University of Groningen Carbon-carbon bond formations using organolithium reagents Heijnen, Dorus

University of Groningen

Carbon-carbon bond formations using organolithium reagents

Heijnen, Dorus

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Chapter 4 : One-Pot Str

at

egies for Developing

Synthetic Methods with Or

g

anolithium Reagents

Parts of this chapter have been published in A. T. Wolters, V. Hornillos, D.

Heijnen, M. Giannerini, and B. L. Feringa ACS Catal, 2016, 6 (4), pp 2622-2625

4.1 Introduction

In this chapter several methods of utilizing organolithium reagents in a multi-step, one-pot procedure for the synthesis of small functionalized molecules are described. The obvious advantages of one-pot procedures in terms of time, ease of reaction and purification often outweigh a slightly lower yield per step. The use of organolithium reagents for one pot procedures has additional challenges due to the high reactivity of the organometallic reagent. Excess nucleophile meant for the primary transformation is likely to react with other added reagents or solvents that are necessary for the consecutive functionalization. Utilizing organolithium reagents as a nucleophile in the 1,2-addition to (Weinreb) amides, a tetrahedral intermediate is formed, that can acts as a temporary protecting group for carbonyl compounds. Upon heating, this tetrahedral intermediate collapses into the carbonyl compound, thereby liberating a lithium amide base. This base is capable of taking part in further reactions. It is because of this in situ formation of a stoichiometric amount of lithium amide that the use of additional base is no longer required in the consecutive, one-pot alpha arylation of ketones, or the Buchwald-Hartwig amine coupling with aryl bromides. The use of these metal aminal intermediates as protecting groups, or lithium amide releasing compounds is described in this chapter, and can lead to functionalized ketones, aldehydes or anilines.

4.2 One-Pot, Modular Approach to Functionalized Ketones via Nucleophilic

Addition of Alkyllithium Reagents to Benzamides and Pd-Catalyzed

α-Arylation

An efficient, in situ sequential 1,2-addition of alkyllithium reagents to benzamides followed by α-arylation of the resulting alkyl ketones is described in this part of the chapter. The use of Pd[P(tBu)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 α-arylation. 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.

4.2.1 Introduction

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 procedures}5 _{and methods involving α-arylation of}

auxiliary,11 _aldehydes,12 _{and nitriles}13 _{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 to 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.

Our group has recently described a highly efficient one-pot synthesis of functionalized ketones via sequential 1,2-addition, Pd-catalyzed cross-coupling of Weinreb amides using two distinct organolithium reagents.14 After 1,2-addition of the first organolithium reagent to the Weinreb amide, the tetrahedral intermediate formed acts as a masked ketone moiety allowing for an in situ cross-coupling 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 4.1).

Scheme 4.1 General scheme for the one pot 1,2-addition/alpha arylation approach

The realization of this process would not only eliminate an extra synthetic step and the eventual purification of ketone intermediate, but it 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 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 three-component strategy which to the best of our knowledge is unprecedented in the literature.

4.2.2 Optimization

We selected the reaction between n-BuLi and the Weinreb amide 1a, at 0 °C, as a model for the first step, then screened a variety of palladium catalysts for the subsequent α-arylation reaction using 2 equiv. of 4-bromotoluene (Table 4.1).

Table 4.1. 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, (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 13c THF/60 Pd[P(t-Bu)3]2 (C3) CH3 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 4-bromotoluene (2 eq.). bDetermined by GC and 1HNMR. 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 α-arylated product 3a and nonarylated ketone 2a in a 34:66 and 39:61 ratio, respectively (Table 4.1, entries 1 and 2). Low conversion toward 3a was also obtained using 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 (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 (Table 4.1, 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 (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 less expensive and simple N,N-dimethyl benzamide (1b) 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 (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 (entry 14). Decreasing the reaction temperature to 50 °C still gave 3a with high selectivity although the conversion decreased slightly (entry 15).

4.2.3 Scope of the reaction

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 4.2).

Table 4.2. Scope of (hetero)aryl bromidesa,b,c

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 (C3) (5 mol

%) and (hetero)aryl bromide (1.2 eq.). b_{Selectivity >98% as determined by GCMS and} 1_HNMR. c_{Isolated 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 with 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 4.3, alkyllithium reagents bearing different linear or branched aliphatic substituents provided the desired products in high selectivity and good overall yields.22

Table 4.3. Scope of organolithium reagents and benzamides.a,b,c

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 (C3) (5 mol %) and (hetero)aryl bromide (1.2 eq.). b_{Selectivity >98% as determined by GC and} 1_{HNMR unless otherwise noted.} c

Isolated 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 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). 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 C-sp2_{–Cl bond remained untouched during the} reaction (3u).

4.2.4 Competition studies

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 1b together with 4-bromoanisole and the palladium catalyst. As shown in Scheme 4.4, 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 4.4. Study of the one-pot, nucleophilic addition of 1, Pd-catalyzed α-arylation in the presence of butyrophenone and hexanophenone. 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.), hexanophenone (1.0 eq.) and 4-bromoanisole (1.2 eq.). Relative product distribution determined by GC.

4.2.5 Other use of the tetrahedral intermediate

The tetrahedral intermediate (th) described at the beginning of this chapter was found to split of lithium dimethylamide, deprotonating the formed carbonyl moiety and triggering selective mono arylation with aryl bromides (scheme 4.5, top reaction). The Buchwald-Hartwig coupling that led to side product 4a was suppressed by optimizing the reaction conditions. We were interested, however, to see if this undesired amination reaction pathway could be promoted, and lead to an alternative one-pot procedure, to give substituted anilines (scheme 4.5, bottom reaction)

Scheme 4.5 Alternative use of liberated lithium-amide base.

When tertiary alkyl or aryl nucleophiles (= tBuLi, ArLi shown in red) were chosen for the first step, the tetrahedral intermediate, and (after collapse) the corresponding ketone does not have any acidic alpha protons. The liberated lithium amide (scheme 4,3 shown in pink) therefore cannot act as a base (pathway 1), and thus participates in the cross coupling cycle instead. Reacting with an aryl bromide moiety, Buchwald-Hartig amination leads to substituted anilines (pathway 2). This alternative route, and the synthesis of substituted anilines is currently being investigated

4.2.6 Conclusions

In conclusion, we have developed a mild, modular, and highly efficient one-pot 1,2-addition of organolithium reagents to benzamides, followed by a palladium-catalyzed α-arylation of the resulting ketones. The method is based on the use of commercially available Pd[P(t-Bu)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 α-position 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. The alternative use of the tetrahedral intermediate towards the synthesis of substituted anilines could prove to be a promising method for the one pot preparation of these building blocks.

4.2.7 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, 3233-3262; 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, 1739-1750; 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, 465-475.

(9) Fox, J. M.; Huang, X.; Chieffi, A.; Buchwald, S. L. J. Am. Chem. Soc. 2000, 122, 1360-1370.

(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, 5182-5191.

(13) a) Wu, L.; Hartwig, J. F. J. Am. Chem. Soc. 2005, 127, 15824-15832; 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, 1461-1473.

(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 experimental section, Graph 1). 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.

Acknowledgements

The work described in this chapter was performed in collaboration with Alexander Wolters and Valentin Hornillos.

4.2.8 Experimental section

All reactions were carried out under a nitrogen atmosphere using oven dried glassware and using standard Schlenk techniques. THF and toluene were dried and distilled over sodium. Chromatography: Grace Reveleris X2 flash chromatography system used with Grace® Flash Cartridges, TLC: Merck silica gel 60, 0.25 mm. Components were visualized by UV and phosphomolybdic Acid (PMA) or potassium permanganate staining. Progress and conversion of the reaction were determined by GC-MS (GC, HP6890: MS HP5973) with an HP1 or HP5 column (Agilent Technologies, Palo Alto, CA). Mass spectra were recorded on an AEI-MS-902 mass spectrometer (EI+) or a LTQ Orbitrap XL (ESI+). 1H- and 13C-NMR were recorded on a Varian AMX400 (400 and 100.59 MHz, respectively) using CDCl3 as solvent. Chemical shift values are reported in ppm with the solvent

resonance as the internal standard (CHCl3:  7.26 for 1H,  77.0 for 13C). Data are reported as follows:

chemical shifts, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, br = broad, m = multiplet), coupling constants (Hz), and integration. Melting points were measured using a Büchi Melting Point B-545. XPhos, SPhos, Pd2(dba)3, Josiphos (L4), C4, Pd-PEPPSI-IPr and Pd-PEPPSI-IPent were purchased

from Aldrich and used without further purification. Pd[P(t-Bu)3]2, was purchased from Strem.

Methyllithium (MeLi, 1.6 M in diethylether), ethyllithium, (EtLi, 0.5 M in benzene:cyclohexane), hexyllithium (HexLi, 2.3 M in hexane) and sec-butyllithium (s-BuLi, 1.4 M in cyclohexane) were purchased from Sigma Aldrich. n-Butyllithium (n-BuLi, 1.6 M solution in hexane) was purchased from Acros. The benzamides, aryl bromides, acid chlorides, carboxylic acid, and the reagents used for the preparation of the Weinreb amides as well as N,O-dimethylhydroxylamine hydrochloride were purchased from Aldrich. The concentration of alkyllithium solutions was determined by titration in THF over diphenyl acetic acid.1

Synthesis of the amides 1:

4-fluoro-N,N-dimethylbenzamide (1t) was synthesized according to a reported

procedure

starting from 0.24 ml of 4-fluorobenzoyl chloride. Yellow oil, 268 mg, 80% yield.

1

H-NMR (400 MHz, CDCl

): δ 7.42 (dd, J = 8.6, 5.4 Hz, 2H), 7.08 (t, J = 8.7 Hz, 2H), 3.09

(s, 3H), 2.99 (s, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 170.6, 163.2 (d, J = 249.4 Hz),

129.3 (d, J = 8.5 Hz), 115.3 (d, J = 21.8 Hz), 39.6, 35.4 ppm.

4-chloro-N-methoxy-N-methylbenzamide (1u)

was synthesized according to a

reported procedure.

H-NMR (400 MHz, CDCl

): δ 7.65 (d, J = 8.5 Hz, 2H), 7.37 (d, J = 8.6

Hz, 2H), 3.53 (s, 3H), 3.35 (s, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 168.7, 136.7,

132.3, 129.8, 128.3, 61.1, 33.5 ppm.

4-methoxy-N,N-dimethylbenzamide (1v) was synthetized according to a reported

procedure.

H-NMR (400 MHz, CDCl

): δ 7.40 (d, J = 8.7 Hz, 2H), 6.90 (d, J = 8.7 Hz, 2H),

3.83 (s, 3H), 3.05 (s, 6H).

C-NMR (100.59 MHz, CDCl

): δ 171.4, 160.5, 129.0, 128.3,

1

Y. Sunada, H. Kawakami, T. Imaoka, Y. Motoyama, and H. Nagashima, Angew. Chem. Int. Ed. 2009, 48, 9511. 2

T. Niu, W. Zhang, D. Huang, C. Xu, H. Wang and Y. Hu, Org. Lett. 2009, 11, 4474. 3

E. F. Kleinman, WO 00/09504.

General Procedure for the one-pot, 1,2-addition, Pd-catalyzed α-arylation:

In a dry Schlenk flask the corresponding amide 1 (0.5 mmol) was dissolved in 2 mL of

dry THF, the mixture was cooled down to 0 °C and the corresponding alkyllithium reagent

(1.0 eq.) was added dropwise. After one hour, Pd[P(tBu)

]

(5 mol%) and the corresponding

aryl bromide (0.6 mmol, 1.2 eq) were added to the reaction mixsture and the vessel was

heated with a preheated oil bath to 60 ̊C overnight (unless otherwise noted). After allowing

the reaction mixture to cool to rt, a saturated aqueous solution of NH

Cl (2 mL) was added

whereupon the mixture was extracted with ether (3 x 5mL). The organic phases were

combined, dried over MgSO

and filtered, after which evaporation of the solvent under

reduced pressure afforded the crude product 3 that was then purified by column

chromatography using different mixtures of n-pentane/EtOAc as the eluent.

Experimental details and spectral data of compounds

1-Phenyl-2-(p-tolyl)pentan-1-one (3a): Synthesized using N,N-dimethylbenzamide (0.5

mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 4-bromotoluene (0.6 mmol,

103 mg). Colorless oil obtained after column chromatography (SiO

, n-pentane/ EtOAc 98:2),

108 mg, 86% yield. Reaction performed using 6 mmol (895 mg) of substrate 1a: 1.38 g, 86%

yield.

H-NMR (400 MHz, CDCl

): δ 7.96 (d, J = 7.2 Hz, 2H), 7.47 (t, J = 7.3 Hz, 1H), 7.38

(t, J = 7.5 Hz, 2H), 7.19 (d, J = 8.1 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 4.52 (t, J = 7.3 Hz, 1H),

2.28 (s, 3H), 2.19-2.08 (m, 1H), 1.85-1.74 (m, 1H), 1.38-1.19 (m, 2H), 0.92 (t, J = 7.3 Hz,

3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 200.2, 137.0, 136.8, 136.5, 132.7, 129.5, 128.6,

128.5, 128.1, 53.0, 36.1, 21.0, 20.9, 14.1 ppm. HRMS (ESI+, m/z): calcd for C

H

O

[M+H]

: 253.1587; found: 253.1588.

2-([1,1'-Biphenyl]-4-yl)-1-phenylpentan-1-one

(3b):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

4-bromo-1,1'-biphenyl (0.6 mmol, 140 mg). White crystals obtained after column

chromatography and further recrystallization from n-pentane (SiO

, n-pentane/ EtOAc 98:2),

123 mg, 78% yield. M.p.: 117 °C-118 °C.

H-NMR (400 MHz, CDCl

): δ 8.00 (d, J = 7.3 Hz,

2H), 7.56-7.47 (m, 5H), 7.44-7.36 (m, 6H), 7.32 (t, J = 7.3 Hz, 1H), 4.61 (t, J = 7.3 Hz, 1H),

2.24-2.14 (m, 1H), 1.91-1.80 (m, 1H), 1.40-1.24 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 200.1, 140.6, 139.8, 138.8, 137.0, 132.8, 128.7, 128.64,

128.61, 128.5, 127.5, 127.2, 127.0, 53.0, 36.2, 20.9, 14.1 ppm. HRMS (ESI+, m/z): calcd for

C

H

O [M+H]

: 315.1743; found: 315.1745.

2-(Naphthalen-2-yl)-1-phenylpentan-1-one

(3c):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

2-bromonaphthalene (0.6 mmol, 124 mg). Brown waxy solid obtained after column

chromatography (SiO

, n-pentane/ EtOAc 98:2), 98 mg, 68% yield.

H-NMR (400 MHz,

CDCl

): δ 8.00 (d, J = 7.4 Hz, 2H), 7.80-7.55 (m, 3H), 7.74 (s, 1H), 7.48-7.40 (m, 4H), 7.37

(t, J = 7.6 Hz, 2H), 4.72 (t, J = 7.3 Hz, 1H), 2.28-2.18 (m, 1H), 1.96-1.86 (m, 1H), 1.43-1.22

(m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 199.8, 137.4,

137.0, 133.6, 132.8, 132.4, 128.6, 128.51, 128.47, 127.6, 127.5, 127.0, 126.3, 126.1, 125.7,

53.4, 36.1, 20.9, 14.0 ppm. HRMS (ESI+, m/z): calcd for C

H

O [M+H]

: 289.1586; found:

1-Phenyl-2-(o-tolyl)pentan-1-one (3d): Synthesized using N,N-dimethylbenzamide (0.5

mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and 2-bromotoluene (0.6 mmol,

103 mg, 73 µL). Colorless oil obtained after column chromatography (SiO

, n-pentane/

EtOAc 98:2),

leaving the product fraction overnight under vacuum at 60°C, 81 mg, 65%

yield.

H-NMR (400 MHz, CDCl

): δ 7.84 (d, J = 7.1 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.36

(t, J = 7.5 Hz, 2H), 7.16-7.20 (m, 1H), 7.14-7.07 (m, 3H), 4.71 (dd, J = 8.2, 5.8 Hz, 1H), 2.50

(s, 3H), 2.26-2.16 (m, 2H), 1.47-1.37 (m, 1H), 1.34-1.24 (m, 1H), 0.94 (t, J = 7.3 Hz, 3H)

ppm.

C-NMR (100.59 MHz, CDCl

): δ 200.6, 138.6, 137.4, 135.0, 132.6, 130.9, 128.5,

128.3, 127.2, 126.8, 126.6, 49.5, 35.9, 21.2, 19.9, 14.3 ppm. HRMS (ESI+, m/z): calcd for

C

H

O [M+H]

: 253.1586; found: 253.1587.

1-Phenyl-2-(4-(trifluoromethyl)phenyl)pentan-1-one (3e): Synthesized using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

1-bromo-4-(trifluoromethyl)benzene (0.6 mmol, 135 mg). Pale yellow oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under

vacuum at 60°C, 103 mg, 67% yield.

H-NMR (400 MHz, CDCl

): δ 7.95 (d, J = 7.3 Hz, 2H),

7.57-7.49 (m, 3H), 7.46-7.39 (m, 4H), 4.64 (t, J = 7.3 Hz, 1H), 2.23-2.12 (m, 1H), 1.88-1.77

(m, 1H), 1.38-1.20 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ

199.4, 143.78, 143.77, 136.7, 133.1, 129.23 (q, J = 32.4 Hz), 128.7, 128.60, 128.55, 125.73

(q, J = 3.8 Hz), 53.0, 36.2, 20.8, 14.0 ppm.

F-NMR (376 MHz, CDCl

): δ -62.5 ppm. HRMS

(ESI+, m/z): calcd for C

H

F

O [M+H]

: 307.1304; found: 307.1304.

2-(4-Chlorophenyl)-1-phenylpentan-1-one

(3f):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

1-bromo-4-chlorobenzene (0.6 mmol, 115 mg). Colorless oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under

vacuum at 60°C, 92 mg, 67% yield.

H-NMR (400 MHz, CDCl

): δ 7.94 (d, J = 7.3 Hz, 2H),

7.50 (t, J = 7.4 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H), 7.25 (m, 4H), 4.55 (t, J = 7.3 Hz, 1H),

2.19-2.08 (m, 1H), 1.85-1.73 (m, 1H), 1.38-1.20 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm.

C-NMR

(100.59 MHz, CDCl

): δ 199.8, 138.3, 136.8, 133.0, 132.8, 129.6, 129.0, 128.58, 128.56,

52.6, 36.1, 20.8, 14.0 ppm. HRMS (ESI+, m/z): calcd for C

H

ClO [M+H]

: 273.1040;

2-(4-Methoxyphenyl)-1-phenylpentan-1-one

(3g):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

4-bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography

(SiO

, n-pentane/ EtOAc 95:5), 114 mg, 85% yield.

H-NMR (400 MHz, CDCl

): δ 7.95 (d, J

= 7.1 Hz, 2H), 7.48 (t, J = 7.3 Hz, 1H), 7.38 (t, J = 7.5 Hz, 2H), 7.21 (d, J = 8.7 Hz, 2H), 6.82

(d, J = 8.8 Hz, 2H), 4.50 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 2.16-2.06 (m, 1H), 1.84-1.73 (m,

1H), 1.36-1.20 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ

200.3, 158.2, 137.0, 132.7, 131.8, 129.2, 128.6, 128.5, 114.2, 55.1, 52.5, 36.1, 20.8, 14.1 ppm.

HRMS (ESI+, m/z): calcd for C

H

O

[M+H]

: 269.1536; found: 269.1536.

2-(4-(Methylthio)phenyl)-1-phenylpentan-1-one (3h): Synthesized using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

4-bromothioanisole (0.6 mmol, 122 mg). White solid obtained after column chromatography

(SiO

, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under vacuum at 60°C,

116 mg, 82% yield. M.p.: 56 -57 °C.

H-NMR (400 MHz, CDCl

): δ 7.96 (d, J = 7.6 Hz, 2H),

7.50 (t, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.3 Hz,

2H), 4.53 (t, J = 7.4 Hz, 1H), 2.45 (s, 3H), 2.19-2.09 (m, 1H), 1.86-1.76 (m, 1H), 1.38-1.22

(m, 2H), 0.93 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 200.0, 136.93,

136.90, 136.6, 132.8, 128.7, 128.6, 128.5, 127.0, 52.8, 36.0, 20.8, 15.8, 14.0 ppm. HRMS

(ESI+, m/z): calcd for C

H

OS [M+H]

: 285.1307; found: 285.1308.

2-(4-(Dimethylamino)phenyl)-1-phenylpentan-1-one (3i): Synthesized using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

4-bromo-N,N-dimethylaniline (0.6 mmol, 120 mg). Yellow solid obtained after column

chromatography (SiO

, n-pentane/ EtOAc 90:10), 114 mg, 81% yield. M.p.: 75 °C-76 °C.

H-NMR (400 MHz, CDCl

): δ 7.96 (d, J = 7.1 Hz, 2H), 7.45 (t, J = 7.3 Hz, 1H), 7.37 (t, J = 7.5

Hz, 2H), 7.15 (d, J = 8.7 Hz, 2H), 6.65 (d, J = 8.7 Hz, 2H), 4.45 (t, J = 7.3 Hz, 1H), 2.89 (s,

6H), 2.17-2.04 (m, 1H), 1.84-1.73 (m, 1H), 1.36-1.20 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm.

13

C-NMR (100.59 MHz, CDCl

): δ 200.4, 149.4, 137.2, 132.4, 128.8, 128.5, 128.3, 127.3,

112.8, 55.3, 40.4, 36.0, 20.8, 14.1 ppm. HRMS (ESI+, m/z): calcd for C

H

NO [M+H]

:

282.1852; found: 282.1853.

Ethyl

4-(1-oxo-1-phenylpentan-2-yl)benzoate

(3j):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and ethyl

4-bromobenzoate (0.6 mmol, 137 mg, 98 µL). Yellow oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 95:5), 59 mg, 38% yield.

H-NMR (400 MHz,

CDCl

): δ 7.99-7.91 (m, 4H), 7.49 (t, J = 7.4 Hz, 1H), 7.39 (m, 4H), 4.62 (t, J = 7.3 Hz, 1H),

4.34 (q, J = 7.1 Hz, 2H), 2.22-2.12 (m, 1H), 1.88-1.77 (m, 1H), 1.38-1.18 (m, 5H), 0.92 (t, J =

7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 199.5, 166.3, 144.9, 136.7, 133.0,

130.1, 129.2, 128.6 (2C), 128.2, 60.9, 53.4, 36.0, 20.8, 14.3, 14.0 ppm. HRMS (ESI+, m/z):

calcd for C

H

O

[M+H]

: 311.1641; found: 311.1642.

2-(4-Benzoylphenyl)-1-phenylpentan-1-one

(3k):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

4-bromobenzophenone (0.6 mmol, 157 mg). Yellow oil obtained after column chromatography

(SiO

, n-pentane/ EtOAc 98:2), leaving the product fraction overnight under vacuum at 60°C,

147 mg, 86% yield.

H-NMR (400 MHz, CDCl

): δ 7.99-7.96 (m, 2H), 7.77-7.73 (m, 4H),

7.57 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.4 Hz, 1H), 7.48-7.40 (m, 6H), 4.67 (t, J = 7.3 Hz, 1H),

2.25-2.16 (m, 1H), 1.91-1.81 (m, 1H), 1.40-1.27 (m, 2H), 0.94 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 199.5, 196.2, 144.6, 137.5, 136.7, 136.2, 133.1, 132.4, 130.7,

129.9, 128.64, 128.62, 128.2, 128.2, 53.3, 36.1, 20.9, 14.1 ppm. HRMS (ESI+, m/z): calcd for

C

H

O

[M+H]

: 343.1692; found: 343.1693.

2-(4-(1,3-Dioxolan-2-yl)phenyl)-1-phenylpentan-1-one (3l): Synthesized using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

2-(4-bromophenyl)-1,3-dioxolane (0.6 mmol, 137 mg). Colorless oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 95:5), 121 mg, 78% yield.

H-NMR (400 MHz,

CDCl

): δ 7.93 (d, J = 7.2 Hz, 2H), 7.53-7.45 (m, 1H), 7.42-7.31 (m, 6H), 5.74 (s, 1H), 4.57

(t, J = 7.2 Hz, 1H), 4.15-3.98 (m, 4H), 2.19-2.09 (m, 1H), 1.85-1.75 (m, 1H), 1.36-1.18 (m,

2H), 0.91 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 199.9, 140.9, 136.9,

136.5, 132.8, 128.6, 128.5, 128.3, 127.0, 103.5, 65.3, 65.2, 53.2, 36.1, 20.8, 14.0 ppm. HRMS

(ESI+, m/z): calcd for C

H

O

[M+H]

: 311.1641; found: 311.1642.

1-Phenyl-2-(pyridin-3-yl)pentan-1-one

(3m):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

3-bromopyridine (0.6 mmol, 95 mg, 58 µL). Colorless oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 95:5), 83 mg, 69% yield.

H-NMR (400 MHz,

CDCl

): δ 8.60 (s, 1H), 8.47 (d, J = 3.3 Hz, 1H), 7.96 (d, J = 7.3 Hz, 2H), 7.66 (d, J = 7.9 Hz,

1H), 7.53 (t, J = 7.4 Hz, 1H), 7.43 (t, J = 7.6 Hz, 2H), 7.23 (dd, J = 7.9, 4.8 Hz, 1H), 4.62 (t, J

= 7.3 Hz, 1H), 2.12-2.23 (m, 1H), 1.87-1.77 (m, 1H), 1.40-1.22 (m, 2H), 0.93 (t, J = 7.3 Hz,

3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 199.4, 150.0, 148.4, 136.5, 135.3, 133.2, 128.7,

128.5 (2C), 123.7, 50.3, 36.1, 20.8, 13.9 ppm. HRMS (ESI+, m/z): calcd for C

H

NO

[M+H]

: 240.1382; found: 240.1383.

5-bromo-1-methyl-1H-indole

Synthesized using 5-bromo-1H-indole (4.0 mmol, 790 mg). Yellow oil, 555 mg, 66%

yield.

H-NMR (300 MHz, CDCl

): δ 7.74 (d, J = 1.6 Hz, 1H), 7.29 (dd, J = 8.7, 1.7 Hz, 1H),

7.18 (d, J = 8.7 Hz, 1H), 7.04 (d, J = 3.1 Hz, 1H), 6.42 (d, J = 3.0 Hz, 1H), 3.77 (s, 3H) ppm.

13

C-NMR (100.59 MHz, CDCl

): δ 135.5, 130.3, 130.2, 124.3, 123.3, 112.7, 110.9, 100.6,

2-(1-methyl-1H-indol-5-yl)-1-phenylpentan-1-one (3n): Synthesized using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

5-bromo-1-methyl-1H-indole (0.6 mmol, 126 mg). Yellow oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 95:5), 110 mg, 75% yield. 1H-NMR (400 MHz,

CDCl

): δ 7.99 (d, J = 7.3 Hz, 2H), 7.54 (s, 1H), 7.42 (t, J = 6.7 Hz, 1H), 7.34 (t, J = 7.7 Hz,

2H), 7.24 (d, J = 10.9 Hz, 1H), 7.16 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 3.1 Hz, 1H), 6.41 (d, J =

3.1 Hz, 1H), 4.62 (t, J = 7.3 Hz, 1H), 3.73 (s, 3H), 2.23-2.13 (m, 1H), 1.91-1.81 (m, 1H),

1.38-1.22 (m, 2H), 0.92 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 200.6,

137.3, 135.8, 132.5, 130.7, 129.2, 128.9, 128.7, 128.4, 121.9, 120.5, 109.6, 100.8, 53.6, 36.5,

32.8, 20.9, 14.2 ppm. HRMS (ESI+, m/z): calcd for C

H

NO [M+H]+: 292.1695; found:

292.1696.

2-(4-Methoxyphenyl)-1-phenylpropan-1-one

(3o):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), EtLi (1.6 ml, 0.31 M, 0.5 mmol, 1.0 eq) and

4-bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography

(SiO

, n-pentane/ EtOAc 95:5), 63 mg, 53% yield.

H-NMR (400 MHz, CDCl

): δ 7.94 (d, J

= 7.0 Hz, 2H), 7.47 (t, J = 7.4 Hz, 1H), 7.38 (t, J = 7.6 Hz, 2H), 7.20 (d, J = 8.6 Hz, 2H), 6.82

(d, J = 8.7 Hz, 2H), 4.64 (q, J = 6.9 Hz, 1H), 3.75 (s, 3H), 1.50 (d, J = 6.9 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 200.5, 158.5, 136.5, 133.5, 132.7, 128.78, 128.74, 128.5,

114.4, 55.2, 47.0, 19.5 ppm. HRMS (ESI+, m/z): calcd for C

H

O

[M+H]

: 241.1223;

found: 241.1223.

2-(4-Methoxyphenyl)-1-phenylheptan-1-one

(3p):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), n-HexLi (0.22 ml, 2.3 M, 0.5 mmol, 1.0 eq) and

4-bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography

(SiO

, n-pentane/ EtOAc 95:5), 119 mg, 80% yield.

H-NMR (400 MHz, CDCl

): δ 7.95 (d, J

(d, J = 8.4 Hz, 2H), 4.48 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 2.18-2.07 (m, 1H), 1.84-1.70 (m,

1H), 1.36-1.19 (m, 6H), 0.85 (t, J = 5.5 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ

200.3, 158.5, 137.1, 132.7, 131.9, 129.2, 128.6, 128.5, 114.3, 55.1, 52.8, 34.0, 31.8, 27.4,

25.5, 14.1 ppm. HRMS (ESI+, m/z): calcd for C

H

O

[M+H]

: 297.1849; found: 297.1849.

2-(4-Methoxyphenyl)-2-methyl-1-phenylbutan-1-one (3q): Synthesized using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), s-BuLi (0.5 ml, 1.0 M, 0.5 mmol, 1.0 eq) and

4-bromoanisole (0.6 mmol, 112 mg, 75 µL) using toluene as solvent, heated to reflux for the

α-arylation step. Colorless oil obtained after column chromatography (SiO

, n-pentane/ EtOAc

95:5), 67 mg, 50% yield.

H-NMR (400 MHz, CDCl

): δ 7.44 (d, J = 7.2 Hz, 2H), 7.35 (t, J =

7.4 Hz, 1H), 7.24-7.18 (m, 4H), 6.89 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 2.18-1.98 (m, 2H),

1.52 (s, 3H), 0.74 (t, J = 7.4 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 204.1, 158.3,

137.2, 136.2, 131.4, 129.4, 127.9, 127.3, 114.2, 55.2, 54.2, 32.1, 23.7, 8.6 ppm. HRMS (ESI+,

m/z): calcd for C

H

O

[M+H]

: 269.1536; found: 269.1536.

2-(2,6-Dimethoxyphenyl)-1-phenylethan-1-one

(3s):

Synthesized

using

N,N-dimethylbenzamide (0.5 mmol, 75 mg), MeLi (0.39 ml, 1.28 M, 0.5 mmol, 1.0 eq) and

2-bromo-1,3-dimethoxybenzene (0.6 mmol, 130 mg). Yellow oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 90:10), 67 mg, 52% yield.

H-NMR (400 MHz,

CDCl

): δ 8.04 (d, J = 7.3 Hz, 2H), 7.54 (t, J = 7.3 Hz, 1H), 7.45 (t, J = 7.4 Hz, 2H), 7.22 (t, J

= 8.3 Hz, 1H), 6.57 (d, J = 8.3 Hz, 2H), 4.33 (s, 2H), 3.76 (s, 6H) ppm.

C-NMR (100.59

MHz, CDCl

): δ 198.0, 158.3, 137.4, 132.6, 128.4, 128.2 (2C), 112.2, 103.7, 55.7, 33.9 ppm.

HRMS (ESI+, m/z): calcd for C

H

O

[M+H]

: 257.1172; found: 257.1172.

1-(Fluorophenyl)-2-(methoxyphenyl)pentan-1-one (3t): Synthesized using

4-fluoro-N,N-dimethylbenzamide (0.5 mmol, 84 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0

eq) and 4-bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column

chromatography (SiO

, n-pentane/ EtOAc 95:5), 80 mg, 56% yield.

H-NMR (400 MHz,

CDCl

): δ 7.97 (dd, J = 8.7, 5.6 Hz, 2H), 7.19 (d, J = 8.6 Hz, 2H), 7.05 (t, J = 8.6 Hz, 2H),

6.82 (d, J = 8.7 Hz, 2H), 4.43 (t, J = 7.3 Hz, 1H), 3.75 (s, 3H), 2.15-2.05 (m, 1H), 1.83-1.69

(m, 1H), 1.34-1.19 (m, 2H), 0.91 (t, J = 7.3 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ

198.7, 165.4 (d, J = 254.4 Hz), 158.6, 133.4 (d, J = 3.0 Hz), 131.6, 131.2 (d, J = 9.2 Hz),

129.1, 115.5 (d, J = 21.8 Hz), 114.3, 55.1, 52.5, 36.1, 20.8, 14.0 ppm.

F-NMR (376 MHz,

CDCl

): δ -105.8 ppm. HRMS (ESI+, m/z): calcd for C

H

FO

[M+H]

: 287.1441; found:

287.1442.

1-(Chlorophenyl)-2-(methoxyphenyl)propan-1-one (3u): Synthesized using

4-chloro-N-methoxy-N-methylbenzamide (0.5 mmol, 100 mg), EtLi (1.6 ml, 0.31 M, 0.5 mmol,

1.0 eq) and 1-bromo-4-methoxybenzene (0.6 mmol, 112 mg). Colorless oil obtained after

column chromatography (SiO

, n-pentane/ EtOAc 95:5), 88 mg, 64% yield.

H-NMR (400

MHz, CDCl

): δ 7.87 (d, J = 8.7 Hz, 2H), 7.33 (d, J = 8.8 Hz, 2H), 7.17 (d, J = 8.6 Hz, 2H),

6.83 (d, J = 8.7 Hz, 2H), 4.57 (q, J = 6.8 Hz, 1H), 3.75 (s, 3H), 1.50 (d, J = 6.8 Hz, 3H) ppm.

13

C-NMR (100.59 MHz, CDCl

): δ 199.2, 158.6, 139.0, 134.8, 133.2, 130.2 (2C), 128.7,

128.7, 114.5, 55.2, 47.2, 19.4 ppm.

1,2-Bis(4-methoxyphenyl)pentan-1-one (3v): Synthesized using

methoxy-N,N-dimethylbenzamide (0.5 mmol, 90 mg), n-BuLi (0.31 ml, 1.6 M, 0.5 mmol, 1.0 eq) and

4-bromoanisole (0.6 mmol, 112 mg, 75 µL). Yellow oil obtained after column chromatography

(SiO

, n-pentane/ EtOAc 90:10), 90 mg, 60% yield.

H-NMR (400 MHz, CDCl

): δ 7.97 (d, J

= 8.9 Hz, 2H), 7.23 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H),

4.47 (t, J = 7.3 Hz, 1H), 3.83 (s, 3H), 3.76 (s, 3H), 2.17-2.07 (m, 1H), 1.84-1.73 (m, 1H),

1.37-1.21 (m, 2H), 0.92 (t, J = 7.4 Hz, 3H) ppm.

C-NMR (100.59 MHz, CDCl

): δ 198.8,

163.2, 158.4, 132.3, 130.9, 130.0, 129.1, 114.2, 113.6, 55.4, 55.2, 52.0, 36.2, 20.9, 14.1 ppm.

HRMS (ESI+, m/z): calcd for C

H

O

[M+H]

: 299.1641; found: 299.1642.

3

Additional experimental data:

Figure S1. Conversion of 1a into 3a followed in time by GC analysis. aConditions: n-BuLi (1.0 eq, 1.6 M) is added to a solution of amide 1a (0.5 mmol) in THF (2 mL) followed by addition of Pd[P(t-Bu)3]2 (5 mol %) and 4-bromotoluene (1.2 eq.) heated to 60 °C.

0 10 20 30 40 50 60 70 80 90 100 0 2 t (h) 4 6 8 Conversion (%)

4.3 The Synthesis of Substituted Benzaldehydes via a Two-Step, One-Pot

Reduction/Cross-Coupling Procedure

The synthesis of functionalized (benz)aldehydes via a two-step, one-pot procedure, is presented in this chapter. The method employs a stable aluminium hemiaminal as tetrahedral intermediate, suitable for subsequent cross-coupling with (strong nucleophilic) organometallic reagents, leading to a variety of alkyl and aryl substituted benzaldehydes. This methodology was also applied to effectively synthesize a 11C radiolabeled aldehyde. An aluminium-ate complex plays a crucial role in the transmetallation of alkyl fragments onto palladium and allows the synthesis of an industrially relevant isobutyl substituted benzylic alcohol by two fold use of DIBAL-H.

4.4.1 Introduction

The synthesis of small, highly functionalized molecules lies at the basis of many areas of chemistry, ranging from drug design, to (hetero-) cyclic materials for photovoltaics and substituted metallocene ligands for transition metal catalysis.1 Transition metal catalyzed cross-coupling methods for derivatization of these compounds mostly rely on rather expensive coupling partners with reduced reactivity and therefore require higher temperatures and long reaction times, as well as traditional protecting group strategies.2 Facing environmental awareness, catalytic methods with lighter reagents that produce less waste and of lower toxicity should be favored according to the principles of green chemistry.3 The application of cheaper and more reactive organometallic reagents as coupling partners in combination with carbonyl functional groups has some precedence, but still remains a synthetic challenge.4 The reactive aldehyde functionality in particular is prone to side reactions with organometallic reagents. It is this high reactivity with a range of reagents that make aldehydes such useful building blocks in organic synthesis, and therefore a general and facile synthesis of substituted (benz)aldehydes would be highly desirable. In order to prevent the fast 1,2-addition of a nucleophile to the aldehyde (Scheme 4.1a), or over 1,2-addition to a synthetic precursor, Weinreb amides (1) have proven themselves to be valuable precursors to aldehydes moiety (2). By addition of an organometallic compound to 1, a stable reaction intermediate 4 (Scheme 4.1b) is created in situ, which is unsusceptible to further nucleophilic attack.5 We discovered that these metal chelated intermediates are stable towards organolithium cross-coupling conditions. As a consequence, a method for the synthesis of cross-coupled ketones, with organolithium reagents and bromo-substituted Weinreb amides as the coupling partners via reaction intermediate 4 was developed (scheme 4.1b).6 Adding to the already known transformations of Weinreb amides, this method provides an easy approach to cross-coupled carbonyl compounds, and we envisioned that reduction with a (aluminium-) hydride source would yield a hemiaminal with similar stability, facilitating a procedure for the cross-coupling of masked aldehydes.

Scheme 4.1 Reduction of Weinreb amides and stabile cross coupling intermediates

The Weinreb amides are easily prepared on a multigram scale from cheap, commercially available benzoic acids, thus providing a viable synthetic pathway for laboratory scale and the semi preparative synthesis of aldehyde building blocks.

4.4.2 Optimization

Reduction of the Weinreb amide was performed with the reductants diisobutylaluminium hydride (DIBAL-H) and sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al) due to their ease of handling and their availability. The screening of Pd-based carbene and phosphine catalysts showed the latter to be more reactive and selective for the cross-coupling of aryl bromides with organolithium reagents. In agreement with our previously observed increase in reactivity pre-oxidation of the phosphine based catalyst Pd(PtBu3)2 leads to a higher yield, and allowed for a drastic reduction of the

reaction time, while maintaining excellent conversion and selectivity towards the desired aldehyde.7 By switching the reductant to Red-Al, the conversion towards the aldehyde remained quantitative, but selectivity in the subsequent coupling reaction dropped due to dehalogenation of the aryl bromide. The formation of benzaldehyde is attributed to the lithium halogen exchange, promoted by the chelating effect of the ether moieties in the Red-Al.5b

Entry Cat “H”/Solvent Yield1

1 Pd(PtBu3)2 DIBAL-H(1 eq.)/Toluene 85

2 Pd(PtBu3)2 DIBAL-H(1 eq.)2/Toluene 87

3 Pd(PtBu3)2 DIBAL-H(1 eq.)/THF 40

4 Pd(PtBu3)2, O2 DIBAL-H(1 eq.)2/Toluene 92

5 Pd(PtBu3)2, O2 DIBAL-H(1 eq.)2/Toluene 903

6 Pd(PtBu3)2, O2 Red-Al (1eq.)/Toluene 304

Table 4.1. Reaction optimization 1Yield determined by GC/MS analysis. 2DIBAL-H added over 1 min. 3 The

4.4.3 Substrate scope

Having established the optimal conditions for the reduction/aryl cross-coupling (fast DIBAL-H addition at 0°C in toluene over 1 min, and Ar-Li addition at rt over 5 min, table 4.1, entry 5), a range of organolithium reagents were employed, including phenyllithium, (functionalized) aryllithium reagents (6,7), enol ether derivatives (8) and lithiated heterocycles that are commercially available, or easily prepared via direct deprotonation (9, 10). Finally, the direct deprotonation and coupling of ferrocene provided aldehyde, paving the way for the cheap and easy synthesis of functionalizable ferrocenes (11). Expanding the scope of the organolithium coupling partner to alkyl fragments, allowed the formation of methyl (12), ethyl (13), trimethylsilylmethylene (14) and cyclopropyl (15) substituted benzaldehydes with little or no modification of the previously optimized procedure. The relatively light and volatile aldehydes showed significant loss in yield during isolation due to evaporation.

Figure 4.1 Scope of the one pot reduction/Cross-coupling strategy for substituted benzaldehydesa

a) Yields refer to isolated yields after column chromatography. b) Lower yield due to volatile product c) Yield corrected for minor isobutylbenzaldehyde impurities. d) performed on 1 mmol scale

The less volatile naphthyl-analogue 16 proved less prone to evaporation, and was isolated in 63% yield. We have previously successfully incorporated the short lived 11C isotope (t½ = 20.3 min) by

means of a palladium catalyzed cross-coupling of methyllithium with aryl bromides. Expanding the scope of the organolithium cross-coupling, radiolabeled aldehydes remain a synthetically challenging goal.7b,7c Due to the limited amount of methods available for the preparation7d,7e or functionalization

7f-i

of radiolabeled aldehydes, we set out to design a method for the 11C incorporation in (substituted) benzaldehydes. Employing the general reduction/cross-coupling strategy introduced here we aimed to synthesize compound [methyl-11C]16 as a model substrate. Taking advantage of our previously

reported method for making [11C]methyllithium from [11C]methyliodide by means of an in situ lithium halogen exchange with n-BuLi, the one pot procedure described above yields the isolated target molecule in a 23% decay corrected yield with a radiochemical purity of >99% (Scheme 4.2).

Scheme 4.2 Synthesis of radiolabelled 6-methyl-2-naphthaldehyde

This is one of the few examples of the radiolabeling of (substituted) benzaldehydes, and we envision an important role in the synthesis of new PET-tracers, vital for mapping of processes and biological targets in the human body.7b,7c

Though near perfect selectivity for the desired product was observed when using MeLi, (Figure 4.1,

12) we sometimes found the competing coupling of an isobutyl group, originating from the

DIBAL-hemiaminal intermediate, while employing other alkyllithium coupling partners. It is known that in cross-coupling reactions, mixed aryl/alkyl aluminum species selectively transmetallate the sp2 hybridized carbon fragment, and only trialkyl-aluminum species transfer the sp3 moiety.8,9 We expected the isobutyl to originate from the aluminium-ate complex, which is formed after addition of the alkyllithium reagent.

entry R-Li T (°C) Selectivitya

17a/17b 1 nBuLi 23 95-60b/5-40 2 nBuLi 0 65/35 3 nBuLi 45 85/15 4 iPr-Li 23 68/32 5 iPr-Li 0 61/39 6 tBu-Li 23 <1/99c,d 7 tBu-Li 0 <1/99c,d

Table 4.2 Scrambling of alkyl fragments upon alkyllithium addition and cross coupling.

a

As determined by GC/MS analysis. b Selectivity varied under identical reaction conditions. c Varying amounts of homocoupling (bis-benzaldehyde) were also observed.d Reversed selectivity : only the isobutyl coupled benzaldehyde

Table 4.2 shows the selectivity of isobutyl versus the added alkyl fragment. Tetrahedral intermediate

1-th is formed upon DIBAL-H addition, which is the precursor to the anionic aluminium-ate complex

1-ate upon alkyllithium addition. For both n-butyl- (entry 1-3), and isopropyl- lithium (entry 4 and 5), poor or varying selectivity for the alkyl substituted benzaldehyde was found, regardless of addition speed or reaction temperature. We were unable to find reaction conditions that gave satisfactory selectivity towards the desired product 17a. In order to force the selectivity towards isobutyl (originating from the DIBAL-H fragment) coupling, we decided to add the reluctant coupling partner t-BuLi, which showed full selectivity in alkyl transfer towards the isobutyl coupled benzaldehyde. Similar to our previous findings on homocoupling reactions of arylbromides the lithium halogen exchange is a prominent reaction pathway, and thus a substantial amount of of 4,4’-bisbenzaldehyde was observed. - 2 .0 -1 .8 -1 .6 - 1 .4 -1 .2 - 1 .0 -0 .8 -0 .6 - 0 .4 - 0 .2 0 .0 0 .2 0 .4 0 .6 0 .8 1 .0 1 .2 1 .4 1 .6 1 .8 2 .0 2 .2 2 .4 f1 (p p m ) 1 2 3 4 5 6 7

Figure 4.2 1H-NMR studies of DIBAL-H reduction of Weinreb amide 1.

Conditions : concentration of all reagents : 0.1 mmol in 0.5 ml tol-d8, Reduction and n-BuLi addition performed at 0°C.

In order to check for the formation of free isobutyllithium (displacement of the alkyl fragment by n-butyllithium), a selection of starting materials and reaction mixtures was subjected to 1H-NMR analysis (Figure 4.2). The CH2 fragment of the isobutyl in DIBAL-H (spectrum 1) is clearly visible at

0.44 ppm, and is completely consumed upon addition to the Weinreb amide (spectrum 2). The large number of signals between 0 and 0.4 ppm can be explained by the generation of unequal alkyl fragments at the aluminium center, in combination with diastereotopic protons. Upon addition of n-butyllithium, the CH2 fragment of the linear alkyl chains becomes apparent at -0.17 ppm (spectrum

3). A similar trend is visible when the trialkyl-aluminium complex (doublet at 0.38, spectrum 4) is also mixed with nbutyllithium (spectrum 5) where an upfield shift is observed that leads to a signal at -0.32 ppm. When this mixture is added to a stirred solution of Pd-catalyst and 1-bromonaphthalene, a similar product distribution (table 2 entry 1) between n- and iso- butyl coupled naphthalene is observed. Finally, the pure sample of both n-butyllithium (spectrum 6) and isobutyllithium (spectrum 7) provided the reference for the hypothesis that no free alkyllithium is present in sample/spectrum 3 and 5. These observations, together with literature precedence supports the hypothesis of the unselective alkyl transmetallation from aluminium to palladium.11

4.4.4 In situ reduction of ketones.

The reduction/cross-coupling strategy could be further expanded from Weinreb amides to ketones. Ketones such as acetophenones are easily prepared via Friedel-Craft acetylation, and make up an important class of chemical intermediates. Reduction of the acetophenone moiety yields a substituted benzylic alcohol that can be further functionalized. Unlike carbonyl moieties, benzylic alcohols do not act as a electrophiles with organolithium reagents and as such do not have to be protected, but the acidic proton would nevertheless consume a stoichiometric amount of organolithium reagent. It is therefore that this group is suitably protected as a metal alkoxide (for example an aluminium alkoxide). The isobutyl transfer observed in previous examples, led us to the attempt of the two fold use of DIBAL-H in the reaction with 4-bromoacetophenone. The transfer of the hydride leads to an aluminium alkoxide, and addition of tert-butyllithium is hypothesized to generate the intermediate shown in scheme 4.3. Selective isobutyl transmetallation from aluminium to palladium and consecutive cross-coupling was found to provide industrially relevant alcohol 18, a precursor to anti-inflammatory agent Ibuprofen, in 43 % yield (scheme 4.3).10

Scheme 4.3 Two fold use of DIBAL-H in the reduction and cross coupling of 4-bromoacetophenone

4.4.5 Conclusions

In conclusion, we have shown that the DIBAL-H reduction of Weinreb amides, yields a masked aldehyde in the form of a stable aluminum hemiaminal intermediate, providing a platform for subsequent functionalization with nucleophilic cross-coupling partners. The scrambling of alkyl fragments in the cross-coupling of alkyllithium reagents is caused by a mixed aluminium-ate complex, as observed by 1H-NMR analysis. The method was also applied to an industrially relevant ketone, yielding an Ibuprofen precursor, and showcased the two fold use (reducing agent and alkyl transfer agent) of DIBAL-H in the synthesis of secondary alcohols. Further research on the use of these aluminium hemiaminal intermediates is currently ongoing.

4.4.6 References

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