Ruthenium-Catalyzed Asymmetric Allylic Alkylation of Isatins

Ruthenium-Catalyzed Asymmetric Allylic Alkylation of Isatins

Letter

Barry M. Trost,* Christopher A. Kalnmals, Divya Ramakrishnan, Michael C. Ryan, Rebecca W. Smaha,

and Sean Parkin

Cite This: https://dx.doi.org/10.1021/acs.orglett.0c00504

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sı Supporting Information

ABSTRACT: A new ruthenium-based catalytic system for

branched-selective asymmetric allylic alkylation is disclosed and

applied to the synthesis of chiral isatin derivatives. The catalyst,

which is generated in situ from commercially available CpRu-

(

MeCN) PF and a BINOL-derived phosphoramidite, is both

3 6

highly active (TON up to 180) and insensitive to air and moisture.

Additionally, the N-alkylated isatins accessible using this method-

ology are versatile building blocks that are readily transformed into

chiral analogs of achiral drug molecules.

symmetric allylic alkylation (AAA) is a powerful

Scheme 1. Summary of Prior Work and Initial Results

technique for the enantioselective formation of carbon−

carbon and carbon−heteroatom bonds. With unsymmetrically

substituted electrophiles, linear and branched products can

form and while the regioselectivity can be tuned using ligands,

it is typically dictated by the metal. Although many metals can

catalyze allylic alkylations, palladium and iridium are the most

widely used. While both metals tolerate a broad range of

nucleophiles, they exhibit complementary regioselectivity; Pd-

catalyzed allylic alkylations are typically linear-selective,

whereas branched products are favored with iridium.

Although iridium is the most frequently used metal for

branched-selective allylic alkylation, ruthenium is an attractive

alternative; while both metals can catalyze branched-selective

allylic alkylations with carbon and heteroatom nucleophiles,

ruthenium is roughly six times cheaper than iridium.

Curiously, while the use of ruthenium in branched-selective

allylic alkylation predates the use of iridium, the former has

12,13

AAA reactions.

Using cinnamyl chloride (8a) as a model

received considerably less attention.

electrophile, we initiated our screening with sodium azide (4)

but observed no reaction, even at 40 °C (Scheme 2). Switching

to N-Boc sulfonamide 5 gave full conversion, and while the

linear regioisomer was favored, the branched product was

isolated in 81:19 er. With potassium phthalimide (6),

regioselectivity improved to 2:1 in favor of the branched

product, while enantioselectivity remained the same. Gratify-

ingly, with isatin (7a), near-perfect regioselectivity was

observed, and while the conversion based on the nucleophile

As part of our ongoing interest in transition-metal-catalyzed

cycloisomerization reactions, we recently developed a novel

ligand L1 that, in conjunction with CpRu(MeCN) PF ,

catalyzed a stereoselective interrupted metallo-ene reaction

that transformed 1,6- and 1,7-chlorodienes 1 into ﬁve- and six-

membered rings 2 (Scheme 1a). During these studies, we

discovered that our Ru/L1 system could also function as an

allylic alkylation catalyst. When 1a was subjected to the

standard cycloisomerization conditions, none of the expected

product 2a was observed, but allylic alcohol 3 formed as a

single regioisomer in a promising 93:7 er (Scheme 1b).

Intrigued by this result, we set out to investigate this

unexpected reactivity more closely. We were particularly

interested in evaluating nitrogen nucleophiles, which in

Received: February 7, 2020

10,11

contrast to carbon and especially oxygen nucleophiles

have only been used a handful of times in intermolecular Ru-

XXXX American Chemical Society

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 2. Evaluation Nitrogen Nucleophiles

simply replacing triethylamine with DIPEA enabled complete

conversion of both reaction partners and led to substantially

increased yields of 9aa, even at reduced catalyst loadings

(

entries 4 and 5). Fortunately, these changes had no impact on

either regio- or enantioselectivity.

While acetone was optimal for selectivity, we found that

reactions in this solvent were often accompanied by the

formation of aldol product 11, resulting in diminished yields of

aa. We hypothesized that by using a less enolizable carbonyl-

containing solvent, we could both avoid the formation of aldol

side products and retain the selectivity observed with acetone.

While ethyl acetate (entry 6) oﬀered no improvement, both 3-

pentanone (entry 7) and dimethyl carbonate (entry 8) gave

increased yields and high enantioselectivities of 96.5:3.5 er and

All reactions at 0.05 mmol scale at 0.5 M. Yields are isolated yields of

pure branched isomer. Conversion and branched−linear (b/l) ratios

determined by crude H NMR; er determined by chiral HPLC.

Room temperature to 40 °C. Without Et N.

99:1 er, respectively. Although dimethyl carbonate gave better

results than 3-pentanone in this particular case, we found that

this was not general and evaluated both solvents in most

subsequent examples.

was only 50%, the branched product was obtained in 98.5:1.5

er.

While the excellent regio- and enantioselectivity were

certainly encouraging, we were excited by this result for a

variety of other reasons. In addition to being versatile synthetic

In evaluating the scope of nucleophiles (Scheme 3), we were

pleased to ﬁnd that halogens were generally well-tolerated.

With 4-bromoisatin, near-perfect regioselectivity was observed

and 9ba was isolated in 82% yield and 93:7 er. While the

branched−linear ratio decreased to 11:1 with 5-ﬂuoroisatin

intermediates, isatins and isatin derivatives are common

motifs in biologically active molecules. Furthermore, while

isatins are common substrates for asymmetric catalysis, most

(

7c), excellent regio- and enantioselectivities were obtained

transformations target the highly electrophilic C3 carbonyl;

general asymmetric methods that utilize isatins as nucleophiles

with the analogous 5-chloro- (7d) and 5-iodo- (7e) substrates.

This trend continued for 6-chloroisatin (7f) and 6-bromoisatin

7,18

are rare.

(

7g), which aﬀorded 9fa and 9ga, respectively, in comparable

Having identiﬁed isatin as a promising nucleophile for

yields and selectivities. Although halogenation at the 7-position

resulted in reduced selectivityperhaps due to increased steric

hindrance adjacent to the nucleophilic sitegood reactivity

was retained and 9ha was isolated in 55% yield. With 4,6-

diﬂuoroisatin, 9ia formed with 13:1 branched−linear selectiv-

ity and 99:1 er. While the regioselectivity dropped with a 5,6-

dihalogenated substrate, 9ja was still isolated in 59% yield.

Electron-rich isatins were also suitable nucleophiles.

Methoxy substituents at the 5- and 6-positions were equally

well tolerated, aﬀording 9ka and 9la, respectively, with nearly

identical levels of regio- and enantioselectivity. With 5-

methylisatin, 9ma was isolated in 70% yield in 91:9 er, and

with 4,6-dimethylisatin, 9na was isolated in 62% yield with

near-perfect enantioselectivity. Finally, fusing an additional ring

further study, we set out to optimize the reaction conditions

(Table 1). Changing the solvent from acetone (entry 1) to

either DCE (entry 2) or THF (entry 3) did not improve

conversion of 7a, and while excellent regioselectivity was

maintained, enantioselectivity dropped slightly. Curiously,

while incomplete conversion of 7a was observed regardless

of the solvent, the electrophile (8a) was always fully consumed.

Examination of the crude reaction mixtures revealed signiﬁcant

amounts of triethylammonium salt 10, suggesting that a side

reaction between the base and the allylating agent was

responsible for the low yields of 9aa.

Fortunately, this undesired pathway, which occurred without

the catalyst, could be mitigated by using a diﬀerent base.

Whereas Cs CO aﬀorded a complicated mixture of products,

Table 1. Reaction Optimization

entry

solvent

acetone

DCE

base

yield

Et N

5.0

1.25

0.50

50%

98.5:1.5

92:8

90:10

99.5:0.5

>99.5:0.5

96:4

96.5:3.5

99:1

Et N

31%

30%

75%

76%

66%

83%

91%

THF

Et N

acetone

EtOAc

DIPEA

40 °C

3-pentanone

(MeO) CO

Yields are isolated yields. Conversion and branched−linear (b/l) selectivity determined by crude H NMR; er determined by chiral HPLC. 0.050

mmol scale at 0.5 M. Conversion of isatin. 0.20 mmol scale at 2.0 M. 0.50 mmol scale at 5.0 M.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

Scheme 3. Scope of Nucleophiles

Scheme 4. Scope of Electrophiles

All reactions performed on 0.5 mmol scale at 5.0 M. Yields are

isolated yields of pure branched isomer. Branched−linear (b/l) ratios

determined by crude H NMR; er determined by chiral HPLC.

determined by crude H NMR; er determined by chiral HPLC. X =

Cl. Initial reaction stirred overnight at 40 °C, then 0.5 mol %

CpRu(MeCN) PF and 0.6 mol % L1 were added, and reaction

to the isatin core had no adverse eﬀects, and 9oa was isolated

in 64% yield and 94:6 er.

stirred overnight at 40 °C. X = Br.

Substituted cinnamyl chlorides were also suitable electro-

philes, but they did not fully react under the standard reaction

conditions. Fortunately, full conversion could be achieved by

adding a second charge of catalyst (Scheme 4). Similar yields

and selectivities were obtained with ortho- (9ab), meta- (9ac),

and para-substituted (9ad) aromatic rings. While extending

the π-system did not impact the yield of 9de, regio- and

enantioselectivity decreased slightly. Alkyl-substituted allylic

halides were also viable substrates. Switching from cinnamyl

chloride to crotyl chloride (8f) had a negligible impact on the

branched−linear ratio of 9af, which was isolated in 78% yield

and 85:15 er. Replacing the methyl group on the allyl fragment

with an alkyne aﬀorded 9mg in 40% yield due to incomplete

conversion and a reduced 4:1 branched−linear ratio.

loading, all reactions were performed in bulk solvents under

ambient atmosphere. Moreover, all reactions were carried out

at high concentration in environmentally benign solvents.

Finally, our process is scalable; on 2.0 mmol scale, 9da was

isolated in 73% yield, albeit with diminished branched−linear

selectivity (11:1) and enatioselectivity (90:10 er).

To demonstrate the utility of our products, we used them to

synthesize analogs of several biologically active molecules.

Unlike the predominantly achiral literature compounds we

targeted, our derivatives always contain enantioenriched N-allyl

moieties which provide versatile chiral handles for structure−

activity relationship studies (Scheme 5). Oleﬁnation of 9da

with a (2-furyl)methyl Wittig reagent furnished 12, which

resembles the anti-inﬂammatory drug candidate tenidap.

Semithiocarbazide condensed with 9af to aﬀord metisazone

analog 13 in near-quantitative yield, while condensation of 9ab

with 3-(triﬂuoromethyl)aniline provided access to a relative of

We were pleased to ﬁnd that allylic bromides (8h−8j) were

also suitable electrophiles, and while the regioselectivities with

these substrates were lowerperhaps due to higher back-

ground reactivityenantioselectivities were excellent. Partial

conversion of Meldrum’s acid derived electrophile 8h

contributed to the moderate yield of 9mh, which was

nonetheless isolated in 95:5 er. Allylic bromides with protected

hydroxymethyl (8i) and aminomethyl (8j) side chains reacted

uneventfully, giving rise to 9ei and 9mj in 93:7 er and 98:2 er,

respectively. The absolute conﬁguration of 9mj was unequiv-

ocally determined to be (R) by X-ray crystallography (CCDC

GAL-3 antagonist HT-2157 (14). In the presence of basic

peroxide, 9da was quantitatively converted to 15, a notable

result given that structurally similar anthranilic acids appear in

both natural products (e.g., JBIR-120) and drugs (e.g.,

tromaril). In acetic acid, 4,5-dimethyl-1,2-phenylenediamine

condensed with 9da to aﬀord quinoxaline 16, which maps

perfectly onto the aromatic core of the antiarthritic drug

981346), and the stereochemistry of all adducts 9 was

candidate rabeximod. In the presence of TBHP, the same

assigned by analogy. While monosubstituted electrophiles are

well-suited for our reaction, di- and trisubstituted electrophiles

are unreactive. Allylic alkylations catalyzed by other branched-

diamine reacted with 9ja to generate 17, which contains a

tetracyclic benzimidazole scaﬀold similar to the one found in

toposiomerase inhibitor 18. Finally, treating 9ab with a

selective metalsincluding irdium, tungsten, and molybde-

combination of benzaldehyde and tosyl hydrazone promoted a

27,28

num exhibit similar limitations.

ring expansion to generate quinolinone 19,

providing

In addition to exhibiting broad scope and good selectivities,

our method is quite practical. In spite of the low catalyst

convenient access to chiral, N-substituted derivatives of the

viridicatin family of alkaloids.

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

The Supporting Information is available free of charge at

Letter

Scheme 5. Derivatization Reactions

ASSOCIATED CONTENT

sı Supporting Information

■

https://pubs.acs.org/doi/10.1021/acs.orglett.0c00504.

Experimental procedures, characterization data, and

H/ C NMR spectra for 8, 9, 12−17, and 19 (PDF)

Accession Codes

CCDC 1981346 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif , or by emailing

data_request@ccdc.cam.ac.uk , or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

Corresponding Author

■

Barry M. Trost − Department of Chemistry, Stanford University,

Stanford, California 94305, United States; orcid.org/0000-

001-7369-9121 ; Email: bmtrost@stanford.edu

Authors

Christopher A. Kalnmals − Department of Chemistry, Stanford

University, Stanford, California 94305, United States;

orcid.org/0000-0003-3233-290X

Divya Ramakrishnan − Department of Chemistry, Stanford

University, Stanford, California 94305, United States

Michael C. Ryan − Department of Chemistry, Stanford

University, Stanford, California 94305, United States

Rebecca W. Smaha − Department of Chemistry, Stanford

University, Stanford, California 94305, United States;

orcid.org/0000-0002-8349-2615

Sean Parkin − Department of Chemistry, University of Kentucky,

Lexington, Kentucky 40506, United States; orcid.org/0000-

001-5777-3918

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.orglett.0c00504

Author Contributions

^§C.A.K. and D.R. contributed equally.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

We thank the Tamaki Foundation and Chugai Pharmaceuticals

for their generous partial ﬁnancial support of our program. Part

of this work was performed at the Stanford Nano Shared

Facilities (SNSF), supported by the National Science

Foundation under Award ECCS-1542152. D.R. thanks

Stanford Chemistry for two Undergraduate Summer Research

Fellowships. We also thank Dr. Elumalai Gnanamani (Stanford

University) and Dr. Jana Maclaren (Stanford University) for

assistance in obtaining a crystal structure of 9mj.

In conclusion, we discovered a new branched-selective allylic

alkylation catalyst and used it to achieve a regio- and

enantioselective synthesis of N-alkylated isatins. In addition

to being a rare example of Ru-catalyzed asymmetric allylic

alkylation using nitrogen nucleophiles, this process is also just

the third general asymmetric method to use isatins as

nucleophiles. Our catalyst is both active and robust and

exhibits good levels of regio- and enantioselectivity across a

broad range of nucleophiles and electrophiles. Finally, our

products are excellent building blocks that can be rapidly

transformed into a variety of structurally diverse natural

product and drug analogs.

REFERENCES

■

(

1) For an overview of this topic, see: Transition Metal Catalyzed

Enantioselective Allylic Substitution in Organic Synthesis; Kazmaier, U.,

Ed.; Topics in Organometallic Chemistry, Vol. 38; Springer-Verlag:

Berlin, 2012.

2) (a) Helmchen, G.; Dahnz, A.; Dubon, P.; Schelwies, M.;

Weihofen, R. Iridium-catalysed asymmetric allylic substitutions. Chem.

(

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

18697 −18704. (f) Suzuki, Y.; Seki, T.; Tanaka, S.; Kitamura, M.

Letter

Commun. 2007, 675−691. (b) Hartwig, J. F.; Pouy, M. J. Iridium-

Catalyzed Allylic Substitution. In Iridium Catalysis; Andersson, P., Ed.;

Topics in Organometallic Chemistry, Vol. 34; Springer-Verlag: Berlin,

Intramolecular Tsuji-Trost-type Allylation of Carboxylic Acids:

Asymmetric Synthesis of Highly π -Allyl Donative Lactones. J. Am.

Chem. Soc. 2015, 137, 9539−9542. (g) Egger, L.; Tortoreto, C.;

2010; pp 169 −208. (c) Hartwig, J. F.; Stanley, L. M. Mechanistically

Driven Development of Iridium Catalysts for Asymmetric Allylic

Substitution. Acc. Chem. Res. 2010, 43, 1461−1475. (d) Liu, W.-B.;

Xia, J.-B.; You, S.-L. Iridium-Catalyzed Asymmetric Allylic Sub-

stitutions. In Transition Metal Catalyzed Enantioselective Allylic

Substitution in Organic Synthesis; Kazmaier, U., Ed.; Topics in

Organometallic Chemistry, Vol. 38; Springer-Verlag: Berlin, 2012;

pp 155 −209. (e) Tosatti, P.; Nelson, A.; Marsden, S. P. Recent

advances and applications of iridium-catalysed asymmetric allylic

substitution. Org. Biomol. Chem. 2012, 10, 3147−3163. (f) Cheng, Q.;

Tu, H.-F.; Zheng, C.; Qu, J.-P.; Helmchen, G.; You, S.-L. Iridium-

Catalyzed Asymmetric Allylic Substitution Reactions. Chem. Rev.

Achard, T.; Monge, D.; Ros, A.; Fernandez, R.; Lassaletta, J. M.;

Lacour, J. Regio- and Enantioselective Allylation of Phenols via

Decarboxylative Allylic Etherification of Allyl Aryl Carbonates

Catalyzed by (Cyclopentadienyl)ruthenium(II) Complexes and

Pyridine-Hydrazone Ligands. Adv. Synth. Catal. 2015, 357, 3325−

3331. (h) Shinozawa, T.; Terasaki, S.; Mizuno, S.; Kawatsura, M.

Kinetic Resolution of Racemic and Branched Monosubstituted Allylic

Acetates by a Ruthenium-Catalyzed Regioselective Allylic Ether-

ification. J. Org. Chem. 2016, 81, 5766−5774.

(11) For an alternative approach, see: Trost, B. M.; Fraisse, P. L.;

Ball, Z. T. A Stereospecific Ruthenium-Catalyzed Allylic Alkylation.

Angew. Chem., Int. Ed. 2002, 41, 1059−1061.

4) Zhang, S.-W.; Mitsudo, T.; Kondo, T.; Watanabe, Y. Ruthenium

019, 119, 1855−1969.

3) Johnson Matthew Price Charts. http://www.platinum.matthey.

com/prices/price-charts (accessed July 9, 2019).

(12) (a) Matsushima, Y.; Onitsuka, K.; Kondo, T.; Mitsudo, T.;

Takahashi, S. Asymmetric Catalysis of Planar-Chiral Cyclopentadie-

nylruthenium Complexes in Allylic Amination and Alkylation. J. Am.

Chem. Soc. 2001, 123, 10405−10406. (b) Kanbayashi, N.; Takenaka,

K.; Okamura, T.; Onitsuka, K. Asymmetric Auto-Tandem Catalysis

with a Planar-Chiral Ruthenium Complex: Sequential Allylic

Amidation and Atom-Transfer Radical Cyclization. Angew. Chem.,

Int. Ed. 2013, 52, 4897−4901. (c) Kawatsura, M.; Uchida, K.;

Terasaki, S.; Tsuji, H.; Minakawa, M.; Itoh, T. Ruthenium-Catalyzed

Regio- and Enantioselective Allylic Amination of Racemic 1-Arylallyl

Esters. Org. Lett. 2014, 16, 1470−1473.

complex-catalyzed allylic alkylation of carbonucleophiles with allylic

carbonates. J. Organomet. Chem. 1993 , 450 , 197 −207.

(5) Takeuchi, R.; Kashio, M. Highly Selective Allylic Alkylation with

a Carbon Nucleophile at the More Substituted Allylic Terminus

Catalyzed by an Iridium Complex: An Efficient Method for

Constructing Quaternary Carbon Centers. Angew. Chem., Int. Ed.

Engl. 1997, 36, 263−265.

(6) Whereas multiple book chapters and reviews have been

published on Ir-catalyzed allylic alkylation, we found only one short

review on Ru-catalyzed allylic alkylation; see: Begouin, J.-M.; Klein, J.

E. M. N.; Weickmann, D.; Plietker, B. Allylic Substitutions Catalyzed

by Miscellaneous Metals. In Transition Metal Catalyzed Enantiose-

lective Allylic Substitution in Organic Synthesis; Kazmaier, U., Ed.;

Topics in Organometallic Chemistry, Vol. 38; Springer-Verlag: Berlin,

(13) For intramolecular examples, see: (a) Miyata, K.; Kutsuna, H.;

Kawakami, S.; Kitamura, M. A Chiral Bidentate sp -N Ligand, Naph-

diPIM: Application to CpRu-Catalyzed Asymmetric Dehydrative C-,

N-, and O-Allylation. Angew. Chem., Int. Ed. 2011 , 50 , 4649 −4653.

(b) Miyata, K.; Kitamura, M. Asymmetric Dehydrative C-, N-, and O-

Allylation Using Naph-diPIM-dioxo-i-Pr −CpRu/p-TsOH Combined

Catalyst. Synthesis 2012 , 44 , 2138 −2146. (c) Seki, T.; Tanaka, S.;

Kitamura, M. Enantioselective Synthesis of Pyrrolidine-, Piperidine-,

and Azepane-Type N-Heterocycles with α -Alkenyl Substitution: The

CpRu-Catalyzed Dehydrative Intramolecular N-Allylation Approach.

Org. Lett. 2012 , 14 , 608 −611. (d) Kanbayashi, N.; Okamura, T.;

Onitsuka, K. New Method for Asymmetric Polymerization:

Asymmetric Allylic Substitution Catalyzed by a Planar-Chiral

Ruthenium Complex. Macromolecules 2014, 47, 4178−4185. For

asymmetric polymerizations, see: (e) Kanbayashi, N.; Okamura, T.;

Onitsuka, K. New Synthetic Approach for Optically Active Polymer

Bearing Chiral Cyclic Architecture: Combination of Asymmetric

Allylic Amidation and Ring-Closing Metathesis Reaction. Macro-

molecules 2015, 48, 8437−8444.

(14) For recent reviews on the chemistry of isatins, including their

reactivity, see: (a) da Silva, J. F. M.; Garden, S. J.; Pinto, A. C. The

Chemistry of Isatins: a Review from 1975 to 1999. J. Braz. Chem. Soc.

2001, 12, 273−324. (b) Singh, G. S.; Desta, Z. Y. Applications of

Isatin Chemistry in Organic Synthesis and Medicinal Chemistry. In

Chemistry and Pharmacology of Naturally Occurring Bioactive

Compounds; Brahmachari, G., Ed.; CRC Press: Boca Raton, FL,

2013; pp 77 −109. (c) Liu, Y.-C.; Zhang, R.; Wu, Q.-Y.; Chen, Q.;

Yang, G.-F. Recent Developments in the Synthesis and Applications

of Isatins. Org. Prep. Proced. Int. 2014 , 46 , 317 −362. (d) Varun;

Sonam; Kakkar, R. Isatin and its derivatives: a survey of recent

syntheses, reactions, and applications. MedChemComm 2019, 10,

351−368.

012; pp 280−288.

7) (a) Trost, B. M. Palladium-catalyzed cycloisomerizations of

b) Trost, B. M.; Toste, F. D.; Pinkerton, A. B. Non-metathesis

ruthenium-catalyzed C-C bond formation. Chem. Rev. 2001, 101,

067 −2096. (c) Trost, B. M.; Frederiksen, M. U.; Rudd, M. T.

Ruthenium-catalyzed reactions - a treasure trove of atom-economic

transformations. Angew. Chem., Int. Ed. 2005 , 44 , 6630 −6666.

(8) Trost, B. M.; Ryan, M. C. A Ruthenium/Phosphoramidite-

Catalyzed Asymmetric Interrupted Metallo-ene Reaction. J. Am.

Chem. Soc. 2016, 138, 2981−2984.

(9) For selected recent examples, see: (a) Kanbayashi, N.; Hosoda,

K.; Kato, M.; Takii, K.; Okamura, T.; Onitsuka, K. Enantio- and

diastereoselective asymmetric allylic alkylation catalyzed by a planar-

chiral cyclopentadienyl ruthenium complex. Chem. Commun. 2015,

1, 10895−10898. (b) Kanbayashi, N.; Yamazawa, A.; Takii, K.;

Okamura, T.; Onitsuka, K. Planar-Chiral Cyclopentadienyl-Ruthe-

nium-Catalyzed Regio- and Enantioselective Asymmetric Allylic

Alkylation of Silyl Enolates under Unusually Mild Conditions. Adv.

Synth. Catal. 2016, 358, 555−560.

(

10) For selected recent examples, see: (a) Onitsuka, K.; Okuda, H.;

Sasai, H. Regio- and Enantioselective O-Allylation of Phenol and

Alcohol Catalyzed by a Planar-Chiral Cyclopentadienyl Ruthenium

Complex. Angew. Chem., Int. Ed. 2008 , 47 , 1454 −1457. (b) Tanaka,

S.; Seki, T.; Kitamura, S. Asymmetric Dehydrative Cyclization of w-

Hydroxy Allyl Alcohols Catalyzed by Ruthenium Complexes. Angew.

Chem., Int. Ed. 2009 , 48 , 8948 −8951. (c) Kanbayashi, N.; Onitsuka,

K. Enantioselective Synthesis of Allylic Esters via Asymmetric Allylic

Substitution with Metal Carboxylates Using Planar-Chiral Cyclo-

pentadienyl Ruthenium Catalysts. J. Am. Chem. Soc. 2010 , 132 , 1206 −

(15) For selected reviews, see: (a) Pandeya, S. N.; Smitha, S.; Jyoti,

M.; Sridhar, S. K. Biological activities of isatin and its derivatives. Acta

Pharm. 2005, 55, 27−46. (b) Medvedev, A.; Buneeva, O.; Glover, V.

Biological targets for isatin and its analogues: Implications for therapy.

Biologics 2007, 1, 151−162. (c) Vine, K. L.; Matesic, L.; Locke, J. M.;

Skropeta, D. Recent Highlights in the Development of Isatin-Based

Anticancer Agents. In Advances in Anticancer Agents in Medicinal

Chemistry; Prudhomme, M., Ed.; Bentham Science Publishers:

Sharjah, UAE, 2013; pp 254−312. Also, see refs 8−22 in ref 16

below.

1207. (d) Kanbayashi, N.; Onitsuka, K. Ruthenium-Catalyzed Regio-

and Enantioselective Allylic Substitution with Water: Direct Synthesis

of Chiral Allylic Alcohols. Angew. Chem., Int. Ed. 2011 , 50 , 5197 −

5199. (e) Trost, B. M.; Rao, M.; Dieskau, A. P. A Chiral Sulfoxide-

Ligated Ruthenium Complex for Asymmetric Catalysis: Enantio- and

Regioselective Allylic Substitution. J. Am. Chem. Soc. 2013, 135,

Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters

Letter

16) Singh, G. S.; Desta, Z. Y. Isatins As Privileged Molecules in

Design and Synthesis of Spiro-Fused Cyclic Frameworks. Chem. Rev.

012, 112, 6104−6155.

17) We could ﬁnd only two examples of general asymmetric

(

methods where isatins are used as nucleophiles; see: (a) Zhao, M.-X.;

Chen, M.-X.; Tang, W.-H.; Wei, D.-K.; Dai, T.-L.; Shi, M. Cinchona

Alkaloid Catalyzed Regio- and Enantioselective Allylic Amination of

Morita −Baylis −Hillman Carbonates with Isatins. Eur. J. Org. Chem.

012 , 2012 , 3598 −3606. (b) Li, G.; Feng, X.; Du, H. Palladium-

catalyzed asymmetric allylic amination of racemic butadiene

monoxide with isatin derivatives. Org. Biomol. Chem. 2015, 13,

(

826−5830.

18) For isolated examples of isatin nucleophiles in asymmetric

processes, see: (a) Trost, B. M.; Burns, A. C.; Tautz, T. Readily

Accessible Chiral Diene Ligands for Rh-Catalyzed Enantioselective

Conjugate Additions of Boronic Acids. Org. Lett. 2011, 13, 4566−

569. (b) Xie, M.-S.; Wang, Y.; Li, J.-P.; Du, C.; Zhang, Y.-Y.; Hao,

E.-J.; Zhang, Y.-M.; Qu, G.-R.; Guo, H.-M. A straightforward entry to

chiral carbocyclic nucleoside analogues via the enantioselective[3 + 2]

cycloaddition of α -nucleobase substituted acrylates. Chem. Commun.

015 , 51 , 12451 −12454. (c) Dou, X.; Yao, W.; Jiang, C.; Lu, Y.

Enantioselective N-alkylation of isatins and synthesis of chiral N-

alkylated indoles. Chem. Commun. 2014, 50, 11354−11357 For

asymmetric process methods where isatin was screened as a

nucleophile but ultimately not used, see:. (d) Zari, S.; Kudrjashova,

M.; Pehk, T.; Lopp, M.; Kanger, T. Remote Activation of the

Nucleophilicity of Isatin. Org. Lett. 2014, 16, 1740−1743.

(19) When equimolar amounts of cinnamyl chloride and triethyl-

amine were combined in acetone-d (0.5 M), 40% conversion to

triethylammonium salt 10 was observed by H NMR after 9 h.

(

20) See Supporting Information for crystallographic details.

21) Moberg, C. Molybdenum-Catalyzed and Tungsten-Catalyzed

Enantioselective Allylic Substitutions. In Transition Metal Catalyzed

Enantioselective Allylic Substitution in Organic Synthesis; Kazmaier, U.,

Ed.; Topics in Organometallic Chemistry, Vol. 38; Springer-Verlag:

Berlin, 2012; pp 209−234.

(

22) For a critical review of green chemistry principles, see:

(

a) Anastas, P.; Eghbali, N. Green Chemistry: Principles and Practice.

Chem. Soc. Rev. 2010, 39, 301−312. For an evaluation of green

solvents, see: (b) Prat, D.; Wells, A.; Hayler, J.; Sneddon, H.;

McElroy, C. R.; Abou-Shehada, S.; Dunn, P. J. CHEM21 selection

guide of classical- and less-classical solvents. Green Chem. 2016, 18,

(

88−296.

23) For an excellent analysis of E/Z isomerism in 3-(alkylidene)

oxindoles, see: (a) Sun, L.; Tran, N.; Tang, F.; App, H.; Hirth, P.;

McMahon, G.; Tang, C. Synthesis and Biological Evaluations of 3-

Substituted Indolin-2-ones: A Novel Class of Tyrosine Kinase

Inhibitors That Exhibit Selectivity toward Particular Receptor

Tyrosine Kinases. J. Med. Chem. 1998, 41, 2588−2603.

(24) Like HT-2157, compound 14 was isolated as a 4:1 mixture of

imine isomers; see: Konkel, M. J.; Lagu, B.; Boteju, L. W.; Jimenez,

H.; Noble, S.; Walker, M. W.; Chandrasena, G.; Blackburn, T. P.;

Nikam, S. S.; Wright, J. L.; Kornberg, B. E.; Gregory, T.; Pugsley, T.

A.; Akunne, H.; Zoski, K.; Wise, L. D. 3-Arylimino-2-indolones Are

Potent and Selective Galanin GAL Receptor Antagonists. J. Med.

Chem. 2006, 49, 3757−3758.

(25) Dai, Z.; Li, S.; Li, Y.; Feng, L.; Ma, C. Metal-free synthesis of

benzimidazo[1,2-c]quinazolin-6-ones with indole and benzenedi-

amine oxidized by I2/TBHP. Tetrahedron 2019, 75, 2012−2017.

(26) Matteucci, M.; Duan, J.-X.; Rao, P. Topoisomerase Inhibitors

and Prodrugs. U. S. Pat. Appl. US 2008/0214576 A1, September 4,

008.

27) Tangella, Y.; Manasa, K. L.; Krishna, N. H.; Sridhar, B.; Kamal,

(

A.; Babu, B. N. Regioselective Ring Expansion of Isatins with In Situ

Generated α -Aryldiazomethanes: Direct Access to Viridicatin

Alkaloids. Org. Lett. 2018, 20, 3639−3642.

(

28) A regioisomeric ring-expansion product was also isolated in

33% yield; see the Supporting Information for further details.