Letter pubs.acs.org/OrgLett
Hydropyridylation of Olefins by Intramolecular Minisci Reaction Samuele Bordi† and Jeremy T. Starr* Pfizer Worldwide R&D, Eastern Point Road, Groton, Connecticut 06340, United States † School of Science and Technology, Chemistry Division, University of Camerino, via S. Agostino 1, I-62032 Camerino (MC), Italy S Supporting Information *
ABSTRACT: An unprecedented cheap, mild and easy methodology for an intramolecular Minisci reaction based on a hydrogen atom transfer (HAT) initiated hydrofunctionalization of olefins was developed. The method is suitable for the construction of unusual dihydropyrano-pyridine and 1,2,3,4tetrahydronaphthiridine structures and, unlike most similar reactions, does not require exclusion of air from the reaction medium.
T
Scheme 1. Minisci Reaction and Alkene Radical Hydrofunctionalizations
he radical substitution of protonated heteroarenes, often called the “Minisci” reaction, is enjoying a resurgence in popularity for late stage functionalization of heteroaromatic structures in the synthesis of natural and biologically active products.1 The scope of the reaction has been widely expanded, including many methods for radical generation and new radical sources,2 but intramolecular variants are comparatively rare. The main limitation faced by an intramolecular Minisci reaction is often the necessity of an excess of the radical source, making the reaction seem untenable when the radical nucleophile is in a 1:1 stoichiometry with the electrophile, as in an intramolecular case. However, we believe the close proximity of nucleophile and electrophile may overcome the kinetic limitations of some Minisci reactions. Among the methods for radical based carbon−carbon and carbon−heteroatom bond formation, the hydrofunctionalization of olefins has proved to be an effective approach and has been used in total synthesis for the construction of structures difficult to obtain in other ways.3 The main advantage of this reaction over the Brønsted acid promoted hydrofunctionalization of olefins is that it proceeds by way of a carbon centered radical, which may be intercepted to form a new carbon− carbon bond. Additional advantages include its relative mildness and the tolerance for the presence of other functional groups, making it useful in the late stage of a synthetic pathway, where it may be necessary to deal with complex structures or undesirable to use protecting groups. In the last 30 years, many transition metal based catalytic systems were developed for hydrofunctionalization of double bonds, among them, Carreira’s Co/Salen complexes,4 Shigehisa’s Co/fluoropyridinium system,5 and, lately, Baran’s Fe(III)/ hydrosilane system (Scheme 1).6 In particular, the latter has proved to be a useful methodology for both inter- and intramolecular reductive olefin coupling and has been used for the synthesis of alkylated styrene derivatives,7 unnatural amino acids,8 and substituted phenols.9 Moreover, Baran’s protocol has been used as key step in the total synthesis of Hippolachnin A10 and Emindol SB.11 © 2017 American Chemical Society
We were attracted to the Baran method in particular as a starting point for an intramolecular Minisci reaction because of its mildness, versatility, and simplicity. Herein we describe the extension of the Fe(acac)3/PhSiH3 system to a convenient method for heteroannulation of pyridine to give semisaturated heterobicycles. Despite the method having been substantially optimized for reductive olefin coupling, we found optimization was necessary in order to adapt it for a net redox neutral process under the Received: March 20, 2017 Published: April 25, 2017 2290
DOI: 10.1021/acs.orglett.7b00833 Org. Lett. 2017, 19, 2290−2293
Letter
Organic Letters Table 2. Optimization of Additivesa
acidic conditions required for activation of the heteroarene. We started our optimization with the pyridine 1a as substrate, using 2.5 equiv of PhSiH3 and 1 equiv of Fe(acac)3 and trifluoroacetic acid in a series of solvents, heating at 60 °C for 18 h. Table 1 Table 1. Initial Solvent and Additive Screena
entry
conditions
conv (%)b
chemoselb
1 2 3 4 5 6 7
MeOH, EtOH, or iPrOH as solvent H2O as solvent DMF or THF as solvent TFA (7 equiv) no TFA added PhSiH3 (5 equiv) entry 1, degassed solvents
50−60 55 traces 45 65 90 30−40
5:1 1:10
TFA (equiv)
Fe(acac)3 (equiv)
solvent
1 2
4 4
1 1
55 60
4 4
1 1
80 68
5 6
MeOH MeOH/H2O (4:1) EtOH EtOH/H2O (4:1) EtOH EtOH
2 2
2 0.5
7
EtOH
2
0.5
8
EtOH
2
0.5
9
EtOH
2
0.1
3 4
>20:1 1:10 1:1 5:1
a
General conditions: 1a (0.3 mmol), phenylsilane (2.5 equiv), Fe(acac)3 (1 equiv), and trifluoroacetic acid (1 equiv) were mixed in the chosen solvent (1.5 mL) and stirred at 60 °C for 18 h. b Conversions and chemoselectivity determined by GC−MS analysis (chemoselectivity calculated as (2 + 3)/4 ratio).
additive
conv (%)b
entry
DTBP (1.5 equiv) DTBP (3 equiv) DTBP (3 equiv) DTBP (5 equiv)
100 90 100 (82)c 0d 95
a
General conditions: 1b (0.3 mmol), phenylsilane (2.5 equiv), Fe(acac)3, and trifluoroacetic acid were mixed in the chosen solvent (1.5 mL), then the additive was eventually added and the mixture stirred at 60 °C for 18 h. bConversions determined by GC−MS analysis. cIn brackets, isolated yield on 1 mmol scale. dReaction performed without phenylsilane. Starting material was recovered.
summarizes the early results in terms of conversion and chemoselectivity. The reaction worked well in protic solvents, with good selectivity for cyclization over alkene reduction, except in water where reduction was strongly favored. It did not proceed at all in aprotic solvents such as DMF or THF. An excess of TFA was crucial for a good outcome of the reaction, leading to nearly complete suppression of the reduced olefin product. Generally, the conversions were observed between 50% and 60%, leaving a considerable amount of unreacted substrate, we believe due to the known instability of phenylsilane in acidic media.12 Unfortunately increasing the amount of phenylsilane led only to a decrease in chemoselectivity (albeit with improved conversions). In these initial experiments it was found that degassed reactions, excluding oxygen, performed poorly compared with those run in the presence of air. Typically, radical reactions exhibit the opposite trend, often producing unwanted side reactions with adventitious oxygen13 and often needing to be degassed in order to work properly. In our case, oxygen seemed to play an important role, perhaps in the reoxidation of Fe(II) to Fe(III) or in the direct rearomatization of the radical addition product. From these preliminary results, we switched to the pyridine 1b as substrate to further optimize conditions, reasoning that the longer lived and more stable tertiary radical would undergo the desired addition reaction at a faster rate than reduction to the alkane (Table 2). Using ethanol as solvent and decreasing the TFA to 2 equiv, we observed full conversion of starting material to desired product as a mixture of regioisomers 2b and 3b (entry 5). The addition of 3 equiv of di-tert-butylperoxide (DTBP) as a substitute for air as oxidant resulted in an 82% isolated yield of the product, even after decreasing Fe(acac)3 from 2 to 0.5 equiv. Further decreasing the amount of Fe(acac)3 to 0.1 equiv together with an increase of DTBP also leads to excellent conversions, but with an increase in deleterious side reactions leading to impurities in crude product. Next, we investigated the scope of the reaction by using a series of olefin chain-containing pyridines where the method proved to be general.
Scheme 2 shows that across a variety of substrates, good yields of products, occurring where possible as a regioisomeric Scheme 2. Substrate Scopea
a
General conditions: 1 (1 mmol), phenylsilane (2.5 mmol), Fe(acac)3 (0.5 mmol), and trifluoroacetic acid (2 mmol) were mixed in ethanol (5 mL), then DTBP (3 mmol) was added and the mixture stirred at 60 °C for 18 h. b30% of 3b was isolated. cStarting material was fully recovered. dNo trace of the other regioisomer was detected. 2291
DOI: 10.1021/acs.orglett.7b00833 Org. Lett. 2017, 19, 2290−2293
Letter
Organic Letters mixture of the 2- and 4-position adducts, were observed. One exception was compound 2j, where only the 2-position adduct formed, presumably due to a preference of the pyridyl C−N bond to orient with the 2-position proximal to the amide in the precursor. When a bromine atom is present at the 2-position (example 2d) it directs the addition to occur exclusively at the 4-position; however, the bromine itself was partially reduced from the product during the reaction, resulting in a mixture of 2d (46%) and 3b (30%). Interestingly, the rate of bromine reduction is sufficiently slow to permit exclusive formation of a single regioisomer suggesting Br is a convenient control element in cases where an unsubstituted position may be vulnerable to nucleophilic attack. Unfortunately, we could not get the complete reduction of the bromine to occur in situ even using additional equivalents of silane and longer reaction times. The reaction tolerates benzyl radicals (2g), aminopyridine derivatives (2h and 2j), and an amide in the cyclizing tether (2j). When the reaction had a choice between positions on a 6aza-indole electrophile, addition to the pyridine nucleus was the exclusive product (albeit in low yield, 2i). An ester in the cyclizing tether proved problematic, however, and the attempted product 2f was not formed after 18 h. The reaction performs better in the case of external double bonds as compared with internal ones. Comparing the results on the cyclization of compound 1c with compound 1k (both leading to the pyranopyridine 2c) we observed a substantial decrease in yield in the case of the compound 1k with an internal double bond, where the reaction does not go to completion even after 48 h or using a greater amount of phenylsilane (Scheme 3). Nevertheless, the yields are preparatively useful even with internal double bonds, making access to unusual spirocycles, such as 21, straightforward.
Scheme 4. Proposed Mechanism
of an internal oxidant may be due to the depletion of the Fe(III) species, probably by single electron transfer (SET) from intermediate C in the rearomatization step. Supporting this hypothesis is our observation that full conversion of starting material can be obtained with excess Fe(acac)3 (Table 2, entry 5). In conclusion, we have described a methodology for the cyclization of olefin chains on pyridines, based on a HAT initiated mechanism promoted by an Fe(III)/silane system. The method does not require exclusion of air or moisture and has proved useful for the construction of unusual dihydropyrano-pyridine and 1,2,3,4-tetrahydronaphtiridine rings, which would be difficult to obtain in other ways.
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Scheme 3. Internal Double Bonds
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00833. Experimental procedures and characterization and spectral data for new compounds (PDF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail: jeremy.starr@pfizer.com. ORCID
Jeremy T. Starr: 0000-0001-8651-507X Notes
The proposed mechanism (Scheme 4) envisions a redox neutral process, catalytic in Fe, as a fusion of Baran’s ironmediated olefin coupling6a and a Minisci reaction. The mechanism starts with a hydrogen atom transfer (HAT) from the Fe-hydride complex II, formed in situ from phenylsilane and the iron catalyst I, to the olefin A, followed by addition of the carbon radical B to the protonated pyridine residue. The intermediate radical cation C is subsequently oxidatively rearomatized to give the observed product(s). The roles of di-tert-butylperoxide (or oxygen from air) may be to generate product by rearomatization of the intermediate C and to regenerate the active Fe(III) species I that delivers hydride to the olefin. Low conversions obtained in the absence
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This paper is in memory of Pfizer scientist Robert Oliver who worked in the next hood over and who passed far too young. The authors wish to acknowledge Jotham Coe, Mike Chen, Dan Uccello of Pfizer and Susanna Sampaolesi of University of Camerino for helpful discussions, and Jennifer Young of Pfizer for final editing of the manuscript and Supporting Information. Finally, we wish to thank Prof. Enrico Marcantoni of University of Camerino for providing S.B. the opportunity to do this work at Pfizer. 2292
DOI: 10.1021/acs.orglett.7b00833 Org. Lett. 2017, 19, 2290−2293
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Organic Letters
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REFERENCES
(1) Duncton, M. A. MedChemComm 2011, 2, 1135 and references therein. (2) For a review of the Minisci reaction and its variations see: Tauber, J.; Imbri, D.; Opatz, T. Molecules 2014, 19, 16190. (3) For a comprehensive review of radical hydrofunctionalization and its exploitation in total synthesis see: Crossley, S. W. M.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Chem. Rev. 2016, 116, 8912. (4) (a) Waser, J.; Carreira, E. M. J. Am. Chem. Soc. 2004, 126, 5676. (b) Waser, J.; Gonzalez-Gomez, J. C.; Nambu, H.; Huber, P.; Carreira, E. M. Org. Lett. 2005, 7, 4249. (c) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. (d) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2007, 46, 4519. (e) Gaspar, B.; Carreira, E. M. Angew. Chem., Int. Ed. 2008, 47, 5758. (f) Gaspar, B.; Carreira, E. M. J. Am. Chem. Soc. 2009, 131, 13214. (5) (a) Shigehisa, H.; Aoki, T.; Yamaguchi, S.; Shimizu, N.; Hiroya, K. J. Am. Chem. Soc. 2013, 135, 10306. (b) Shigehisa, H.; Nishi, E.; Fujisawa, M.; Hiroya, K. Org. Lett. 2013, 15, 5158. (c) Shigehisa, H.; Koseki, N.; Shimizu, N.; Fujisawa, M.; Niitsu, M.; Hiroya, K. J. Am. Chem. Soc. 2014, 136, 13534. (d) Shigehisa, H.; Hayashi, M.; Ohkawa, H.; Suzuki, T.; Okayasu, H.; Mukai, M.; Yamazaki, A.; Kawai, R.; Kikuchi, H.; Satoh, Y.; Fukuyama, A.; Hiroya, K. J. Am. Chem. Soc. 2016, 138, 10597. (e) Shigehisa, H.; Kikuchi, K.; Hiroya, K. Chem. Pharm. Bull. 2016, 64, 371. (f) Shigehisa, H.; Ano, T.; Honma, H.; Ebisawa, K.; Hiroya, K. Org. Lett. 2016, 18, 3622. (6) (a) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 1304. (b) Dao, H. T.; Li, C.; Michaudel, Q.; Maxwell, B. D.; Baran, P. S. J. Am. Chem. Soc. 2015, 137, 8046. (c) Gui, J.; Pan, C. M.; Jin, Y.; Qin, T.; Lo, J. C.; Lee, B. J.; Spergel, S. H.; Mertzman, M. E.; Pitts, W. J.; La Cruz, T. E.; Schmidt, M. A.; Darvatkar, N.; Natarajan, S. R.; Baran, P. S. Science 2015, 348, 886. (7) Zheng, J.; Wang, D.; Cui, S. Org. Lett. 2015, 17, 4572. (8) Zhang, H.; Li, H.; Yang, H.; Fu, H. Org. Lett. 2016, 18, 3362. (9) Shen, Y.; Qi, J.; Mao, Z.; Cui, S. Org. Lett. 2016, 18, 2722. (10) Ruider, S. A.; Sandmeier, T.; Carreira, E. M. Angew. Chem., Int. Ed. 2015, 54, 2378. (11) George, D. T.; Kuenstner, E. J.; Pronin, S. V. J. Am. Chem. Soc. 2015, 137, 15410. (12) Miura, K.; Tomita, M.; Ichikawa, J.; Hosomi, A. Org. Lett. 2008, 10, 133. (13) Maillard, B.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc. 1983, 105, 5095.
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