One-Pot Synthesis of Polycyclic Spirooxindoles via Montmorillonite

Subscriber access provided by - Access paid by the | UCSB Libraries

Article

One-pot Synthesis of Polycyclic Spirooxindoles via Montmorillonite K10-Catalyzed C-H Functionalization of Cyclic Amines Xiaofeng Zhang, Miao Liu, Weiqi Qiu, Jason Evans, Manpreet Kaur, Jerry P Jasinski, and Wei Zhang ACS Sustainable Chem. Eng., Just Accepted Manuscript • DOI: 10.1021/ acssuschemeng.8b00555 • Publication Date (Web): 26 Feb 2018 Downloaded from http://pubs.acs.org on February 28, 2018

Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.

ACS Sustainable Chemistry & Engineering is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.

Page 1 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

ACS Sustainable Chemistry & Engineering

Submitted to ACS Sustainable Chemistry & Engineering for the special issue in honor of István Horváth

One-pot Synthesis of Polycyclic Spirooxindoles via Montmorillonite K10-Catalyzed C-H Functionalization of Cyclic Amines Xiaofeng Zhang,† Miao Liu,† Weiqi Qiu,† Jason Evans,† Manpreet Kaur,§ Jerry P. Jasinski,§ Wei Zhang*†‡ †

Center for Green Chemistry and Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA §

[email protected] Department of Chemistry, Keene State College, 229 Main Street, Keene, NH 03435 USA

Abstract. A method for pot and atom economic synthesis of polycyclic spirooxindoles through α-C−H

functionalization of cyclic amines has been developed. This highly efficient three-component [3+2] cycloaddition reaction was catalyzed by recyclable montmorillonite K10 and only water was produced as a byproduct. KEYWORDS: [3+2] cycloaddition, spirooxindoles, montmorillonite K10, heterogeneous catalysis, recyclable, α-C-H functionalization

ACS Paragon Plus Environment

1

ACS Sustainable Chemistry & Engineering 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 2 of 16

INTRODUCTION Spirooxindole is a biologically interested scaffold which can be found in a variety of natural products and medicinal chemicals, such as horsfiline, elacomine, spirotryprostatin A, MDM2 inhibitor pteropodine, antibacterial agent and antimalarial drug NITD609 (Figure 1).1-6 The development of cyclization, cycloaddition and asymmetric reactions for spirooxindole-based structures with potential biological activity continuously attracts attention of synthetic chemists.7-9 In recent years, we have developed a series of [3+2] cycloadditions and organocatalysis reactions in the synthesis of diverse heterocyclic structures, including spirooxindole-containing compounds.10-18 The 1,3-dipolar azomethine ylides used for [3+2] cycloadditions were generated from the reaction of α-amino acids with aldehydes. It has been reported that 1,3-dipolar azomethine ylides could also be generated from cyclic amines instead of α-amino acids.20-23 Brønsted acids were used as catalysts for the activation of α-C-H of cyclic amines.24-31 Introduced in this paper is our effort on the development of a new synthetic method for polycyclic spirooxindole compounds through one-pot [3+2] cycloaddition of cyclic amines, isatins and maleimides using a low cost, environmentally compatible, and recyclable montmorillonite K10 as a catalyst.32-41

Figure 1. Bioactive polycyclic spirooxindoles

RESULTS AND DISCUSSION The development of one-pot [3+2] cycloaddition conditions for heterocyclic spirooxindole 1a was explored using isatin 2a, 1,2,3,4-tetrahydroisoquinoline (THIQ) 3a, and N-ethylmaleimide 4a as model compounds. After screening reaction temperatures and times, solvents, and acid catalysts,


2

Page 3 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


it was found that under microwave heating at 150 oC for 25 min and in the presence of 3 Å molecular sieves, 1:1.3:1.2 of 2a:3a:4a in EtOH using zeolite YH, montmorillonite K30 or K10 as a heterogeneous catalyst, the one-pot reactions gave 1a in >81% LC yields (Table 1, entries 8-10). A slightly excess amount of 3a and 4a were used to push the reaction to completion. Reactions with other catalysts including BzOH, TfOH, AlCl3 gave significantly lower yields (Table 1, entries 1-7). Homogenous catalyst perfluorononanoic acid (Rf8CO2H) afforded 1a in 81% LC yield and 78:28 dr (entry 5). The dr is lower than that from the reaction of solid catalysts such as K10 of 89:11 (Table 1, entry 10). K10 has a three-dimensional pore structure which may be more stereoselective than homogenous catalysts. Since K10 was the choice of catalyst for the [3+2] cycloaddition, its recyclability test was conducted. After the reaction was over, the K10 powder was isolated from the reaction mixture by centrifuge, and used for three more rounds of reactions for the evaluation of product yield and dr. Results shown in Figure 2 indicate that no significant yield change in four

Table 1. [3+2] Cycloaddition conditions for 1a

a

b

entry

solvent

cat.

T (oC)

t (min)

1

toluene

BzOH

150

35

2

dioxane

BzOH

135

50

33

75:25

3

EtOH

BzOH

125

50

71

70:30

4

EtOH

--

125

50

63

66:34

5

EtOH

Rf8CO2H

150

25

81

78:28

6

EtOH

TfOH

150

25

77

71:29

c

EtOH

AlCl3

150

25

50

75:25

c

EtOH

Zeolite YH

150

25

80

89:11

c

EtOH

K30

150

25

86

85:15

EtOH

K10

7 8 9

c

10

11 12 13

EtOH EtOH EtOH

1a (%) 50

dr

67:33

150

25

86 (80)

89:11

nd

150

25

83

88:12

rd

150

25

88

85:15

th

150

25

86

82:18

(2 rd) (3 rd) (4 rd)

a

Detected by LC, isolated yield in parenthesis. bDetermined by 1H NMR of crude reaction mixture. cCatalyst loading 100 mg/1 mmol. _______________________________________________________________


3


Catalyst recycling Yield

100 89 90 Yield (%)/Dr (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 4 of 16

88

86

88 85

83

Dr

86 82

80 70 60 50 1

2

3

4

No. of round

Figure 2. Recyclability of K10 catalyst

rounds, but the dr decreased slightly from 89:11 to 82:18. The one-pot reaction has an inherit high pot economy. This three-component [3+2] cycloaddition also has a good atom economy since all the starting materials were incorporated in the product and only one equiv. of water was released as a side-product. Under the optimized reaction conditions using K10 as a catalyst, [3+2] cycloadditions of THIQ with diverse isatins 2 and maleimides 4 were carried out for the synthesis of polycyclic spirooxindoles 1 with different R1-R3 groups (Table 2). The isolated yields of products 1a-h were in the range of 43-83% and dr 83:17 to 91:9. Only a trace amount of product 1i was detected from the reaction mixture probably due to the steric hindrance of 4-bromo in the isatin interacting with the THIQ moiety. The stereochemistry of the major diastereomers was established by X-ray crystal structure analysis of 1f (Figure 3). As a solid catalyst, K10 has surface Brønsted acid centers, peculiar charge characteristics, and three-dimensional pore structure. It has been widely used for chemical transformations in research and production scales. The mechanism of K10-catalzed [3+2] cycloaddition for polycyclic spirooxindoles 1 is proposed in Scheme 1.

The acid-catalyzed nucleophilic addition of THIQ to

isatin followed by dehydration results an iminium ion. It is then converted to an azomethine ylide after deprotonation and then undergoes 1,3-dipolar cycloaddition with a maleimide to afford polycyclic spirooxindoles 1. The stereorigid solid catalyst may provide a good environment for more diastereoselective cycloaddition than using homogenous catalysts such as BzOH, TfOH, and Rf8CO2H. ACS Paragon Plus Environment

4

Page 5 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 2. [3+2] Cycloaddition for polycyclic spirooxindoles 1a

a

Isolated yield, reaction conditions are same as Table 1, entry 10.

_______________________________________________


5


Page 6 of 16

Figure 3. X-ray structure of 1f

Scheme 1. α-C-H Activation of THIQ by K10 for [3+2] cycloaddition

The applications of the one-pot [3+2] cycloaddition for the synthesis of diverse polycyclic spirooxindoles 5 were attempted by conducting the reaction of isatins with cyclic amines 6 including

isoindoline

piperidine,

morpholine,

methyl

prolinate,

and

2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole, and with different activated alkenes 7 such as

Z-dimethyl maleate, naphthalene-1,4-dione, and benzoquinone (Table 3). Heavily polycyclic spirooxindoles 5a and 5b derived from 2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole were produced in 73% and 71% yield, respectively. Reactions using isoindoline, piperidine, morpholine, or methyl prolinate as a cyclic amine afforded products 5c-5f in 40-83% yields. Except 5b which has a dr of 86:14, other products have dr values greater than 90:10. However, the reactions of benzoquinone or naphthalene-1,4-dione only resulted a trace amount of products 5g and 5h. Reaction with an acyclic dibenzylamine failed to give expected product 5i.

It is believed that electron-rich benzene ring of

benzoquinone reduced its reactivity as a dipolarophile,42 while aphthalene-1,4-dione could easily converted to hydroquinone which is no longer a dipolarophile,43 and acyclic dibenzylamine may not efficiently generate azomethine ylide for the [3+2] cycloaddition.


6

Page 7 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


Table 3. Table 2. [3+2] Cycloaddition for polycyclic spirooxindoles 5a

a

Isolated yield. Reaction conditions are same as Table 1, entry 10.

b

180 oC, 35 min

_______________________________________________________________________________________

CONCLUSION This study has established a practical and highly efficient synthesis for polycyclic spirooxindoles with diverse structures. Readily available, environmentally benign and recyclable montmorillonite K10 was used as a heterogeneous catalyst to activate α-C-H of cyclic amines in the formation of azomethine ylides for the [3+2] cycloaddition. Reactions with K10 were found to afford products with a better diastereoselectivity than with homogenous acid catalysts. This new reaction process also has high pot and atom economy which only produced water as a byproduct.

EXPERIMENTAL SECTION


7


Page 8 of 16

Chemicals and solvents were purchased from Sigma and Oakwood. Montmorillonite K10 from Sigma, surface area, 220-270m2/g, PH= 3-4. 1H NMR (400 MHz) and 13C NMR spectra (101 MHz) were recorded on Agilent NMR spectrometers. Chemical shifts were reported in parts per million (ppm). LC-MS were performed on an Agilent 2100 LC with a 6130 quadrupole MS spectrometers. A C18 column (5.0 µm, 6.0 x 50 mm) was used for the separation. The mobile phases were MeOH and H2O both containing 0.05% CF3CO2H. Low resolution mass spectra were recorded in APCI (atmospheric pressure chemical ionization). Flash chromatography separations were performed on YAMAZEN AI-580 flash column system with Agela silica gel columns (230-400 µm mesh). General procedure for the one-pot synthesis of compounds 1 & 5. To a solution of isatin 2 (1.2 mmol), cyclic amine 3 (1.3 mmol), and activated alkene 4 (1.0 mmol) in 2.5 mL of EtOH was added montmorillonite K10 (100 mg/mmol). The reaction mixture was heated under microwaves at 150 oC or 180 oC for 25 min. Upon the completion of the reaction as monitored by LC-MS, the reaction mixture was centrifuged to separate the K10, and the concentrated reaction solution was isolated on YAMAZEN AI-580 flash column system to give product 1 or 5. Compound 1a was obtained as a white solid (80% yield, 89:11 dr). MP: 230-232 oC. 1H NMR (400 MHz, CDCl3) δ 7.98 – 7.91 (m, 2H), 7.32 – 7.26 (m, 3H), 7.20 (ddd, J = 7.4, 2.1, 1.3 Hz, 1H), 7.09 (m, 2H), 6.87 – 6.80 (m, 1H), 4.95 (d, J = 8.0 Hz, 1H), 3.77 (d, J = 9.7 Hz, 1H), 3.64 – 3.56 (m, 3H), 3.00 – 2.88 (m, 1H), 2.81 – 2.65 (m, 2H), 2.65 – 2.58 (m, 1H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 176.9, 176.8, 175.4, 141.7, 136.8, 133.8, 130.0, 128.6, 127.8, 126.9, 126.6, 126.3, 124.4, 123.4, 110.2, 71.2, 61.4, 54.0, 49.7, 42.4, 34.1, 29.5, 12.7. HRMS (EI, m/z): calcd. for C23H21N3O3 (M+H)+ 388.1661, Found: 388.1659. Compound 1b was obtained as a white solid (83% yield, 83:17 dr). MP: 197-199 oC. 1H NMR (400 MHz, CDCl3) δ 7.96 (d, J = 7.7 Hz, 1H), 7.38 – 7.26 (m, 3H), 7.19 (m, 2H), 7.10 (m, 2H), 6.86 (t, J = 9.7 Hz, 1H), 4.97 (d, J = 8.0 Hz, 1H), 3.75 (d, J = 9.7 Hz, 1H), 3.58 (dd, J = 9.7, 8.1 Hz, 1H), 3.52 – 3.45 (m, 2H), 3.15 (s, 3H), 2.93 (m, 2H), 2.72 – 2.62 (m, 2H), 2.52 (dd, J = 10.4, 6.9 Hz, 1H), 1.68 – 1.57 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 177.0, 175.5, 175.0, 144.7, 136.9, 133.9, 130.0, 128.6, 127.5, 126.8, 126.7, 126.3, 123.9, 123.4, 108.4, 71.0, 61.6, 54.1, 49.6, 42.3, 40.7, 29.4, 25.8, 20.9, 11.4. HRMS (EI, m/z): calcd. for C25H25N3O3 (M+H)+ 416.1974, Found: 416.1979. Compound 1c was obtained as a white solid (76% yield, 88:12 dr). MP: 173-176 oC. 1H NMR (400 MHz, CDCl3) δ 7.51 (dd, J = 13.6, 4.5 Hz, 1H), 7.37 – 7.25 (m, 7H), 7.21 – 7.14 (m, 1H), 7.10 – ACS Paragon Plus Environment

8

Page 9 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


7.00 (m, 2H), 6.81 (dt, J = 8.5, 4.3 Hz, 1H), 6.75 (d, J = 7.8 Hz, 1H), 5.49 (d, J = 6.6 Hz, 1H), 5.15 – 5.05 (d, J = 8.3, 1H), 4.65 (d, J = 13.4 Hz, 1H), 4.03 – 3.95 (m, 1H), 3.64 (d, J = 7.5 Hz, 1H), 2.96 (s, 3H), 2.65 (ddd, J = 11.2, 9.1, 3.7 Hz, 2H), 2.59 – 2.49 (m, 2H).; 13C NMR (101 MHz, CDCl3) δ 176.7, 175.5, 174.8, 143.4, 135.5, 133.9, 132.9, 130.1, 128.9, 128.8, 127.8, 127.7, 127.2, 126.6, 125.6, 125.0, 124.8, 123.0, 109.4, 70.6, 61.0, 51.7, 46.3, 43.7, 42.5, 30.1, 24.9. HRMS (EI, m/z): calcd. for C29H25N3O3 (M+H)+ 464.1974, Found: 464.1968. Compound 1d was obtained as a white solid (77% yield, 89:11 dr). MP: 201-203 oC. 1H NMR (400 MHz, CDCl3) δ 7.99 (s, 1H), 7.50 (d, J = 7.7 Hz, 1H), 7.36 – 7.26 (m, 5H), 7.22 – 7.14 (m, 2H), 7.09 (d, J = 7.6 Hz, 1H), 6.75 (td, J = 7.6, 1.0 Hz, 1H), 6.67 (d, J = 7.7 Hz, 1H), 6.20 (d, J = 6.9 Hz, 1H), 5.40 (d, J = 6.5 Hz, 1H), 4.71 (d, J = 13.9 Hz, 1H), 4.52 (d, J = 13.9 Hz, 1H), 3.95 (dd, J = 7.4, 6.6 Hz, 1H), 3.66 (d, J = 7.5 Hz, 1H), 2.91 – 2.78 (m, 1H), 2.65 – 2.53 (m, 2H), 2.51 – 2.42 (m, 1H); 13

C NMR (101 MHz, CDCl3) δ 178.4, 175.1, 174.7, 141.1, 135.6, 134.1, 132.9, 129.8, 129.3, 128.8,

128.5, 128.0, 127.7, 126.6, 126.3, 125.1, 125.1, 122.9, 109.9, 70.8, 60.8, 51.2, 46.3, 42.5, 42.3, 30.2. HRMS (EI, m/z): calcd. for C28H23N3O3 (M+H)+ 450.1818, Found: 450.1819. Compound 1e was obtained as a white solid (61% yield, 90:10 dr). MP: 233-236 oC. 1H NMR (400 MHz, CDCl3) δ 7.67 (s, 1H), 7.49 (d, J = 7.7 Hz, 1H), 7.31 – 7.25 (m, 1H), 7.24 – 7.21 (m, 1H), 7.18 (t, J = 7.4 Hz, 1H), 7.07 (d, J = 7.6 Hz, 1H), 7.00 (dd, J = 8.1, 7.6 Hz, 1H), 6.75 (d, J = 7.5 Hz, 1H), 5.38 (d, J = 6.5 Hz, 1H), 3.97 – 3.91 (m, 1H), 3.64 (d, J = 7.6 Hz, 1H), 3.52 – 3.48 (m, 2H), 2.94 – 2.84 (m, 1H), 2.62 (m, 3H), 1.14 (t, J = 7.2 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 177.3, 174.9, 174.3, 138.9, 133.8, 132.6, 130.0, 128.8, 127.8, 126.9, 126.7, 125.1, 124.2, 123.7, 115.3, 71.7, 60.9, 51.5, 46.0, 42.6, 34.0, 30.0, 13.0. HRMS (EI, m/z): calcd. for C23H20ClN3O3 (M+H)+ 422.1272, Found: 422.1273. Compound 1f was obtained as a white solid (79% yield, 91:9 dr) MP: 260-263oC. 1H NMR (400 MHz, CDCl3) δ 8.65 (s, 1H), 7.47 (d, J = 7.6 Hz, 1H), 7.34 (dd, J = 8.3, 2.0 Hz, 1H), 7.30 – 7.21 (m, 1H), 7.22 – 7.14 (m, 1H), 7.09 (d, J = 7.5 Hz, 1H), 6.95 (d, J = 2.0 Hz, 1H), 6.49 (d, J = 8.4 Hz, 1H), 5.30 (d, J = 6.2 Hz, 1H), 3.95 (dd, J = 7.5, 6.3 Hz, 1H), 3.80 (d, J = 7.5 Hz, 1H), 3.55 (q, J = 7.2 Hz, 2H), 2.99 – 2.87 (m, 1H), 2.71 – 2.57 (m, 2H), 2.53 (dd, J = 9.9, 6.0 Hz, 1H), 1.21 (t, J = 7.2 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 178.2, 175.6, 175.0, 140.3, 133.8, 132.7, 132.6, 128.9, 128.7, 127.9, 127.5, 126.8, 125.1, 115.5, 112.0, 70.8, 61.0, 51.5, 46.4, 42.5, 34.2, 30.0, 13.1. HRMS (EI, m/z): calcd. for C23H20BrN3O3 (M+H)+ 466.0766, Found: 466.0768.


9


Page 10 of 16

Compound 1g was obtained as an off-white solid (43% yield, 83:17 dr). MP: 179-181 oC. 1H NMR (400 MHz, CDCl3) δ 8.59 (s, 1H), 8.27 – 8.18 (m, 2H), 7.92 (d, J = 7.7 Hz, 1H), 7.29 (t, J = 7.5 Hz, 1H), 7.21 (t, J = 7.5 Hz, 1H), 7.09 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 9.2 Hz, 1H), 4.91 (d, J = 8.0 Hz, 1H), 3.83 (d, J = 9.7 Hz, 1H), 3.63 (ddd, J = 21.6, 12.0, 7.7 Hz, 3H), 3.03 – 2.91 (m, 1H), 2.82 – 2.67 (m, 2H), 2.58 (dd, J = 10.2, 7.1 Hz, 1H), 1.19 (t, J = 7.2 Hz, 3H).; 13C NMR (101 MHz, CDCl3) δ 177.1, 176.2, 175.2, 147.5, 144.2, 136.0, 133.4, 129.1, 128.6, 127.2, 127.0, 126.5, 126.5, 120.6, 110.2, 70.9, 61.7, 54.4, 49.5, 42.6, 34.2, 29.3, 12.7. HRMS (EI, m/z): calcd. for C23H20N4O5 (M+H)+ 433.1512, Found: 433.1509. Compound 1h was obtained as a white solid (59% yield, 86:14 dr). MP: 270-273 oC. 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.6 Hz, 1H), 7.81 (s, 1H), 7.28 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.4 Hz, 1H), 7.12 (d, J = 9.8 Hz, 1H), 7.08 (d, J = 5.3, 2H), 6.73 (d, J = 7.9 Hz, 1H), 4.94 (d, J = 8.0 Hz, 1H), 3.75 (t, J = 8.4 Hz, 1H), 3.64 – 3.55 (m, 3H), 3.02 – 2.90 (m, 1H), 2.78 – 2.59 (m, 3H), 2.32 (s, 3H), 1.21 (t, J = 7.2 Hz, 3H).13C NMR (101 MHz, CDCl3) δ 176.8, 175.4, 139.2, 136.8, 133.9, 133.0, 130.4, 128.6, 127.8, 126.9, 126.6, 126.3, 125.1, 109.9, 71.3, 61.4, 54.0, 49.7, 42.4, 34.0, 29.5, 21.1, 12.7.HRMS (EI, m/z): calcd. for C24H23N3O3 (M+H)+ 402.1818, Found: 402.1822. Compound 5a was obtained as a light yellow solid (73% yield, 92:8 dr). MP: 240-242 oC. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 8.00 (s, 1H), 7.48 – 7.37 (m, 2H), 7.34 – 7.25 (m, 2H), 7.18 (t, J = 7.6 Hz, 1H), 7.09 (t, J = 7.4 Hz, 1H), 6.78 (d, J = 8.3 Hz, 1H), 5.03 (d, J = 8.9 Hz, 1H), 3.75 (d, J = 9.3 Hz, 1H), 3.62 (q, J = 7.2 Hz, 2H), 3.50 (dd, J = 14.8, 5.7 Hz, 1H), 2.83 – 2.65 (m, 4H), 1.22 (t, J = 7.2 Hz, 3H);

13

C NMR (101 MHz, CDCl3) δ 176.8, 176.7, 175.3, 140.1, 136.0, 131.9, 130.2,

129.7, 128.9, 126.8, 124.9, 121.9, 119.6, 118.3, 111.3, 111.3, 107.9, 71.1, 57.7, 54.8, 48.3, 42.4, 34.2, 22.3, 12.8. HRMS (EI, m/z): calcd. for C25H21ClN4O3 (M+H)+ 461.1380, Found: 461.1382. Compound 5b was obtained as a light yellow solid (71% yield, 86:14 dr). MP: 228-230 oC. 1H NMR (400 MHz, CDCl3) δ 9.32 (s, 1H), 8.36 (s, 1H), 7.41 (dd, J = 19.6, 8.0 Hz, 2H), 7.24 – 7.21 (m, 1H), 7.21 – 7.12 (m, 1H), 7.12 – 7.03 (m, 2H), 6.81 (d, J = 8.3 Hz, 1H), 4.97 (dt, J = 10.4, 5.2 Hz, 1H), 3.93 – 3.87 (m, 2H), 3.87 (s, 3H), 3.31 (s, 3H), 2.92 – 2.85 (m, 1H), 2.73 – 2.62 (m, 3H); 13

C NMR (101 MHz, CDCl3) δ 179.5, 172.7, 170.0, 139.8, 135.6, 132.8, 129.9, 129.4, 128.5, 126.8,

125.8, 121.7, 119.3, 118.2, 111.2, 110.8, 108.2, 70.8, 57.3, 53.9, 53.1, 52.1, 49.2, 42.5, 22.2. HRMS (EI, m/z): calcd. for C25H22ClN3O5 (M+H)+ 480.1326, Found: 480.1329. Compound 5c was obtained as an off-white solid (83% yield, 92:8 dr). MP: 258-261 oC. 1H NMR (400 MHz, CDCl3) δ 8.56 (s, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.38 (dd, J = 8.3, 1.8 Hz, 1H), 7.32 (t, J ACS Paragon Plus Environment

10

Page 11 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


= 7.5 Hz, 1H), 7.26 – 7.21 (m, 1H), 7.03 (d, J = 7.4 Hz, 1H), 6.78 (dd, J = 13.1, 5.1 Hz, 2H), 5.62 (d, J = 9.6 Hz, 1H), 4.12 – 4.01 (m, 1H), 3.95 (q, J = 14.1 Hz, 2H), 3.78 – 3.62 (m, 2H), 1.93 – 1.81 (m, 1H), 1.79 – 1.65 (m, 3H), 1.55 (d, J = 10.5 Hz, 1H), 1.30 (d, J = 12.3 Hz, 1H), 1.22 – 1.03 (m, 4H); 13

C NMR (101 MHz, CDCl3) δ 177.3, 175.1, 174.6, 140.7, 139.7, 137.8, 133.0, 131.3, 128.2, 127.5,

125.8, 125.3, 122.1, 114.6, 111.6, 73.1, 71.0, 55.2, 53.2, 51.8, 49.2, 28.3, 27.8, 25.6, 24.8. HRMS (EI, m/z): calcd. for C26H24BrN3O3 (M+H)+ 506.1079, Found: 506.1075. Compound 5d was obtained as a white solid (71% yield, 91:9 dr). MP: 138-140 oC. 1H NMR (400 MHz, CDCl3) δ 8.14 (s, 1H), 7.51 – 7.26 (m, 5H), 6.61 (dd, J = 6.9, 5.1 Hz, 2H), 4.71 (dd, J = 52.6, 14.1 Hz, 2H), 3.74 – 3.67 (m, 1H), 3.51 – 3.46 (m, 1H), 3.36 (d, J = 7.9 Hz, 1H), 2.30 (d, J = 10.3 Hz, 1H), 2.10 (dd, J = 8.5, 5.4 Hz, 2H), 1.79 (d, J = 6.1 Hz, 1H), 1.45 (t, J = 15.0 Hz, 1H), 1.34 – 1.13 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 178.2, 175.7, 174.6, 140.2, 135.6, 132.5, 130.0, 128.9, 128.6, 128.1, 127.3, 115.2, 111.2, 72.7, 60.3, 50.2, 47.3, 46.4, 42.6, 28.7, 25.1, 24.0. HRMS (EI, m/z): calcd. for C24H22BrN3O3 (M+H)+ 480.0923, Found: 480.0925. Compound 5e was obtained as a white solid (53% yield, 92:8 dr). MP: 150-152 oC. 1H NMR (400 MHz, CDCl3) δ 8.44 (s, 1H), 7.46 – 7.28 (m, 6H), 6.61 (d, J = 8.3 Hz, 1H), 6.56 (d, J = 1.9 Hz, 1H), 4.81 – 4.60 (m, 2H), 4.29 (dd, J = 11.3, 2.8 Hz, 1H), 3.94 – 3.85 (m, 1H), 3.70 (dd, J = 11.2, 2.7 Hz, 1H), 3.58 (t, J = 7.8 Hz, 1H), 3.42 (d, J = 7.9 Hz, 1H), 3.36 – 3.28 (m, 1H), 3.20 (td, J = 11.2, 2.6 Hz, 1H), 2.40 (td, J = 11.0, 3.3 Hz, 1H), 2.15 (d, J = 9.3 Hz, 1H); 13C NMR (101 MHz, CDCl3) δ 177.6, 175.0, 174.3, 140.3, 135.5, 133.0, 130.0, 129.0, 128.7, 128.3, 126.1, 115.4, 111.5, 72.4, 69.9, 66.2, 57.7, 50.0, 46.4, 45.8, 42.8. HRMS (EI, m/z): calcd. for C23H20BrN3O4 (M+H)+ 482.0716, Found: 482.0719. Compound 5f was obtained as a white solid (40% yield, 91:9 dr). MP: 105-108 oC. 1H NMR (400 MHz, CDCl3) δ9.54 (s, 1H), 7.24 – 7.20 (m, 1H), 7.03 (d, J = 1.9 Hz, 1H), 6.88 (dd, J = 9.4, 4.3 Hz, 1H), 4.23 (t, J = 11.2 Hz, 1H), 4.00 (dt, J = 9.4, 6.8 Hz, 1H), 3.75 (s, 3H), 3.35 – 3.29 (m, 1H), 3.26 (s, 3H), 2.62 (dt, J = 10.0, 5.8 Hz, 1H), 2.43 (dt, J = 9.9, 7.3 Hz, 1H), 2.14 (td, J = 12.2, 5.9 Hz, 1H), 1.92 – 1.84 (m, 2H), 1.76 (dt, J = 7.0, 5.1 Hz, 1H);

13

C NMR (101 MHz, CDCl3) δ 180.3, 171.5,

169.2, 140.1, 129.9, 127.7, 127.4, 125.8, 111.7, 72.8, 68.1, 57.7, 52.4, 52.0, 50.7, 47.6, 31.9, 27.9. APCIMS m/z: 378.1 (M+ + 1). HRMS (EI, m/z): calcd. for C18H19ClN2O5 (M+H)+ 379.1061, Found: 379.1059.

AUTHOR INFORMATION


11


Page 12 of 16

Support information The Supporting Information is available free of charge on the ACS Publications website at DOI: NMR spectra and x-ray crystal data for compound 1f (PDF)

AUTHOR INFORMATION Corresponding Author E-mail: [email protected] ORCID Xiaofeng Zhang: 0000-0003-4529-1158 Wei Zhang: 0000-0002-6097-2763 Notes The authors declare no competing financial interest.

DEDICATION ‡

Dedicated to István Horváth on the occasion of his 65th birthday.

REFERENCES (1) (2)

(3)

(4) (5)

(6) (7)

(8)

Jossang, A.; Jossang, P.; Hadi, H. A.; Sevenet, T.; Bodo, B. Horsfiline, an oxindole alkaloid from horsfieldia-superba. J. Org. Chem. 1991, 56, 6527-6530. DOI:10.1021/jo00023a016. Miyake, F. Y.; Yakushijin, K.; Horne, D. A. Preparation and synthetic applications of 2-halotryptamines: Synthesis of elacomine and isoelacomine. Org. Lett. 2004, 6, 711-713. DOI:10.1021/ol030138x Kang, T. H.; Matsumoto, K.; Tohda, M.; Murakami, Y.; Takayama, H.; Kitajima, M.; Aimi, N.; Watanabe, H. Pteropodine and isopteropodine positively modulate the function of rat muscarinic M-1 and 5-HT2 receptors expressed in Xenopus oocyte. Eur. J. Pharmacol. 2002, 444, 39-45. DOI:10.1016/S0014-2999(02)01608-4. Onishi, T.; Sebahar, P. R.; Williams, R. M. Concise, asymmetric total synthesis of spirotryprostatin A. Org. Lett. 2003, 5, 3135-3137. DOI: 10.1021/ol0351910. Thangamani, A. Regiospecific synthesis and biological evaluation of spirooxindolopyrrolizidines via [3+2] cycloaddition of azomethine ylide. Eur. J. Med. Chem. 2010, 45, 6120-6126. DOI: 10.1016/j.ejmech.2010.09.051. Barnett, D. S.; Guy, R. K. Antimalarials in development in 2014. Chem. Rev. 2014, 114, 11221-11241. DOI:10.1021/cr500543f. Zhang, M.; Fu, Q. Y.; Gao, G.; He, H. Y.; Zhang, Y.; Wu, Y. S.; Zhang, Z. H. Catalyst-free visible-light promoted one-pot synthesis of spirooxindole-pyran derivatives in aqueous ethyl lactate. ACS Sustain. Chem. Eng. 2017, 5, 6175-6182. DOI:10.1021/acssuschemeng.7b01102. Yang, R. Y.; Sun, J.; Sun, Q.; Yan, C. G. Selective construction of polycyclic spirooxindoles via a Cu(OTf)2/HOTf-catalyzed domino reaction of o-arylalkynylacetophenones and 3-phenacylideneoxindoles. Org. Biomol. Chem. 2017, 15, 6353-6357.


12

Page 13 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(9)

(10) (11) (12) (13)

(14)

(15)

(16)

(17)

(18)

(19)

(20)

(21)

(22)

(23)

DOI:10.1039/C7OB01292F. Zhao, J. Q.; Wu, Z. J.; Zhou, M. Q.; Xu, X. Y.; Zhang, X. M.; Yuan, W. C. Zn-catalyzed diastereo- and enantioselective cascade reaction of 3-isothiocyanato oxindoles and 3-nitroindoles: stereocontrolled syntheses of polycyclic spirooxindoles. Org. Lett. 2015, 17, 5020-5023. DOI:10.1021/acs.orglett.5b02489. Zhang, W. Fluorous synthesis of heterocyclic systems. Chem. Rev. 2004, 104, 2531-2556. DOI:10.1021/cr030600r. Zhang, W. Fluorous linker-facilitated chemical synthesis. Chem. Rev. 2009, 109, 749-795. DOI:10.1021/cr800412s. Zhang, W. 1,3-Dipolar cycloaddition-based synthesis of diverse heterocyclic scaffolds. Chem. Lett. 2013, 42, 676-681. DOI: 10.1246/c1.130504. Zhang, X. F.; Pham, K.; Liu, S.; Legris, M.; Muthengi, A.; Jasinski, J. P.; Zhang, W. Stereoselective synthesis of fused tetrahydroquinazolines through one-pot double [3+2] dipolar cycloadditions followed by [5+1] annulation. Beilstein J. Org. Chem. 2016, 12, 2204-2210. DOI:10.3762/bjoc.12.211. Zhang, X. F.; Zhi, S. J.; Wang, W.; Liu, S.; Jasinski, J. P.; Zhang, W. A pot-economical and diastereoselective synthesis involving catalyst-free click reaction for fused-triazolobenzodiazepines. Green Chem. 2016, 18, 2642-2646. DOI:10.1039/C6GC00497K. Zhang, X. F.; Legris, M.; Muthengi, A.; Zhang, W. [3+2] Cycloaddition-based one-pot synthesis of 3,9-diazabicyclo[4.2.1] nonane-containing scaffold. Chem. Heterocycl. Compd. 2017, 53, 468-473. DOI:10.1007/s10593-017-2072-2. Lu, Q.; Song, G. H.; Jasinski, J. P.; Keeley, A. C.; Zhang, W. One-pot double [3+2] cycloaddition for diastereoselective synthesis of tetracyclic pyrrolidine compounds. Green Chem. 2012, 14, 3010-3012. DOI:10.1039/C2GC36066G. Huang, X.; Pham, K.; Yi, W. B.; Zhang, X. F.; Clamens, C.; Hyatt, J. H.; Jasinsk, J. P.; Tayvah, U.; Zhang, W. Recyclable organocatalyst-promoted one-pot asymmetric synthesis of spirooxindoles bearing multiple stereogenic centers. Adv. Synth. Catal. 2015, 357, 3820-3824. DOI:10.1002/adsc.201500748. Huang, X.; Liu, M.; Pham, K.; Zhang, X. F.; Yi, W. B.; Jasinski, J. P.; Zhang, W. Organocatalytic one-pot asymmetric synthesis of thiolated spiro-γ-lactam oxindoles bearing three stereocenters. J. Org. Chem. 2016, 81, 5362-5369. DOI:10.1021/acs.joc.6b00653. Du, Y. L.; Yu, A. M.; Jia, J. R.; Zhang, Y. Q.; Meng, X. T. Direct N-H/α,α,β,β-C(sp3)-H functionalization of piperidine via an azomethine ylide route: synthesis of spirooxindoles bearing 3-substituted oxindoles. Chem. Commun. 2017, 53, 1684-1687. DOI:10.1039/C6CC08996H. Mantelingu, K.; Lin, Y. F.; Seidel, D. Intramolecular [3+2]-cycloadditions of azomethine ylides derived from secondary amines via redox-neutral C-H functionalization. Org. Lett. 2014, 16, 5910-5913. DOI:10.1021/ol502918g. Ma, L. L.; Paul, A.; Breugst, M.; Seidel, D. Redox-neutral aromatization of cyclic amines: mechanistic insights and harnessing of reactive intermediates for amine α- and β-C-H functionalization. Chem-Eur. J. 2016, 22, 18179-18189. DOI:10.1002/chem.201603839. Kumar, C. S. P.; Harsha, K. B.; Sandhya, N. C.; Ramesha, A. B.; Mantelingu, K.; Rangappa, K. S. Highly diastereoselective synthesis of polycyclic amines via redox neutral C-H functionalization. New J. Chem. 2015, 39, 8397-8404. DOI:10.1039/C5NJ01706H. Seidel, D. The azomethine ylide route to amine C-H functionalization: redox-versions of


13


(24) (25) (26) (27) (28) (29)

(30) (31)

(32) (33) (34) (35)

(36) (37) (38) (39)

(40)

(41)

(42)

Page 14 of 16

classic reactions and a pathway to new transformations. Acc. Chem. Res. 2015, 48, 317-328. DOI:10.1021/ar5003768. Min, C.; Seidel, D. Asymmetric Bronsted acid catalysis with chiral carboxylic acids. Chem. Soc. Rev. 2017, 46, 5889-5902. DOI:10.1039/C6CS00239K. Akiyama, T.; Mori, K. Stronger Bronsted acids: recent progress. Chem. Rev. 2015, 115, 9277-9306. DOI:10.1021/acs.chemrev.5b00041. Zhu, Z. B.; Seidel, D. Acetic acid promoted redox annulations with dual C-H functionalization. Org. Lett. 2017, 19, 2841-2844. DOI:10.102/acs.orglett.7b01047. Chen, W. J.; Seidel, D. Redox-annulation of cyclic amines and β-Ketoaldehydes. Org. Lett. 2016, 18, 1024-1027. DOI:10.1021/acs.orglett.6b00151. Zhu, Z. B.; Seidel, D. An Ugi reaction incorporating a redox-neutral amine C-H functionalization Step. Org. Lett. 2016, 18, 631-633. DOI:10.1021/acs.orglett.5b03529. Richers, M. T.; Breugst, M.; Platonova, A. Y.; Ullrich, A.; Dieckmann, A.; Houk, K. N.; Seidel, D. Redox-neutral α-oxygenation of amines: reaction development and elucidation of the mechanism. J. Am. Chem. Soc. 2014, 136, 6123-6135. DOI:10.1021/ja501988b. Peng, B.; Maulide, N. The redox-neutral approach to C-H functionalization. Chem-Eur. J. 2013, 19, 13274-13287. DOI:10.1002/chem.201301522. Liang, J.; Liang, Z. B.; Zou, R. Q.; Zhao, Y. L. Heterogeneous catalysis in zeolites, mesoporous silica, and metal-organic frameworks. Adv. Mater. 2017, 29, 1701139. DOI:10.1002/adma.201701139. Schlogl, R. Heterogeneous catalysis. Angew. Chem. Int. Edit. 2015, 54, 3465-3520. DOI:10.1002/anie.201410738. Nagendrappa, G. Organic synthesis using clay and clay-supported catalysts. Appl. Clay Sci. 2011, 53, 106-138. DOI:10.1016/j.clay.2010.09.016. Mizuno, N.; Misono, M. Heterogeneous catalysis. Chem. Rev. 1998, 98, 199-218. DOI:10.1021/cr960401q. Varadwaj, G. B. B.; Parida, K.; Nyamori, V. O. Transforming inorganic layered montmorillonite into inorganic-organic hybrid materials for various applications: a brief overview. Inorg. Chem. Front. 2016, 3, 1100-1111. DOI:10.1039/C6QI00179C. Jheeta, S.; Joshi, P. C. Prebiotic RNA synthesis by montmorillonite catalysis. Life 2014, 4, 318-330. DOI:10.3390/life4030318. Nasreen, A. Montmorillonite. Synlett 2001, 2001, 1341-1342. DOI:10.1055/s-2001-16061. Polshettiwar, V.; Varma, R. S. Microwave-assisted organic synthesis and transformations using benign reaction media. Acc. Chem. Res. 2008, 41, 629-639. DOI:10.1021/ar700238s. Kumar, B. S.; Dhakshinamoorthy, A.; Pitchumani, K. K10 montmorillonite clays as environmentally benign catalysts for organic reactions. Catal. Sci. Technol. 2014, 4, 2378-2396. DOI:10.1039/C4CY00112E. Flessner, U.; Jones, D. J.; Roziere, J.; Zajac, J.; Storaro, L.; Lenarda, M.; Pavan, M.; Jimenez-Lopez, A.; Rodriguez-Castellon, E.; Trombetta, M.; Busca, G. A study of the surface acidity of acid-treated montmorillonite clay catalysts. J. Mol. Catal. A-Chem. 2001, 168, 247-256. DOI:10.1016/S1381-1169(00)00540-9. Shanmugam, P.; Singh, P. R., Montmorillonite K10 clay-microwave assisted isomerisation of acetates of the Baylis-Hillman adducts: A facile method of stereoselective synthesis of (E)-trisubstituted alkenes. Synlett 2001, 2001, 1314-1316. DOI:10.1055/s-2001-16040. Geittner, J. ; Huisgen, R. Kinetics of 1,3-dipolar cycloaddition reactions of diazomethane; a correlation with homo-lumo energies. Tetrahedron Letters 1977, 18, 881–


14

Page 15 of 16 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


884. DOI:10.1016/S0040-4039(01)92781-9. (43) Potowski, M.; Schürmann, M.; Preut, H.; Antonchick, A. P.; Herbert Waldmann, H. Programmable enantioselective one-pot synthesis of molecules with eight stereocenters. Nat. Chem. Biol. 2012, 8, 428-430. DOI:10.1038/nchembio.901.


15


Page 16 of 16

For Table of Contents Use Only

Synopsis. The title compounds are synthesized through pot economic reactions, using recyclable montmorillonite K10 as a catalyst, and only generating water as a byproduct


16

One-Pot Synthesis of Polycyclic Spirooxindoles via Montmorillonite

Recommend Documents