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One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed #-Arylation. Alexander Thomas Wolters, Valentín Hornillos, Dorus Heijnen, Massimo Giannerini, and Ben L. Feringa ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b00134 • Publication Date (Web): 07 Mar 2016 Downloaded from http://pubs.acs.org on March 7, 2016
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One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed α-Arylation. Alexander T. Wolters,a Valentin Hornillos,*a Dorus Heijnen,a Massimo Giannerini,a and Ben L. Feringa*a. a
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
ABSTRACT: An efficient in situ sequential 1,2-addition of alkyllithium reagents to benzamides followed by α-arylation of the resulting alkyl ketones is reported. The use of Pd[P(t-Bu)3]2, as catalyst for the α-arylation reaction, allows access to a wide variety of functionalized benzyl ketones in a modular way. The decomposition of the tetrahedral intermediate originated from the 1,2-addition liberates in situ a lithium amide, therefore avoiding the need of an external base for the αarylation. The method affords good overall yields with a variety of alkyl lithium reagents, benzamides and aryl bromides bearing a range of functional groups with complete selectivity toward the monoarylated products.
KEYWORDS: α-Arylation, palladium, ketones, organolithium, amides, One-pot. Palladium-catalyzed α-arylation of carbonyl and related compounds has emerged as an effective Csp2-Csp3 bond forming methodology that does not generally require preformation of an organometallic reaction partner.1 This is an important transformation in organic chemistry as the α-aryl carbonyl moiety is found in a wide variety of biologically active molecules of interest in medicinal chemistry.2 Moreover, α-arylated carbonyl compounds are precursors to functionalized molecules carrying amine, olefin, nitrile, alcohol and other groups located α or β to the aryl ring.3 The groups of Buchwald, Hartwig, and Miura independently reported methods based on palladium catalysts for the intermolecular α-arylation of ketones.4 Improved procedures5 and methods involving α-arylation of simple acetone,6 esters,7 α-amino acid esters,8 nitroalkanes,9 amides,10 imides bearing the Evans auxiliary,11 aldehydes12 and nitriles13 have since been described. A requirement frequently found in α-arylation reactions is that an excess of a strong base is employed to reach full conversion into the final product, and to avoid quenching of the starting enolate by the more acidic benzylic protons of the tertiary α-aryl carbonyl product, which can lead to the formation of diarylated compounds. The use of an excess of base can also limit the functional group tolerance, and promote racemization of carbonyl compounds with an α-proton at a stereogenic center under the reaction conditions.
Weinreb amide, the tetrahedral intermediate formed acts as a masked ketone moiety allowing for an in situ crosscoupling reaction with the second organolithium compound. The corresponding ketones are then obtained without the necessity to separately prepare, purify and protect/deprotect the ketone intermediate. Inspired by this process, we envisioned the possibility to combine, in a one pot procedure, the 1,2-addition of an alkyllithium reagent to a benzamide 1 with a Pd-catalyzed α-arylation of the resulting alkylketone 2, where the lithium amide expelled after the collapse of the tetrahedral intermediate th could act as a base in the arylation process, therefore avoiding the use of an external base (Scheme 1).
Our group has recently described a highly efficient onepot synthesis of functionalised ketones via sequential 1,2addition, Pd-catalyzed cross-coupling of Weinreb amides using two distinct organolithium reagents.14 After 1,2addition of the first organolithium reagent to the
The realization of this process would not only eliminate an extra synthetic step, and eventual purification of ketone intermediate, but also allows the arylation reaction to occur in the presence of rather low amount of base, as this is slowly released from th and then consumed in the
Scheme 1. One-pot, 1,2-addition of alkyllithium reagents to benzamides, Pd-catalyzed α-arylation.
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catalytic reaction. The modular combination of organolithium reagents, benzamides and aryl bromides would allow easy access to a variety of structurally diverse α-aryl ketones from simple starting materials. Here we describe the implementation of this 3-component strategy which to the best of our knowledge is unprecedented in literature. We selected the reaction between n-Buli and the Weinreb amide 1a, at 0 °C, as a model for the first step, and we then screened a variety of palladium catalysts for the subsequent α-arylation reaction using 2 eq of 4bromotoluene (Table 1). Table 1. Optimization for the one-pot, nucleophilic addition, Pd-catalyzed α-arylation
Entrya
Solvent/T °C
Pd cat. (5 mol%)
R
2a/3a/4a (%)b
1
Toluene/80
Pd-PEPPSI-IPr (C1)
OCH3
66:34:0
2
Toluene/80
Pd-PEPPSI-IPent (C2)
OCH3
61:39:0
3
Toluene/80
Pd2(dba)3, XPhos (L1)
OCH3
51:17:32
4
Toluene/80
Pd[P(t-Bu)3]2 (C3)
OCH3
27:56:17
5
THF/60
Pd-PEPPSI-IPr (C1)
OCH3
71:29:0
6
THF/60
Pd-PEPPSI-IPent (C2)
OCH3
59:17:24
7
THF/60
Pd2(dba)3, XPhos (L1)
OCH3
54:4:42
8
THF/60
Pd2(dba)3, SPhos (L2)
OCH3
52:10:38
9
THF/60
PdCl2(dppf) (C4)
OCH3
100:0:0
10
THF/60
Pd2(dba)3, Josiphos (L4)
OCH3
100:0:0
11
THF/60
Pd[P(t-Bu)3]2 (C3)
OCH3
3:88:9
12
THF/60
Pd[P(t-Bu)3]2 (C3)
CH3
2:98:0
c
THF/60
Pd[P(t-Bu)3]2 (C3)
CH3
13
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Pd2(dba)3/XPhos16 as catalyst, and the presence of the Buchwald-Hartwig17 coupling product between lithium methoxy(methyl)amide generated and 4-bromotoluene was detected in the reaction mixture (Table 1, entry 3). The formation of 4a involves the consumption of LiNMe(OMe) that consequently cannot further act as a base for the α-arylation reaction resulting in drastically reduced yields of 3a. Employing Pd[P(t-Bu)3]218 as catalyst the conversion toward 3a was increased although large amounts of 2a and 4a were still observed in the mixture (Entry 4). With the aim to reduce the stability of the tetrahedral intermediate th and then increase the conversion toward 3a, we moved to the more polar solvent THF with heating at 60 °C. A further survey of different palladium catalysts (Table 1, entries 5-11) revealed Pd[P(t-Bu)3]2 (C3) to be optimal although the presence of product 4a was still observed (Entry 11). To our delight, when the more inexpensive and simple N,N-dimethyl benzamide was used as substrate, the α-arylated product 3a was obtained with excellent selectivity (98%), inhibiting the formation of the Buchwald-Hartwig amination product 4a (Entry 12). Moreover, the amount of aryl bromide could be reduced from 2.0 to 1.2 eq, still affording product 3a as the exclusive product in 86% isolated yield (Table 1, entry 13).19 Importantly, when this reaction was performed on a larger scale (6 mmol), using a lower catalyst loading (2.5 mol%), product 3a was still obtained with similar yield (Table 1, entry 14). Decreasing the reaction temperature to 50 °C still gave 3a with high selectivity although the conversion decreased slightly (Table 1, entry 15). With the optimized reaction conditions in hand, we next evaluated the efficacy of this catalyst system in the arylation of a variety of aryl bromides (Table 2). Table 2. Scope of (hetero)aryl bromidesa,b,c
1:99:0 86% yieldd
14
THF/60
Pd[P(t-Bu)3]2 (C3)
CH3
86% yieldd,e
15c
THF/50
Pd[P(t-Bu)3]2 (C3)
CH3
8:92:0
a
Reaction conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd complex and 4bromotoluene (2 eq.). bDetermined by GC and 1H NMR. cUsing 1.2 eq. of 4-bromotoluene. dIsolated yield. e6.0 mmol (0.9 g) scale reaction using 2.5 mol% of catalyst.
For this step, the reaction mixture was warmed to 80 °C in toluene to promote the collapse of the tetrahedral intermediate as it is stable at rt. The use of Pd-PEPPSI-iPr or Pd-PEPPSI-iPent15 provided a mixture of the desired αarylated product 3a and non-arylated ketone 2a in a 34:66 and 39:61 ratio, respectively (Table 1, entries 1 and 2). Low conversion toward 3a was also obtained using
a
Reaction conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd[P(t-Bu)3]2 (5 mol %)
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and (hetero)aryl bromide (1.2 eq.). bSelectivity >98% as determined by GC and 1H NMR. cIsolated yield.
Both electron rich (3a-3d, 3g-3i, 3l and 3n) and electron poor aryl bromides (3e, 3f, 3j, 3k and 3m) participate in this reaction affording high selectivity and good overall yields. A sterically more congested aryl bromide could also be converted to the corresponding arylated ketone without loss of selectivity (3d). The reaction proceeds successfully in the presence of a variety of functional groups including CF3 (3e), OMe (3g), SMe (3h), NMe2 (3i), an ester (3j), a ketone (3k) and an acetal-protected aldehyde (3l). Using p-chloro-bromobenzene, the coupling occurs exclusively at the bromine-substituted carbon, leaving the chloride untouched, thereby providing an opportunity for subsequent Pd-catalyzed cross-coupling reactions (3f).20 Heterocyclic bromides could also be coupled in high selectivity as demonstrated in the preparation of 3m and 3n. Importantly, no traces of isomerized products derived from β-hydride elimination-reinsertion reactions in the alkyl chain were observed in any of these examples.21 We next explored the scope of the reaction with respect to the alkyl lithium and benzamide components. As shown in Table 3, alkyllithium reagents bearing different linear or branched aliphatic substituents provided the desired products in high selectivity and good overall yields.22
nucleophile also allowed the formation of product 3r in the subsequent arylation reaction with 4-bromoanisole, although the presence of some diarylated and triarylated products was also observed (3r, Table 3). Nonetheless, a more sterically hindered aryl bromide afforded exclusively the monoarylated product in good overall yield (3s). In addition, this protocol was also found efficient with different benzamides bearing electron-withdrawing (3t, 3u) and electron donating substituents (3v). As mentioned before, the Csp2-Cl bond remained untouched after the reaction (3u). To further determine if the ketone enolate is formed directly from the tetrahedral intermediate or in a subsequent stage by reaction with the lithium amide released in the reaction media, we performed a competition experiment. One equivalent of butyrophenone and hexanophenone, respectively, were added after the 1,2-addition reaction of n-BuLi and benzamide 1 together with 4bromoanisole and the palladium catalyst. As shown in Scheme 2, the formation of a mixture of the three possible α-aryl ketones and the corresponding starting materials was observed, supporting therefore the pathway involving lithium amide release prior to arylation. Scheme 2. Study of the one-pot, nucleophilic addition of 1, Pd-catalyzed α-arylation in the presence of butyrophenone and hexanophenone.a
Table 3. Scope of organolithium reagents and benzamides.a,b,c
a
Conditions: n-BuLi (1 eq., 1.6 M) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd complex, butyrophenone (1.0 eq.), hexylphenone (1.0 eq.) and 4-bromoanisole (1.2 eq.). Relative product distribution determined by GC.
a
Reaction conditions: R2Li (1 eq.) is added to a solution of amide 1 (0.5 mmol) followed by addition of Pd[P(t-Bu)3]2 (5 mol %) and (hetero)aryl bromide (1.2 eq.). bSelectivity >98% as determined by GC and 1H NMR unless otherwise noted. cIsolated yield. dReaction performed in refluxing toluene. eGC selectivity (monoarylated/diarylated/triarylated 60:34:6). fThe corresponding Weinreb amide was used instead.
The use of the more challenging s-BuLi allows for the synthesis of a more congested α-quaternary carbon (3q) without isomerization of the alkyl chain, presumably due to a fast reductive elimination step.20c The use of MeLi as
In conclusion, we have developed a mild, modular and highly efficient one-pot 1,2-addition of organolithium reagents to benzamides, followed by a palladiumcatalyzed α-arylation of the resulting ketones. The method is based on the use of commercially available Pd[P(tBu)3]2 as catalyst for the α-arylation reaction and does not need the addition of an external base to proceed. Moreover, the formation of di- and triarylated side products is prevented while arylation is observed solely at the αposition without isomerized products. The substrate scope encompasses primary and secondary alkyllithium reagents, benzamides and aryl bromides. It comprises a range of functional groups or ortho-substitution, allowing rapid access to functionalized ketones in a three component modular approach.
ASSOCIATED CONTENT
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19
Experimental procedures, characterization data, and H, F 13 and C NMR spectra for new compounds are included in the supporting information. This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION Corresponding Author *
[email protected],
[email protected] Notes The authors declare no competing financial interests.
ACKNOWLEDGMENTS This work was supported financially by the European Research Council (Advanced Investigator Grant, No. 227897 to B.L.F.); The Netherlands Organization for Scientific Research (NWO-CW); funding from the Ministry of Education, Culture and Science (Gravitation program 024.001.035); The Royal Netherlands Academy of Arts and Sciences (KNAW); and NRSC-Catalysis are gratefully acknowledged.
REFERENCES (1) a) Bellina, F.; Rossi, R. Chem. Rev. 2010, 110, 1082-1146; b) Johansson, C. C. C.; Colacot, T. J. Angew. Chem. Int. Ed. 2010, 49, 676-707; c) Culkin, D. A.; Hartwig, J. F. Acc. Chem. Res. 2003, 36, 234-245; d) Novak, P.; Martin, R. Curr. Org. Chem. 2011, 15, 32333262; e) Potukuchi, H. K.; Spork, A. P.; Donohoe, T. J. Org. Biomol. Chem. 2015, 13, 4367-4373; f) Sivanandan, S. T.; Shaji, A.; Ibnusaud, I.; Seechurn, C. C. C. J.; Colacot, T. J. Eur. J. Org. Chem. 2015, 38-49. (2) a) Dörwald, F. Z. in Lead Optimization for Medicinal Chemists: Pharmacokinetic Properties of Functional Groups and Organic Compounds, Chapter 30, ed. Dörwald, F. Z. Wiley-VCH, Weinheim, 2012; b) For a recent example see: Donohoe, T. J.; Pilgrim, B. S.; Jones, G. R.; Bassuto, J. A. Proc. Natl. Acad. Sci. USA 2012, 109, 11605-11608. (3) a) Lawrence, N. J. Chem. Soc., Perkin Trans. 1 1998, 17391750; b) Otera, J. Modern Carbonyl Chemistry, Wiley-VCH, Weinheim, 2000. (4) a) Palucki, M.; Buchwald, S. L. J. Am. Chem. Soc. 1997, 119, 11108-11109; b) Hamann, B. C.; Hartwig, J. F. J. Am. Chem. Soc. 1997, 119, 12382-12383; c) Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Angew. Chem. Int. Ed. 1997, 36, 1740-1742. (5) Hamada, T.; Chieffi, A.; Åhman, J.; Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 1261-1268. (6) a) Hesp, K. D.; Lundgren, R. J.; Stradiotto, M. J. Am. Chem. Soc. 2011, 133, 5194-5197; b) Alsabeh, P. G.; Stradiotto, M. Angew. Chem. Int. Ed. 2013, 52, 7242-7246; c) Gäbler, C.; Korb, M.; Schaarschmidt, D.; Hildebrandt, A.; Lang, H. Adv. Synth. Catal. 2014, 356, 2979-2983. e) Ackermann, L.: Mehta, V. P. Chem. Eur. J. 2012, 18, 10230-10233; f) Rotta-Loria, N. L.; Borzenko, A.; Alsabeh, P. G., Lavery; C. B.; Stradiotto, M. Adv. Synth. Catal. 2015, 357, 100-106; g) Fu, W. C.; So, C. M.; Chow, W. K.; Yuen, O. Y.; Kwong, F. Y. Org. Lett. 2015, 17, 4612-4615; h) MacQueen, P. M.; Chisholm, A. J.; Hargreaves, Br. K. V.; Stradiotto, M. Chem. Eur. J. 2015, 21, 11006-11009. For a recent review see: Schranck, J.; Rotzler, J. Org. Process Res. Dev. 2015, 19, 1936-1943. (7) Moradi, W. A.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123, 7996-80002. (8) Gaertzen, O.; Buchwald, S. L. J. Org. Chem. 2002, 67, 465475. (9) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370.
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(10) a) Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998, 63, 6546-6553; b) Hama, T.; Culkin, D. A.; Hartwig, J. F. J. Am. Chem. Soc. 2006, 128, 4976-4985. (11) Liu, X.; Hartwig, J. F. J. Am. Chem. Soc. 2004, 126, 51825191. (12) Terao, Y.; Fukuoka, Y.; Satoh, T.; Miura, M.; Nomura, M. Tetrahedron Lett. 2002, 43, 101-104. (13) a) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 1582415832; b) You, J.; Verkade, J. G. Angew. Chem., Int. Ed. 2003, 42, 5051-5053. (14) Giannerini, M.; Vila, C.; Hornillos, V.; Feringa, B. L. Chem. Commun. 2016, 52, 1206-1209. (15) a) O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.; Hopkinson, A. C.; Organ, M. G. Chem. Eur. J. 2006, 12, 4743-4748; b) Valente, C.; Çalimsiz, S.; Hoi, K. H.; Mallik, D.; Sayah, M.; Organ, M. G. Angew. Chem. Int. Ed. 2012, 51, 3314-3332. (16) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 14611473. (17) a) Surry, D. S.; Buchwald, S. L. Chem. Sci., 2011, 2, 27-50; b) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534-1544. (18) a) Fu, G. C. Acc. Chem. Res. 2008, 41, 1555; b) He, L.-Y. Synlett 2015, 26, 851-852. (19) Following the conversion of 1a into 3a in time showed that 97% conversion was achieved in 6 h (see Supporting Information, Figure S1). However, for practicality, the reactions were conducted overnight. (20) Negishi, E. Angew. Chem. Int. Ed. 2011, 50, 6738-6764; b) Suzuki, A. Angew. Chem. Int. Ed. 2011, 50, 6723-6737; c) de Meijere, A.; Diederich, F. Metal-Catalyzed Cross-Coupling Reactions, Vol. 1, Wiley-VCH, Weinheim, 2004. (21) Vila, C.; Giannerini, M.; Hornillos, V.; Fañanás-Mastral, M.; Feringa, B. L. Chem. Sci. 2014, 5, 1361-1367. (22) The reaction using the corresponding Grignard reagents for the 1,2-addition step led to a complex mixture of products under the optimized conditions.
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