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Four series of heterocyclic compounds were obtained using Ugi-type multicomponent reactions (MCRs) with methyl 2-formylbenzoate as one of the starting materials. A facile and efficient one-pot procedure was suitable for all the MCRs under acidic conditions. This process provided access to four series of complex and potentially biologically active scaffolds.
Mol Divers (2016) 20:859865 DOI 10.1007/s11030-016-9679-6
ORIGINAL ARTICLE
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Web End = Synthesis of isoindolin-1-one derivatives via multicomponent reactions of methyl 2-formylbenzoate and intramolecular amidation
Jie Lei1,2,3 Zhi-Gang Xu3 Shi-Qiang Li3 Jia Xu3
Jin Zhu2,3 Zhong-Zhu Chen3
Received: 11 January 2016 / Accepted: 22 May 2016 / Published online: 7 June 2016 Springer International Publishing Switzerland 2016
Abstract Four series of heterocyclic compounds were obtained using Ugi-type multicomponent reactions (MCRs) with methyl 2-formylbenzoate as one of the starting materials. A facile and efcient one-pot procedure was suitable for all the MCRs under acidic conditions. This process provided access to four series of complex and potentially biologically active scaffolds.
Keywords Cyclization Heterocycles Ugi-type multicom
ponent reactions UDC strategy Intramolecular amidation
One-pot procedure MCRs
Introduction
Multicomponent reactions (MCRs) by Dmling, Ugi, Ban and Moliner [14] involve three or more starting materials
Electronic supplementary material The online version of this article (doi:http://dx.doi.org/10.1007/s11030-016-9679-6
Web End =10.1007/s11030-016-9679-6 ) contains supplementary material, which is available to authorized users.
B Zhi-Gang Xu
B Zhong-Zhu Chen
1 Key Laboratory for Asymmetric Synthesis and ChiralTechnology of Sichuan Province, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, China
2 University of Chinese Academy of Sciences, Beijing 100049, China
3 Chongqing Engineering Laboratory of Targeted and Innovative Therapeutics, Chongqing Key Laboratory of Kinase Modulators as Innovative Medicine, IATTI, Chongqing University of Arts and Sciences, No. 319 Honghe Ave., Yongchuan, Chongqing 402160, China
reacting to form the nal product [5]. The use of this versatile synthetic approach represents a powerful and efcient route for the discovery of pharmacologically active molecular probes [6,7]. The one-pot Ugi reaction, whereby a carboxylic acid, a primary amine, an aldehyde, and an isocyanide are combined to afford N-substituted acyl aminoamides, can provide scaffolds that are useful intermediates in drug discovery [8,9]. The use of formyl acids as starting materials for the reaction with isocyanides and primary amines in a three-component Ugi reaction can provide pyrazino [1,2-]benzimidazole derivatives [1014].
Methyl 2-formylbenzoate is a useful starting material that has been used in several MCRs [1519]. Ring closure to form an amide from the methyl ester group was postulated as an effective strategy to construct novel scaffolds. Methyl 2-formylbenzoate may be expected to be a more suitable reagent than 2-formylbenzoic acid [20] because the methyl ester group would be stable to decomposition in the rst MCR step and the opportunity it provides for the additional derivatization of the MCR products.
Results and discussion
An Ugi-type reaction was used to investigate an amide ring closure from the ester group in methyl 2-formylbenzoate. This is a straightforward Ugi-type reaction [2124] that affords a free secondary amine precursor for the amide group. The formation of the amide may also be carried out under acidic conditions [25,26]. For the present work, a series of isoindolin-1-ones were prepared via a ring closure involving intramolecular amidation as shown in Scheme 1.
Isonitrile 1, amine 2, and methyl 2-formylbenzoate 3 reacted together in a three-component, acid-free Ugi-type reaction to afford intermediate 4 using phenylphosphonic
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860 Mol Divers (2016) 20:859865
Scheme 1 Synthesis of isoindolin-1-one compounds 5ah
CHO
COOMe
R2 NH2
R1
1
2
3
N
R1
R1
phenylphosphonicacid as catalyst COOMe
NH
O NH
O NH
R2
10% TFA/DCE
MW 120 oC, 10 min.
R2
N
O
MeOH, r.t.
4
5
Br
Br
O O F O
O
F
5a (67%) 5b (58%) 5c (56%) 5d (64%)
O NH
O NH
N
O
O F O Br
N
O
5e (72%) 5f (57%) 5g (66%) 5h (70%)
acid (PPOA) as catalyst. After stirring overnight at room temperature, the solvent was removed under a stream of nitrogen and the residue was taken forward to the cyclization step, which used microwave irradiation. To optimize the reaction conditions, two different solvent systems (10% TFA/DCE and 5% HCl/AcOH) were tested. The preferred system for the desired cyclization involved heating at 120C for 10min using 10% TFA/DCE. A series of isoindolin-1-ones 5a
h in 5762% yields were obtained using these conditions (Scheme 1).
For the Ugi four-component intramolecular amidation of methyl 2-formylbenzoate, an amino group is necessary. In some reports [2729], (2,4-dimethoxyphenyl)methanamine 6 was used as a convertible group for ring closure under acidic conditions under microwave irradiation conditions.With this in mind, a synthetic scheme for another series of isoindolinones was designed (Scheme 2).
The four-component Ugi reaction involving (2,4-dimethoxyphenyl)methanamine afforded the desired intermediate 8 and 2,4-dimethoxybenzyl group as the convertible group was removed using microwave irradiation under acidic conditions. The resulting intermediate 9 could undergo one of two possible pathways for the intramolecular amidation reaction. Based on the NMR spectra of the products 10af obtained, it was determined that pathway A was considered the most realistic given that led to the nal products (see
supporting information). Compounds 10af were formed in 5168% yields, suggesting that this one-pot procedure was suitable for a range of these compound collections.
The benzimidazole scaffold can be readily produced via an Ugi-deprotection-cyclization (UDC) strategy as demonstrated in previous reports [25,26]. In this context, it is possible to introduce another benzimidazole ring to the isoindolin-1-one structure. Herein, the isocyanide 1 was replaced by 2-(N-Boc-amino)-phenyl-isocyanide 11 to afford the desired benzimidazole core, which was then treated with aniline and methyl 2-formylbenzoate, with phenylphosphonic acid (PPOA) as a catalyst, to afford compound 12. Using microwave irradiation (120C, 10min)
and 10% TFA/DCE, intermediate 13 was deprotected to produce aniline intermediate 14, which then underwent cyclization to produce the desired product 15. The scope for synthesis of isoindolinone-bis benzimidazole is shown in Scheme 3.
The results show that using PPOA as a catalyst without removing it did not signicantly reduce yields in the following deprotection and cyclization steps. This two-step, one-pot procedure afforded the desired products in good yields (5770%). A free amino group is essential for amide formation with the ester group in methyl 2-formylbenzoate. Another Ugi-type reaction involving TMS azide 16 could provide the necessary secondary amine group [3032]. Mar-
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Mol Divers (2016) 20:859865 861
Scheme 2 Synthesis ofisoindolin-1-one compounds10af NH2
O
O
O
R4
6
R4 COOH
7
MeOH, r.t.
N
O
COOMe
COOMe
O
NH
R1
R1
N
O
CHO
8
1 3
R1
R4
O
O R
R4
H
N
1
O NH
N
B
10% TFA/DCE MW 120 oC, 10min.
O
COOMe
N
A
O
10
9
O NH
O
O NH
O
O
N
F
NH
O
O
F
N
N
O
Cl
O
10a (66%) 10b
(68%) 10c (53%)
O NH
O
O NH
O
O NH
O
Cl
N
N
N
Cl
OMe
Cl
O
O
O
10d (51%) 10e
(56%) 10f (58%)
cos et al. [33] reported a similar idea, and discussed the synthesis of tetrazolyl-isoindolinones via a tandem Ugi four-component intramolecular amidation. In this study, the cyclization reaction was carried out in EtOH with the strong base NaOEt. The basic conditions did not allow for the deprotection of the Boc group; however, this reaction may proceed under acidic conditions. A Boc-protected di-amine was initially tested in the reaction affording the fused scaffold 20 (Scheme 4).
The synthesis still involves a three-step, one-pot procedure to afford the target compounds. Intermediate 18 was isolated by removing the solvent and used directly in the next step. The subsequent deprotection and cyclization were also carried out using the previously optimized 10% TFA/DCE system. Tetrazolyl-isoindolinone intermediate 19 was not isolated, and microwave irradiation resulted in the formation of the benzimidazole ring in 20. The nal fused isoindolinone-benzimidazoles were obtained in 53 71% yields.
Conclusions
Methyl 2-formylbenzoate has been used successfully as a starting material in four Ugi-type reactions resulting in four distinct scaffolds. A one-pot procedure was suitable for all the reactions investigated suggesting the approach offers new opportunities for design and synthesis of isoindolin-1-one compounds in medicinal chemistry.
Experimental section
All reagents, unless otherwise stated, were used as received from commercial suppliers. 1H NMR (400MHz) and 13C NMR (100MHz) spectra were recorded on a Bruker Avance 400 spectrometer using CDCl3 or DMSO-d6 as solvent and
TMS as internal standard ( in ppm). Abbreviations used for NMR signals are s singlet, d doublet, dd doublet of doublets, dt doublet of triplets, q quartet, t triplet, td triplet of
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862 Mol Divers (2016) 20:859865
R2 NH2
CHO
COOMe
BocHN
2
phenylphosphonic
acid as catalyst
NH
N
NHBoc
11
HN
O
COOMe
10% TFA/DCE
MW 120 oC, 10 min.
MeOH, r. t.
R2
3
12
O
H2N
14
R2
O
N
H
O
N
N
N
H
O
R2
BocHN
13
15
HN
HN
HN
Cl
Br
N
O
Br
N
O
N
O
15a (62%) 15b (59%)
15c (64%) 15d (57%)
HN
Br
HN
HN
F
HN
F N O
N
O
Cl
N
O
N
O
15e (70%) 15f (66%)
15g (63%) 15h (68%)
Scheme 3 Synthesis of isoindolinone-bis benzimidazoles 15ah
doublets, and m multiplet. LC/MS were recorded on a Shimadzu LCMS-2020 and high-resolution mass spectra were obtained using a high-resolution ESI-TOF mass spectrometer Shimadzu LCMS-IT-TOF. All microwave irradiation experiments were carried out in a Biotage[circleR] Initiator Classic microwave apparatus with continuous irradiation power from 0 to 400W with utilization of the standard absorbance level of 250W maximum power.
General procedure for isoindolin-1-one products 5ah
To a magnetically stirred solution of an aldehyde (0.50mmol) in MeOH (1.0mL), an amine (0.50mmol) was added in a 5-mL microwave vial. The solution was stirred for 10min at room temperature. Then, an isonitrile (0.50mmol) and a catalytic amount of phenylphosphonic acid (PPOA; 0.05mmol) were added. The mixture was stirred at room temperature overnight. The reaction was monitored by TLC and the sol-
vent was removed under a nitrogen stream. The residue in the same microwave vial was dissolved in 10% TFA/DCE(3.0mL), placed back in the microwave synthesizer and heated at 120C (250W) for 10min. The microwave vial was then cooled to room temperature, the solvent removed under reduced pressure, and the residue dissolved with EtOAc(15.0mL) and washed with sat. Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was puried by silica gel column chromatography using a gradient of ethyl acetate/hexane (1100%) to afford isoindolin-1-one products 5ah. (Compound 5a, white solid, 67% yield), 1H NMR (CDCl3, 400MHz) : 7.827.64 (m, 4H), 7.66 (t, J = 7.5 Hz, 1H), 7.53 (t, J = 7.4 Hz, 1H), 7.42
(t, J = 7.8 Hz, 2H), 7.24 (d, J = 7.6 Hz, 1H), 7.187.06
(m, 3H), 6.75 (d, J = 7.0 Hz, 2H), 6.19 (s, 1H), 5.74 (s,
1H), 4.48 (dd, J = 15.1, 6.7Hz, 1H), 4.13 (dd, J = 11.1,
4.4Hz, 1H). 13C NMR (100MHz, CDCl3) : 168.0, 167.6, 140.0, 137.8, 137.0, 133.1, 130.9, 129.6, 129.5, 128.6, 127.4,
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Mol Divers (2016) 20:859865 863
Scheme 4 Synthesis and yields for the isolated fused isoindolinone-benzimidazoles 20ad. aCompound 20d is an N-Boc protected compound when 2-(N-Boc-amino)-phenylisocyanide (1d) was used; see the supporting information for details
TMSN3
NH2
NHBoc 16 17
3
1
BocHN
10% TFA/DCE
MW 120 oC, 20 min.
MeOH, r.t.
HN
R1
R1
N
CHO
COOMe
COOMe N
N N
N
18
O
H2N
N
N
N
N
R1
N
N N
N
N N
N
R1
19
20
N
N
N
N
N
N
N
N
N
N N
N
N
N
N
N N
N
N N
N N
NH2
20a (71%) 20b (53%) 20c (66%) 20d (61%)a
127.0, 125.4, 124.4, 122.9, 120.2, 65.2, 43.3. HRMS calculated for C22H19N2O2[M+H]+: 343.1441, found 343.1449.
General procedure for fused isoindolinone-benzimidazoles 10af
To a magnetically stirred solution of an aldehyde (0.50mmol) in MeOH (1.0mL), (2,4-dimethoxyphenyl)methanamine 6(0.50mmol) was added in a 5-mL microwave vial. The solution was stirred for 10min at room temperature. Then, an acid (0.50mmol) and an isonitrile (0.50mmol) were added separately. The mixture was stirred at room temperature overnight. The reaction was monitored by TLC and the solvent was removed under a nitrogen stream. The residue in the same microwave vial was dissolved in 10% TFA/DCE (3mL) and placed back in microwave and heated at 120C (250W) for 10min. The microwave vial was then cooled to room temperature, the solvent removed under reduced pressure, and the residue dissolved with EtOAc (15.0mL) and washed with sat. Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was puried by silica gel column chromatography using a gradient of ethyl acetate/hexane (1100%) to afford fused isoindolinone-benzimidazoles 10af. (Compound 10a, white solid, 66% yield), 1H NMR (400MHz, CDCl3) 7.81 (d,
J = 7.6 Hz, 1H), 7.70 (dt, J = 15.1, 7.4Hz, 2H), 7.52
(dd, J = 14.9, 7.5Hz, 3H), 7.22 (dd, J = 14.3, 7.3Hz,
6H), 7.147.05 (m, 1H), 6.63 (s, 1H), 5.81 (s, 1H), 4.51
(dd, J = 14.9, 5.7Hz, 1H), 4.40 (dd, J = 14.9, 5.4Hz,
1H). 13C NMR (100MHz, CDCl3) : 166.6, 166.2, 165.3, 161.1, 158.6, 140.9, 137.3, 135.0, 133.3, 129.9, 129.6, 129.4, 128.7, 127.6, 127.5, 125.6, 124.5, 123.4, 115.5, 62.6, 43.9. HRMS calculated for C23H18FN2O3[M + H]+: 389.1296,
found 389.1290.
General procedure for compounds 15ah
To a magnetically stirred solution of an aldehyde (0.50mmol) in MeOH (1.0mL), an amine (0.50mmol) was added in a 5-mL microwave vial. The solution was stirred for 10min at room temperature. Then, an isonitrile (0.50mmol) and a catalytic amount of phenylphosphonic acid (PPOA; 0.05mmol) were added separately. The mixture was stirred at room temperature overnight. The reaction was monitored by TLC and the solvent was removed under a nitrogen stream. The residue in the same vial was dissolved in 10% TFA/DCE (3.0mL) and placed back in microwave and heated at 120C (250W)
for 10min. The microwave vial was then cooled to room temperature, the solvent removed under reduced pressure, and the residue dissolved with EtOAc (15.0mL) and washed with sat. Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was puried by silica gel column chromatography using a gradient of ethyl acetate/hexane (1100%) to afford isoindolin-1-one products 15ah. (Compound 15a, yellow solid, 62% yield) 1H
NMR (400MHz, CDCl3) : 7.65 (d, J = 8.8 Hz, 3H), 7.58
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(d, J = 7.6 Hz, 1H), 7.52 (t, J = 7.2 Hz, 1H), 7.367.26
(m, 5H), 7.17 (dt, J = 14.6, 7.4Hz, 2H), 6.61 (s, 1H).
13C NMR (100MHz, CDCl3) : 168.8, 149.8, 141.7, 136.5, 133.4, 132.2, 130.2, 129.6, 123.7, 123.4, 122.2, 118.7, 60.4.HRMS calculated for C21H14ClN3O[M + H]+: 360.0842,
found 360.0843.
General procedure for fused isoindolinone-benzimidazoles 20ad
To a magnetically stirred solution of an aldehyde (0.50mmol) in MeOH (1.0mL), an amine (0.50mmol) was added in a 5-mL microwave vial. The solution was stirred for 10min at room temperature. Then, an isonitrile (0.50mmol) and TMS azide (0.50mmol) were added separately. The mixture was stirred at room temperature overnight. The reaction was monitored by TLC and the solvent was removed under a nitrogen stream. The residue in the same microwave vial was dissolved in 10% TFA/DCE (3mL) and heated using microwave irradiation at 120 C (250W) for 20min. The microwave vial was then cooled to room temperature, the solvent removed under reduced pressure, and the residue dissolved with EtOAc(15.0mL) and washed with sat. Na2CO3 and brine. The organic layer was dried over MgSO4 and concentrated. The residue was puried by silica gel column chromatography using a gradient of ethyl acetate/hexane (1100%) to afford compounds 20ad. (Compound 20a, white solid, 71% yield),
1H NMR (400MHz, CDCl3) 8.32 (d, J = 7.7 Hz, 1H),
7.817.67 (m, 2H), 7.657.55 (m, 1H), 7.36 (d, J = 7.8 Hz,
1H), 7.337.28 (m, 1H), 7.257.20 (m, 1H), 7.077.01 (m,
2H), 6.95 (t, J = 7.4 Hz, 1H), 6.82 (t, J = 7.7 Hz, 2H),
6.28 (d, J = 7.6 Hz, 2H), 5.14 (d, J = 15.7 Hz, 1H),
4.49 (d, J = 15.8 Hz, 1H). 13C NMR (100MHz, CDCl3) :
154.8, 149.1, 142.1, 141.8, 132.4, 131.5, 131.0, 129.8, 128.7, 128.6, 127.3, 126.3, 125.5, 125.4, 125.0, 124.7, 124.2, 119.1, 110.0, 53.8, 51.7. HRMS calculated for C22H17N6[M+H]+
:365.1509, found 365.1506.
Acknowledgments The authors thank the Chongqing Research Program of Basic Research and Frontier Technology (cstc2015jcyjA1328), the Scientic Research Foundation of Chongqing University of Arts and Sciences (Grant Nos. R2013XY01, R2013XY02), and SRF for ROCS, SEM. We would also like to thank Ms H.Z. Liu for obtaining the LC/MS and NMR data.
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