Regio- and Stereoselective Synthesis of Isoindolin-1-ones through

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Regio- and Stereoselective Synthesis of Isoindolin-1-ones through BuLi-mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides Dhirendra Brahmchari, Akhilesh K. Verma, and Saurabh Mehta J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b02903 • Publication Date (Web): 19 Feb 2018 Downloaded from http://pubs.acs.org on February 19, 2018

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The Journal of Organic Chemistry

Regio- and Stereoselective Synthesis of Isoindolin-1-ones through BuLi-mediated Iodoaminocyclization of 2-(1-Alkynyl)benzamides Dhirendra Brahmchari,† Akhilesh K. Verma‡ and Saurabh Mehta†, †

Department of Applied Chemistry, Delhi Technological University, Delhi, 110042 India. Synthetic Organic Chemistry Research Laboratory, Department of Chemistry, University of Delhi, Delhi 110007 India

‡

Abstract

A simple and straightforward synthesis of isoindolin-1-ones is reported. Exclusive Ncyclization of the amide functional group, an ambident nucleophile, has been accomplished for the cyclization of 2-(1-alkynyl)benzamides using n-BuLi-I2/ICl. The methodology works with the primary amide and affords the desired isoindolinones in yields of 38-94%. Interestingly, the isolated products exhibit a Z-stereochemistry across the C=C double bond. The reaction mechanism involving the formation of either a vinylic anion or an intimate ion pair intermediate is proposed.

Isoindolinones or phthalimidines represent an important class of nitrogen-containing heterocycles. This benzo-fused lactam scaffold is present in several naturally occurring, pharmacologically active substances such as alkaloids, e.g. Fumaridine, Chilenine, Nuevamine, Lennoxamine, and Stachybotrin C, etc.1–3 Moreover, numerous molecules containing isoindolin-1-one scaffold display a wide array of important biological activities

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such as vasodilatory,4 anti-HIV,5 antilcancer,6 antimicrobial,7 anticonvulsant,8 sedative & hypnotic,9 etc. A few specific examples of such drugs and other medicinally important compounds containing isoindolin-1-one scaffold include Chlortalidone,10 JM-1232,11 (S)-PD 172938,12 Pagoclone (Cl-1043),13 Pazinaclone (DN 2327), etc.14 Owing to their widespread medicinal importance, there has been a continuous interest in developing new syntheses of isoindolin-1-ones that improve accessibility to a broad array of structurally related analogues. Several research groups have developed various interesting approaches (>200 research articles in the recent literature) for the synthesis of the isoindolin-1-ones.15,16 More particularly, alkyne annulation reactions have been used for the synthesis of isoindolinones, e.g. through metal catalyzed, including Pd-catalyzed,17–21 Cu-catalyzed/mediated,22–26 Rucatalyzed;27 base-mediated annulations,28–35 etc.36,37 The electrophilic cyclization, particularly the iodocyclization of functionalized alkynes has emerged as a powerful method for the synthesis of a wide variety of heterocyclic and carbocyclic compounds.38–40 These reactions have several practical advantages including the ease of performing the reactions, fast reactions, simple workup, compatibility with most functional groups, and importantly the fact that the products contain Iodine atom, which provides easy handle for various metal-catalyzed coupling reactions.41 We have also studied this methodology and have used it to make a variety of heterocyclic compounds in the past.42,43 Moreover, efforts have been made previously by Yao et al. for the iodocyclization of o-(1-alkynyl)benzamides for the synthesis of isoindolin-1-ones,44 however, later it was found that the methodology resulted in the cyclization via the O-atom of the amide group leading to the formation of the cyclic imidates rather than isoindolin-1-ones, which was later on confirmed and corrected by us and others (Scheme 1).45,46 SCHEME 1. Previous work


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O

O R1

N

R2

N

R1

R2

R3 I I Reported/mischaracterized products (isoindolinones/Isoquinolinones) Yao et. al. J. Org. Chem. 2005, 70, 1432-1437 R3

O R1

NHR2

I2 or ICl NaHCO3/MeCN

R3 R1

2 N R

O

N R1

R2 O

R3 R3 I I Actually formed products (cyclic imidates) Mehta et al. J. Org. Chem. 2012, 77, 10938-10944 Schlemmer et al. J. Org. Chem. 2012, 77, 10118-10124

Furthermore, to the best of our knowledge, the synthesis of isoindolin-1-ones has not been accomplished via iodocyclization, probably due to the challenge posed by the ambident nucleophilic nature of the amide functionality (N- Vs. O-cyclization). Nonetheless, such methodology would be synthetically useful and would lead to diverse isoindolin-1-ones with interesting substitution patterns. Due to our continuous interest in developing new methodologies for heterocyclic synthesis, we became interested in tuning the reactivity of these 2-(1-alkynyl)benzamides to achieve regioselective synthesis of isoindolinones (Scheme 2), and report our findings here. SCHEME 2. Present work

Amide group (–CONH2) is an ambident nucleophile and is known to undergo N vs O cyclization in alkyne annulation reactions,47,48 therefore, the choice of the suitable reagents is important for tuning the reactivity of the nucleophilic site.29 Our efforts were directed towards the development of a suitable methodology employing I2/ICl as efficient electrophile for the N-cyclization of 2-(1-alkynyl)benzamides to furnish isoindolin-1-ones. During a thorough literature survey, we came across an interesting methodology developed by Fujita et al. that involves a regiocontrolled iodoaminocyclization of the protected amide group at the



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activated double bond (eq 1).49 The authors also presented a rationale of N- Vs O-cyclization of unsaturated amides based on HSAB theory. Furthermore, the authors achieved regiocontrol (N-cyclization) in the iodocyclization of allyl or homoallyl carbamates, etc. through the use of suitable base/additives, n-BuLi/LiAl(Ot-Bu)4 (eq 1). The authors postulated that the reaction proceeds through the formation of a metal imino alkolate intermediate and explained the achieved regiocontrol through the increased reactivity of amide nitrogen atom. O nX

O N H

(i) n-BuLi or LiAl(Ot-Bu)4 OR (ii) I2

O X

n = 1, 2 X = O, NR', CH2 R = Et, t-Bu, Bn

Li N

O

O

O OR

OR eq.143 I

N

X n

n

62-88%

I2 Regiocontrolled N-cyclization

Inspired by the methodology developed by Fujita et.al, we envisioned a similar intramolecular iodoaminocyclization of 2-(1-alkynyl)benzamide derivatives. The required alkyne substrates would be conveniently prepared from the commercially available starting materials using the following approach (Scheme 3). SCHEME 3. Strategy for preparing 2-(1-alkynyl)benzamides O

O R1 X 1 X = Br, I

OH (i) SOCl2 R1 (ii) R2-NH2

N H

R2

R3 3 Pd/Cu

O N H

R1

R2

X 2

4

R3

Initially, we started our reactions (eq 2) with the cyclization of tert-butyl(2(phenylethynyl)benzoyl)carbamate (4a), which involves the (-CO-NH-CO-) group for the formation of a metal imino alkolate intermediate with metallic base that makes the nitrogen atom more nucleophilic, leading to the formation of N-cyclized product. Although the desired product 5a was isolated, however, it was not stable enough and isolated yield (27%) was poor.


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O

O N H

Li

O OtBu

n-BuLi

N

Ph

O

O OtBu

I2

NBoc eq.2

Ph

4a

5a I

Ph 27%

We attributed the formation of unstable product and low reaction yield to the presence of the labile protecting group (N-Boc) and/or the sterically hindered substrate, and we decided

to

use

the

unprotected

amide

group

instead.

We

then

took

2-(1-

phenylethynyl)benzamide (4b) as a model substrate for determining the optimum reagents/conditions for the cyclization reaction, using I2/ICl as the iodine source (Table S1). To our pleasant surprise, the use of n-BuLi as base worked and the cyclized product 5b was isolated with a yield of 67% (eq 3). The procedure involved the addition of n-BuLi to the alkyne substrate in THF at 0 °C, followed by the addition of I2/ICl and stirring the reaction mixture at 0 °C. The cyclized product was thoroughly characterized using spectroscopy (IR, 1

H-NMR,

13

C-NMR), mass spectrometry (HRMS) as well as single crystal X-ray

crystallography (see ORTEP diagram in eq 3). It is noteworthy that the cyclized product 5b was found to possess Z-geometrical configuration. Also, the reaction at lower temperature (78 oC) resulted in a mixture of stereoisomers (E:Z 1:9). The reaction also worked with ICl, however the yield was slightly lower (63%). It was attempted to improve the reaction yield through the use of other bases and other reaction parameters (reaction time, temperature, solvent, etc.) and the details are summarized in the optimization Table S1 (See Supplementary Information).

Overall, the yield could not be improved for this substrate. Therefore, we decided to proceed further and to study the scope and limitations of the cyclization reaction using the



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same reaction conditions (eq 3). The required alkyne substrates 4b-4t were prepared (Scheme 3) in yields ranging from 48-95% by using the palladium/copper-catalyzed Sonogashira cross coupling50 and the results are summarized in Table S2 (See supporting information). Thus a variety of 2-(1-Alkynyl)benzamides were subjected to the cyclization conditions and the results are summarized in Table 1. TABLE 1: BuLi-mediated Cyclization of 2-(1-Alkynyl)benzamidesa

entr y 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. 15. 16. 17. 18. 19.

subst rate 4b 4b 4c 4c 4d 4d 4e 4e 4f 4g 4g 4h 4i 4j 4j 4k 4k 4l 4m

R1

R2

R3

I+

H

H

Ph

H

H

4-MePh

H

H

3-MePh

H

H

4-OMePh

H H

H H

4-NMe2Ph 4-FPh

H H H

H H H

4-BrPh 2-BrPh 3-ClPh

H

H

n-hexyl

H H

H H

cyclohexyl cyclohexe nyl TMS H 3-thienyl Ph

I2 ICl I2 ICl I2 ICl I2 ICl I2 I2 ICl I2 I2 I2 ICl I2 ICl I2 I2

prod uct 5b 5b 5c 5c 5d 5d 5e 5e 5f 5g 5g 5h 5i 5j 5j 5k 5k 5l 5m

yield (%) 67 63 71 61 89 71 52 44 67 69 67 41b,c -b,d 74 73 75 69 94 57

H H I2 -e 5n H H I2 82 5o H H I2 75 5p 3,4H I2 78 5q (OM e)2 24. H Me Ph I2 -f 4r 5r 25. H Ph Ph I2 -g 4s 5s 26. H Ph n-hexyl I2 -g 4t 5t a All reactions were run using 0.25 mmol of 2-(1-alkynyl)benzamide in 2 mL THF and 1.2 equiv of n-BuLi (1.6 M in Hexane), stirred for 10 minutes, followed by the dropwise addition (approx.1 min) of 3.0 equiv I2/ICl in 1 mL THF and the reaction mixture was stirred at 0 °C for 20 minutes under Argon atmosphere (total reaction time 30 min). b1.0 equiv of n-BuLi (1.6 M in Hexane) was used. c corresponding debrominated product was also formed (yield: 9%). d only the corresponding debrominated product was isolated (yield: 38%). ecorresponding desilylated product was isolated (yield: 75%). f O-cyclized product was formed (yield: 47%). gcomplex reaction mixture was obtained. 20. 21. 22. 23.

4n 4o 4p 4q


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The reaction worked well with the substrates 4b-4g containing electron donating and withdrawing groups, e.g. Me, OMe, NMe2, F, etc. (Table 1, entries 3-11). The cyclization of bromine containing substrates 4h and 4i resulted in the isolation of partially (entry 12) or completely debrominated (entry 13) products. The cyclization of the substrate 4j containing chloro group (entries 14 and 15) resulted in the formation of desired product. The substrate 4k with n-hexyl group at the distal end of the alkyne was also cyclized to give good yield (entries 16 and 17). Even a cyclohexyl group containing substrate 4l was successfully cyclized with an excellent yield (entry 18). Cyclization of alkyne substrate 4m with unsaturation (cyclohexenyl group) resulted in moderate yield (entry 19). The cyclization of the substrate 4n with TMS group resulted in the formation of desilylated product in 75% yield (entry 20). The reaction worked well for the terminal alkyne 4o and the expected product was isolated in 82% yield (entry 21). The methodology also worked for the substrate 4p with a heterocyclic moiety and resulted in the thienyl containing isoindolinone 5p in 75% yield (entry 22). The substrate 4q with electron donating methoxy groups at the benzamide ring in substrate was successfully converted to the desired product in 78% yield (entry 23). We then attempted the cyclization of secondary amide substrates (4r-4t). The N-Me substituted amide 4r underwent cyclization (entry 24), however, the product was found to be the corresponding imidate (O-cyclized product) instead of the expected isoindollin-1-one. Furthermore, the cyclization of N-phenyl substituted amides 4s and 4t (entries 25 and 26 respectively) resulted in the formation of complex mixtures that could not be resolved. These results (entries 24-26) indicate that the steric hindrance due to the Methyl or Phenyl substituent on the nitrogen atom of the amide group presumably disfavors the desired Ncyclization under these reaction conditions. All the cyclized products were characterized using the spectroscopy (IR, 1H-NMR, 13

C-NMR) and Mass Spectrometry (HRMS). The stereochemistry of the cyclized products



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was assigned by correlating the spectroscopic data with that of 5b. It is noteworthy that the N-cyclized products were differentiated from the O-cyclized products by the presence of the diagnostic signals in the 13C-NMR spectra of these compounds (Figure 1). O R1

NR2 R3

NR2

 >162 ppm 

Regio- and Stereoselective Synthesis of Isoindolin-1-ones through

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