Self-induced stereoselective in situ trifluoromethylation: Preparation of spiro[indoline-3,3′-quinoline] via palladium-catalyzed cascade reaction

Article abstract of DOI:10.1021/ol501246f

An efficient method to prepare 1′H-spiro[indoline-3,3′- quinoline]-2′,4′-diones and their trifluoromethylated products was developed via a palladium-catalyzed Sonogashira coupling/Wacker-type oxypalladation/cyclization cascade reaction. The amount of wate

Full text of DOI:10.1021/ol501246f

Letter
pubs.acs.org/OrgLett
Self-Induced Stereoselective in Situ Trifluoromethylation:
Preparation of Spiro[indoline-3,3′-quinoline] via Palladium-Catalyzed
Cascade Reaction
Hongjian Song, Yongxian Liu, Yuxiu Liu, and Qingmin Wang*
State Key Laboratory of Elemento-Organic Chemistry, Research Institute of Elemento-Organic Chemistry, Collaborative Innovation
Center of Chemical Science and Engineering (Tianjin), Nankai University, Tianjin 300071, China
S
* Supporting Information
ABSTRACT: An efficient method to prepare 1′H-spiro-
[indoline-3,3′-quinoline]-2′,4′-diones and their trifluorome-
thylated products was developed via a palladium-catalyzed
Sonogashira coupling/Wacker-type oxypalladation/cyclization
cascade reaction. The amount of water in the reaction system
played an important role in the in situ trifluoromethylation
reaction, and the trifluoromethylation exhibited excellent
molecular self-induced stereoselectivity.
alladium-catalyzed intramolecular attack of nucleophiles on
the π-ligands of palladium−alkyne complexes is a powerful
unprecedented competitive intermolecular oxypalladation of
the alkyne, in which trace water in the reaction system acted as
a nucleophile (Scheme 1). Moreover, we found that the
P
method for the construction of heterocycles.1 For example,
intramolecular aminopalladation and oxypalladation are widely
used to synthesize nitrogen- and oxygen-containing hetero-
cyclic compounds, respectively.2 In addition, oxy/amino-
palladation−reductive elimination domino reactions with
organopalladium derivatives can be used in the synthesis of
regiospecifically substituted heterocyclic compounds.3 Unlike
the reactions mentioned above, intermolecular oxypalladation
reactions of alkynes have not been extensively investigated.4 In
this study, we used a palladium-catalyzed Sonogashira
coupling/Wacker-type oxypalladation/cyclization cascade reac-
tion to construct a spiro[indoline-3,3′-quinoline]skeleton.
Spirocyclic indoline moieties are found in many natural
products5 and pharmaceuticals.6 Their biological activities and
challenging structures make them attractive synthetic targets,
and numerous strategies for their synthesis have recently been
developed.7 Spiro[indoline-3,3′-quinoline] is an important
scaffold in various natural products, but only a few synthetic
methods, including an FeCl3-catalyzed tandem 1,5-hydride
transfer/cyclization,8 a Michael/Michael cascade reaction,9 and
a domino Heck reaction/C−H arylation,10 have been reported.
In addition, the reported methods have certain limitations: for
example, in one case, the starting material is limited to
oxindoles, and in other cases, the starting materials are difficult
to synthesize. The method described herein provides a new,
operationally simple strategy for the synthesis of these spiro
compounds from readily accessible starting materials.
Scheme 1. Palladium-Catalyzed Competitive Intermolecular
Oxypalladation of Alkynes
amount of water in the system regulated the in situ
trifluoromethylation of the cascade reaction products 3.12
Unlike previously reported trifluoromethylation methods,13 our
method relies on a trifluoromethyl source that is generated in
situ. Herein, we describe this interesting cascade reaction and
the in situ trifluoromethylation reaction in detail, and we
discuss the overall mechanism of the process.
First, we optimized the conditions by investigating the
palladium catalyst, ligand, base, and solvent (Table 1). With 5
mol % Pd(OAc)2 and 20 mol % PPh3, Sonogashira coupling
product 3aa′ was obtained in 60% yield (entry 1). When the
amounts of catalyst and phosphine ligand were doubled, a 15%
yield of cascade reaction product 3aa was obtained in addition
to 3aa′ (entry 2). Little to no reaction occurred when
triphenylphosphine was replaced by P(o-tol)3 or X-Phos
(entries 3 and 4) or when Pd(OAc)2 was replaced with
PdCl2(MeCN)2 or PdCl2(PhCN)2 (entries 5 and 6). We also
tried Pd2(dba)3 (entry 7) and Pd(PPh3)4 (entry 8) as catalysts,
but the yield of the coupling product was low (35%) with the
Our method arose from a pleasantly surprising discovery we
made during an attempt to synthesize 6,7-dihydro-5H-indolo-
[2,3-c]quinoline (4aa) from simple precursors 1a and 2a.
Instead of the expected product, we obtained spiro compound
3aa, the structure of which was confirmed by X-ray diffraction
analysis.11 This compound was presumed to have formed via an
Received: May 2, 2014
© XXXX American Chemical Society
A
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Letter
Table 1. Optimization of Reaction Conditions
Scheme 2. Preparation of 1′H-Spiro[indoline-3,3′-
a
quinoline]-2′,4′-diones
entry
PdLn (mol %)
PXm (mol %)
3aa′
3aa
1
2
3
4
5
6
7
8
Pd(OAc)2 (5%)
PPh3 (20%)
PPh3 (40%)
P(o-tol)3 (40%)
X-Phos (40%)
X-Phos (40%)
X-Phos (40%)
−
60%
61%
<5%
−
−
−
35%
56%
−
35%
49%
45%
30%
5%
<5%
15%
−
−
−
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
Pd(OAc)2 (10%)
PdCl2(MeCN)2 (10%)
PdCl2(PhCN)2 (10%)
Pd2(dba)3 (5%)
−
−
Pd(PPh3)4 (10%)
Pd(OAc)2 (20%)
Pd(OAc)2 (20%)
Pd(OAc)2 (20%)
Pd(OAc)2 (20%)
Pd(OAc)2 (20%)
Pd(OAc)2 (20%)
−
10%
76%
15%
−
10%
<5%
22%
a
9
PPh3 (80%)
PPh3 (80%)
PPh3 (80%)
PPh3 (80%)
PPh3 (80%)
PPh3 (80%)
PPh3 (80%)
b
10
c
11
d
12
e
a
13
The yields given in the scheme are isolated yields.
f
14
g
15
Pd(OAc)2 (20%)
51%
−
a
b
c
substituent on the nitrogen of 2 had little influence: 3ae and
3af were obtained from the reactions of 1a with 2e and 2f in
78% and 46% yields, respectively.
Isolated yield. 4 equiv of Cs2CO3 were used instead of K2CO3. 4
equiv of NEt3 were used. Acetonitrile was used as the solvent, and the
mixture was heated for 48 h. Toluene was used as the solvent, and the
mixture was heated for 48 h. Tetrabutylammonium bromide was not
d
e
f
As mentioned above, water regulated the in situ trifluor-
omethylation of coupling products 3. To study the effect of the
water, we conducted a series of experiments on the relationship
between the amount of water and the proportion of
trifluoromethylated product 5aa. We observed that the
proportion of 5aa increased as the amount of water was
increased; the proportion peaked at 4 equiv of water. When the
amount of water was increased above 4 equiv, an extended
reaction time was required and the yield of 5aa was low (see
Supporting Information (SI)).
g
added. 4 Å molecular sieves were added.
former, and yields similar to those shown in entry 2 were
obtained with the latter. To our delight, when we increased the
amount of Pd(OAc)2 to 20 mol % and the amount of the PPh3
to 80 mol %, we obtained 3aa in 76% yield (entry 9). Next we
investigated the effect of the base. When Cs2CO3 was used
instead of K2CO3, 3aa′ and 3aa were obtained in 35% and 15%
yields respectively (entry 10). However, with triethylamine,
only the coupling product was obtained (49%, entry 11). We
also evaluated other solvents: with acetonitrile, 3aa′ and 3aa
were obtained in 45% and 10% yields, respectively, after a
prolonged reaction time (entry 12); the yields were even lower
in toluene (entry 13). These low yields were probably due to
the poor solubility of K2CO3 in these solvents. The phase-
transfer catalyst strongly influenced the reaction: the yields
were much lower in the absence of tetrabutylammonium
bromide (entry 14).14 We also carried out a control reaction
with molecular sieves and found that only coupling product
3aa′ was obtained (51% yield, entry 15).
Notably, the in situ trifluoromethylation reaction exhibited
excellent stereoselectivity in the only obtained product, CF3,
and the adjacent phenyl is in a trans position that was
confirmed by the X-ray diffraction analysis of 5aa.15 Similarly,
the reaction of 3aa with trimethyl(trifluoromethyl)silane also
afforded the trifluoromethylation product 5aa stereospecifically
1
which was determined by the crude H NMR spectrum of the
reaction mixture (Scheme 3).
We also examined the substrate scope of this new method for
introducing a trifluoromethyl group into organic molecules
(Scheme 4). Impressively, intentionally adding water (4 equiv)
was sufficient to speed up the reaction (see SI). Substituted 1
With the optimum conditions in hand, we investigated the
substrate scope of the reaction (Scheme 2). First, we evaluated
the electronic effects of substituents on the benzene ring of 1 by
carrying out reactions of 1a−1g with 2a to afford compounds
3aa−3ga, respectively. We found that substrates with electron-
donating substituents (1f and 1g) and with weak electron-
withdrawing substituents (1b and 1c) afforded the desired spiro
compounds (3fa, 3ga, 3ba, and 3ca, respectively) in good to
excellent yields. Even when there was a strong electron-
withdrawing group, such as a methoxycarbonyl or a nitrile, on
the benzene ring, the desired products (3da and 3ea) were still
obtained in moderate yields. The position of the electron-
withdrawing Cl substituent had no effect on the reaction (3ba
and 3ca). In contrast, the introduction of a substituent on the
benzene ring of 2 adversely affected the yields of spiro products
3ab−3ad. In particular, spiro product 3ad was not obtained
from the reaction of ester-substituted aniline 2d with 1a. The
Scheme 3. Control Experiments
B
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Letter
added to the reaction system, only Sonogashira coupling
product 3aa′ was obtained (Table 1, entry 15). These results
suggest that the oxygen of the carbonyl group comes from
water under these reaction conditions. Compound 6aa, the
product of an intramolecular aminopalladation reaction, was
obtained when bromobenzene (1.2 equiv) was added to the
reaction system (Scheme 5c); this result indicates that the
selectivity between the intermolecular Wacker-type oxy-
palladation and the intramolecular aminopalladation was due
to the high reaction energy barrier of intramolecular amino-
palladation of 3aa′. Compound 3aa could also be obtained in
20% yield from the reaction of 1a with 2a (Scheme 5d).
On the basis of the results described above, we propose the
reaction mechanism depicted in Scheme 6 for substrates 1a and
Scheme 4. Water-Regulated Trifluoromethylation of 1′H-
a
Spiro[indoline-3,3′-quinoline]-2′,4′-diones
Scheme 6. Proposed Mechanism
a
The configuration of compounds 5 is the relative configuration.
reacted with 2 to afford trifluoromethylation products 5 in
moderate to good yields. The reaction of methyl-substituted
aniline 1g with 2a afforded the highest proportion of the
trifluoromethylation product (3ga/5ga = 1:2.9). When 4-
methylbenzenesulfonamide 2a was replaced with methane-
sulfonamide 2e in the reaction with 1a, the proportion of the
trifluoromethylation product (5ae) increased slightly. In
addition, all the products 5 exhibited excellent stereospecificity
(see SI).
To gain insight into the mechanism, we performed a series of
control experiments (Scheme 5). 3aa′ could be transformed
Scheme 5. Control Experiments
2b. First, palladium(II) acetate is reduced to zerovalent
palladium by the excess triphenylphosphine. Then, 1a and 2a
undergo a Sonogashira coupling reaction to form 3aa′ (cycle I).
The π-ligand of palladium−alkyne intermediate C forms after
oxidative addition of bromobenzene. In the subsequent step,
competitive intramolecular aminopalladation (route 1) and
regioselective Wacker-type intermolecular oxypalladation
(routes 2 and 3) can occur to form three different intermediates
(D1, D2, and D3), which lead to three different products (4aa,
8aa, and 3aa, respectively). D1 and D2 are seven-membered
cyclic palladium intermediates, whereas D3 is a six-membered
cyclic intermediate. Because we obtained only 3aa, we speculate
that the energy barrier for the formation of D1 and D2 is
substantially higher than that for the formation of D3, which
gives the process its high selectivity. Intermediate 4aa″, which
forms by reductive elimination, affords 3aa by a sequential enol
isomerization, nucleophilic attack on the carbonyl carbon of the
trifluoroacetyl group, and removal of the trifluoromethyl group.
into target compound 3aa under the cascade reaction
conditions (Scheme 5a), which indicates the occurrence of a
tandem Sonogashira coupling followed by a Wacker-type
oxypalladation. To investigate the source of the carbonyl
oxygen in the product, we added 4 equiv of H218O to the
reaction system and found that more than 30% of the oxygen-
18 was detected in 3aa and more than 50% was detected in 5aa
(Scheme 5b). Conversely, when 4 Å molecular sieves were
−
Subsequent stereoselective nucleophilic attack of CF3 on the
ketone carbonyl group of 3aa affords 5aa′ which is supposed to
be a reversible reaction. In the presence of water, 5aa′ is readily
protonated to give 5aa, and the amount of water will influence
the equilibrium of the reversible reaction and then result in a
different ratio of 3aa and 5aa.
C
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Letter
Chemistry for Organic Synthesis; Negishi, E.-i., Ed.; John Wiley &
Sons: New York, 2002; Vol. II, pp 2227−2244.
In summary, we have developed an efficient method to
prepare1′H-spiro[indoline-3,3′-quinoline]-2′,4′-diones and
their trifluoromethylated products via a palladium-catalyzed
Sonogashira coupling/Wacker-type oxypalladation/cyclization
cascade reaction. The Wacker-type intermolecular oxypallada-
tion reaction of an alkyne that occurred during this process has
rarely been investigated. We found that the amount of water
played an important role in the in situ trifluoromethylation
reaction and the reaction exhibited excellent stereoselectivity
via a molecular self-induced mechanism. Further studies on the
application of this cascade reaction are in progress in our
laboratory.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data for 1, 2, 3, 5, 6,
and related spectra are included in the Supporting Information.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
(9) Mao, H. B.; Lin, A. J.; Tang, Y.; Shi, Y.; Hu, H. W.; Cheng, Y. X.;
Zhu, C. J. Org. Lett. 2013, 15, 4062.
Corresponding Author
*E-mail: wangqm@nankai.edu.cn; wang98@263.net.
Notes
(10) Piou, T.; Neuville, L.; Zhu, J. P. Org. Lett. 2012, 14, 3760.
(11) CCDC 980718 contains the supplementary crystallographic
data for 3aa. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(12) For water-promoted trifluoromethylation, see: (a) Hu, M. Y.;
Ni, C. F.; Hu, J. B. J. Am. Chem. Soc. 2012, 134, 15257. (b) He, Z. B.;
Luo, T.; Hu, M. Y.; Cao, Y. J.; Hu, J. B. Angew. Chem., Int. Ed. 2012,
51, 3944.
(13) For reviews of trifluoromethylation, see: (a) Schlosser, M.
Angew. Chem., Int. Ed. 2006, 45, 5432. (b) Ma, J. A.; Cahard, D. J.
Fluorine Chem. 2007, 128, 975. (c) Ma, J. A.; Cahard, D. Chem. Rev.
2008, 108, PR1. (d) Tomashenko, O. A.; Grushin, V. V. Chem. Rev.
2011, 111, 4475. (e) Furuya, T.; Kamlet, A. S.; Ritter, T. Nature 2011,
473, 470.
(14) The role of phase transfer catalyst in coupling reaction, see:
(a) Reetz, M. T.; Westermann, E. Angew. Chem., Int. Ed. 2000, 39, 165.
(b) Lu, B. Z.; Wei, H. X.; Zhang, Y. D.; Zhao, W. Y.; Dufour, M.; Li, G.
S.; Farina, V.; Senanayake, C. H. J. Org. Chem. 2013, 78, 4558.
(15) CCDC 995418 contains the supplementary crystallographic
data for 5aa. These data can be obtained free of charge from the
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif.
■
We are grateful to the National Key Project for Basic Research
(2010CB126100), the National Natural Science Foundation of
China (21132003, 21121002, 21372131), and the Specialized
Research Fund for the Doctoral Program of Higher Education
(20130031110017) for generous financial support for our
research.
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