, we then examined ularly in Tables 2B and C, demonstrated that chemistry described
the scope of oxindole substrates (Table 2). As shown in Table 2A, herein can be applicable for late stage cyclopropanation of
reactions of substrates containing electron-rich or electron- important building blocks and complex drug-like molecules.
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Table 2 Zn(OTf)2-mediated cyclopropanation of oxindoles without Table 3 Cyclopropanation of oxindoles with N-substituentsa
N-substituents
a
Reaction conditions: oxindole (0.2 mmol), vinyl diphenyl sulfonium
triate (0.24 mmol), DBU (0.6 mmol), in 1 mL DMF, at room
b
temperature (21 ꢁC), under air, stirring for 12 h.
Yields in
parentheses correspond to similar conditions with 0.2 mmol of
c
Zn(OTf)2 being used. Reaction conditions: oxindole (0.2 mmol), vinyl
diphenyl sulfonium triate (0.21 mmol), in 1 mL DMSO, 130 ꢁC,
microwave, 1 h. Isolated yields for all substrates described in the table.
To our delight, for substrates with sufficient aqueous solu-
bility, cyclopropanation with vinyl diphenyl sulfonium triate
also proceeded well at room temperature (Scheme 2). Different
from reported vinyl selenone chemistry,2e neither a strong base
(NaOH) nor a surfactant (cetyltrimethyl ammonium bromide)
was needed in our case. Oxindole 11d demonstrated adequate
solubility with DBU in water and reacted with vinyl diphenyl
sulfonium triate smoothly to afford 12d in 93% yield. For
substrates with less optimal aqueous solubility, such as 11a,
a co-solvent system was sufficient to obtain a satisfactory yield
(90% for 12a).
A series of experiments were performed to understand the
effect of Zn(OTf)2. We initially thought that N-alkylation could
be reversible under Zn(OTf)2-mediated conditions, while the C–
C bond formation may be irreversible. Furthermore, the N-
alkylation product could potentially be used to provide a “vinyl
intermediate” for another desirable cyclopropanation in the
a
Reaction conditions for 7b–l, and 7o–s: oxindole (0.2 mmol), vinyl
diphenyl sulfonium triate (0.24 mmol), Zn(OTf)2 (0.2 mmol), DBU
(0.6 mmol), in 1 mL DMF, at room temperature (ca. 21 ꢁC), under air,
b
stirring for 4 h. For 7m and 7n: condition similar to 7b–l with 0.3
mmol of Zn(OTf)2 being used. For 1a, 2a, and 3a: conditions similar
to 7b–l with reaction time extended to 12 h. Isolated yields for all
substrates described in the gure.
c
In addition to N-nonsubstituted oxindoles, we also examined
cyclopropanation with N-substitued oxindole substrates (Table
3). Addition of Zn(OTf)2 is not necessary for high yields, due to
the presence of “N-protecting” substitutions (11a–c). Results are
comparable with or without Zn(OTf)2 (11a and 11d). In the case
of Boc-protected oxindole 11b, the yield with Zn(OTf)2 was lower
than the conditions without Zn(OTf)2 (50% vs. 85%). About 30%
of de-Boc product was observed, presumably due to the Lewis
acidity of Zn(OTf)2. Functional groups such as carboxyl acid
(12d) and primary amine (12e) were well tolerated for cyclo-
propanation. No O-alkylation by-products were observed in the
case of carboxyl acid (11d). For unprotected aniline containing
substrate 11e, the reaction was sluggish under standard condi-
tions with Zn(OTf)2. Partial conversion and N-alkylation were
observed with only 42% product (12e) isolated. In the absence of
Zn(OTf)2, at higher temperature (130 ꢁC) under microwave for 1
hour, 11e did undergo cyclopropanation smoothly with full
conversion, leading to 12e in 82% yield. Only minor amount
(<10% by LC/MS) of the N-alkylation byproduct was observed.
Scheme 2 The use of water as the solvent/co-solvent areaction
conditions: oxindole (0.2 mmol), vinyl diphenyl sulfonium triflate (0.24
mmol), DBU (0.6 mmol), in 1 mL H2O, room temperature (21 ꢁC),
stirring for 4 h. Isolated yield; bconditions similar to above with 0.65 mL
H2O and 0.35 mL DMF as co-solvent. Isolated yield.
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presence of Zn(OTf)2. In order to test this hypothesis, as shown undesired N-alkylation product. A similar result was also
in Scheme 3A, with 3.0 equivalents of DBU and 1.0 equivalent of observed with 7m. Thus we propose that the Zn coordination to
vinyl diphenyl sulfonium triate, oxindole 7a underwent the oxindole nitrogen could account for the observed regiose-
a partial conversion to 8a along with signicant amount of N- lectivity under our Zn-mediated conditions. Furthermore, the
alkylated 10a (cannot be isolated), as suggested by the LC/MS proposed zinc complex 14a could enhance the acidity of the
analysis. We then added 1.0 equivalent of Zn(OTf)2 and benzylic proton which is adjacent to the lactam. Therefore,
a different oxindole 11a, in which the N-alkylation was impos- weaker bases could be applied to signicantly boost functional
sible to occur. No cyclopropanation product 12a could be group compatibility. As shown in Scheme 3D, the Zn complex-
detected up to 12 hours. In Scheme 3B, a similar reaction with ation on the nitrogen could directly block the N-alkylation
oxindole 7a was conducted with Et3N as the base. Interestingly, pathway. Results with oxindole 11e in Table 3 under the Zn-
a different N-alkylation product 13a was observed, and 13a medicated conditions also suggest that an extra coordinating
could be even isolated. The reaction of isolated 13a in the group, such as the amino group of aniline, could presumably
presence of 1.0 equivalent of oxindole 11a, 1 equivalent of complete with the complexation of Zn(OTf)2 to the oxindole
Zn(OTf)2, and 3.0 equivalents of DBU in DMF gave no spi- nitrogen thereby slowing down the reaction. This observation
rocyclopropyl oxindole 12a. Conversion of 13a to 10a was further corroborates the depicted mechanism in Scheme 3D.
detected by LC/MS. The above results indicated that there was
In summary, we have developed an efficient cyclo-
no transfer of vinyl group (10a) or vinyl group precursor (13a) to propanation method for both N-nonsubstituted and N-
11a. This suggested that the role of Zn(OTf)2 was not to promote substituted oxindoles with the commercially readily available
reversibility of N-alkylation, thereby offering a vinyl interme- vinyl diphenylsulfonium triate. The conditions are convenient
diate for subsequent cyclopropanation reaction leading to more and mild, with no requirement of inert atmosphere or alkalis
desired cyclopropyl products.
bases. A broad reaction scope is observed, with applications on
In Scheme 3C, we studied the reaction in more detail with late stage cyclopropanation of three medicinally interesting
oxindole 7n. Substitution close to the oxindole nitrogen showed compounds. We envision that this synthetic methodology could
negative inuence on the effect of Zn(OTf)2. For example, 1.5 be widely adopted by the medicinal chemistry community.
equivalents of Zn(OTf)2 were necessary to block the N-alkyl- Particularly, the employment of zinc triate can block the N-
ation, suggesting that the adjacent Cl could hinder the alkylation byproduct using N-nonsubstituted oxindoles. It is
complexation of nitrogen with Zn, which in turn rendered the conceivable that such concept could be applied in other cases
where regioselectivity issue exists.
Acknowledgements
We thank Professor Guangbin Dong (University of Chicago) and
Professor Xiaoguang Lei (Peking University) for helpful discus-
sions. We also thank Mr Sheng Zhong (Roche Innovation Center
Shanghai) for mass spectrometry.
Notes and references
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Scheme 3 Investigation of the reaction mechanism. aRatio deter-
mined by LC/MS; bisolated by crystalization; cisolated by silica gel
chromatography.
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