Ruthenium-Catalyzed Decarboxylative CâH Alkenylation in Aqueous

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Ruthenium-Catalyzed Decarboxylative C-H Alkenylation in Aqueous Media: A Synthesis of Tetrahydropyridoindoles Xiao-Yang Jin, Li-Jun Xie, Hou-Ping Cheng, An-Di Liu, Xue-Dong Li, Dong Wang, Liang Cheng, and Li Liu J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00229 • Publication Date (Web): 26 Apr 2018 Downloaded from http://pubs.acs.org on April 26, 2018

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The Journal of Organic Chemistry

Ruthenium-Catalyzed Decarboxylative C-H Alkenylation in Aqueous Media: A Synthesis of Tetrahydropyridoindoles

Xiao-Yang Jin,†,‡ Li-Jun Xie,†,‡ Hou-Ping Cheng,†,‡ An-Di Liu,†,‡ Xue-Dong Li,†,‡ Dong Wang,† Liang Cheng,†,‡,* and Li Liu,†,‡,*

†

Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular

Recognition and Function, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China ‡

University of Chinese Academy of Sciences, Beijing 100049, China

* [email protected] (L.C.); [email protected] (L.L.)

TOC

Abstract: We disclosed herein a Ru(II)-catalyzed decarboxylative and oxidative coupling of N-substituted indolyl carboxylic acids with broad substrate scopes in an aqueous solution.

This method provides a

sustainable and efficient access to synthesize various indole-fused cyclohexanyl acetic acids under mild conditions.

The indole-fused cyclohexanyl acetic acid core, like its parent molecule – indole or pyrrole, is a frequent motif in numerous pharmaceutical candidates and natural products that have been shown to exhibit significant physiological effects (Figure 1).1-2

For example, the natural product Cimicidin showed

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considerable inhibition of acetylcholinesterase activity in vitro,2a while the carbocycle fused indole 1 exhibits subnanomolar affinity for the human CRTH2 receptor and thus represents a potent and selective CRTH2 agonist,2b the synthetic cyclohexanyl acetic acid 2 is a potent modulators of the S1P1 receptor.2f Considering the presence of this indole skeleton in various biologically active compounds, the development of facile methods for the rapid synthesis of this substituted indole-fused acetic acid is strongly desired.

Figure 1. Selected natural alkaloid and biological compounds based on indole-fused cyclohexanyl acetic acids

Until now, most of the reported synthetic process for the construction of the desired cyclohexanyl core involved a transition metal-catalyzed cyclization (Fujiwara-Moritani reaction)3 of indole-based precursors (Scheme 1). The activation of C-H bond activation is controlled by a directing group at C-3 position (aldehyde, ketone, amide, etc.)4 or by a protecting group at the nitrogen atom (amide, ketone, heteroaryl, etc.)5.

However, the installation and removal of these chelating groups adds additional steps,

compromising the step-economical nature of the overall C-H activation strategy.

Further transformation

(other than removal) with the existing directing groups in the final products always encountered problems. Thus, there has been a strong drive from the synthetic community to develop traceless directing groups (TDG).6 Apart from substantial improvement of the transition metal-catalyzed cyclization, the reaction of (hetero)aryl carboxylic acids is of particular interest because of their wide availability as building blocks. 7 Furthermore, the carboxylic group can be easily removed during the process, which eliminates additional steps for the decarboxylation and releases the block site for further installation of other desired groups.


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However, its application to indolyl carboxylic acids was limited.4x

In connection with our interest in transit metal catalyzed C-C coupling transformations, 8 we envisaged that an intramolecular decarboxylative and oxidative alkenylation might be attractive way to form a cyclohexanyl acetic acid structure which could be converted into a diversely functionalized indole derivatives (Scheme 1).

On the other hand, remarkable progress has been achieved in the catalyzed

functionalizations of unreactive C-H bonds by the use of water as an environmentally benign, nonflammable, and nontoxic reaction medium, however, the insolubility of starting materials, reagents or catalysts has been a common challenge to organic reactions. 9

As part of our continuous interest in C-H

functionalizations and aqueous reactions,10 we describe an efficient, regiospecific, decarboxylative and general oxidative C-H alkenylation of simple N-alkenylalkyl indoles to generate a wide range of indolefused cyclohexenyl acrylate in an aqueous solution.

We also demonstrated that the carboxylic acid group

serve as an effective anchor for the ortho-functionalization and can be tracelessly cleaved in the decarboxylative coupling for further derivation.

The details of these findings are described herein.

Previous works DG

DG cat. [Pd], [Ru] +

N H

R

R

oxidant

N H

DG = CHO, COR', CONHR', COOR'

R

cat. [Pd], [Rh], [Ru] +

N

R

oxidant

N

DG

DG

DG = COR, CONR'R'', SO2Py, CH2Py, (Hetero)Aryl, etc.

This work HO

O traceless directing group (TDG) H

N

Scheme 1.

COOR

C-C bond formation COOR

[Ru], O2

Aqueous solution

N

Transition-metal-catalyzed oxidative C-2 olefination protocols of indoles with alkenes

We carried our work to establish a practical approach by changing the nature of the directing group from commonly used aldehyde, ketone, amide, etc. to a removable carboxylic acid.


Our optimization studies


Page 4 of 27

began with the C-3 carboxylic acid derivative of indole 3a as a model substrate being subjected to previously developed conditions for C-2 alkenylation with carboxylic acid directing group 4a, 4c (Table 1). Trace or none product was generated in all cases (entries 1-2). Thus, we were compelled to optimize the reaction condition and established an ideal combination for the alkenylation reaction. optimization, an aqueous mixture was proven to be the solvent of choice.11

Through the

The Ru(II) catalyst12 was only

soluble in water but the indolyl carboxylic acid was not and thus a high efficiency was ensured by a homogeneous solution with methanol.

The intramolecular cyclization was eventually optimized with 5

mol% of Ru(II) catalyst and O2 as a benign oxidant and the desired product 4a was also confirmed from Xray analysis of single-crystals obtained from the decarboxylation reaction (entry 3). The aerobic oxidative alkenylation in pure organic solvents was viable, but with reduced efficacy (entries 4-6). Direct oxidation in organometallic reactions by molecular oxygen is often kinetically unfavored.

It is worthy to mention

that in our case the best result was obtained when molecular oxygen was used as the terminal oxidant, while other commonly used oxidants like Cu(OAc)2 (entry 7), V2O5 (entry 8) were proven to be unsuccessful.

The product was also obtained smoothly under Air (entry 9). The use of other bases like

KOAc except CsOAc was less effective (entries 10-11). Again, to demonstrate the importance of carboxylic acid as the directing group, we prepared two analogous 5a-b, which both didn’t undergo cyclization and only the starting materials were recovered (entries 12-13).

Table 1.

Screening of metal complexes, additives and solventsa

entry

Variations from standard condition

Yield (%)

1

Pd(OAc)2, Cu(OAc)2.H2O, MS 4A, LiOAc, DMAc, 140 oC, N2

6

2

[RuCl2(p-cymene)]2, Cu(OAc)2.H2O,

3

none

79

4

n-butanol instead of H2O-MeOH

31

5

THF instead of H2O-MeOH

12

6

toluene instead of H2O-MeOH

22

DMF, 80

oC,


N2, 6 hrs

NRb

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a

7c

Cu(OAc)2

16

8c

V2O5

41

9

Under Air

65

10

No CsOAc

NDd

11

KOAc instead of CsOAc

35e

12

5a instead of 3a

NR

13

5b instead of 3a

NR

Standard condition: 3a (0.5 mmol, 144 mg), [RuCl2(p-cymene)]2 (0.025 mmol, 15 mg) and CsOAc (0.5

mmol, 96 mg) in H2O-MeOH (3/7, total 1 mL) at 90 oC for 18 hours under oxygen (balloon).

Isolated

yield for 4a was given. b

NR: No reaction.

c

2 Equiv of oxidant was used.

d

ND: not detected.

e

Reaction conducted in methanol at 60 oC.

Only decarboxylated starting product (5a) was observed.

With this optimized catalytic system in hand, we explored its scope in the intramolecular oxidative alkenylation of indolyl carboxylic acids 3a-o (Table 2).

Thus, the catalytic C-H bond formation in

aqueous mixture allowed for a rapid and efficient conversion of a series of substituted tetrahydropyrido[1,2-a]indolyl carboxylic acids 4a-o in good to excellent yields.

Electron-rich (4f-g, i-l)

and electron-poor (4b-e, 4h) groups were tolerated in the reaction for C-4/5/6/7-substituted indolyl carboxylic acids.

Other acrylate derivatives, namely, ethyl (4m), tert-butyl (4n) and benzyl (4o), were

found to furnish good to excellent yields.

However, simple acrylic acid (4p), phenylvinylsulfone (4q) or

terminal alkene without activating group (4r) gave inferior results comparing with their ester counterparts. Interestingly, when methylvinyl ketone was used, a conjugate adduct 4s rather than the coupling product was isolated in 78% yield4g (vide infra). It is worthy to mention that in all cases only Z-4 isomers were detected and isolated.

Table 2.

Substrate scopea



HO 1

O H

R

N

[RuCl2(p-cymene)] 2 (5 mol%) CsOAc (1.0 equiv), O2 (balloon) H2O-MeOH, 90 oC

COOR 2

Page 6 of 27

COOR2

R1

N

3a-s

4a-s Br

Cl

COOMe N 4a (79 %)

4b (40 %)

COOMe I N

4e (26 %)

COOMe N 4h (49 %)

COOMe

OMe 4l (72 %)

4f (75 %)

4g (70 %)

4j (76 %)

COOEt

4k (72 %)

COOBu-t N

COOBn N

4n (68 %)

4m (75 %)

COOMe N

N

MeO

N

COOMe N

COOMe

4i (74 %)

N

MeO

N

COOMe N

4c (65 %)

COOMe

COOMe N

4d (40 %)

Cl

N

N

Br

COOMe

COOMe

4o (40 %) O

SO2Ph

COOH N 4p (17 %) (92b %)

a

N

N 4q (18 %) (89b %)

4r (8 %)

N 4s (74 %)

Standard condition: 3a-s (0.5 mmol), [RuCl2(p-cymene)]2 (0.025 mmol, 15 mg) and CsOAc (0.5 mmol,

96 mmol) in H2O-MeOH (3/7, total 1 mL) at 90 oC for 18 hours under oxygen (balloon).

Isolated yield

for 4a-s was given. b

brsm yield.

Applying this efficient oxidative coupling led to the formation of the corresponding indole-fused cyclohexanyl acetic acids 1 and 2, respectively.

Selective hydrogenation of the acrylate 4a followed by

sulfenylation, both steps in water, gave the sulfane 7a.

Saponification of the resultant sulfane 7a with

lithium hydroxide afforded the target molecule 1 as a prostaglandin D2 receptor antagonist (Scheme 2).2a On the other hand, hydrogenation of 4g followed by demethylation provided phenol 5b.

Etherification

and subsequent saponification of the ester under basic conditions afforded the substituted tricyclic acid


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derivative 2, which was used as an S1P1 receptor agonist in the treatment of autoimmune and inflammatory disorders (Scheme 3).

Scheme 2.

Synthesis of 3-sulfenyl-indole-fused cyclohexanyl acetic acid 1

Scheme 3.

Application of the decarboxylative coupling for the synthesis of indole-fused cyclohexanyl

acetic acid 2

Based on our results and previous mechanistic studies of the other researchers on the decarboxylative C-H functionalizations,13 a tentative mechanism was proposed as shown in Scheme 4. The reaction was initiated by a base promoted dissociation of the dinuclear ruthenium catalyst [RuCl 2(p-cymene)]2. The resulting ruthenium biscarboxylate I underwent a C-H cyclometalation assisted by the carboxyl acid to furnish II.

The cyclometalated intermediate II coordinated with the intramolecular acrylate (III) and

proceeded via a migratory alkene insertion to deliver a seven-membered metallacyle IV.

A sequential -

elimination and decarboxylation/proto-demetallation afforded the product 4 while releasing CO2 and the Ru intermediate VI, which was later oxidized by molecular oxygen at ambient pressure to regenerate the catalyst I.

The reason that an adduct 4s was generated other than coupling product may be ascribed to the

-H elimination step, in which the acidity of α-H in the intermediate IV is strong enough for the following proto-demetallation, and thus an addition reaction occurred.4g The excellent stereoselectivity that in our case only Z- 4 was obtained was probably due to the syn-conformation required in the -elimination (See



Page 8 of 27

Fig. S1 in the Supporting Information for a detailed conformation analysis of the transition state for the elimination).

Scheme 4.

A proposed mechanism

In summary, we have reported a mild selective Ru(II)-catalyzed decarboxylative and oxidative coupling to access substituted indole-fused cyclohexanyl acetic acids in good to excellent yields.

Notably, the

carboxylic acid group acts as an essential and traceless directing group, which allows for a selective oxidative coupling at the ortho-position.

Furthermore, we have shown that the reaction solvent has a

strong effect on the cyclization and an aqueous solution was proven to be optimal for this coupling. Further studies will aim at enlightening our understanding on the detailed mechanism for extending this application in related synthetically versatile processes.


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EXPERIMENTAL SECTION General method for the synthesis of 3a-s: To a mixture of sodium hydride (60 %, 2.285 g, 57.14 mmol) in dry N,N-dimethylformamide (25 mL) was added dropwise a solution of methyl 1H-indole-3-carboxylate (5.0 g, 28.57mmol in 25 mL of N,N-dimethylformamide). The mixture was stirred for 10 min and then added 4-bromobut-1-ene (4.4 mL, 37.14 mmol).

The reaction continued stirring for another 2 hours at

room temperature and then diluted with ethyl acetate (200 mL).

The organic layer was washed by water

(200 mL * 2) and brine (200 mL * 2), dried over anhydrous sodium sulfate, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate 10/1) to afford the intermediate methyl 1-(pent-4-en-1-yl)-1H-indole-3-carboxylate as a colorless oil (6.89 g, yield 99%).

A mixture of methyl 1-

(pent-4-en-1-yl)-1H-indole-3-carboxylate (6.89 g, 28.4 mmol), potassium hydroxide (6.35 g, 113.4 mmol) in methanol (40 mL) and water (30 mL) was heated to reflux for 16 hours. The solution was acidified to pH 6 with 1N hydrochloride and the intermediate 1-(pent-4-en-1-yl)-1H-indole-3-carboxylic acid 3r was filtrated as a white solid (5.77 g, yield 88%).

To a solution of 1-(pent-4-en-1-yl)-1H-indole-3-carboxylic

acid 3r (5.0 g, 21.83 mmol), methyl acrylate (39.5 mL, 436.6 mmol) and 2nd Grubbs catalyst (925 mg, 1.091 mmol) was added dichloromethane (150 mL) under nitrogen.

The mixture was stirred for 16 hours

at room temperature, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate 3/1) to afford the product (E)-1-(6-methoxy-6-oxohex-4-en-1-yl)-1H-indole-3carboxylic acid 3a as a white solid (4.39 g; yield 74%).

(E)-1-(6-methoxy-6-oxohex-4-en-1-yl)-1H-indole-3-carboxylic acid 3a. 1

White solid, m.p. 132-134 oC.

H NMR (300 MHz, CDCl3) δ 8.26-8.23 (m, 1H), 7.90 (s, 1H), 7.37-7.29 (m, 3H), 6.96-6.86 (m, 1H), 5.86-

5.81 (d, J = 15.6 Hz, 1H), 4.21-4.17 (m, 2H), 3.73 (s, 3H), 2.27-2.20 (m, 2H), 2.11-2.02 (m, 2H).

13

C

NMR (300 MHz, CDCl3) δ 170.7, 166.8, 147.0, 136.7, 135.4, 127.1, 123.2, 122.5, 122.4, 122.1, 110.1, 106.8, 51.7, 46.3, 29.3, 28.2.

IR νmax (KBr, film, cm-1): 2948, 1720, 1659, 1532, 1276, 751.

HRMS

(ESI, orbitrap): calcd for C16H16O4N [M-H+] 286.1084, found: 286.1081.

(E)-4-bromo-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3b.


Gray solid, 148 mg


(from 0.45 mmol), 89% yield, m.p. 122-124 oC.

1

Page 10 of 27

H NMR (300 MHz, CDCl3) δ 7.96 (s, 1H), 7.52-7.49 (d,

J = 7.5 Hz, 1H), 7.31-7.26 (m, 1H), 7.15-7.09 (m, 1H), 6.94-6.85 (m, 1H), 5.86-5.80 (d, J = 15.6 Hz, 1H), 4.19-4.10 (m, 2H), 3.73 (s, 3H), 2.26-2.19 (m, 2H), 2.09-2.02 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ

167.4, 165.6, 145.5, 137.2, 136.2, 126.8, 124.6, 122.8, 121.3, 113.6, 108.2, 106.4, 50.5, 45.3, 28.0, 26.9. IR νmax (KBr, film, cm-1): 2920, 1720, 1645, 1523, 1167, 763.

HRMS (ESI, orbitrap): calcd for

C16H16O4NBrNa [M+Na+] 388.0154, found: 388.0147.

(E)-5-chloro-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3c. (from 1.52 mmol), 86% yield, m.p. 144-146 oC.

1

Gray solid, 421 mg

H NMR (300 MHz, CDCl3) δ 8.21 (s, 1H), 7.88 (s, 1H),

7.24 (s, 2H), 6.95-6.85 (m, 1H), 5.86-5.81 (d, J = 15.9 Hz, 1H), 4.19-4.14 (m, 2H), 3.73 (s, 3H), 2.26-2.19 (m, 2H), 2.08-2.03 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 170.3, 166.6, 146.6, 136.1, 134.9, 128.3,

127.9, 123.5, 122.4, 121.6, 111.0, 106.4, 51.6, 46.4, 29.1, 28.1. 1661, 1533, 1160, 775.

IR ν max (KBr, film, cm-1): 2926, 1719,

HRMS (ESI, orbitrap): calcd for C16H15O4NCl [M-H+] 320.0695, found:

320.0698.

(E)-5-bromo-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3d. (from 0.9 mmol), 83% yield, m.p. 122-124 oC.

1

Gray solid, 275 mg

H NMR (300 MHz, CDCl3) δ 8.40-8.39 (d, J = 1.5

Hz,1H), 7.87 (s, 1H), 7.41-7.38 (dd, J = 1.8, 9.0 Hz, 1H), 7.24-7.21 (d, J = 9.0 Hz, 1H), 6.95-6.85 (m, 1H), 5.87-5.81 (d, J = 15.6 Hz, 1H), 4.20-4.16 (m, 2H), 3.73 (s, 3H), 2.27-2.20 (m, 2H), 2.11-2.02 (m, 2H). 13

C NMR (500 MHz, CDCl3) δ 170.1, 166.7, 146.6, 136.0, 135.3, 128.6, 126.1, 124.7, 122.4, 116.1, 111.4,

106.4, 51.7, 46.5, 29.1, 28.1.


HRMS

(ESI, orbitrap): calcd for C16H15O4NBr [M-H+] 364.0189, found: 364.0196.

(E)-5-iodo-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3e. 1.3 mmol), 78% yield, m.p. 148-149 oC.

1

Gray solid, 421 mg (from

H NMR (300 MHz, CDCl3) δ 8.59 (s, 1H), 7.83 (s, 1H), 7.58-

7.55 (d, J = 8.4 Hz, 1H), 7.13-7.10 (d, J = 8.7 Hz, 1H), 6.95-6.85 (m, 1H), 5.86-5.81 (d, J = 15.6 Hz, 1H), 4.19-4.14 (m, 2H), 3.73 (s, 3H), 2.26-2.19 (m, 2H), 2.10-2.03 (m, 2H).


13


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169.9, 166.6, 146.5, 135.7, 135.6, 131.6, 130.8, 129.1, 122.4, 111.8, 106.1, 86.6, 51.6, 46.3, 29.0, 28.0. IR νmax (KBr, film, cm-1): 2923, 1718, 1660, 1532, 1160, 775.


C16H15O4NI [M-H+] 412.0051, found: 412.0050.

(E)-methyl 2-(2-methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 3f. (from 2.0 mmol), 56% yield, m.p. 157-159 oC.

1

Gray solid, 342 mg

H NMR (300 MHz, CDCl3) δ 8.05 (s, 1H), 7.85 (s, 1H),

7.25-7.22 (d, J = 8.4 Hz, 1H), 7.13-7.10 (d, J = 8.4 Hz, 1H), 6.95-6.85 (m, 1H), 5.86-5.80 (d, J = 15.6 Hz, 1H), 4.17-4.10 (m, 2H), 3.72 (s, 3H), 2.49 (s, 3H), 2.24-2.17 (m, 2H), 2.08-1.99 (m, 2H).

13

C NMR (300

MHz, CDCl3) δ 169.9, 165.8, 146.0, 134.4, 134.0, 131.0, 126.3, 123.7, 121.3, 120.8, 108.7, 105.2, 50.6, 45.3, 28.2, 27.2, 20.6.


HRMS (ESI,

orbitrap): calcd for C17H18O4N [M-H+] 300.1241, found: 300.1241.

(E)-5-methoxy-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3g. (from 1.93 mmol), 98% yield, m.p. 110-111 oC.

1

Gray solid, 600 mg

H NMR (300 MHz, CDCl3) δ 7.85 (s, 1H), 7.71-7.70 (d,

J = 2.1 Hz, 1H), 7.25-7.22 (d, J = 9.6 Hz, 1H), 6.96-6.86 (m, 2H), 5.86-5.81 (d, J = 15.6 Hz, 1H), 4.1813

4.13 (m, 2H), 3.92 (s, 3H), 3.73 (s, 3H), 2.26-2.19 (m, 2H), 2.10-2.03 (m, 2H).

C NMR (400 MHz,

CDCl3) δ 170.7, 166.6, 156.1, 146.8, 135.2, 131.5, 127.8, 122.2, 113.6, 110.8, 106.2, 103.2, 55.8, 51.5, 46.4, 29.1, 28.1. IR νmax (KBr, film, cm-1): 2921, 1721, 1657, 1529, 1223, 776.

HRMS (ESI, orbitrap):

calcd for C17H18O5N [M-H+] 316.1190, found: 316.1191.

(E)-6-chloro-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3h. (from 1.9 mmol), 70% yield, m.p. 155-157 oC.

1

Gray solid, 430 mg

H NMR (300 MHz, CDCl3) δ 8.15-8.12 (d, J = 8.4 Hz,

1H), 7.87 (s, 1H), 7.35 (s, 1H), 7.28-7.26 (d, J = 6.9 Hz, 1H), 6.96-6.86 (m, 1H), 5.87-5.82 (d, J = 15.9 Hz, 1H), 4.17-4.12 (m, 2H), 3.73 (s, 3H), 2.27-2.21 (m, 2H), 2.11-2.01 (m, 2H).

13

C NMR (400 MHz, CDCl3)

δ 169.7, 166.6, 146.5, 136.9, 135.7, 129.2, 125.4, 123.05, 123.02, 122.4, 111.0, 106.9, 51.6, 46.3, 29.1, 28.0.


C16H15O4NCl [M-H+] 320.0695, found: 320.0696.




(E)-1-(6-methoxy-6-oxohex-4-enyl)-6-methyl-1H-indole-3-carboxylic acid 3i. (From 1.64 mmol), 98% yield, m.p. 143-145 oC.

1

Page 12 of 27

Gray solid, 486 mg


1H), 7.82 (s, 1H), 7.14 (s, 2H), 6.97-6.87 (m, 1H), 5.87-5.82 (d, J = 15.6 Hz, 1H), 4.18-4.13 (m, 2H), 3.73 (s, 3H), 2.50 (s, 3H), 2.24-2.20 (m, 2H), 2.10-2.03 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 170.5, 166.7,

146.9, 136.9, 134.7, 133.0, 124.8, 124.0, 122.2, 121.6, 109.9, 106.6, 51.5, 46.1, 29.1, 28.0, 21.8. IR ν max (KBr, film, cm-1): 2924, 1721, 1658, 1533, 1276, 811. HRMS (ESI, orbitrap): calcd for C17H18O4N [MH+] 300.1241, found: 300.1244.

(E)-6-methoxy-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3j. (from 2.0 mmol), 37% yield, m.p. 154-156 oC.

1

Gray solid, 238 mg


1H), 7.79 (s, 1H), 6.97-6.89 (m, 2H), 6.78 (s, 1H), 5.87-5.82 (d, J = 15.6 Hz, 1H), 4.14-4.10 (m, 2H), 3.88 (s, 3H), 3.72 (s, 3H), 2.27-2.20 (m, 2H), 2.09-2.00 (m, 2H).

13

C NMR (300 MHz, CDCl3) δ 170.6, 166.8,

157.1, 147.0, 137.5, 134.4, 122.8, 122.3, 121.1, 111.7, 106.8, 93.8, 55.8, 51.6, 46.1, 29.1, 28.0. IR ν max (KBr, film, cm-1): 2949, 1720, 1659, 1533, 1275, 817.

HRMS (ESI, orbitrap): calcd for C17H18O5N [M-

H+] 316.1190, found: 316.1188.

(E)-1-(6-methoxy-6-oxohex-4-enyl)-7-methyl-1H-indole-3-carboxylic acid 3k. (from 1.64 mmol), 90% yield, m.p. 126-128 oC.

1

Gray solid, 446 mg


1H), 7.83 (s, 1H), 7.19-7.15 (m, 1H), 7.03-7.00 (d, J = 6.9 Hz, 1H), 6.97-6.87 (m, 1H), 5.88-5.83 (d, J = 15.9 Hz, 1H), 4.39-4.35 (m, 2H), 3.73 (s, 3H), 2.70 (s, 3H), 2.27-2.23 (m, 2H), 2.04-1.99 (m, 2H).

13

C

NMR (500 MHz, CDCl3) δ 170.0, 166.6, 146.6, 135.9, 135.2, 128.5, 126.0, 124.6, 122.3, 116.0, 111.4, 106.3, 51.6, 46.4, 29.3, 29.1, 28.0.


HRMS (ESI, orbitrap): calcd for C17H18O4N [M-H+] 300.1241, found: 300.1244.

(E)-7-methoxy-1-(6-methoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3l. (from 1.93 mmol), 59% yield, m.p. 136-137 oC.

1

Gray solid, 361 mg

H NMR (300 MHz, DMSO-d6) δ 11.9 (s, 1H), 7.96 (s,


Page 13 of 27 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


1H), 7.63-7.61(d, J = 7.8 Hz, 1H), 7.10-7.05 (m, 1H), 6.95-6.86 (m, 1H), 6.78-6.75 (d, J = 8.1 Hz, 1H), 5.91-5.86 (d, J = 15.6 Hz, 1H), 4.42-4.37 (m, 2H), 3.90 (s, 3H), 3.64 (s, 3H), 2.22-2.16 (m, 2H), 1.94-1.90 (m, 2H).

13

C NMR (500 MHz, DMSO-d6) δ 166.5, 166.0, 149.1, 147.6, 136.4, 129.4, 125.9, 122.5, 121.5,

113.9, 107.0, 104.1, 55.9, 51.6, 49.0, 30.1, 28.9. IR νmax (KBr, film, cm-1): 2950, 1722, 1659, 1538, 1155, 790. HRMS (ESI, orbitrap): calcd for C17H18O5N [M-H+] 316.1190, found: 316.1189.

(E)-1-(6-ethoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3m. mmol), 96% yield, m.p. 87-88 oC.

1

Gray solid, 315 mg (From 1.09

H NMR (300 MHz, CDCl3) δ 8.27-8.24 (m, 1H), 7.91 (s, 1H), 7.38-

7.29 (m, 3H), 6.96-6.86 (m, 1H), 5.86-5.81 (d, J = 15.6 Hz, 1H), 4.22-4.15 (m, 4H), 2.28-2.21 (m, 2H), 13

2.12-2.03 (m, 2H), 1.31-1.26 (m, 3H).

C NMR (300 MHz, CDCl3) δ 170.5, 166.4, 146.6, 136.6, 135.3,

127.1, 123.1, 122.8, 122.4, 122.1, 110.0, 106.8, 60.5, 46.3, 29.2, 28.2, 14.3. IR ν max (KBr, film, cm-1): 2927, 1714, 1661, 1532, 1276, 751.

HRMS (ESI, orbitrap): calcd for C17H19O4NNa [M+Na+] 324.1206,

found: 324.1207.

(E)-1-(6-tert-butoxy-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3n. mmol), 96% yield, m.p. 116-118 oC.

1

Gray solid, 345 mg (from 1.09

H NMR (300 MHz, CDCl3) δ 8.27-8.24 (m, 1H), 7.93-7.91 (d, J =

6.9 Hz, 1H), 7.38-7.29 (m, 3H), 6.86-6.76 (m, 1H), 5.79-5.73 (d, J = 15.6 Hz, 1H), 4.21-4.17 (m, 2H), 2.24-2.18 (m, 2H), 2.10-2.01 (m, 2H), 1.48 (s, 9H).

13

C NMR (300 MHz, CDCl3) δ 170.7, 165.8, 145.3,

136.7, 135.4, 127.1, 124.5, 123.1, 122.4, 122.2, 110.1, 106.8, 80.5, 46.4, 29.1, 28.2.

IR νmax (KBr, film,

cm-1): 2930, 1708, 1661, 1532, 1158, 751. HRMS (ESI, orbitrap): calcd for C19H23O4NNa [M+Na+] 352.1519, found: 352.1519.

(E)-1-(6-(benzyloxy)-6-oxohex-4-enyl)-1H-indole-3-carboxylic acid 3o. mmol), 82% yield, m.p. 115-117 oC.

1


H NMR (300 MHz, CDCl3) δ 8.26-8.23 (m, 1H), 7.89 (s, 1H), 7.36-

7.28 (m, 8H), 7.00-6.90 (m, 1H), 5.90-5.85 (d, J = 15.6 Hz, 1H), 5.17 (s, 2H), 4.20-4.15 (m, 2H), 2.26-2.19 (m, 2H), 2.10-2.01 (m, 2H).

13

C NMR (300 MHz, CDCl3) δ 170.7, 166.1, 147.3, 136.7, 136.1, 135.4,

128.7, 128.3, 127.1, 123.2, 122.5, 122.4, 122.2, 110.1, 106.9, 66.3, 46.3, 29.3, 29.2, 28.2. IR νmax (KBr,



film, cm-1): 2920, 1717, 1658, 1532, 1274, 751.

Page 14 of 27

HRMS (ESI, orbitrap): calcd for C22H21O4NNa [M+Na+]

386.1362, found: 386.1364.

(E)-1-(5-carboxypent-4-enyl)-1H-indole-3-carboxylic acid 3p. 38% yield, m.p. 181-183 oC.

1

Gray solid, 230 mg (from 2.18 mmol),

H NMR (300 MHz, DMSO-d6) δ 12.0 (s, 2H), 8.08 (s, 1H), 8.03-8.01 (d, J

= 7.2 Hz, 1H), 7.59-7.56 (d, J = 7.8 Hz, 1H), 7.26-7.16 (m, 2H), 6.87-6.18 (m. 1H), 5.78-5.73 (d, J = 15.6 Hz, 1H), 4.28-4.24 (m, 2H), 2.17-2.15 (m, 2H), 1.98-1.92 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 167.4,

166.0, 147.9, 136.7, 135.6, 126.9, 122.8, 122.6, 121.7, 121.3, 111.1, 106.9, 45.9, 29.0, 28.3.

IR ν max (KBr,

film, cm-1): 2922, 1658, 1532, 1276, 1210, 1162, 751. HRMS (ESI, orbitrap): calcd for C15H14O4N [MH+] 272.0928, found: 272.0927.

(E)-1-(5-(phenylsulfonyl)pent-4-enyl)-1H-indole-3-carboxylic acid 3q. mmol), 38% yield, m.p. 82-84 oC.

1


H NMR (300 MHz, CDCl3) δ 8.23-8.21 (m, 1H), 7.86-7.84 (m, 3H),

7.63-7.50 (m, 3H), 7.32-7.28 (m. 3H), 6.97-6.88 (m, 1H), 6.34-6.29 (d, J = 15.3 Hz, 1H), 4.19-4.15 (m, 2H), 2.27-2.20 (m, 2H), 2.10-2.01 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 170.3, 144.3, 140.2, 136.4,

135.1, 133.5, 131.9, 129.3, 127.6, 126.9, 123.1, 122.3, 122.0, 109.8, 106.8, 46.0, 28.4, 27.7. film, cm-1): 2923, 1660, 1533, 1145, 752, 592.

IR νmax (KBr,

HRMS (ESI, orbitrap): calcd for C20H18O4NS [M-H+]

368.0962, found: 368.0963.

(E)-1-(6-oxooct-4-enyl)-1H-indole-3-carboxylic acid 3s. yield, m.p. 106-108 oC.

1

Gray solid, 280 mg (from 1.31 mmol), 75%

H NMR (300 MHz, CDCl3) δ 8.26-8.23 (m, 1H), 7.90 (s, 1H), 7.38-7.29 (m,

3H), 6.79-6.69 (m, 1H), 6.12-6.07 (d, J = 15.9 Hz, 1H), 4.23-4.18 (m, 2H), 2.54-2.46 (m, 2H), 2.27-2.20 (m, 2H), 2.13-2.03 (m, 2H), 1.10-1.05 (m, 3H).

13

C NMR (500 MHz, CDCl3) δ 200.6, 170.4, 144.0,

136.5, 135.3, 130.8, 127.0, 123.0, 122.3, 122.0, 109.9, 106.7, 46.3, 33.6, 29.3, 28.1, 8.0. IR ν max (KBr, film, cm-1): 2923, 1661, 1531, 1207, 1162, 752.

HRMS (ESI, orbitrap): calcd for C17H18O3N [M-H+]

284.1292, found: 284.1293. 1-(Pent-4-en-1-yl)-1H-indole-3-carboxylic acid 3r.

Intermediate in the preparation of staring materials.


Page 15 of 27 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


White solid, 3.06 g (From 13.66 mmol), 98% yield, m.p. 122-123 oC. 1H NMR (400 MHz, CDCl3) δ 8.278.24 (m, 1H), 7.92 (s, 1H), 7.39-7.36 (m, 1H), 7.32-7.28 (m. 2H), 5.84-5.74 (m, 1H), 5.09-5.07 (d, J = 9.2, 13

1H), 5.04 (s, 1H), 4.19-4.15 (m, 2H), 2.13-2.08 (m, 2H), 2.03-1.96 (m, 2H).

C NMR (300 MHz, CDCl3)

δ 170.6, 136.89, 136.80, 135.6, 127.1, 123.0, 122.3, 122.1, 116.3, 110.2, 106.5, 46.4, 30.7, 28.8. (KBr, film, cm-1): 2924, 1660, 1532, 1396, 1276, 1232, 750.

IR ν max

HRMS (ESI, orbitrap): calcd for C14H16O2N

[M+H+] 230.1175, found: 230.1177.

General method for the synthesis of 4a-s: To a solution of (E)-1-(6-methoxy-6-oxohex-4-en-1-yl)-1Hindole-3-carboxylic acid 3a (0.5 mmol, 143 mg) in a mixture of water-methanol (3/7, 1 mL total) was added Caesium acetate (0.5 mmol, 96 mg) and [RuCl2(p-cymene)]2 (0.025 mmol, 15 mg). The mixture was stirred at 90 oC under O2 for 18 hours, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate = 40/1) to afford the product (E)-methyl 2-(7,8-dihydropyrido[1,2a]indol-9(6H)-ylidene)acetate 4a as a light yellow solid (95.4 mg, yield 79%).

(E)-methyl 2-(7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4a. 79% yield, m.p. 87-89 oC.

Light yellow solid, 95.4 mg,

1

H NMR (400 MHz, CDCl3) δ 7.62-7.60 (d, J = 8.0 Hz, 1H), 7.30-7.28 (dd, J

= 0.4, 8.4 Hz, 1H), 7.23-7.21 (dd, J = 1.2, 8.4 Hz, 1H), 7.13-7.09 (m, 1H), 6.95 (s, 1H), 6.48-6.47 (m, 1H), 4.14-4.11 (m, 2H), 3.75 (s, 3H), 3.31-3.28 (m, 2H), 2.17-2.10 (m, 2H).

13


167.4, 147.1, 137.5, 134.7, 127.5, 123.1, 121.4, 120.7, 111.3, 109.4, 99.5, 51.2, 41.8, 25.3, 22.9. IR ν max (KBr, film, cm-1): 2920, 1703, 1619, 1520, 1159, 749. HRMS (ESI, orbitrap): calcd for C15H16O2N [M+H+] 242.1175, found: 242.1177.

(E)-methyl 2-(1-bromo-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4b. 32.7 mg, 40% yield, m.p. 74-75 oC.

1

Light yellow solid,

H NMR (300 MHz, CDCl3) δ 7.29-7.21 (m, 2H), 7.10-7.02 (m, 1H),

6.97 (s, 1H), 6.54 (s, 1H), 4.13-4.07 (m, 2H), 3.76 (s, 3H), 3.31-3.27 (m, 2H), 2.17-2.11 (m, 2H).


13

C


Page 16 of 27

NMR (400 MHz, CDCl3) δ 167.2, 146.1, 137.5, 135.2, 128.3, 123.7, 123.4, 115.3, 112.4, 108.5, 99.6, 51.2, 42.2, 25.0, 22.6. IR νmax (KBr, film, cm-1): 2920, 1702, 1618, 1520, 1154, 782.

HRMS (ESI, orbitrap):

calcd for C15H15O2NBr [M+H+] 320.0280, found: 320.0283.

(E)-methyl 2-(2-chloro-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4c. 89.8 mg, 65% yield, m.p. 144-146 oC.

1

Light yellow solid,

H NMR (300 MHz, CDCl3) δ 7.56-7.55 (d, J = 1.2 Hz, 1H), 7.21-

7.14 (m, 2H), 6.85 (s, 1H), 6.46 (s, 1H), 4.11-4.07 (m, 2H), 3.75 (s, 3H), 3.30-3.25 (m, 2H), 2.17-2.09 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 167.2, 146.4, 135.9, 135.8, 128.4, 126.3, 123.4, 120.5, 112.2, 110.4,

98.8, 51.3, 42.0, 25.1, 22.7. IR νmax (KBr, film, cm-1): 2957, 1708, 1617, 1517, 1159, 787.

HRMS (ESI,

orbitrap): calcd for C15H16O2NCl [M+H+] 276.0785, found: 276.0786.

(E)-methyl 2-(2-bromo-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4d. 65.2 mg, 40% yield, m.p. 138-140 oC.

1

Light yellow solid,


7.27 (dd, J = 1.5, 8.7 Hz 1H), 7.17-7.14 (d, J = 8.7 Hz, 1H), 6.85 (s, 1H), 6.47 (s, 1H), 4.12-4.08 (m, 2H), 3.76 (s, 3H), 3.30-3.26 (m, 2H), 2.17-2.09 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 167.1, 146.2, 135.9,

135.6, 128.9, 125.8, 123.5, 113.7, 112.1, 110.7, 98.6, 51.1, 41.8, 24.9, 22.5. IR νmax (KBr, film, cm-1): 2920, 1705, 1622, 1517, 1158, 858. HRMS (ESI, orbitrap): calcd for C15H15O2NBr [M+H+] 320.0280, found: 320.0285.

(E)-methyl 2-(2-iodo-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4e. 26% yield, m.p. 177-179 oC.

1

Gray solid, 47.9 mg,

H NMR (400 MHz, CDCl3) δ 7.943-7.940 (d, J = 1.2 Hz, 1H), 7.46-7.44

(dd, J = 1.6, 8.8 Hz 1H), 7.08-7.05 (d, J = 8.8 Hz, 1H), 6.84 (s, 1H), 6.49 (s, 1H), 4.12-4.08 (m, 2H), 3.76 (s, 3H), 3.30-3.26 (m, 2H), 2.16-2.10 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 167.2, 146.3, 136.4, 135.4,

131.3, 130.1, 129.9, 112.3, 111.3, 98.4, 84.2, 51.3, 41.9, 25.1, 22.7. IR νmax (KBr, film, cm-1): 2920, 1706, 1698, 1436, 1163, 855.

HRMS (ESI, orbitrap): calcd for C15H15O2NI [M+H+] 368.0142, found: 368.0148.

(E)-methyl 2-(2-methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4f.


Light yellow solid,

Page 17 of 27 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


96.3 mg, 75% yield, m.p. 116-118 oC.

1

H NMR (300 MHz, CDCl3) δ 7.37 (s, 1H), 7.18-7.15 (d, J = 8.4

Hz, 1H), 7.06-7.03 (d, J = 8.4 Hz, 1H), 6.85 (s, 1H), 6.44 (s, 1H), 4.09-4.06 (m, 2H), 3.74 (s, 3H), 3.293.25 (m, 2H), 2.42 (s, 3H), 2.14-2.06 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 167.5, 147.2, 136.0, 134.6,

129.9, 127.7, 125.0, 120.8, 110.9, 109.0, 98.9, 51.1, 41.8, 25.2, 22.8, 21.5. IR ν max (KBr, film, cm-1): 2920, 1702, 1608, 1480, 1160, 787. HRMS (ESI, orbitrap): calcd for C16H18O2N [M+H+] 256.1332, found: 256.1334.

(E)-methyl 2-(2-methoxy-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4g. White solid, 95.4 mg, 70% yield, m.p. 145-147 oC. 1H NMR (300 MHz, CDCl3) δ 7.20-7.17 (d, J = 8.7 Hz, 1H), 7.03-7.02 (d, J = 2.1 Hz, 1H), 6.92-6.88 (dd, J = 2.4, 11.4 Hz, 1H), 6.86 (s, 1H), 6.44 (s, 1H), 4.11-4.07 (m, 2H), 3.84 (s, 3H), 3.75 (s, 3H), 3.30-3.26 (m, 2H), 2.17-2.09 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 167.3, 154.7,

146.9, 134.9, 132.9, 127.7, 114.3, 110.8, 110.1, 101.7, 98.8, 55.7, 51.0, 41.7, 25.0, 22.7. IR ν max (KBr, film, cm-1): 2920, 1708, 1626, 1480, 1163, 799.

HRMS (ESI, orbitrap): calcd for C16H18O3N [M+H+]

272.1281, found: 272.1284.

(E)-methyl 2-(3-chloro-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4h. 68 mg, 49% yield, m.p. 110-112 oC.

1

Light yellow solid,

H NMR (300 MHz, CDCl3) δ 7.51-7.48 (d, J = 8.4 Hz, 1H), 7.27 (s,

1H), 7.08-7.05 (dd, J = 1.5, 8.4 Hz, 1H), 6.89 (s, 1H), 6.45 (s, 1H), 4.08-4.04 (m, 2H), 3.75 (s, 3H), 3.293.26 (m, 2H), 2.16-2.08 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 167.1, 146.4, 137.6, 135.3, 128.9, 125.9,

122.1, 121.4, 111.7, 109.2, 99.4, 51.1, 41.8, 25.0, 22.5. IR νmax (KBr, film, cm-1): 2920, 1704, 1617, 1348, 1159, 810.

HRMS (ESI, orbitrap): calcd for C15H15O2NCl [M+H+] 276.0785, found: 276.0791.

(E)-methyl 2-(3-methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4i. 94.3 mg, 74% yield, m.p. 118-120 oC.

1

Light yellow solid,

H NMR (300 MHz, CDCl3) δ 7.49-7.47 (d, J = 8.1 Hz, 1H), 7.07

(s, 1H), 6.96-6.93 (d, J = 7.8 Hz, 1H), 6.90 (s, 1H), 6.44 (s, 1H), 4.10-4.06 (m, 2H), 3.74 (s, 3H), 3.30-3.26 (m, 2H), 2.47 (s, 3H), 2.15-2.07 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 167.4, 147.2, 137.8, 134.0,

133.1, 125.3, 122.6, 120.9, 110.5, 109.1, 99.3, 51.0, 41.6, 25.2, 22.7, 22.0. IR ν max (KBr, film, cm-1):



Page 18 of 27

2945, 1703, 1609, 1516, 1151, 810. HRMS (ESI, orbitrap): calcd for C16H18O2N [M+H+] 256.1332, found: 256.1334.

(E)-methyl 2-(3-methoxy-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4j. 103 mg, 76% yield, m.p. 105-106 oC.

1

Light yellow solid,

H NMR (300 MHz, CDCl3) δ 7.48-7.45 (d, J = 8.7 Hz, 1H), 6.89

(s, 1H), 6.80-6.77 (dd, J = 1.5, 8.7 Hz, 1H), 6.69 (s, 1H), 6.39 (s, 1H), 4.07-4.03 (m, 2H), 3.86 (s, 3H), 3.74 (s, 3H), 3.30-3.26 (m, 2H), 2.16-2.08 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 167.5, 157.3, 147.1, 138.2,

133.7, 122.1, 121.8, 111.5, 109.6, 99.7, 91.9, 55.5, 51.0, 41.7, 25.1, 22.7. 1701, 1619, 1355, 1152, 814.

IR νmax (KBr, film, cm-1): 2947,

HRMS (ESI, orbitrap): calcd for C16H18O3N [M+H+] 272.1281, found:

272.1284.

(E)-methyl 2-(4-methyl-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4k. Light yellow solid, 91.9 mg, 72% yield, m.p. 129-130 oC.

1


6.90 (m, 3H), 6.45 (s, 1H), 4.57-4.53 (m, 2H), 3.75 (s, 3H), 3.26-3.22 (m, 2H), 2.74 (s, 3H), 2.13-2.05 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 167.4, 147.5, 136.8, 134.7, 128.1, 126.0, 121.3, 120.5, 119.4, 110.8,

100.4, 51.0, 45.1, 24.9, 23.4, 20.5.


HRMS

(ESI, orbitrap): calcd for C16H18O2N [M+H+] 256.1332, found: 256.1333.

(E)-methyl 2-(4-methoxy-7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4l. 98.2 mg, 72% yield, m.p. 91-92 oC.

1

Light yellow solid,

H NMR (300 MHz, CDCl3) δ 7.18-7.15 (d, J =8.1 Hz, 1H), 6.98-

6.93 (m, 1H), 6.89 (s, 1H), 6.60-6.58 (d, J = 7.8 Hz, 1H), 6.43 (s, 1H), 4.60-4.57 (m, 2H), 3.90 (s, 3H), 3.74 (s, 3H), 3.25-3.20 (m, 2H), 2.10-2.02 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 167.4, 147.8, 147.5,

134.6, 129.3, 127.7, 120.6, 113.9, 110.8, 103.3, 99.9, 55.3, 51.0, 45.1, 25.1, 23.3. 1

IR ν max (KBr, film, cm-

): 2946, 1704, 1606, 1256, 1158, 728. HRMS (ESI, orbitrap): calcd for C16H18O3N [M+H+] 272.1281,

found: 272.1283.

(E)-ethyl 2-(7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4m.



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75% yield, m.p. 84-86 oC.

1

H NMR (300 MHz, CDCl3) δ 7.61-7.58 (d, J = 7.5 Hz, 1H), 7.29-7.19 (m,

2H), 7.12-7.08 (m, 1H), 6.93 (s, 1H), 6.47 (s, 1H), 4.24-4.17 (m, 2H), 4.11-4.08 (m, 2H), 3.28 (s, 2H), 2.122.09 (m, 2H), 1.34-1.30 (m, 2H).

13

C NMR (500 MHz, CDCl3) δ 170.0, 166.6, 146.6, 135.9, 135.2, 128.5,

126.0, 124.6, 122.3, 116.0, 111.4, 106.3, 51.6, 46.4, 29.1, 28.0. 1618, 1521, 1154, 749.

IR νmax (KBr, film, cm-1): 2922, 1699,

HRMS (ESI, orbitrap): calcd for C16H18O2N [M+H+] 256.1332, found: 256.1335.

(E)-tert-butyl 2-(7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4n. 68% yield, m.p. 87-89.

1


H NMR (300 MHz, CDCl3) δ 7.60-7.58 (d, J = 7.8 Hz, 1H), 7.29-7.18 (m, 2H),

7.12-7.07 (m, 1H), 6.92 (s, 1H), 6.40 (s, 1H), 4.12-4.08 (m, 2H), 3.27-3.24 (m, 2H), 2.14-2.09 (m, 2H), 13

1.52 (s, 9H).

C NMR (300 MHz, CDCl3) δ 166.6, 145.6, 137.4, 135.0, 127.6, 122.8, 121.3, 120.6, 113.8,

109.3, 99.1, 80.1, 41.9, 28.5, 28.3, 28.2, 25.1, 22.9. 1138, 748.

IR νmax (KBr, film, cm-1): 2922, 1699, 1618, 1366,

HRMS (ESI, orbitrap): calcd for C18H22O2N [M+H+] 284.1656, found: 284.1651.

(E)-benzyl 2-(7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetate 4o. 40% yield, m.p. 78-80 oC.


1


8H), 7.12-7.07 (m, 1H), 6.93 (s, 1H), 6.52 (s, 1H), 5.19 (s, 2H), 4.11-4.07 (m, 2H), 3.31-3.28 (m, 2H), 2.122.08 (m, 2H).

13

C NMR (300 MHz, CDCl3) δ 166.7, 147.5, 137.5, 136.5, 134.6, 128.7, 128.4, 128.3,

128.2, 127.5, 123.1, 121.4, 120.7, 111.3, 109.4, 99.6, 65.8, 41.8, 25.3, 22.8. IR νmax (KBr, film, cm-1): 2921, 1701, 1617, 1520, 1147, 748. HRMS (ESI, orbitrap): calcd for C21H20O2N [M+Na+] 318.1488, found: 318.1493.

(E)-2-(7,8-dihydropyrido[1,2-a]indol-9(6H)-ylidene)acetic acid 4p. 92% b.r.s.m, m.p. 186-189 oC.

1

Yellow soild, 10 mg, 17% yield,


2H), 7.15-7.10 (m, 1H), 7.02 (s, 1H), 6.51 (s, 1H), 4.17-4.13 (m, 2H), 3.33-3.30 (m, 2H), 2.18-2.14 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 171.7, 149.2, 137.5, 134.3, 127.4, 123.3, 121.5, 120.7, 110.6, 109.3,

100.2, 41.7, 25.4, 22.7. IR νmax (KBr, film, cm-1): 2923, 1674, 1598, 1517, 1474, 1249, 1227, 1190, 748. HRMS (ESI, orbitrap): calcd for C14H12O2N [M-H+] 226.0873, found: 226.0871.



(E)-9-(phenylsulfonylmethylene)-6,7,8,9-tetrahydropyrido[1,2-a]indole 4q. yield, 89% b.r.s.m, m.p. 132-134 oC.

1

Page 20 of 27

White soild, 30 mg, 18%

H NMR (300 MHz, CDCl3) δ 7.99-7.96 (m, 2H), 7.61-7.52 (m,

4H), 7.25-7.21 (m, 2H), 7.13-7.08 (m, 1H), 6.89-6.88 (d, J =3.3 Hz, 2H), 4.11-4.07 (m, 2H), 3.21-3.16 (m, 2H), 2.17-2.09 (m, 2H).

13

C NMR (300 MHz, CDCl3) δ 144.1, 142.5, 137.5, 133.1, 132.2, 129.2, 127.2,

127.1, 123.7, 121.6, 121.2, 120.9, 109.4, 100.7, 41.6, 24.1, 22.4.

IR ν max (KBr, film, cm-1): 2922, 1586,

1516, 1445, 1301, 1142, 1082, 749. HRMS (ESI, orbitrap): calcd for C19H17O2NNaS [M+Na+] 346.0872, found: 346.0864.

9-Methylene-6,7,8,9-tetrahydropyrido[1,2-a]indole 4r.14 100% b.r.s.m. m.p. 82-84 oC.

1

White soild, 8 mg (From 0.5 mmol), 8% yield.

H NMR (300 MHz, CDCl3) δ 7.58-7.56 (d, J =7.8 Hz, 1H), 7.27-7.24 (m,

1H), 7.18-7.06 (m, 2H), 6.74 (s, 1H), 5.61 (s, 1H), 4.997-4.995 (d, J =0.6 Hz 1H), 4.12-4.08 (m, 2H), 2.632.59 (m, 2H), 2.16-2.08 (m, 2H).

13

C NMR (400 MHz, CDCl3) δ 136.53, 136.52, 136.2, 128.0, 121.5,

120.6, 120.1, 109.2, 109.1, 96.1, 42.2, 30.2, 23.8.

IR νmax (KBr, film, cm-1): 2923, 1476, 1329, 1162, 897,

791. HRMS (ESI, orbitrap): calcd for C13H14N [M+H+] 184.1120, found: 184.1120.

1-(6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)butan-2-one 4s. m.p. 67-68 oC.

1

Light yellow soild, 90 mg, 74% yield,

H NMR (300 MHz, CDCl3) δ 7.52-7.50 (d, J = 7.5 Hz, 1H), 7.25-7.23 (d, J = 7.5 Hz,

1H), 7.16-7.04 (m, 2H), 6.15 (s, 1H), 4.19-4.12 (m, 1H), 3.92-3.83 (m, 1H), 3.60-3.53 (m, 1H), 3.05-2.98 (dd, J = 17.1, 5.1 Hz,1H), 2.72-2.63 (q, J = 8.7 Hz, 1H), 2.54-2.43 (m, 2H), 2.19-1.99 (m, 3H), 1.50-1.40 (m, 1H), 1.13-1.08 (t, 3H).

13

C NMR (500 MHz, CDCl3) δ 209.9, 140.3, 136.2, 127.9, 120.5, 119.8,

119.7, 108.7, 96.8, 47.9, 42.2, 36.7, 30.6, 27.4, 22.1, 7.8. 1457, 1411, 1311, 770, 748.

IR νmax (KBr, film, cm-1): 2924, 1711, 1534,

HRMS (ESI, orbitrap): calcd for C16H20ON [M+H+] 242.1539, found:

242.1537.

General procedure for the synthesis of 6a-b: To a solution of (E)-methyl 2-(7,8-dihydropyrido[1,2a]indol-9(6H)-ylidene)acetate 4a (1.2 mmol, 300 mg) in a mixture of tetrahydrofuran (3 mL) and H2O (3


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mL) was added Pd/C (60 mg). The mixture was stirred at room temperature for 12 hours under H2. Then the mixture was filtered through celite and the filtrate was concentrated.

The residue was purified

by silica column chromatography (elute: petroleum ether/ethyl acetate = 30/1) to afford the product methyl 2-(6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6a as a light yellow oil (260 mg, yield 87%).

Methyl 2-(6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6a. 1

Light yellow oil, 260 mg, 87% yield.

H NMR (300 MHz, CDCl3) δ 7.53-7.51 (d, J = 7.2 Hz, 1H), 7.24-7.21 (d, J = 7.8 Hz, 1H), 7.16-7.04 (m,

2H), 6.22 (s, 1H), 4.16-4.09 (m, 1H), 3.89-3.80 (m, 1H), 3.72 (s, 3H), 3.52-3.43 (m, 1H), 2.97-2.90 (dd, J =5.4, 15.6 Hz,1H), 2.59-2.51 (q, J = 8.7 Hz, 1H), 2.17-2.07 (m, 2H), 2.05-1.96 (m, 1H), 1.60-1.48 (m, 1H). 13

C NMR (400 MHz, CDCl3) δ 172.7, 139.6, 136.3, 128.0, 120.7, 119.9, 119.8, 108.8, 97.1, 51.7, 42.2, IR νmax (KBr, film, cm-1): 2948, 1738, 1459, 1169, 1012, 775.

39.8, 31.9, 27.3, 22.1.

HRMS (ESI,

orbitrap): calcd for C15H18O2N [M+H+] 244.1332, found: 244.1335.

Methyl 2-(2-methoxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6b. yield, m.p. 88-90 oC.

1

White solid, 309 mg, 97%

H NMR (300 MHz, CDCl3) δ 7.14-7.11 (d, J = 8.7 Hz, 1H), 7.02-7.01 (d, J = 1.8

Hz, 1H), 6.82-6.78 (dd, J = 1.8, 8.7 Hz, 1H), 6.15 (s, 1H), 4.83 (s, 1H), 4.14-4.06 (m, 1H), 3.88-3.87 (m, 1H), 3.82 (s, 3H), 3.73 (s, 3H), 3.50-3.43 (m, 1H), 2.97-2.90 (dd, J = 5.4, 15.9 Hz,1H), 2.59-2.51 (q, J =9.0 Hz, 1H), 2.20-2.11 (m, 2H), 2.09-1.97 (m, 1H), 1.61-1.48 (m, 1H).

13

C NMR (300 MHz, CDCl3) δ 172.7,

154.4, 140.3, 131.7, 128.4, 110.8, 109.5, 102.1, 96.9, 56.0, 51.8, 42.3, 39.9, 31.9, 27.3, 22.1. (KBr, film, cm-1): 2948, 1737, 1484, 1163, 1034, 794.

IR ν max

HRMS (ESI, orbitrap): calcd for C16H20O3N

[M+H+] 274.1437, found: 274.1441.

Procedure for the synthesis of 6c: To a solution of methyl 2-(2-methoxy-6,7,8,9-tetrahydropyrido[1,2a]indol-9-yl)acetate 6b (100 mg, 0.36 mmol) in dichloromethane (5 mL) was added dropwise boron tribromide (1M in dichloromethane, 1.44 mL, 1.44 mmol) at 0 oC.

The reaction continued stirring

overnight at room temperature and then quenched by saturated sodium bicarbonate, diluted with ethyl acetate (20 mL).

The organic layer was washed by water (10 mL) and brine (10 mL), dried over



Page 22 of 27

anhydrous sodium sulfate, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate = 2/1) to afford the intermediate methyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2a]indol-9-yl)acetate 6c as a colorless oil (48.1 mg, yield 48%).

Methyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate 6c. 48% yield.

1

Light yellow oil, 45.1 mg,

H NMR (300 MHz, CDCl3) δ 7.09-7.07 (d, J = 8.7 Hz, 1H), 6.94-6.93 (d, J = 2.1 Hz, 1H),

6.73-6.69 (dd, J = 2.4, 8.7 Hz, 1H), 6.09 (s, 1H), 4.83 (s, 1H), 4.12-4.06 (m, 1H), 3.87-3.78 (m, 1H), 3.74 (s, 3H), 3.51-3.41 (m, 1H), 2.96-2.89 (dd, J = 5.4, 15.6 Hz,1H), 2.59-2.51 (q, J = 8.7 Hz, 1H), 2.10-2.06 (m, 2H), 2.03-1.94 (m, 1H), 1.60-1.48 (m, 1H).

13

C NMR (400 MHz, CDCl3) δ 172.9, 149.8, 140.6,

131.9, 128.7, 110.4, 109.4, 104.6, 96.5, 51.9, 42.3, 39.8, 32.0, 27.3, 22.1. 2922, 1733, 1451, 1175, 848.

IR νmax (KBr, film, cm-1): 3366,

HRMS (ESI, orbitrap): calcd for C15H16O3N [M-H+] 258.1135, found:

258.1136.

Procedure for the synthesis of 1: To a solution of methyl 2-(6,7,8,9-tetrahydropyrido[1,2-a]indol-9yl)acetate 6a (0.37mmol, 100 mg) in water (2 mL) was added 4-chlorothiophenol (0.37 mmol, 60 mg), iodine (0.037 mmol, 10 mg,) and dimethyl sulfoxide (1.1 mmol, 0.088 mL). 100 oC for 4 hours and then diluted with ethyl acetate (20 mL).

The mixture was stirred at

The organic layer was washed by water

(10 mL), saturated Sodium thiosulfate (10 mL*2) and brine (10 mL), dried over anhydrous sodium sulfate, evaporated to afford the crude intermediate methyl 2-(10-(4-chlorophenylthio)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetate as a light yellow oil.

A mixture of the crude intermediate

methyl 2-(10-(4-chlorophenylthio)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate and aqueous lithium hydroxide (1M in water, 1.5 mL) was heated to 60 oC for 4 hours and then acidified to pH 6 with 1N hydrochloride. The solution was diluted with ethyl acetate (20 mL), washed by water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate = 5/1) to afford 2-(10-(4-chlorophenylthio)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetic acid 1 as a light yellow solid (37 mg, yield 25%, 2 steps).


Page 23 of 27 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


2-(10-(4-chlorophenylthio)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid 1. solid, 37 mg, 25% yield.

1

Light yellow

H NMR (300 MHz, Acetone-d6) δ 10.72 (br, 1H), 7.48-7.41 (m, 2H), 7.24-7.09

(m, 4H), 7.02-7.00 (d, J = 8.7 Hz, 1H), 4.36-4.31 (m, 1H), 4.06-3.98 (m, 1H), 3.82-3.77 (m, 1H), 2.90-2.69 (m, 2H), 2.31-2.21 (m, 1H), 2.11-2.04 (m, 3H).

13

C NMR (500 MHz, Acetone-d6) δ 172.7, 145.7, 139.4,

137.5, 130.7, 130.5, 129.6, 127.5, 122.6, 121.7, 118.7, 110.7, 95.6, 43.4, 38.8, 30.1, 25.4, 19.6. HRMS (ESI, orbitrap): calcd for C20H17O2NClS [M-H+] 370.0674, found: 370.0674.

Procedure for the synthesis of 2: To a solution of methyl 2-(2-hydroxy-6,7,8,9-tetrahydropyrido[1,2a]indol-9-yl)acetate 6c (0.28 mmol, 75 mg) in dry dimethylformamide (5 mL) was added Caesium carbonate (0.58 mmol, 189 mg) and 1-(chloromethyl)-3,5-bis(trifluoromethyl)benzene (0.38 mmol, 48 mg). The mixture was then stirred at 75 oC for 3 hours under nitrogen, then diluted with ethyl acetate (50 mL). The organic layer was washed by water (40 mL) and brine (40 mL*2), dried over anhydrous sodium sulfate, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate = 30/1) to afford the intermediate methyl 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9tetrahydropyrido[1,2-a]indol-9-yl)acetate as a white solid (90.3 mg, yield 64%).

To a solution of methyl

2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetate (0.1 mmol, 51 mg) in dioxane (2.5 mL) was added aqueous Lithium hydroxide (1M, 0.6 mL, 0.6 mmol).

The mixture

was stirred at 50 oC for 2 hours and then acidified to pH 6 with 1N hydrochloride. The solution was diluted with ethyl acetate (20 mL), washed by water (10 mL) and brine (10 mL), dried over anhydrous sodium sulfate, evaporated and purified by silica column chromatography (elute: petroleum ether/ethyl acetate = 2/1) to afford 2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9yl)acetic acid 2 as a white solid.

2-(2-(3,5-bis(trifluoromethyl)benzyloxy)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl)acetic acid 2. White solid, 31.5 mg, 66% yield.

1

H NMR (300 MHz, DMSO-d6) δ 12.31 (s, 1H), 8.16 (s, 2H), 8.06 (s,

1H), 7.27-7.25 (d, J = 6.6 Hz, 1H), 7.10-7.09 (d, J = 1.5 Hz, 1H), 6.86-6.83 (dd, J = 1.8, 6.6 Hz, 1H), 6.18 (s, 1H), 5.30 (s, 2H), 4.16-4.11 (m, 1H), 3.83-3.76 (m, 1H), 3.33-3.28 (m, 1H), 2.88-2.82 (dd, J = 4.2, 12.0



Hz,1H), 2.49-2.43 (q, J = 6.3 Hz, 1H), 2.12-2.01 (m, 2H), 1.99-1.93 (m, 1H), 1.53-1.45 (m, 1H). HRMS (ESI, orbitrap): calcd for C23H18O3NF6 [M-H+] 470.1196, found: 470.1195.

ASSOCIATED CONTENT The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/xxxx.

1

H and 13C NMR spectra of all new products and intermediates, X-ray crystallography data

and CIF file of 4a (PDF).

AUTHOR INFORMATION Corresponding Authors *E-mail: [email protected] (L.C.); [email protected] (L.L.) Notes The authors declare no competing financial interest.

ACKNOWLEDGMENTS This work was supported by the National Key R&D Program of China (2016YFA0602900), National Natural Science Foundation of China (21778057, 21502201 and 21420102003), Beijing Natural Science Foundation (2162049), Young Elite Scientist Sponsorship Program by CAST (2015QNRC001) and Chinese Academy of Sciences.

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[2] (a) Mroue, M. A.; Euler, K. L.; Ghuman, M. A.; Alam, M. J. Nat. Prod. 1996, 59, 890-893. (b) Gervais,


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