Divergent Product Selectivity in Gold- versus Silver-Catalyzed

Letter pubs.acs.org/OrgLett

Divergent Product Selectivity in Gold- versus Silver-Catalyzed Reaction of 2‑Propynyloxy-6-fluoropyridines with Arylamines Colombe Gronnier, Pierre Faudot dit Bel, Guilhem Henrion, Søren Kramer, and Fabien Gagosz* Laboratoire de Synthèse Organique, UMR 7652 CNRS/Ecole Polytechnique, Ecole Polytechnique, 91128 Palaiseau, France S Supporting Information *

ABSTRACT: A study of the reaction of easily accessible 2-propynyloxy-6-fluoropyridines with arylamines under gold or silver catalysis is described. It has been shown that two types of isomeric oxazolopyridine imine derivatives, which represent unusual heterocyclic motifs, can be selectively obtained in moderate to excellent yields depending on the nature of the metal employed.

A

Scheme 1. Potential Reactivity of 2-Propynyloxypyridines 1 under Au Catalysis by Analogy with the Chemistry of Propargylic Carboxylates 5

fter 10 years of intensive development, homogeneous gold catalysis1 can now be rightfully considered as a synthetic tool of choice for the nucleophilic functionalization of carbon π-systems. Indeed, electrophilic gold species have proven to generally outperform the capacity of other metal catalysts in this field. If cheaper silver salts can be used as substitutes to gold in a limited number of transformations,2 they however do not allow the same reaction diversity and are generally less efficient and/or selective. Of the characteristic features of this typical gold-catalyzed transformation, the possibility of employing a large variety of carbon-, nitrogen-, oxygen-, or sulfur-based species as suitable nucleophilic partners is perhaps one of the most valuable. In this respect, we recently realized that the pyridine motif had received very little attention.3 This might appear as relatively surprising when one considers the large number of gold-catalyzed transformations involving the nucleophilic addition of aromatic compounds or nitrogen species to a carbon π-system that have been reported. Such a situation may however be partly explained by the reduced nucleophilicity of the pyridine ring when compared to aryl derivatives, making the Friedel−Crafts type reaction more difficult. The few gold-catalyzed transformations described to date all involve an intra- or intermolecular initial attack of the pyridine (or by extension azine) sp2 nitrogen atom onto a goldactivated alkyne.3 In this context and following our continuous interest in gold catalysis,4 we were interested in investigating the general reactivity of the pyridine motif and more specifically the chemistry of 2-propynyloxypyridines 1 (Scheme 1). 2-Propynyloxypyridines 1 were chosen for the following reasons: (a) they are easily accessible by an SNAr reaction between the commercially available 2,6-difluoropyridine 2 and a propargylic alcohol 3;5 (b) they can be considered as stable analogues of propargylic imidates 4 which have been rarely studied in gold catalysis, probably due to their lability;6 and (c) they should share some common reactivity modes with propargylic carboxylates 5 under gold catalysis.7 We indeed © 2014 American Chemical Society

surmized that, by analogy with the chemistry of 5 (Scheme 1, eq 1), 2-propynyloxypyridines 1 could rearrange into the 1,2Received: February 4, 2014 Published: April 10, 2014 2092

dx.doi.org/10.1021/ol500939v | Org. Lett. 2014, 16, 2092−2095

Organic Letters

Letter

led however to a reduced reaction rate which could be remarkably enhanced by working under microwave irradiation (entry 9). Under these conditions, the isomeric oxazolopyridine imine 9a could be obtained in an optimal 91% isolated yield.14 Given the novelty of this reaction and the possibility to selectively produce some unusual heterocyclic oxazolopyridine motifs of type 8a or 9a, we deciced to explore its scope. The two sets of experimental conditions noted in entries 1 and 9 of Table 1 were retained for this purpose. We first focused our attention on the variation of the amine nucleophilic partner in the reaction of alkynyl substrate 1a. As seen from the results compiled in Table 2, the reaction can be applied to a variety of arylamines and the corresponding oxazolopyridine imines 8a−j and 9a−j were obtained in moderate to good yields. The transformation is compatible with the presence of various aromatic substituents such as halogen atoms (entries 2−4) as well as electron-donating (entries 5, 6) and electron-withdrawing groups (entries 7, 8). Under gold catalysis, a limit in reactivity was observed in the cases of 2-pyridylamine and benzylamine (entries 11, 12) as the corresponding compounds could not be formed. In contrast, the isomeric oxazolopyridine imines 9k and 9l were produced under silver catalysis (entries 11, 12). However, they proved to be instable and could not be isolated. We then examined the possibility of using 2-propynyloxypyridines with different substitution patterns. As seen in Table 3, this chemistry can be applied with the same efficiency to the synthesis of the isomeric oxazolopyridine imines 8m−r and 9m−r from substrates 1b−g. It should be noted that substrates 1b,c,e possessing two substituents of a different nature at the propargylic position lead to the formation of compounds 9m,n,p as E/Z mixtures of isomers. A ketal (entry 5) and a carbamate (entry 6) also survive the experimental conditions, thus expanding the functional group compatibility. When aryland alkyl-substituted alkynes 1h and 1i were reacted under gold or silver catalysis, no oxazolopyridine imines of type 8 or 9 could be obtained. Instead, the reactions delivered respectively allenes 11a and 11b, which could not be further transformed even after a prolonged reaction time. A series of others functionalized allenes 11c−e could be similarly obtained from alkynes 1j−l. A mechanistic overview that accounts for the observed reactivities of 2-propynyloxypyridines 1 under Au or Ag catalysis and in the presence of arylamines is proposed in Scheme 2. Some similarities with the behavior of the analogous propargylic carboxylates 5 can be noted. Indeed, both 5-exo and 6-endo Au- or Ag-induced cyclizations of 1 into intermediates 12 and 13 respectively seem to be possible. 7 From fluoropyridinium 12, one can explain the formation of the oxazolopyridine imines 8 by a sequence of nucleophilic trapping by an arylamine followed by a loss of HF and a protodemetalation step (path A: 1 → 12 → 8).15 An alternative reaction pathway (path C: 1 → 14 → 8) involving an initial aromatic subtitution of the fluoride atom by the arylamine can be ruled out. Indeed, 17 which lacks the alkyne moiety did not lead to the formation of 18 under the typical experimental conditions allowing the formation of 8 (bottom part of Scheme 2). Regarding the formation of the isomeric oxazolopyridine imines 9, the N-allenyl pyridone intermediate 15, resulting from the 3,3 rearrangement of 1 (path B: 1 → 13 → 15),16 first undergoes a rare 5-endo cyclization at the central carbon of the allene.17 This would generate the intermediate fluoropyridinium 16 which, similarly to case of 12, would then react with an

pyridinoxy shift gold carbenoid product 6 or into the goldcoordinated N-allenyl pyridone 7 via a 3,3-rearrangement8 and that these potential intermediates could then be trapped by a nucleophilic species. We report herein some preliminary results of our studies regarding the reaction of 1 with arylamines in the presence of a gold or a silver catalyst.9 Our study started with alkyny1 substrate 1a. In a first attempt, 1a was reacted with [(Ph3P)Au]NTf210 (5 mol %) in chloroform (60 °C) and in the presence of aniline (2.1 equiv) as a potential nucleophilic partner. A completely unexpected result was obtained: 1a was indeed cleanly converted after 7 h of reaction into oxazolopyridine imine 8a, which was isolated in an excellent 97% yield (Table 1, entry 1).11 The reaction Table 1. First Attempted Reaction with 1a and Optimization of the Catalytic Systems towards the Selective Formations of 8a and 9aa

a Substrate concentration: 0.2 M. bAu catalysts, 5 mol %; AgNTf2, 10 mol %. cDetermined by 1H NMR spectroscopy of the crude reaction mixture. dIsolated yields unless otherwise stated. eAr = 2,6-(t-Bu)2C6H3. fNMR yields. gNot determined. hSubstrate concentration: 0.05 M. iNo reaction observed.

proved to be less efficient when it was performed with a reduced amount of aniline (1.1 equiv) and in the presence of an inorganic base (1.1 equiv) to trap the HF formed as a coproduct in the coupling process leading to 8a (entry 2). All attempts to reduce the reaction time by employing a different gold catalyst were unsucessful (entries 3−5).12 Interestingly, when [(IAd)Au]NTf2 and [(ArO)3PAu]NTf2 were used, the transformation was not selective, and the N-allenylpyridine 10 (entry 4) or the isomeric oxazolopyridine imine 9a (entry 5) was formed alongside 8a. A low selectivity was also obtained when the reaction was attempted with the simple AgNTf2 salt (10 mol %, entry 6). While every attempt to selectively produce compound 8a using AgNTf2 as the catalyst unfortunately failed, we were however able to optimize the catalytic system toward the formation of the isomeric compound 9a. When the quantity of aniline was limited to 1.1 equiv and Na2CO3 (1.1−4.0 equiv)13 was added as a potential HF scavenger, the formation of 9a was indeed favored (entries 7 and 8). This modification 2093

dx.doi.org/10.1021/ol500939v | Org. Lett. 2014, 16, 2092−2095

Organic Letters

Letter

Table 2. Substrate Scope: Variation of the Amine

conditions A (Au)a entry

R

product

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

C6H5 4-F(C6H4) 4-Br(C6H4) 3-I(C6H4) 3-MeO(C6H4) 4-MeO(C6H4) 4-NO2(C6H4) 3-CF3(C6H4) 2,3-Me2(C6H3) 2-naphthyl 2-pyridyl benzyl

8a 8b 8c 8d 8e 8f 8g 8h 8i 8j 8k 81

conditions B (Ag)b

time

yieldc

product

7 14 17 5 36 10 72 7.5 7.5 12 24 24

97% 79% 84% 84% 74% 82% 45%d 75% 80% 81% 0% 0%

9a 9b 9c 9d 9e 9f 9g 9h 9i 9j 9k 91

h h h h h h h h h h h h

time

yieldc

1 2 2 2 2 2 2 2 2 2 2 2

91% 98% 36% 43% 64% 44% 60% 39% 46% 50%e 50%e 71%e

h h h h h h h h h h h h

[(Ph3P)Au]NTf2 (5 mol %), RNH2 (2.1 equiv), CHCl3 (0.2 M, 60 °C). bAgNTf2 (10 mol %), RNH2 (1.1 equiv), Na2CO3 (4 equiv), CHCl3 (0.05 M, μw 100 °C). cIsolated yields. d60% conversion. eEstimated NMR yields (unstable compounds which could not be isolated). a

Table 3. Substrate Scope: Variation of the Alkynyl Substratea

Scheme 2. Mechanistic Proposal for the Reaction of 1 with Arylamines under Au and Ag Catalysis

a [(Ph3P)Au]NTf2 (5 mol %), RNH2 (2.1 equiv), CHCl3 (0.2 M, 60 °C). bAgNTf2 (10 mol %), RNH2 (1.1 equiv), Na2CO3 (4 equiv), CHCl3 (0.05 M, μw 100 °C). cIsolated yields. dE/Z selectivity from 1:1 to 1:1.6 (see Supporting Information). eWith aniline instead of 4fluoroaniline. fWithout aniline.

arylamine to ultimately deliver 9 after the loss of HF and regeneration of the catalyst. While both oxazolopyridine imines 8 and 9 could be accessed under either gold or silver catalysis 2094

dx.doi.org/10.1021/ol500939v | Org. Lett. 2014, 16, 2092−2095

Organic Letters

Letter

Rottländer, M.; Gagosz, F.; Skrydstrup, T. Angew. Chem. Int. Ed 2011, 50, 5090. (5) For recent examples of the use of 2-oxy-6-fluoropyridine derivatives, see: (a) Charrier, N.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 2008, 130, 8898. (b) Braun, M.-G.; Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 2011, 133, 15954. (6) (a) Hashmi, A. S. K.; Rudolph, M.; Schymura, S.; Visus, J.; Frey, W. Eur. J. Org. Chem. 2006, 4905. (b) Kang, J.-E.; Kim, H.-B.; Lee, J.W.; Shin, S. Org. Lett. 2006, 8, 3537. (c) Huang, X.; Zhang, L. J. Organomet. Chem. 2009, 694, 520. (7) For reviews on Au-catalyzed reactions of propargylic carboxylates, see: (a) Wang, S.; Zhang, G.; Zhang, L. Synlett 2010, 692. (b) Marion, N.; Nolan, S. Angew. Chem., Int. Ed. 2007, 46, 2750. (c) MarcoContelles, J.; Soriano, E. Chem.Eur. J. 2007, 13, 1350. (8) For the use of the 2-oxypyridine moiety as a 3,3-migrating group, see for instance: With Au: Reference 3c. With Pd: (a) Rodrigues, A.; Lee, E. E.; Batey, R. A. Org. Lett. 2010, 12, 260. (b) Itami, K.; Yamazaki, D.; Yoshida, J.-I. Org. Lett. 2003, 5, 2161. With Pt, Sn: (c) Stewart, H. F.; Seibert, R. P. J. Org. Chem. 1968, 33, 4560. (9) To the best of our knowledge, there is only a single report on a gold-catalyzed transformation of 2-propargyloxypyridines (ref 3c). (10) Mézailles, N.; Ricard, L.; Gagosz, F. Org. Lett. 2005, 7, 4133. (11) The core structures of 8a and 9a were confirmed by X-ray diffraction studies performed on analogous compounds. (12) The catalytic conditions noted in entry 3 were not retained in the study of the scope and limitations, because the [(XPhos)Au]NTf2 complex is significantly more expensive than the simple [(Ph3P)Au] NTf2. (13) The exact role played by the Na2CO3 salt remains unclear. (14) No reaction was observed in the absence of a gold or silver catalyst. (15) Cheng, D.; Croft, L.; Abdi, M.; Lightfoot, A.; Gallagher, T. Org. Lett. 2007, 9, 5175. (16) No evidence was found regarding a possible reversibility of the 3,3-rearrangment pathway (1→15): reaction of 15 under gold catalysis and in the presence of ArNH2 did not furnish 8. (17) For Au-catalyzed nucleophilic additions on the central carbon of allenes, see for instance: (a) Buzas, A. K.; Istrate, F. M.; Gagosz, F. Org. Lett. 2007, 9, 985. (b) Winter, C.; Krause, N. Angew. Chem., Int. Ed. 2009, 48, 6339. (c) Hashmi, A. S. K.; Schuster, A. M.; Litters, S.; Rominger, F.; Pernpointner, M. Chem.Eur. J. 2011, 17, 5661.

(see Table 1), the use of a gold catalyst seems to favor the formation of 8 via path A, and the use of a silver catalyst, the formation of 9 via path B. In conclusion, we have studied the reaction of 2propynyloxy-6-fluoropyridines with arylamines under gold and silver catalysis. These substrates were shown to share some common reactivity modes with propargylic carboxylates. Two sets of catalytic conditions have been developed that allow the divergent and selective synthesis of two types of isomeric oxazolopyridine imines. A series of these unusual heterocyclic motifs possessing various commonly employed functional groups could be produced in moderate to excellent yields. Further studies on the extension of this chemistry to the synthesis of other heterocyclic motifs by the reaction of 2propynyloxypyridines with other nucleophilic partners are underway.

■

ASSOCIATED CONTENT

S Supporting Information *

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

■

AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Notes

The authors declare no competing financial interest.

■

ACKNOWLEDGMENTS We are deeply appreciative of generous financial support from the Ecole Polytechnique (C.G., G.H., and S.K.), ANR (P.F.), the Carlsberg Foundation, the Danish National Research Foundation, H. Lundbeck A/S, the OChem graduate school, and Aarhus University (S.K.). The authors thank Dr. X. F. Le Goff (Ecole Polytechnique) for X-ray analysis and Dr. F. Metz (Rhodia Chimie Fine) for a generous gift of HNTf2.

■

REFERENCES

(1) For selected reviews on gold catalysis, see: (a) Fürstner, A. Chem. Soc. Rev. 2009, 38, 3208. (b) Jiménez-Núñez, E.; Echavarren, A. M. Chem. Rev. 2008, 108, 3326. (c) Li, Z.; Brower, C.; He, C. Chem. Rev. 2008, 108, 3239. (d) Arcadi, A. Chem. Rev. 2008, 108, 3266. (e) Gorin, D. J.; Toste, F. D. Chem. Rev. 2008, 108, 3351. (f) Hashmi, A. S. K. Chem. Rev. 2007, 107, 3180. (g) Fürstner, A.; Davies, P. W. Angew. Chem., Int. Ed. 2007, 46, 3410. (h) Hashmi, A. S. K.; Hutchings, G. J. Angew. Chem., Int. Ed. 2006, 45, 7896. (2) For a selected review, see: Weibel, J.-M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149. (3) See for instance: (a) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc. 2006, 128, 12050. (b) Seregin, I. V.; Schammel, A. W.; Gevorgyan, V. Org. Lett. 2007, 9, 3433. (c) Romero, N. A.; Klepser, B. M.; Anderson, C. E. Org. Lett. 2012, 14, 874. See also: (d) Yadav, J. S. B.; Reddy, V. S.; Yadav, N. N.; Gupta, M. K.; Sridhar, B. J. Org. Chem. 2008, 73, 6857. (d1) Vachhani, D. D.; Modha, S. G.; Sharma, A.; Van der Eycken, E. V. Tetrahedron 2013, 69, 359. (e) Yan, B.; Liu, Y. Org. Lett. 2007, 9, 4323. (4) For selected recent contributions from our group, see: (a) Gronnier, C.; Boissonnat, G.; Gagosz, F. Org. Lett. 2013, 15, 4234. (b) Henrion, G.; Chavas, T. E. J.; Le Goff, X.; Gagosz, F. Angew. Chem., Int. Ed. 2013, 52, 6277. (c) Cao, Z.; Gagosz, F. Angew. Chem., Int. Ed. 2013, 52, 9014. (d) Bolte, B.; Gagosz, F. J. Am. Chem. Soc. 2011, 133, 7696. (e) Kramer, S.; Odabachian, Y.; Overgaard, J.; 2095

dx.doi.org/10.1021/ol500939v | Org. Lett. 2014, 16, 2092−2095