Letter pubs.acs.org/OrgLett
Pd-Catalyzed Regioselective 1,2-Dicarbofunctionalization of Unactivated Olefins by a Heck Reaction/Enolate Cyclization Cascade Roshan K. Dhungana, Bijay Shrestha, Rajani Thapa-Magar, Prakash Basnet, and Ramesh Giri* Department of Chemistry & Chemical Biology, The University of New Mexico, Albuquerque, New Mexico 87131, United States S Supporting Information *
ABSTRACT: We disclose a Pd-catalyzed reaction protocol that regioselectively difunctionalizes unactivated olefins with aryl iodides and tethered enolates. The current method allows the rapid synthesis of a variety of 1,3,4-trisubstituted pyrrolidinones from simple and readily available amides. We further demonstrate this new method’s application by postsynthetically modifying the arylacetic acid side chains of two commercial nonsteroidal anti-inflammatory drugs, indomethacin and tolmetin, to highly decorated 4-benzylpyrrolidinone frameworks. Mechanistic studies reveal that the reaction proceeds via a Heck reaction/enolate cyclization cascade, a process that exploits β-H elimination in a constructive mode for regioselective 1,2-difunctionalization of unactivated olefins.
C
the reaction can also lead to the formation of 1,2-difunctionalized products5 after the HPdX reinsertion/transmetalation steps.6 In our quest to 1,2-dicarbofunctionalize unactivated olefins, we reasoned that carbonyl compounds would be an attractive alternative to organometallic reagents as a source of Cnucleophiles.7 However, their use as interceptors of the Heck C(sp3)−PdX intermediates8 in olefin dicarbofunctionalization still remains exceptionally rare.9 A prior report by Balme and coworkers indicated that a dicarbonyl compound containing a very acidic tertiary α-proton (DMSO pKa ∼13) could intercept in situ generated Heck C(sp3)−PdX species to form a cyclopentyl ring.10 However, the reaction proceeded with a limited scope and required strong bases such as KH and KOtBu. Herein, we disclose a new reaction protocol that enables a Pd-catalyzed reaction of simple, olefin-tethered amides (DMSO pKa ∼27) with a variety of aryl iodides in the presence of a mild base (K3PO4) to furnish 1,3,4-trisubstituted pyrrolidinone derivatives. Mechanistic studies reveal that, unlike the prior strategies outlined in paths A and B (Scheme 1),10 the current reaction proceeds via a dif ferent reaction pathway in which the Heck products generated in situ af ter β-H elimination trigger a cyclization reaction with tethered enolates to furnish the desired, regioselective 1,2-dicarbof unctionalized products (Scheme 1, path C). The present method affords a highly modular protocol to construct rapidly complex pyrrolidinonyl cores with two contiguous trans-stereocenters, which are privileged motifs11 in a wide range of commercial pharmaceuticals,12 bioactive molecules,13 and natural products.14 In our effort to difunctionalize olefins with aryl halides and enolates, we utilized N-allylamide 1 with an α-carbon poised to intercept Heck addition intermediates. When the amide 1 was
atalytic 1,2-dicarbofunctionalization of unactivated olefins offers tremendous potential toward rapidly constructing complex carbon scaffolds relevant to natural products, bioactive molecules, and pharmaceuticals. The Heck reaction, which monofunctionalizes olefins with organohalides, is a “Holy Grail” for this transformation, but such realization is contingent upon viable strategies to intercept the Heck C(sp3)−PdX intermediates with carbon (C)-nucleophiles (Scheme 1) prior to β-H Scheme 1. Strategies for Olefin Dicarbofunctionalization Initiated by Heck Carbopalladation
elimination that leads to the formation of Heck products.1 Recently, limited but notable examples of olefin 1,2-dicarbofunctionalization reactions based upon this premise have been developed wherein Heck C(sp3)−PdX species are intercepted by organometallic C-nucleophiles (path A).2 Alternatively, Sigman and co-workers have demonstrated in some cases where β-H elimination from the Heck C(sp3)−PdX species becomes imminent that the subsequent Heck products can also follow a HPdX reinsertion/transmetalation sequence3 to furnish 1,1difunctionalized products (Scheme 1, path B).4 The authors further showed that for conjugated dienes where the Heck C(sp3)−PdX species can be stabilized as a π-allyl−PdX complex © 2017 American Chemical Society
Received: March 16, 2017 Published: April 6, 2017 2154
DOI: 10.1021/acs.orglett.7b00794 Org. Lett. 2017, 19, 2154−2157
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Organic Letters
Addition of 1 equiv of KBr increased the yield of 2 to 73% by facilitating further consumption of the amide 1 and decreasing side reactions (entry 2).15 However, in the absence of 18-crown6 or both 18-crown-6 and KBr, only the Heck product 3 was formed (entries 3 and 4). Reactions could also be conducted in NMP and DMA, which formed the product 2 in comparable yields (entries 5 and 6). The product 2 was formed in low yield in DMSO (entry 7). Reactions in toluene and dioxane only formed the Heck product 3, and a significant amount of the starting material 1 was left unreacted (entries 8). Use of KH, KOtBu, and KHMDS did not furnish 2 or 3 but led to the decomposition of some starting amide 1 (entries 9). Use of NaOMe or K2CO3 as a base only generated the Heck product 3 without the formation of the expected product 2 (entries 10 and 11). Use of 4bromobenzotrifluoride instead of 4-iodobenzotrifluoride furnished the expected product 2 in lower yield, while a significant amount of the starting material remained unreacted (entry 12).16 After optimizing the reaction conditions, we examined the scope of the current transformation (Scheme 2). While electronneutral and electron-rich aryl iodides did not require KBr, its addition remained important for electron-deficient aryl iodides for better conversion of N-allylarylacetamides and increased the product yields by 10−20%. Generally, scale-up from 0.1 to 0.5 mmol required a slightly longer time (3 h instead of 2 h) to complete the reaction. Some reactions also required a higher temperature (120−140 °C) and longer hours to furnish best product yields. A wide variety of electron-rich, -neutral, and -deficient aryl iodides can be utilized as coupling partners with Nallylphenylacetamide 1, which furnishes trans-3-phenyl-4benzylpyrrolidinone derivatives 4−17 in good to excellent
reacted with 4-iodobenzotrifluoride in the presence of 2 mol % of Pd(dba)2, K3PO4, and 18-crown-6 in DMF at 100 °C, we were pleased to observe the formation of the expected product 2 in 56% yield in 2 h along with 25% of the remaining starting material 1 (Table 1, entry 1). No Heck product 3 was observed. Table 1. Optimization of Reaction Conditionsa
entry
modified conditions
1 (%)
yield (2/3, %)
1 2 3 4 5 6 7 8 9 10 11 12
without KBr standard conditions without 18-crown-6 without 18-crown-6 and KBr NMP instead of DMF DMA instead of DMF DMSO instead of DMF toluene or dioxane instead of DMF KH, KOtBu or KHMDS instead of K3PO4 NaOMe instead of K3PO4 K2CO3 instead of K3PO4 4-CF3C6H4Br instead of 4-CF3C6H4Ib
25 7 trace 6 6 8 14 34−45 31−61 45 5 35
56/0 73 (68)/0 0/81 0/76 70/trace 67/8 38/28 0/38−46 0/0 0/36 0/77 51/0
a
Yields were determined by 1H NMR using pyrene as a standard. Value in parentheses is the isolated yield from a 0.5 mmol scale reaction after 3 h. b5 h.
Scheme 2. 1,2-Dicarbofunctionalization of N-Allylarylacetamide with Aryl Iodidesa
a
Values are isolated yields from 0.5 mmol scale reactions. b140 °C. c8 h. d5 h. e120 °C. f15 h. 2155
DOI: 10.1021/acs.orglett.7b00794 Org. Lett. 2017, 19, 2154−2157
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Organic Letters Scheme 3. Diversification of NSAIDs Indomethacin and Tolmetina
a
Values are isolated yields from 0.5 mmol scale reactions. b3 h. c120 °C. d5 h.
chain was converted to N-allylamide derivative 41 prior to subjecting it to reactions with iodobenzene, 4-iodobenzonitrile, and 4-fluoroiodobenzene under the current reaction conditions. These reactions furnished the expected pyrrolidinone-decorated tolmetin derivatives 45−47 in 72%, 65%, and 66% yields. These six examples combined with the wide substrate scope and functional group tolerance presented in Scheme 2 demonstrate the synthetic competency of the current method to operate on complex molecules with a variety of structural frameworks harboring sensitive functional groups that are routinely encountered in synthetic manipulations of various natural products and pharmaceuticals. We further conducted preliminary mechanistic studies to understand the process of C−C bond formation in the current reaction (Scheme 4). First, we monitored the progress of the
yields. The trans-geometry of the products was confirmed by both NMR spectroscopy as well as single-crystal X-ray crystallography of trans-4-(4-methylbenzyl)-1,3-diphenylpyrrolidin-2-one (4). The reaction tolerates thioalkyls (SMe, 9), amines (NMe2, 10), and halides (F, Cl, 12−14) as substituents as well as sensitive functional groups such as ketones, nitriles, and esters (15−17). The reaction also tolerates an ortho-substituent and steric hindrance as exemplified by the formation of pyrrolidinone derivatives 5 and 6 with 2-iodotoluene and 2isopropyliodobenzene, respectively. We further examined the scope of the reaction by varying substituents on the aryl group of N-allylarylacetamides (Scheme 2). Various N-allylarylacetamides bearing electron-donating groups such as OMe, OBn, and dioxolyl (18−21) and electron-withdrawing groups such as Cl, F, and NO2 (22−27) can be used with a variety of electron-rich, -neutral, and -deficient aryl iodides to afford 1,3,4-trisubstitutituted pyrrolidinones in good to excellent yields. N-Allylarylacetamides bearing orthosubstituents such as 2-F and bulky aryl backbones such as 1naphthyl and 3-indolinyl are also tolerated (27−30). Similarly, ortho-substituted aryl iodides can also be employed as coupling partners (19, 22, and 26). The reaction can also be conducted on large scale (20, 2 mmol, 0.48 g, 55%). In addition, the aryl group on the amido nitrogen of N-allylarylacetamides can also be replaced with other protecting groups such as alkyl (31−35) and benzyl (36−39), which further increase the synthetic utility of the current reaction. To showcase further the competence of the current method in the late-stage synthetic manipulation of complex molecular architectures, we have demonstrated its applications in the postsynthetic modifications of two different commercially marketed drug molecules containing an arylacetic acid framework with multiple functional entities (Scheme 3). For example, the indoleacetic acid side chain of indomethacin, a nonsteroidal anti-inflammatory drug (NSAID), was readily amidated (40) with N-allylaniline to introduce the requisite reaction site for the current transformation. Upon treatment with methyl 4iodobenzoate, 1-iodo-4-(methylthio)benzene, and 2-iodotoluene under the standard reaction conditions, indomethacin amide 40 was transformed into new derivatives with a highly decorated and complex pyrrolidinonyl side chain (42−44) in 65%, 63%, and 62% yields, respectively. Similarly, another commercial NSAID drug tolmetin with a pyrroleacetic acid side
Scheme 4. Mechanistic Studies
reaction over time, which surprisingly indicated that the reaction furnished the Heck product 3 initially. The Heck product 3 was then slowly converted into the desired product 2 through cyclization with the α-carbon of the phenylacetamide moiety (Scheme 4). To confirm the intermediacy of the Heck product 3, we also isolated it in 78% yield by prematurely terminating the reaction. Further treatment of the Heck product 3 under our standard reaction conditions but in the absence of Pd(dba)2 furnished the expected product 2 in 94% GC yield. These experiments provide strong evidence that the reaction indeed follows a Heck reaction/enolate cyclization cascade in which the 2156
DOI: 10.1021/acs.orglett.7b00794 Org. Lett. 2017, 19, 2154−2157
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Organic Letters
(3) (a) Saini, V.; Sigman, M. S. J. Am. Chem. Soc. 2012, 134, 11372. (b) Saini, V.; Liao, L.; Wang, Q.; Jana, R.; Sigman, M. S. Org. Lett. 2013, 15, 5008. (4) For Ni- and Cu-catalyzed dicarbofunctionalization of olefins tethered to aryl-9-BBN, see: (a) Cong, H.; Fu, G. C. J. Am. Chem. Soc. 2014, 136, 3788. (b) You, W.; Brown, M. K. J. Am. Chem. Soc. 2014, 136, 14730. (c) You, W.; Brown, M. K. J. Am. Chem. Soc. 2015, 137, 14578. For Ni-, Co-, and Fe-catalyzed dicarbofunctionalization of olefins tethered to alkyl halides, see: (d) Wakabayashi, K.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2001, 123, 5374. (e) Phapale, V. B.; Buñuel, E.; García-Iglesias, M.; Cárdenas, D. J. Angew. Chem., Int. Ed. 2007, 46, 8790. (f) Xue, W.; Qu, Z.-W.; Grimme, S.; Oestreich, M. J. Am. Chem. Soc. 2016, 138, 14222. (g) McMahon, C. M.; Renn, M. S.; Alexanian, E. J. Org. Lett. 2016, 18, 4148. (h) Nakamura, M.; Ito, S.; Matsuo, K.; Nakamura, E. Synlett 2005, 2005, 1794. (i) Kim, J. G.; Son, Y. H.; Seo, J. W.; Kang, E. J. Eur. J. Org. Chem. 2015, 2015, 1781. (5) (a) Liao, L.; Jana, R.; Urkalan, K. B.; Sigman, M. S. J. Am. Chem. Soc. 2011, 133, 5784. (b) Stokes, B. J.; Liao, L.; de Andrade, A. M.; Wang, Q.; Sigman, M. S. Org. Lett. 2014, 16, 4666. (c) Mizutani, K.; Shinokubo, H.; Oshima, K. Org. Lett. 2003, 5, 3959. (6) For oxidative dicarbofunctionalization of unactivated olefins with identical aryl groups, see: (a) Yahiaoui, S.; Fardost, A.; Trejos, A.; Larhed, M. J. Org. Chem. 2011, 76, 2433. (b) Urkalan, K. B.; Sigman, M. S. Angew. Chem., Int. Ed. 2009, 48, 3146. (7) For a review on conjugate addition/α-enolate interception to dicarbofunctionalize activated olefins, see: (a) Guo, H.-C.; Ma, J.-A. Angew. Chem., Int. Ed. 2006, 45, 354. For a review on the addition of metal enolates to unactivated olefins, see: (b) Dénès, F.; Pérez-Luna, A.; Chemla, F. Chem. Rev. 2010, 110, 2366. (8) For Pd-catalyzed heterocarbofunctionalization of olefins tethered to amines/alcohols, see: (a) Lira, R.; Wolfe, J. P. J. Am. Chem. Soc. 2004, 126, 13906. (b) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644. (c) Hay, M. B.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 16468. (d) White, D. R.; Hutt, J. T.; Wolfe, J. P. J. Am. Chem. Soc. 2015, 137, 11246. (e) Bagnoli, L.; Cacchi, S.; Fabrizi, G.; Goggiamani, A.; Scarponi, C.; Tiecco, M. J. Org. Chem. 2010, 75, 2134. (f) Peng, J.; Lin, W.; Yuan, S.; Chen, Y. J. Org. Chem. 2007, 72, 3145. (g) Hu, N.; Li, K.; Wang, Z.; Tang, W. Angew. Chem., Int. Ed. 2016, 55, 5044. (h) Orcel, U.; Waser, J. Angew. Chem., Int. Ed. 2015, 54, 5250. (i) Borrajo-Calleja, G. M.; Bizet, V.; Mazet, C. J. Am. Chem. Soc. 2016, 138, 4014. (j) Hayashi, S.; Yorimitsu, H.; Oshima, K. J. Am. Chem. Soc. 2009, 131, 2052. (k) Hayashi, S.; Yorimitsu, H.; Oshima, K. Angew. Chem., Int. Ed. 2009, 48, 7224. (9) For a three-component reaction of olefins, enolates, and aryl iodides via a Pd(II)/Pd(IV) catalytic cycle, see: Liu, Z.; Zeng, T.; Yang, K. S.; Engle, K. M. J. Am. Chem. Soc. 2016, 138, 15122. (10) (a) Fournet, G.; Balme, G.; Gore, J. Tetrahedron Lett. 1987, 28, 4533. (b) Bouyssi, D.; Balme, G.; Fournet, G.; Monteiro, N.; Gore, J. Tetrahedron Lett. 1991, 32, 1641. (c) Vittoz, P.; Bouyssi, D.; Traversa, C.; Goré, J.; Balme, G. Tetrahedron Lett. 1994, 35, 1871. (d) Coudanne, I.; Balme, G. Synlett 1998, 1998, 998. (e) Balme, G.; Bouyssi, D.; Lomberget, T.; Monteiro, N. Synthesis 2003, 2003, 2115. (11) Welsch, M. E.; Snyder, S. A.; Stockwell, B. R. Curr. Opin. Chem. Biol. 2010, 14, 347. (12) (a) Golder, F. J.; Hewitt, M. M.; McLeod, J. F. Respir. Physiol. Neurobiol. 2013, 189, 395. (b) Zhu, J.; Mix, E.; Winblad, B. CNS Drug Rev. 2001, 7, 387. (c) Lyseng-Williamson, K. A. Drugs 2011, 71, 489. (13) Dolby, L. J.; Fedoruk, N. A.; Esfandiari, S.; Garst, M. E.; Allergan, USA. US 5675019A 19971007, 1997. (14) (a) Sellès, P. Org. Lett. 2005, 7, 605. (b) Gulder, T. A. M.; Moore, B. S. Angew. Chem., Int. Ed. 2010, 49, 9346. (15) Addition of KBr appears to promote the Heck reaction. The side product could not be identified. For a similar effect of KBr in the Hecktype reaction, see: Mandai, T.; Ogawa, M.; Yamaoki, H.; Nakata, T.; Murayama, H.; Kawada, M.; Tsuji, J. Tetrahedron Lett. 1991, 32, 3397. (16) Six-membered cyclized product was not formed when (Nhomoallyl-N-phenyl)phenylacetamide was used as a substrate. (17) For an example of enolate addition to styrene, see: Rodriguez, A. L.; Bunlaksananusorn, T.; Knochel, P. Org. Lett. 2000, 2, 3285.
Heck products trigger regioselective attack upon the styrenyl moiety by the α-carbon of the arylacetamide group in the presence of a base (Scheme 5).17 Scheme 5. Proposed Pathway for C−C Bond Formation
In summary, we have developed a versatile reaction protocol for regioselective 1,2-dicarbofunctionalization of unactivated olefins in N-allylarylacetamide derivatives that furnishes complex, trisubstituted pyrrolidinone derivatives with two contiguous trans-stereocenters. The reaction is not only characterized by high functional group tolerance but can also be applied to complex drug molecules to diversify them rapidly postsynthetically. Preliminary mechanistic studies indicate that the reaction proceeds via a Heck reaction/enolate cyclization cascade. This method provides an unprecedented approach that exploits the process of β-H elimination in a constructive manner for regioselective 1,2-difunctionalization of unactivated olefins.
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.7b00794. Experimental procedures, characterization data for all compounds, and crystallographic data (PDF) X-ray data for compound 4 (CIF)
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AUTHOR INFORMATION
Corresponding Author
*E-mail:
[email protected]. ORCID
Ramesh Giri: 0000-0002-8993-9131 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We thank the University of New Mexico (UNM) and the National Science Foundation (NSF CHE-1554299) for financial support and upgrades to the NMR (CHE08-40523 and CHE0946690) and MS facilities. The Bruker X-ray diffractometer was purchased via an NSF CRIF:MU award to UNM (CHE0443580).
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REFERENCES
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DOI: 10.1021/acs.orglett.7b00794 Org. Lett. 2017, 19, 2154−2157
