A new synthetic approach to pyrrolo[3,2-b]indoles via regioselective formation of pyrrole and intramolecular CN coupling

Tetrahedron Letters 57 (2016) 4803–4806

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A new synthetic approach to pyrrolo[3,2-b]indoles via regioselective formation of pyrrole and intramolecular CAN coupling Manjusha V. Karkhelikar a, Vijay V. Rao b, Sundar S. Shinde a, Pravin R. Likhar a,⇑ a b

Organometallic Gp., I & PC Division, CSIR-IICT, Hyderabad 500007, India IICT-RMIT Joint Research Center, CSIR-IICT, Hyderabad 500007, India

a r t i c l e

i n f o

Article history: Received 22 August 2016 Revised 9 September 2016 Accepted 10 September 2016 Available online 12 September 2016

a b s t r a c t A new synthetic approach for the synthesis of pyrrolo[3,2-b]indoles has been developed in two steps. First step involves electrophilic iodocyclization of protected 2-alkynylanilines to regioselective formation of pyrroles followed by copper catalyzed intramolecular CAN coupling. Ó 2016 Elsevier Ltd. All rights reserved.

Keywords: Pyrrolo-indole CAN coupling Copper Alkyne Tricyclic heterocycles

Introduction Indoles are important structural motifs that are often found in natural products and have a pivotal position in pharmaceutical, medical, and organic chemistry because of their unique structures and interesting bioactivities.1 Among them, polycyclic indoles have notable biological activities that are explored as new medicinal agents.2 There are various methodologies to synthesize a 2,3-fused indole core such as transition metal catalyzed hydroamination/ hydroarylation, chemical transformation to form diverse 2,3-fused indoles3 such as pyrrolo[2,3-b]indole,4 pyrrolo[3,4-b]indole,5 pyrrolo[3,2-e]indole,6 furo[3,2-b]indole,7 furo[2,3-b]indole,8 pyrimido [1,2-a]indole,9 and pyrrolo[3,2-b]indole.10 Very few synthetic methodologies are established for the synthesis of pyrrolo[3,2-b]indole. They are usually synthesized by Pd-catalyzed chemoselective intramolecular cyclization of bromoanilino alkene nitriles,11 organotransformations,12 and oxidation of a indolo-benzo pyrrolizine derivatives.13 These known methods have some limitations like side products and lower yield due to multistep synthesis. Therefore, an alternative method is warranted for the synthesis of pyrrolo[3,2-b]indole moiety. From few decades CAC, CAN bond formation via copper catalyzed coupling has gained great interest14,15 due to its low cost, high stability, non-toxic nature, and high catalytic activity.

In our previous Letter, we demonstrated the success of cyclization in alkynes bearing competitive nucleophiles depending on the nucleophilicity of functional groups and steric effects.16 Thus, the electronic modification in amine groups (attached to aromatic rings) altered the nucleophilic attack of the amino group and favored the selective formation of the pyrrole nucleus over indole. Herein we report, copper catalyzed intramolecular CAN coupling of 3-iodo-pyrroloanilne, the substrate synthesized from protected 2-alkynylanilines via regioselective formation of pyrroles to access dihydropyrrolo[3,2-b]indole16 (Scheme 1). 3-Iodo-substituted pyrroles 2a–h were obtained in good yields from starting substrates 2-alkynylanilines, 3.0 equiv of iodine and 3.0 equiv of K2CO3 in acetonitrile at room temperature.17 It is interesting to note that cyclization took place regio-selectively and afforded iodo-substituted pyrroles 2 over iodo-substituted indoles by the preferential nucleophilic attack of the amino group of NHTs onto alkynes. The nucleophilic attack of protected secondary amines was thoroughly verified using different protected groups (ethyl formate, Boc, benzoyl, and methyl), however, none of the secondary amines were successful in the initial formation of indole ring. All the iodo-substituted pyrroles were fully characterized by 1 H NMR, 13C NMR, IR, and HRMS.

Results and discussion ⇑ Corresponding author. E-mail address: [email protected] (P.R. Likhar). http://dx.doi.org/10.1016/j.tetlet.2016.09.044 0040-4039/Ó 2016 Elsevier Ltd. All rights reserved.

To optimize the reaction condition, various bases, ligands, and solvents were screened. Initially, the reaction was carried out using

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M. V. Karkhelikar et al. / Tetrahedron Letters 57 (2016) 4803–4806

TsHN

TsHN

N a

R2 NH 1

also been observed that among the tested Boc protected anilines with electron donating (Me, MeO) and electron withdrawing groups (Cl), only later substituted Boc protected aniline was found to be suitable for the intramolecular CAN coupling reaction (Table 3, 3i). In fact, in case of Boc protected anilines with electron donating (Me, MeO) group, the Sonogashira coupling was not successful for the preparation of 2-alkynylanilines. Therefore, ethyl formate protected aniline was thoroughly investigated for the copper catalyzed intramolecular CAN coupling reaction. The substituted groups used on the aromatic ring of aniline, the electron donating substituents namely methoxy and methyl groups afforded excellent yields (95% and 96%, respectively) of desired products 3b and 3c, while electron withdrawing substituents such as F, Cl and NO2 at different position offered lower yields of desired products, 3d to 3g (Table 3).

Ts

a

R1

2 I2/K2 CO3 R

b

I

R2 NH

NH 2

R1 Iodocyclization

R 1= COOEt = Boc

I

R1

CuI, ligand base, solvent

b

110 o C Ts N

I TsHN Intramolecular C-N coupling

R2 N R1

R2 3

N R1

Scheme 1. Copper catalyzed intramolecular CAN coupling.

Dehydrogenation of dihydropyrrolo[3,2-b]indole 10 mol % CuI, (±)-trans-cyclohexane-1,2-diamine (L1) as ligand, K3PO4 as base and toluene at 110 °C in 16 h and obtained 83% yield of compound 3a. By changing the ligands, (±)-trans-cyclohexane1,2-diamine to N,N0 -dimethyl-ethylenediamine (L2), K3PO4 base and toluene solvent, a slight increase in yield was observed. Use of K2CO3 base improved the yield of desired product up-to 94% (Table 1, entry 4) within 8 h only. When the base was swapped to Cs2CO3 or CsOAc, the product yield was lowered (Table 1, entries 8 and 9). Several other solvents were screened and observed that toluene was the most suitable reaction media for the reaction. The yield of the desired product was very low when the reaction was carried out in the absence of ligand (Table 1, entries 3, 5 and 7). After investigating the optimized reaction conditions for the CAN coupling, the protocol was extended to various iodo-substituted pyrrole derivatives to study the scope of intramolecular CAN cyclization. The scope of the reaction was mainly studied by varying the protecting groups at amine group (Table 2) as well as by varying the electron rich groups and the electron poor groups at the aromatic ring. Initially, we examined the various protection groups for aniline group such as ethyl formate, benzoyl, Boc, and methyl group. However, among the tested protection groups, ethyl formate, and Boc were successful for CAN coupling reaction. It has

Recently, biaryl bond formation was achieved from sulfonamide in the presence of palladium via intramolecular oxidative coupling.18 We were interested in attempting analogous intramolecular oxidative coupling with 3. In screening, 3a was used in the presence of palladium acetate, cesiumpivalate, pivalic acid, and silver acetate under various reaction conditions (Scheme 2). But to our surprise, 3a selectively underwent dehydrogenation reaction to yield 91% of 4a. Alternatively, the dehydrogenation of 3a was achieved in the presence of DDQ at room temperature albeit the yield of 4a was only 50% when compared with previously studied dehydrogenation method.19 The mechanism for the CAN couplings is well discussed in the literature by two different pathways in which nucleophilic substitution proceeds first while in an alternative pathway oxidative addition take place first.14a However, based on the reported experimental data, the reactivity of isolated L2Cu(I)amido with aryl halides supports nucleophilic substitution path as the most plausible mechanistic pathways.20a The plausible mechanism for the formation of pyrrolo indole is illustrated in Scheme 320 where copper iodide initially complexes with N,N0 -dimethyl ethylenediamine. In the first step, the nucleophilic substitution occurs at copper(I) through the

Table 1 Optimization of the reaction conditionsa

TsN

Ts N CuI, Ligand

I NHCO 2 Et base, solvent,

N CO 2Et

temp.

2a

3a

Entry

Ligand

Base

Temp (°C)/time (h)

Solvent

Yieldsb (%)

1 2 3 4 5 6 7 8 9 10 11 12

L1 L2 — L2 — L1 — L2 L2 L2 L2 L2

K3PO4 K3PO4 K3PO4 K2CO3 CsOAc K2CO3 Cs2CO3 CsOAc Cs2CO3 K2CO3 K2CO3 K2CO3

110/16 110/24 110/24 110/8 100/24 110/12 90/24 110/24 110/18 70/12 100/16 80/16

Toluene Toluene Toluene Toluene DMSO Toluene DMSO Toluene Toluene THF 1,4-Dioxane MeCN

83 90 20 94 28 88 30 35 50 63 80 67

Entry 4 indicates optimized reaction conditions investigated for Tables 2 and 3. a Reaction was performed using 0.5 mmol of 2a, CuI (10 mol %), base (2.0 equiv), ligand (20 mol %), 2.0 mL of solvent. Ligand L1—(±)-trans-cyclohexane-1,2-diamine, Ligand L2—N,N0 -dimethyl-ethylenediamine. b Isolated yields.

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M. V. Karkhelikar et al. / Tetrahedron Letters 57 (2016) 4803–4806 Table 2 Optimization of the reaction conditionsa

TsN

Ts N I

NHR 1

CuI, Ligand K 2 CO 3 , toluene 110 oC

N

2

a b

R1

3

Entry

Substrate R1

Ligand

Base

Temp (°C)/time (h)

Yieldsb (%)

1 2 3 4 5 6

CO2Et Bz Bz Boc Me Me

L2 L2 L1 L2 L2 L1

K3CO3 K3CO3 K3CO3 K3CO3 K2CO3 K2CO3

110/8 110/24 110/24 110/12 110/24 110/24

94 NR NR 90 NR NR

Reaction was performed using (1 mmol) of 2, CuI (10 mol %), K2CO3 (2.0 equiv), ligand, L1/L2 (20 mol %), toluene (2.0 mL) at 110 °C for 8–24 h. Isolated yields.

Table 3 Synthesis of dihydropyrrolo[3,2-b]indole 3a–ia

O

TsN R2

Ts N I

NHR 1

CuI, DMEDA K2CO 3, toluene 110oC

Ts N

MeO

NR1

Ts N

N CO 2 Et

N CO2Et

Ts N

3c, 96%

N CO2Et

condition B

O S

CH3

N +

4a, Yield for condition A,91% Yield for condition B,49%

3a

Me

3b, 95%

3a, 94%

F

N CO2 Et

3

Ts N

N CO 2 Et

condition A

R2

2

Ts N

Ts N

N CO2 Et 00%

Condition A: 10 mol% Pd(OAc )2 , 20 mol% CsOPiv, 3 equiv AgOAc, PivOH, 130 0 C, 24 h Condition B: DDQ, 1,4-dioxane, rt

Scheme 2. Dehydrogenation of dihydropyrrolo[3,2-b]indole.

Ts N

Ts N Cl

N CO 2 Et 3d, 86%

Ts N O2 N

N CO2 Et

Cl

3e, 72%

N CO 2 Et

CuI

3f, 58%

Ts N

TsN

Ts N

Ts N Cl

N CO 2 Et

L2

L2

(I) Cu

I

I

NHR1

NR1

N Boc

3g, 61%

3h, 90%

Ts N

Ts N

N Boc 3i, 42%

Reductive elimination

Me N Boc NR

N Bz

TsN

TsN

NR

a Reaction was performed using (1 mmol) of 2, CuI (10 mol %), K2CO3 (2.0 equiv), N,N’-dimethyl-ethylenediamine (DMEDA)(20 mol %), toluene (2.0 mL) at 110 °C for 8–16 h.

coordination of secondary amine followed by dehydro-iodination. In the preceding step, an intramolecular oxidative addition of Cu (I) into CAI bond takes place to form Cu(III) intermediate. The coupling of the nucleophile and tosyl pyrrole would give the CAN coupled product 3 through reductive elimination step that would regenerate the active Cu(I) catalyst.

(III) I Cu L2 R1

(I) I H Cu L2 N I R1

N

Intramolecular Oxidative addition

HI Scheme 3. Plausible mechanism for the formation of compound 3.

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Conclusion In conclusion, we have developed a mild and efficient approach for the synthesis of pyrrolo[3,2-b]indole in two steps. The regioselective formation of pyrrole was obtained in a high yield. In a subsequent step, the iodopyrroles were successfully investigated in copper catalyzed intramolecular CAN cyclization. Though the approach for the formation of pyrrolo indole is limited with the use of ethyl formate and Boc protected anilines, we report the synthesis of tricyclic fused two heterocycles for the first time. Further applications of this methodology and bioactivity study of these new heterocycles are in progress. Acknowledgments M.V.K. is grateful to UGC – India for her senior research fellowship. Authors are grateful to DIICT for providing all the facilities. Supplementary data Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2016.09. 044. References and notes 1. For examples, see: (a) Nicolaou, K. C.; Sorensen, E. J. Classics in Total Synthesis, 1st ed.; Wiley-VCH, 1996; (b) Nicolaou, K. C.; Snyder, S. A. Classics in Total Synthesis, 2nd ed.; Wiley-VCH: Weinheim, 2003. 2. (a) Lu, L.-Q.; Chen, J.-R.; Xiao, W.-J. Acc. Chem. Res. 2012, 45, 1278; (b) Bergman, J.; Pelcman, B. Pure Appl. Chem. 1967, 1990, 62; (c) Somei, M.; Yamada, F. Nat. Prod. Rep. 2005, 22, 73; (d) Kawasaki, T.; Higuchi, K. Nat. Prod. Rep. 2005, 22, 761; (e) Sánchez, C.; Méndez, C.; Salas, J. A. Nat. Prod. Rep. 2006, 23, 1007; (f) Ishikura, M.; Yamada, K. Nat. Prod. Rep. 2009, 26, 803; (g) Ishikura, M.; Abe, T.; Choshi, T.; Hibino, S. Nat. Prod. Rep. 2013, 30, 694. 3. For reviews on metal-catalyzed cascade reactions for the synthesis of polycyclic indole skeletons, see: (a) Barluenga, F.; Guez, R.; Fananás, F. J. Chem. Asian J. 2009, 4, 1036; (b) Platon, M.; Amardeil, R.; Djakovitchb, L.; Hierso, J. C. Chem. Soc. Rev. 2012, 41, 3929. 4. (a) Gao, Q.; Zhou, P.; Liu, F.; Hao, W. J. Chem. Commun. 2015, 9519; (b) Tu, D.; Ma, L.; Tong, X.; Deng, Xu; Xia, C. Org. Lett. 2012, 14, 4830; (c) Coste, A.; Toumi, M.; Wright, K.; Razafimahaleo, V.; Couty, F.; Marrot, J.; Evano, G. Org. Lett. 2008, 10, 3841.

5. Pelkey, E. T.; Gribble, G. W. Chem. Commun. 1997, 1873. 6. Trawczyn´ski, A.; Bujoz, R.; Wróbel, Z.; Wojciechowski, K. Beilstein J. Org. Chem. 2013, 9, 934. 7. (a) Unangst, P. C.; Carethers, M. E.; Webster, K.; Janik, G. M.; Robichaudt, L. J. J. Med. Chem. 1984, 27, 1629; (b) Zhuanga, S. H.; Lin, Y. C.; Choua, L. C.; Hsua, M. H.; Lin, H. Y.; Huang, C. H.; Lien, J. C.; Kuoa, S. C.; Huang, L. J. Eur. J. Med. Chem. 2013, 66, 466. 8. (a) Zhu, X.; Xu, X. P.; Sun, C.; Chen, T.; Li, Z.; Ji, S. J. Tetrahedron 2011, 67, 6375; (b) Kulkarni, M. G.; Chavhan, S. W.; Desai, M. P.; Shaikh, Y. B.; Gaikwad, D. D.; Dhondge, A. P.; Borhade, A. S.; Ningdale, V. B.; Birhade, D. R.; Dhatrak, N. R. Tetrahedron Lett. 2010, 51, 4494. 9. (a) Cliffe, I. A.; Lien, J. E. L.; Mansell, H. L.; Steiner, K. E.; Todd, R. S.; White, A. C.; Black, R. M. J. Med. Chem. 1992, 35, 1169; (b) Gupta, S.; Sharma, S. K.; Mandadapu, A. K.; Gauniyal, H. M.; Kundu, B. Tetrahedron Lett. 2011, 52, 4288. 10. Grinev, A. N.; Ryabova, S. Yu. Chem. Heterocycl. Compd. 1982, 18, 155. 11. Yang, C. C.; Tai, H. M.; Sun, P. J. J. Chem. Soc., Perkin Trans. 1 1997, 2843. 12. Aiello, E.; Dattolo, G.; Cirrincione, G. J. Chem. Soc., Perkin Trans. 1 1981, 1. 13. Dave, V.; Warnhoff, E. W. Can. J. Chem. 1971, 49, 1921. 14. (a) Monnier, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 6954; (b) Ley, S. V.; Thomas, A. W. Angew. Chem., Int. Ed. 2003, 42, 5400; (c) Ma, D.; Cai, Q. Acc. Chem. Res. 2008, 41, 1450; (d) Evano, G.; Blanchard, N.; Toumi, M. Chem. Rev. 2008, 108, 3054; (e) Liu, Y.; Wan, J.-P. Org. Biomol. Chem. 2011, 9, 6873; (f) Surry, D. S.; Buchwald, S. L. Chem. Sci. 2010, 1, 13; (g) Rao, H.; Fu, H. Synlett 2011, 745; (h) Das, P.; Sharma, D.; Kumar, M.; Singh, B. Curr. Org. Chem. 2010, 14, 754; (i) Evano, G.; Toumi, M.; Coste, A. Chem. Commun. 2009, 4166; (j) Cacchi, S.; Fabrizi, G.; Goggiamani, A. Org. Biomol. Chem. 2011, 9, 641; (j) Kunz, K.; Scholz, U.; Ganzera, D. Synlett 2003, 2428. 15. (a) Xie, X.; Chen, Y.; Ma, D. J. Am. Chem. Soc. 2006, 128, 16050; (b) Yip, S. F.; Cheung, H. Y.; Zhou, Z.; Kwong, F. Y. Org. Lett. 2007, 9, 3469; (c) Xie, X.; Cai, G.; Ma, D. Org. Lett. 2005, 7, 4693; (d) Mino, T.; Yagishita, F.; Shibuya, M.; Kajiwara, K.; Shindo, H.; Sakamoto, M.; Fujita, T. Synlett 2009, 2457; (e) Yang, X.; Fu, H.; Qiao, R.; Jiang, Y.; Zhao, Y. Adv. Synth. Catal. 2010, 352, 1033; (f) Wang, F.; Liu, H.; Fu, H.; Jiang, Y.; Zhao, Y. Org. Lett. 2009, 11, 2469; (g) Shafir, A.; Buchwald, S. L. J. Am. Chem. Soc. 2006, 128, 8742; (h) Altman, R. A.; Anderson, K. W.; Buchwald, S. L. J. Org. Chem. 2008, 73, 5167; (i) Wang, D.; Ding, K. Chem. Commun. 2009, 1891; (j) Rao, H.; Jin, Y.; Fu, H.; Jiang, Y.; Zhao, Y. Chem. Eur. J. 2006, 12, 3636. 16. Karkhelikar, M. V.; Jha, R. R.; Sridhar, B.; Likhar, P. R.; Verma, A. K. Chem. Commun. 2014, 8526. 17. (a) Verma, A. K.; Aggarwal, T.; Rustagi, V.; Larock, R. C. Chem. Commun. 2010, 4064; (b) Amjad, M.; Knight, D. W. Tetrahedron Lett. 2004, 45, 539. 18. Laha, J. K.; Dayal, N.; Jethava, K. P.; Prajapati, D. V. Org. Lett. 2015, 17, 1296. 19. Takahashi, A.; Kawai, S.; Hachiya, I.; Shimizu, M. Eur. J. Org. Chem. 2010, 191. 20. (a) Evano, G.; Blanchard, N. J. Copper-Mediated Cross-Coupling Reactions, 1st ed.; Wiley & Sons, 2014. 253; (b) Ouali, A.; Spindler, J.-F.; Jutand, A.; Taillefera, M. Adv. Synth. Catal. 2007, 349, 1906; (c) Kaddouri, H.; Vicente, V.; Ouali, A.; Ouazzani, F.; Taillefer, M. Angew. Chem., Int. Ed. 2009, 48, 333; (d) Lefevre, G.; Tlili, A.; Taillefer, M.; Adamo, C.; Ciofini, I.; Jutand, A. J. Chem. Soc., Dalton Trans. 2013, 5348; (e) Cristau, H.-J.; Cellier, P. P.; Spindler, J.-F.; Taillefer, M. Chem. Eur. J. 2004, 10, 5607.