Iron- and Cobalt-Catalyzed Arylation of Azetidines, Pyrrolidines, and

Letter pubs.acs.org/OrgLett

Iron- and Cobalt-Catalyzed Arylation of Azetidines, Pyrrolidines, and Piperidines with Grignard Reagents Baptiste Barré,† Laurine Gonnard,† Rémy Campagne,† Sébastien Reymond,† Julien Marin,‡ Paola Ciapetti,‡ Marie Brellier,‡ Amandine Guérinot,† and Janine Cossy*,† †

Laboratoire de Chimie Organique, Institute of Chemistry, Biology and Innovation (CBI)-UMR 8231 ESPCI ParisTech, CNRS, PSL Research University, 10, Rue Vauquelin 75231 Paris Cedex 05, France ‡ NovAliX, BioParc, 850 Bld Sébastien Brant, BP 30170, F-67405 Illkirch, Cedex, France S Supporting Information *

ABSTRACT: Iron- and cobalt-catalyzed cross-couplings between iodo-azetidines, -pyrrolidines, -piperidines, and Grignard reagents are disclosed. The reaction is efficient, cheap, chemoselective and tolerates a large variety of (hetero)aryl Grignard reagents.

S

azetidines, using the N-Boc-3-iodo-azetidine 1a with phenylmagnesium bromide. In the absence of any catalytic system, no trace of the expected product was observed (Table 1, entry 1). Starting with CoCl2 as catalyst (5 mol %), various ligands were screened and the best result was obtained with the (R,R)-

aturated N-heterocycles are ubiquitous frameworks in natural products and biologically active compounds. Among them, 4-arylpiperidines, 3-arylpyrrolidines, as well as 3arylazetidines are attractive scaffolds in drug discovery.1 Particularly, as they exhibit remarkable biological properties, azetidine moieties are of growing interest in medicinal chemistry.1d,e In this context, the development of modular and robust synthetic methods to access these building blocks could be of high value. Metal-catalyzed cross-couplings meet these criteria and can be considered as powerful strategies to reach molecular diversity.2 In this field, many efforts have been made for the crosscoupling of 4-halogeno-piperidines and 3-(pseudo)halogenopyrrolidines with aromatic organometallic reagents, most of them proceeding under Pd- or Ni-catalysis.3−5 In contrast, crosscouplings between 3-halogeno-azetidines and aryl organometallics have received much less attention as, to the best of our knowledge, only a few examples have been reported in the literature.6 In 2008, Kelly et al. disclosed that a Ni-catalyzed Suzuki-type cross-coupling afforded a variety of 3-arylazetidines in moderate yields.7,8 Consequently, a general, efficient, and sustainable method allowing easy access to 3-arylazetidines as well as 3-arylpyrrolidines and 4-arylpiperidines should be highly valuable. As part of our efforts toward the development of powerful synthetic tools, our group is involved in the field of metal-catalyzed cross-couplings.9 Notably, taking into account the need for sustainable and cheap processes, we have recently focused on iron- and cobalt-catalyzed cross-couplings between alkyl halides and Grignard reagents.10 Herein, we would like to report two catalytic systems involving either an iron or a cobalt complex which enable cross-coupling between aryl Grignard reagents and a large variety of saturated halogenated N‑heterocycles. As very little work has been achieved on the cross-coupling of halogenated four-membered rings, we decided first to examine the challenging metal-catalyzed arylation of 3-halogeno© XXXX American Chemical Society

Table 1. Optimization of the Reaction Conditions

entry

1

[M](mol %)

L(mol %)a

solvent

conversionb (yield)

1 2 3 4 5 6c 7 8 9 10 11 12 13 14

1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1a 1b 1b

CoCl2(5) CoCl2(5) CoCl2(5) CoCl2(5) CoCl2(5) CoCl2(1) CoCl2(5) CoCl2(5) Co(acac)2(5) Co(acac)3(5) FeCl2(10) CoCl2(5) FeCl2(10)

TMEDA(6) TMPDA(6) HMTA(6) L1(6) L1(6) L1(1) L1(6) L1(6) L1(6) L1(6) L1(10) L1(6) L1(10)

THF THF THF THF THF THF THF Et2O MTBE THF THF THF THF THF

0% (0%) 86% (nd) 88% (nd) 86% (nd) 100% (89%) 100% (90%) 100% (58%) 50% (nd) 91% (nd) 45% (nd) 41% (nd) 100% (81%) 46% (nd) 79% (nd)

a

TMEDA = tetramethylethylenediamine; TMPDA = tetramethyl-1,3diaminopropane; HMTA = hexamethylenetetramine. bTransformation of 1 in 2a, determined on the 1H NMR of the crude. cPerformed on a 1.6 g scale.

Received: October 16, 2014

A

dx.doi.org/10.1021/ol503043r | Org. Lett. XXXX, XXX, XXX−XXX

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(Table 2, entry 3). The cobalt and the iron catalytic systems also exhibited similar performances when electron-poor Grignard reagents were involved in the cross-coupling (Table 2, entries 4 and 5). When the O-Boc protected phenol derived Grignard reagent was used in the presence of CoCl2, the expected product 2g was obtained in 84% yield (Table 2, entry 6). However, with FeCl2, an incomplete conversion of 1a was observed (60%) and the desired product could not be isolated (Table 2, entry 6).13 Switching from the O-Boc to a methoxy substituent on the Grignard reagent allowed the access to the coupling product 2h in good yields with both catalytic systems (Table 2, entry 7). Interestingly, an excellent yield of 90% in 2i was reached when the cross-coupling was performed with the Grignard prepared from 3-bromo-pyridine whatever the catalytic system used (Table 2, entry 8). Similarly, when 1a was reacted with 2-thienylmagnesium bromide in the presence of CoCl2, the expected product was delivered in 91% yield (Table 2, entry 9). In contrast, an incomplete conversion of 1a was observed under iron catalysis. These positive results prompted us to explore the reactivity of 2,3-disubstituted iodo-azetidines such as 1c, which was prepared as a 75:25 cis/trans mixture from L-valine according to reported procedures.15,16 Interestingly, when 1c was treated with phenylmagnesium bromide in the presence of CoCl2, the desired product 2k was isolated in an excellent 93% yield with a reverse cis/trans ratio (13:87) (Table 3, entry 1). Decreasing the temperature to −10 °C did not affect the yield nor the diastereomeric ratio (Table 3, entry 2). The evolution of the diastereomeric ratio in favor of the trans compound was more significant when starting with the poorly stereocontrolled 1c (cis/ trans = 63:37) as the resulting product 2k was obtained in 76% yield with a 10:90 cis/trans ratio (Table 3, entry 3). The same results were observed under iron catalysis (Table 3, entries 4 and 5). This loss of stereochemical information at C3 suggests the formation of a radical intermediate at this position and a good diastereoselectivity of the subsequent cross-coupling.

tetramethylcyclohexan-1,2-diamine L1 (6 mol %) as the crosscoupling product 2a was isolated in good yield (89%) (Table 1, entries 2−5).11 Under these conditions, the reaction was successfully scaled up as 1.6 g of 1a were transformed in 1.2 g of 2a (90%) (Table 1, entry 6). Reducing the catalytic loading (1 mol %) led to a lower yield in 2a (58%) (Table 1, entry 7), and among the three solvents evaluated, THF gave the best conversion of 1a (Table 1, entries 5, 8, and 9). Poor conversions were observed with other cobalt salts like Co(acac)2 and Co(acac)3 (Table 1, entries 10 and 11) but, interestingly, a combination of FeCl2 and diamine L1 (10 mol % each) provided 2a in 81% yield (Table 1, entry 12).12 In addition, under both cobalt and iron catalysis, it should be highlighted that a slow addition of the Grignard reagent was not required. Unfortunately, the bromide derivative was less reactive than the iodide and incomplete conversion of 1b was observed under the previous optimized conditions (Table 1, entries 13 and 14). The 3-iodo-azetidine 1a was thus selected to evaluate the scope of the reaction and with the two sets of optimized conditions in hand, a variety of (Het)aryl Grignard reagents was screened. When p-tolylmagnesium bromide was used, good yield in the cross-coupling product 2b was obtained with both catalytic systems (Table 2, entry 1). The reaction was not sensitive to steric hindrance as o-tolylmagnesium bromide was efficiently coupled to 1a under cobalt and iron catalysis (Table 2, entry 2). When 1a was treated with p-dimethylaminophenylmagnesium bromide, the corresponding product 2d was isolated in good yields (79% and 74%) with both CoCl2 and FeCl2 catalysts Table 2. Scope of the Cross-Coupling on Iodoazetidine 1a

Table 3. Cross-Coupling of 2,3-Disubstituted Azetidines

entry

1 (cis/trans)

[cat.]a

temp

yield (%)

cis/transb

1 2 3 4 5

1c (75:25) 1c (75:25) 1c (63:37) 1c (75:25) 1c (63:37)

[Co] [Co] [Co] [Fe] [Fe]

0 °C to rt −10 °C −10 °C −10 °C −10 °C

93 89 76 94 86

13:87 10:90 10:90 7:93 8:92

a

[Co] = CoCl2 (5 mol %)/L1 (6 mol %); [Fe] = FeCl2 (10 mol %)/L1 (10 mol %). bDetermined on the 1H NMR of the crude mixture.

The cross-coupling reaction was next extended to the 3-iodopyrrolidine 3a. Pleasingly, in the presence of phenylmagnesium bromide, under both cobalt and iron catalysis, the expected product was delivered in good yield (84% and 89% respectively) (Table 4, entry 1). Electron-rich and electron-poor Grignard reagents exhibited similar reactivity and no significant difference was noted between the two catalytic systems (Table 4, entries 2− 6). As previously observed with the iodo-azetidine, when the OBoc substituted Grignard reagent was reacted with iodo-

a

1.2−2 equiv, see the Supporting Information for details. b[Co] = CoCl2 (5 mol %)/L1 (6 mol %); [Fe] = FeCl2 (10 mol %)/L1 (10 mol %). cPrepared by Mg insertion in the presence of LiCl.14 B


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group could be changed for a tosyl or a benzyl group even if, in this latter case, the addition of 50 mol % of ligand L1 was necessary to reach full conversion of 5c (Table 5, entries 1 and 2). The N-Boc-iodo-piperidine 5a was successfully coupled to a variety of aromatic Grignard reagents bearing various functionalities such as a dimethylaniline, a trifluoromethyl group, or a OBoc-protected phenol (Table 5, entries 3−7). However, when the p-cyanophenylmagnesium bromide was used, the reaction was sluggish and poor conversion of 5a (30%) was observed (Table 5, entry 8). Heteroaromatic Grignard reagents possessing a pyridyl moiety could be coupled to 5a with moderate yield when the reaction was carried out at rt. Pleasingly, decreasing the temperature to −10 °C resulted in a significant improvement of the yield (96%)(Table 5, entries 9).

pyrrolidine 3a, the cobalt catalytic system revealed to be more powerful compared to the iron one (93% versus 21% yield) (Table 4, entry 7). Similarly, when 3a was reacted with the 3pyridylmagnesium bromide, a good yield in 4h was obtained under cobalt catalysis (74%) whereas an incomplete conversion of 3a (51%)17 was observed in the presence of FeCl2 (Table 4, entry 8). Table 4. Extension to the 3-Iodopyrrolidine 3a

Table 5. Cross-Coupling Involving 4-Iodopiperidine 5a−5c

a

1.2−2 equiv, see the Supporting Information for details. b[Co] = CoCl2 (5 mol %)/L1 (6 mol %); [Fe] = FeCl2 (10 mol %)/L1 (10 mol %). cPrepared by Mg insertion in the presence of LiCl. dIsolated together with some impurities.

Finally, the reactivity of 4-halogeno-piperidines under the cross-coupling conditions was evaluated. When the N-Boc-4iodo-piperidine 5a was treated with phenylmagnesium bromide in the presence of CoCl2 and diamine L1, the corresponding product was isolated in good yield (79%). Unfortunately, when the cobalt salt was replaced by FeCl2, the yield in 6a dropped to 56% due to the formation of various side-products resulting from elimination and/or reduction processes (Scheme 1). Consequently, the cobalt catalytic system was selected to investigate the scope of the cross-coupling of 4-iodo-piperidines with aryl Grignard reagents (Table 5). The N-Boc protecting

a

1.2−2 equiv, see Supporting Information for details. b50 mol % of L1 were used. cAt rt. dAt −10 °C.

The exact mechanism of iron- or cobalt- catalyzed crosscouplings has not been established undoubtedly yet. However, most of the studies favored the existence of a radical pathway.18 In our case, the loss of the stereochemical information at C3 which occurred during the cobalt- and iron-catalyzed cross-coupling of 1c with phenylmagnesium bromide supports the formation of radical intermediates (Table 3). In addition, the reaction of the iodo-pyrrolidine 719 with phenylmagnesium bromide in the presence of CoCl2 exclusively yielded the cyclic product 8 resulting from 5-exo-trig cyclization prior to the cross-coupling (Scheme 2). In summary, we have described an iron- and cobalt-catalyzed arylation of iodinated N-heterocycles such as 3-iodopyrrolidines, 4-iodopiperidines, and particularly 3-iodo-azetidines which have been rarely involved in cross-coupling reactions. The reactions generally proceeded in high yields and tolerated a large variety of functional groups. When a 2,3-disubstituted iodo-azetidine was used, a good diastereoselectivity in favor of the trans compound

Scheme 1. Cross-Coupling between 5a and PhMgBr

C


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Application 20050267096, December 1, 2005. (b) Fleck, M.; Nosse, B.; Roth, G. J. PCT International Application Nouveaux dérivés azetidine, compositions pharmaceutiques correspondantes et leurs utilisations. WO 2013098375, July 4, 2013. (c) Cramp, S. M.; Dyke, H. J.; Pallin, T. D.; Zahler, R. Partially Saturated Tricyclic Compounds and Methods of Making and Using Same. PCT International Application WO 2012154676, November 15, 2012. (d) Kim, R. M.; Parmee, E. R.; Sinz, C. J.; Ziouzina, O. A. Soluble Guanylate Cyclase Activators. U.S. Patent Application 20100216764, August 26, 2010. (e) Billotte, S. Synlett 1998, 379. (7) Duncton, M. J. A.; Estiarte, M. A.; Tan, D.; Kaub, C.; O’Mahony, D. J. R.; Johnson, R. J.; Cox, M.; Edwards, W. T.; Wan, M.; Kincaid, J.; Kelly, M. G. Org. Lett. 2008, 10, 3259. See also (a) Svenstrup, N.; Simonsen, K. B.; Rasmussen, L. K.; Juhl, K.; Langaard, M.; Wen, K.; Wang, Y. PCT International Application WO 2012EP69936, April 18, 2013. (b) Oslob, J. D.; McDowell, R. S.; Johnson, R.; Yang, H.; Evanchik, M.; Zaharia, C. A.; Cai, H.; Hu, L. W. Heterocyclic Modulators of Lipid Synthesis. PCT International Application WO 2014008197, January 09, 2014. (8) For other cross-coupling involving (pseudo)halogeno-azetidines, see (a) Cheung, C. W.; Ren, P.; Hu, X. Org. Lett. 2014, 16, 2566. (b) Molander, G. A.; Traister, K. M.; O’Neill, B. T. J. Org. Chem. 2014, 79, 5771. (c) Allwood, D. M.; Blakemore, D. C.; Brown, A. D.; Ley, S. V. J. Org. Chem. 2014, 79, 328. (d) Ni, C.; Park, M.; Shao, B.; Tafesse, L.; Yao, J.; Youngman, M. Pyrimidines as Sodium Channel Blockers. PCT International Application WO 2013030665, March 7, 2013. (9) (a) Guérinot, A.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2007, 46, 6521. (b) Reymond, S.; Ferrié, L.; Guérinot, A.; Capdevielle, P.; Cossy, J. Pure Appl. Chem. 2008, 80, 1683. (c) Nicolas, L.; Angibaud, P.; Stansfield, I.; Bonnet, P.; Meerpoel, L.; Reymond, S.; Cossy, J. Angew. Chem., Int. Ed. 2012, 51, 11101. (10) For selected Co- and Fe-catalyzed cross-coupling, see (a) Jana, R.; Pathak, T. P.; Sigman, M. S. Chem. Rev. 2011, 111, 1417. (b) Nakamura, E.; Yoshikai, N. J. Org. Chem. 2010, 75, 6061. (c) Sherry, B. D.; Fürstner, A. Acc. Chem. Res. 2008, 41, 1500. (d) Enthaler, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2008, 47, 3317. (e) Bolm, C.; Legros, J.; Le Paih, J.; Zani, L. Chem. Rev. 2004, 104, 6217. (f) Cahiez, G.; Moyeux, A. Chem. Rev. 2010, 110, 1435. (g) Gosmini, C.; Begouin, J.-M.; Moncomble, A. Chem. Commun. 2008, 28, 3221. (h) Steib, A. K.; Thaler, T.; Komeyama, K.; Mayer, P.; Knochel, P. Angew. Chem., Int. Ed. 2011, 50, 3303. (11) This catalytic system has already been described: (a) Ohmiya, H.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2006, 128, 1886. (b) Araki, K.; Inoue, M. Tetrahedron 2013, 69, 3913. (12) With 5 mol % of FeCl2 and 5 mol % of L1, an incomplete conversion of 83% was observed. The use of Fe(acac)3 (10 mol %) with L1 (10 mol %) led to an incomplete conversion of 1a (92%) while the combination of FeCl2 (10 mol %) and TMEDA (10 mol %) allowed the formation of 2a in 75% yield (instead of 81% when 10 mol % of FeCl2 and diamine L1 were used). (13) The coupling product could not be separated from the starting material by flash chromatography on silica gel. (14) Piller, F. M.; Appukkuttan, P.; Gavryushin, A.; Helm, M.; Knochel, P. Angew. Chem., Int. Ed. 2008, 47, 6802. (15) Ishida, N.; Shimamoto, Y.; Yano, T.; Murakami, M. J. Am. Chem. Soc. 2013, 135, 19103. (16) The N-tosyl substrate was found to be easier to prepare than the N-Boc. (17) The isolated yield was not determined. (18) For selected examples, see (a) Martin, R.; Fürstner, A. Angew. Chem., Int. Ed. 2004, 43, 3955. (b) Hölzer, B.; Hoffmann, R. W. Chem. Commun. 2003, 732. (c) Noda, D.; Sonada, Y.; Nakamura, M.; Nagashima, H. J. Am. Chem. Soc. 2009, 131, 6078. (d) Jahn, U. Top. Curr. Chem. 2012, 320, 191. (e) Ohmiya, H.; Wakabayashi, K.; Yorimitsu, H.; Oshima, K. Tetrahedron 2006, 62, 2207. (f) Someya, H.; Ohmiya, H.; Yorimitsu, H.; Oshima, K. Tetrahedron 2007, 63, 8609. (19) Kuriyama, M.; Takeichi, T.; Ito, M.; Yamasaki, N.; Yamamura, R.; Demizu, Y.; Onomura, O. Chem.Eur. J. 2012, 18, 2477.

Scheme 2. Sequential Cyclization/Arylation of 7

was observed. This selectivity as well as the cyclization of the 4allyloxy-3-iodo-pyrrolidine 7 suggests the formation of a radical intermediate. This coupling is efficient, easy-to-run, scalable, cheap and, thus, may appear as a powerful tool for the functionalization of saturated N-heterocycles.

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ASSOCIATED CONTENT

S Supporting Information *

Experimental procedures and spectral data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected] Notes

The authors declare no competing financial interest.

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REFERENCES

(1) (a) Roberts, M. F.; Wink, M. In Alkaloids: Biochemistry, Ecology and Medicinal Applications; Plenum: New York, 1998. (b) Buckingham, J.; Baggaley, K. H.; Roberts, A. D.; Szabó, L. F. In Dictionary of Alkaloids, 2nd ed.; CRC Press: Boca Raton, FL, 2009. (c) De Risi, C.; Fanton, G.; Pollini, G. P.; Trapella, C.; Valente, F.; Zanirato, V. Tetrahedron: Asymmetry 2008, 19, 131. (d) Brandi, A.; Cicchi, S.; Cordero, F. M. Chem. Rev. 2008, 108, 3988. (e) Singh, G. S.; D’hooghe, M.; De Kimpe, N. Azetidines, Azetines and Azetes: Monocyclic. In Comprehensive Heterocyclic Chemistry III; Stevens, C. V., Ed.; Elsevier: Oxford, U.K., 2008; Vol. 2, Chapter 2.01, p 1. (f) Couty, F.; Evano, G. Synlett 2009, 19, 3053 and references therein. (g) Allerton, C. M. N. 3-Phenylazetidine Derivatives As Dopamine Agonists. PCT International Application WO 2006134487, December 21, 2006. (h) Schultz, T.; Braje, W.; Turner, S. C.; Haupt, A.; Lange, U.; Drescher, K.; Wicke, K.; Unger, L.; Mezler, M.; Mayner, M. Azetidine compounds suitable for treating disorders that respond to modulation of the serotonin 5-ht6 receptor. PCT International Application WO 2008116833, October 2, 2008. (2) For a review on cross-coupling reactions involving secondary alkyl halides, see Rudolph, A.; Lautens, M. Angew. Chem., Int. Ed. 2009, 48, 2656. (3) For selected examples of Pd- and Ni-catalyzed arylation of halogeno-piperidines, see (a) Wang, S.; Qian, Q.; Gong, H. Org. Lett. 2012, 14, 3352. (b) Vechorkin, O.; Proust, V.; Hu, X. J. Am. Chem. Soc. 2009, 131, 9756. (c) Strotman, N. A.; Sommer, S.; Fu, G. C. Angew. Chem., Int. Ed. 2007, 46, 3556. (d) Powell, D. A.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 7788. (e) Gonzàlez-Bobes, F.; Fu, G. C. J. Am. Chem. Soc. 2006, 128, 5360. (4) Some examples of Fe- and Co-catalyzed arylation of halogenopiperidines have been reported: (a) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 11, 1794. (b) Bica, K.; Gaertner, P. Org. Lett. 2006, 8, 733. (c) Despiau, C. F.; Dominey, A. P.; Harrowven, D. C.; Linclau, B. Eur. J. Org. Chem. 2014, 4335. (5) For Cu-catalyzed arylation of tosylated pyrrolidines, see Yang, C.T.; Zhang, Z.-Q.; Liang, J.; Liu, J.-H.; Lu, X.-Y.; Chen, H.-H. J. Am. Chem. Soc. 2012, 134, 11124. (6) Some Negishi reactions between the organozinc reagent prepared from iodo-azetidine and aryl halides have been described, see, for example, (a) Allerton, C. M. N.; Hepworth, D.; Miller, D. C. New indazole and indolone derivatives and their use pharmaceuticals. U.S. Patent D


Iron- and Cobalt-Catalyzed Arylation of Azetidines, Pyrrolidines, and

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