Chemoselective Reduction of Sterically Demanding N,N

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Chemoselective Reduction of Sterically Demanding N,N‑Diisopropylamides to Aldehydes Peihong Xiao,† Zhixing Tang,† Kai Wang,† Hua Chen,† Qianyou Guo,† Yang Chu,† Lu Gao,*,† and Zhenlei Song*,†,‡ †

Key Laboratory of Drug-Targeting of Education Ministry and Department of Medicinal Chemistry, West China School of Pharmacy, Sichuan University, Chengdu 610064, P. R. China ‡ State Key Laboratory of Elemento-organic Chemistry, Nankai University, Tianjin 300071, P. R. China S Supporting Information *

ABSTRACT: A sequential one-pot process for chemoselectively reducing sterically demanding N,N-diisopropylamides to aldehydes has been developed. In this reaction, amides are activated with EtOTf to form imidates, which are reduced with LiAlH(OR)3 [R = t-Bu, Et] to give aldehydes by hydrolysis of the resulting hemiaminals. The non-nucleophilic base 2,6-DTBMP remarkably improves reaction efficiency. The combination of EtOTf/2,6-DTBMP and LiAlH(O-t-Bu)3 was found to be optimal for reducing alkyl, alkenyl, alkynyl, and 2monosubstituted aryl N,N-diisopropylamides. In contrast, EtOTf and LiAlH(OEt)3 in the absence of base were found to be optimal for reducing extremely sterically demanding 2,6-disubstituted N,N-diisopropylbenzamides. The reaction tolerates various reducible functional groups, including aldehyde and ketone. 1H NMR studies confirmed the formation of imidates stable in water. The synthetic usefulness of this methodology was demonstrated with N,N-diisopropylamide-directed ortho-metalation and C−H bond activation.

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INTRODUCTION Amide reduction is among the most important transformations in organic synthesis,1 and it poses a particular challenge because the orbital overlap between the nitrogen lone pair and the antibonding orbital of the carbonyl group reduces the electrophilicity of the carbonyl carbon.2 Most investigations in this field have focused on reduction of amides to amines.3 Much more difficult is chemoselective reduction of amides to aldehydes because the corresponding amines and alcohol byproducts form easily. Two approaches have been reported so far for reducing amides to aldehydes, and the approaches differ in hydride source (Scheme 1a). Approach a relies on metal hydride reagents to reduce amide directly. Early protocols were typically suitable for amides with specialized N-substituents that either decrease the delocalization of the nitrogen lone pair4 or, in the case of Weinreb amides, chelate with metal to form a stable complex that prevents further reduction.5 One of the most efficient aluminum hydride based reagents is LiAlH(OEt)3, invented by Brown and co-workers,6 which reduces N,Ndimethyl- and N,N-diethylamides to the corresponding aldehydes. Georg and co-workers succeeded in reducing tertiary amides to aldehydes using Schwartz’s reagent (Cp2ZrHCl).7 Snieckus and co-workers later modified this procedure to form Schwartz’s reagent in situ from Cp2ZrCl2 and LiAlH(O-t-Bu)3.8 Recently, some unique boranehydride reagents9a,b and a modified Red-Al reagent9c have been developed for reduction of tertiary amides to aldehydes. © 2017 American Chemical Society

Scheme 1. (a) Previous Methods Are Limited to Reduction of Non- or Less Sterically Demanding Amides. (b) Reduction of Sterically Demanding N,N-Diisopropyl)amides by a Sequential One-Pot Imidate Formation/Reduction Process

Recent progress on improving functional-group tolerance has been achieved using much milder reducing reagents hydrosilanes (Scheme 1a, approach b). Buchwald and co-workers made the first breakthrough by using stoichiometric amounts of Ti(O-i-Pr)4 in combination with Ph2SiH2.10a Only α-enolizable secondary and tertiary amides can be reduced into aldehydes upon hydrolysis of the initially formed enamines. Charette and Received: November 13, 2017 Published: December 14, 2017 1687

DOI: 10.1021/acs.joc.7b02868 J. Org. Chem. 2018, 83, 1687−1700

The Journal of Organic Chemistry

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Table 1. Screening of Reaction Conditions

entry

activating reagent (equiv)

1 2 3a 4 5 6 7 8 9 10 11 12 13 14 15

EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) EtOTf (1.1) EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) EtOTf (1.5) Tf2O(1.5) MeOTf (1.5) Me3OBF4 (3.0)

additive (equiv)

[H−] (equiv)

T (°C)

2a/3/1ab

yield (2a)c (%)

2,6-DTBMP (3.0) 2,6-DTBMP (2.0) 2,6-DTBMP (3.0) 2,6-lutidine (3.0) 4-TBP (3.0) 2-F-pyridine (3.0) 2,6-DTBMP (3.0) 2,6-DTBMP (3.0) 2,6-DTBMP (3.0) 2,6-DTBMP (3.0) 2,6-DTBMP (3.0) 2,6-DTBMP (3.0) Na2HPO4 (1.5)

LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (3.5) LiAlH(Ot-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0) L-Selectride (2.0) DIBAL-H (2.0) NaBH4 (2.0) Et3SiH (2.0) LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0) LiAlH(O-t-Bu)3 (2.0)

−78 −78 −78 −78 0 −78 −78 −78 −78 −78 −78 rt to 45 −78 −78 −78

100:0:0 100:0:0 100:0:0 78:2:20 49:35:16 48:0:52 ND 100:0:0 ND 24:76:0 0:100:0 ND 100:0:0 76:24:0 70:12:18

67 72 92 74 45 44 NR 70 complex 22 0 NR 90 70 65

a

Reaction conditions: 1a (0.1 mmol), EtOTf (0.15 mmol), 2, 6-DTBMP (0.3 mmol) in CH2Cl2 (2 mL) at rt for 2 h, then THF (4 mL) and LiAlH(O-t-Bu)3 (0.2 mL, 1.1 M in THF) at −78 °C for 4 h. bThe ratios were determined by 1H NMR spectroscopy of the crude products. cYields after purification by silica gel column chromatography.

method is activating amides to more electrophilic imidates, which are reduced with LiAlH(OR)3 to give hemiaminals that hydrolyze into aldehydes. Hwu and co-workers first tested the preliminary version of the reaction with N,N-dimethylamides in 1990.19 However, the protocol suffered from the inconvenient operation, narrow substrate scope, and low to moderate conversion together with substantial amounts of ester byproducts in some cases, therefore, has been barely used in organic synthesis. Here, we substantially improve on this method by developing a more convenient sequential one-pot operation in which the non-nucleophilic base 2,6-DTBMP20 remarkably improves efficiency. Extensive studies indicate that a wide range of N,N-diisopropylamides, including extremely sterically demanding 2,6-disubstituted benzamides, can be reduced to aldehydes in excellent yields. The reaction also shows unprecedented tolerance of functional groups: diverse reducible functionalities survive, including aldehydes and ketones. These attractive properties of this methodology should substantially expand the synthetic potentials of N,N-diisopropylamide as a masked aldehyde group because it is typically inert in a number of transformations due to its steric bulkiness.

co-workers later succeeded in reducing amides in the absence of metals, though the method was limited to secondary amides.11 They used triflic anhydride and 2-F-pyridine12 to transform amides into triflicamidates,13 which were reduced with Et3SiH to generate an iminium species that hydrolyzed to give the desired aldehydes. Using Mo(CO)6 as catalyst and 1,1,3,3tetramethyldisiloxane (TMDS) as the hydride source, Adolfsson and co-workers reduced various tertiary amides to aldehydes chemoselectively at temperatures below 80 °C.14 The Charette and Adolfsson protocols tolerated various reducible functionalities, including aldehydes and ketones. N,N-Diisopropylamide is a unique bulky functionality. It has shown wide utility in organic synthesis, particularly as a good directing group in ortho-metalation15 and C−H bond activation16 (Scheme 1a). Due to its steric bulkiness, N,Ndiisopropylamide is more robust than N,N-dimethyl- and N,Ndiethylamides under some harsh reaction conditions. However, the bulkiness makes this group much more difficult to reduce into an aldehyde. The bulkiness of the N,N-diisopropyl group appears to be not hindered enough to distort the N−CO bond,17 leading a more reducible “ketonic” CO bond.18 In fact, it sterically inhibits the nucleophilic attack of the hydride toward the carbonyl carbon. For example, LiAlH(OEt)3 can reduce N,N-dimethyl- and diethylamides, but it is inert toward bulkier N,N-diisopropylamides.6 Schwartz’s reagent can reduce 2-monosubstituted N,N-diethyl benzamides, but it is much less effective to reduce the corresponding N,N-diisopropyl analogues and nearly inert toward bulkier 2,6-disubstituted benzamides.7,8 Although steric limitations of the approach using hydrosilanes have not been reported in detail, only a few published reactions have involved amides containing an N,Ndiisopropyl group or sterically demanding carbonyl substituents.10,11,14 The inability to efficiently reduce such tertiary amides to aldehydes limits the usefulness of numerous building blocks that can be generated from N,N-diisopropylamide.15,16 Here, we report a general methodology for reducing N,Ndiisopropylamides 1 to aldehydes 2 (Scheme 1b). Key to this

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RESULTS AND DISCUSSION Screening of Reaction Conditions. The reaction was examined using 2-methyl N,N-di(iso-propyl) benzamide 1a as a model scaffold. Initial attempts to directly reduce 1a proved ineffective with either metal hydride regents or hydrosilanes because of the steric hindrance created by the 2-methyl and bulky nitrogen moieties.21 We reasoned that converting the amide to the more reactive imidate might promote subsequent reduction. Indeed, reaction of 1a with EtOTf at room temperature for 2 h followed by sequential one-pot reduction of the resulting imidate with LiAlH(O-t-Bu)3 at −78 °C for 4 h provided the desired aldehyde 2a in 67% yield (entry 1, Table 1). We did not observe over-reduction to amine 3 and ethyl ether, or formation of ester byproduct, and we did not recover any 1a.22 Increasing the loading of LiAlH(O-t-Bu)3 to 3.0 equiv 1688



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Table 2. Scope of N,N-Di(isopropyl)benzamides.a

a

Reaction conditions: 1 (0.3 mmol), EtOTf (0.45 mmol), 2, 6-DTBMP (0.9 mmol) in CH2Cl2 (2 mL), thenTHF (4 mL) and LiAlH(O-t-Bu)3 (0.55 mL, 1.1 M in THF) at −78 °C for 4 h. bYields after purification by silica gel column chromatography. cReaction temperature and time in the first step to form imidate. dThe yield was obtained on a gram-scale reaction using 12.0 mmol of 1j.

served as good substrates, affording aldehydes 2g−i in high yields. Traditionally, these substrates are considered particularly difficult to reduce because of the bulky silyl groups. Only one successful example has been reported, in which the reaction tolerated only furanamide-containing less sterically demanding N,N-diethyl and 2-trimethylsilyl moieties.8 The reaction even tolerated the geminal bis(silyl) group, which exerts a much stronger steric shielding effect than silyl groups;24 the corresponding aldehyde 2j was produced in 89% yield. The reaction was also suitable for synthesizing 2-halogenated and -oxygenated benzaldehydes 2k−p; for reducing 2-PPh2 benzamide to 2q, which is useful in the synthesis of phosphine ligands; and for converting 2,3-disubstituted benzamides into the corresponding benzaldehydes 2r−t in yields >90%. In addition to benzamides, we were able to reduce alkyl-, alkenyl-, alkynyl-, naphthalene-, and heterocycle-substituted amides to the corresponding aldehydes 2u−aa. However, reaction failed to generate the aldehyde 2ab containing a pyridine ring. We suspect that formation of the pyridine salt out-competes formation of the desired imidate intermediate in the presence of EtOTf. Scope of 2,6-Disubstituted N,N-Diisopropylbenzamides. The successes shown in Table 2 led us to examine the more challenging substrates 2,6-disubstituted N,N-diisopropylbenzamides. In these compounds, not only does the nitrogen moiety create steric hindrance, but substituents at the 2- and 6-positions sterically shield both sides of the amide, making imidate formation and subsequent reduction extremely difficult. To the best of our knowledge, only one previous

improved yield slightly to 72% (entry 2). Adding 3.0 equiv of 2,6-DTBMP as a non-nucleophilic base did not obviously promote imidate formation,23 but it improved the overall efficiency, affording 2a in 92% yield (entry 3). Decreasing the loading of both EtOTf and 2,6-DTBMP reduced yield to 80% (entry 4). Performing the reduction at 0 °C led to amine byproduct 3 as the sole product (entry 5). Using less hindered 2,6-lutidine or nonsterically demanding 4-TBP dramatically inhibited imidate formation (entries 6 and 7). Using 2halogenated pyridines such as 2-F-pyridine as additives decreased yield to 70% (entry 8). LiAlH(O-t-Bu)3 was far more effective than other metal hydride reagents: L-selectride caused complex reactions (entry 9), while DIBAL-H or NaBH4 gave the undesired amine 3 as the major product (entries 10 and 11). As expected, hydrosilane was too weak to reduce the imidate (entry 12). Tf2O showed similar activation ability as EtOTf, giving aldehyde 2a in 90% yield (entry 13). MeOTf and Me3OBF4 were much less effective, leading to formation of amine 3 and recovery of amide 1a (entries 14 and 15). Scope of N,N-Diisopropylbenzamides. The reaction proved useful for reducing a wide range of 2-substituted N,Ndiisopropylbenzamides, giving the corresponding aldehydes in yields >90% in most cases (Table 2). The reaction tolerated such substituents as bulky isopropyl (2b) and phenyl groups (2c) as well as terminal silyl-substituted alkenyl (2d) and alkynyl groups (2e), which could be further functionalized in various ways. Although the electron-withdrawing CF3 lowered yield, aldehyde 2f was still obtained in 62% yield. Notably, benzamides possessing various silyl groups at the 2-position 1689



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report involved such a substrate: in that example, 2,6-dichloroN,N-diethylbenzamide was reduced using Schwartz’s reagent (Cp2ZrHCl) to give the aldehyde in 17% yield.7b When we conducted our reaction under standard conditions, we failed to reduce amide 1ac to aldehyde 2ac (not shown). Switching the reducing reagent from LiAlH(O-t-Bu)3 to the less bulky LiAlH(OEt)36b,25 and increasing its loading to 4.0 equiv improved the yield to 67% (Table 3, entry 1). Interestingly,

functional groups, which is the primary limitation when reducing amides with metal hydride reagents. To test the functional group tolerance of our method, N,N-di(isopropyl)benzamides containing a range of substituents at the 4-position were examined under standard reaction conditions. The amide moiety was reduced chemoselectively to give aldehydes 2aj−al in high yields while leaving NO2, CN, and CO2Me groups untouched (Table 4). We were pleasantly surprised to find that

Table 3. Scope of 2,6-Disubstituted N,NDiisopropylbenzamidesa

Table 4. Functional Group Tolerance.a

a

Reaction conditions: 1 (0.3 mmol), EtOTf (0.45 mmol), 2, 6DTBMP (0.9 mmol) in CH2Cl2 (2 mL), then THF (4 mL) and LiAlH(O-t-Bu)3 (0.55 mL, 1.1 M in THF) at −78 °C for 4 h. bYields after purification by silica gel column chromatography. cReaction temperature and time in the first step to form imidate.

the reaction even tolerated much more reducible ketone and aldehyde functionalities (2am and 2an). Such group tolerance has been a long-standing challenge in the reduction of amides with metal hydride reagents. We are aware of only two previous reports of amide reductions that preserve ketone and aldehyde groups; both use hydrosilane as the reducing agent.11,14 Scope of N,N-Disubstituents. We found that the steric characteristics of N-substituents generally did not harm the high yields of aldehyde 2a (Table 5). Suitable substituents included the liner n-Bu group (1ao) and the more sterically demanding Bn and Cy groups (1ap and 1aq). The reaction also tolerated tertiary amides with cyclized nitrogen moieties, such as pyrrolidine (1ar), piperidine (1as), and morpholine (1at). In contrast to steric characteristics, the electronic characteristics of the N-substituent strongly affected the reaction yield. For example, the presence of one or two phenyl groups on the nitrogen (1au and 1av) completely blocked imidate formation. We speculate that the phenyl ring delocalizes the lone electron pair on nitrogen, making the carbonyl oxygen less basic than the oxygen of N,N-alkylamides. Chemoselectivity in 4-Amide- or -Carbamate-Substituted N,N-Diisopropylbenzamides. We next examined whether our sequential one-pot process could chemoselectively reduce one of two different amides in a given substrate. Reduction of 1aw using DIBAL-H afforded aldehyde 2ao, in which the Weinreb amide was reduced, while the N,Ndiisopropylamide was unaffected (Scheme 2a). Conversely, only the N,N-diisopropylamide in 1ax was reduced and the Nphenylamide moiety was untouched, giving amido aldehyde 2ap in 82% yield. The N,N-diisopropylamide in 1ay was selectively reduced while the carbamate group NHBoc survived, giving aldehyde 2aq in 94% yield. This indicates that the proton

a

Reaction conditions: 1 (0.3 mmol), EtOTf (0.6 mmol) in CH2Cl2 (2 mL), then THF (4 mL) and LiAlH(OEt)3 (1.2 mL, 1.0 M in THF) for 8 h. bYields after purification by silica gel column chromatography.

omitting 2,6-DTBMP further increased the yield to 79% (entry 2). The reaction efficiently reduced 2,6-disubstituted amides 1ad−ag to aldehydes 2ad−ag in good yields (entries 3−6). No reduction of SiMe3/Me-substituted amide 1ah occurred at −78 °C (entry 7), but increasing the reduction temperature to −20 °C afforded the desired aldehyde 2ah in 75% yield (entry 8). The imidate of SiMe3/SiMe3-substituted amide 1ai formed readily at 45 °C, but this substrate was too bulky to undergo reduction even at −20 °C. Thus, its N,N-diethyl analogue 1ai′ was reduced instead, giving aldehyde 2ai in 64% yield. Functional Group Tolerance. We envisioned that converting amides to imidates would allow subsequent reduction with LiAlH(O-t-Bu)3 without altering other reducible 1690



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Table 5. Scope of N,N-Disubstituents.a

To verify this mechanism and gain additional insights, we used 1H NMR to analyze formation of imidate from amide 1a and EtOTf in the presence of additive 2,6-DTBMP (Figure 1). Signals for 1a disappeared completely after the reaction had proceeded for 2 h in CD2Cl2 at room temperature. Signals for the two methenyl protons on the nitrogen shifted downfield (0.3−0.5 ppm), consistent with formation of the imidate salt 6. Quenching the reaction with D2O did not lead to regeneration of amide 1a or formation of the corresponding ethyl ester. These results strongly suggest that the imidate salt 6 is stable in the aqueous phase. Consistent with this, the 1H NMR spectrum of the D2O phase clearly shows signals for 6. Imidate stability in water may make our sequential one-pot reduction process useful for developing aqueous-phase organic syntheses.26 Synthetic Applications. This methodology allowed us to rapidly synthesize diverse benzaldehyde derivatives useful in downstream transformations. Amide-directed ortho-metalation (DoM) of 4-MeO benzamide 7 occurred regioselectively with sBuLi/TMEDA (Scheme 4a). Trapping the resulting phenyl lithium with Me3SiCl afforded 2-SiMe3 benzamide 8 in 60% yield,15a which was reduced to aldehyde 9 in 92% yield. This two-step process provides an efficient alternative to traditional methods for synthesizing 2-SiMe3 benzaldehydes via metal− halogen exchange with the corresponding bromobenzene.27 Benzaldehyde 9 is a useful scaffold in the anion relaymediated,28 multicomponent cross-coupling with nucleophilic n-BuLi and electrophilic allyl bromide, leading to benzyl alcohol 10 in 65% yield. N,N-Diisopropylamide has been used widely as a powerful directing group in transition-metal-catalyzed activation of the ortho C−H bond in phenyl rings. However, functionalization of these reaction products has been limited by the inability to reduce the bulky amide group. Our method provides an efficient way to solve this problem by reducing the amide group to aldehyde (Scheme 4b). Benzamide 11 underwent Pd(II)catalyzed ortho C−H bond functionalization with toluene to provide diaryl product 12 in 50% yield.16i Reducing the amide moiety in 12 under standard conditions furnished aldehyde 13 in 86% yield, which underwent TBHP-mediated oxidative cyclization to give lactone 14 in 46% yield.29

a

Reaction conditions: 1 (0.3 mmol), EtOTf (0.45 mmol), 2, 6DTBMP (0.9 mmol) in CH2Cl2 (2 mL), then THF (4 mL) and LiAlH(O-t-Bu)3 (0.55 mL, 1.1 M in THF) at −78 °C for 4 h. bYields of 2a after purification by silica gel column chromatography. cReaction temperature and time in the first step to form imidate.

Scheme 2. Chemoselectivity in 4-Amide- or -CarbamateSubstituted N,N-Diisopropyl)benzamides

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CONCLUSION In summary, we have described an efficient method for reducing sterically demanding N,N-diisopropylamides to aldehydes. This sequential one-pot protocol features activation of amides with EtOTf to form imidates, which can be reduced with LiAlH(OR)3 to give aldehydes chemoselectively. A wide range of alkyl, alkenyl, alkynyl, and aryl tertiary amides, as well as extremely sterically demanding 2,6-disubstituted N,Ndiisopropylbenzamides, can function as good substrates to afford aldehydes in generally excellent yields. Various reducible functional groups, including aldehydes and ketones, are tolerated in this reaction. 1H NMR studies confirmed the formation of imidate and suggest that it is stable in water. The synthetic utility of this methodology has been demonstrated for N,N-diisopropylamide-directed ortho-metalation and C−H bond activation. Further applications of this methodology in organic synthesis are being explored.

in the NHBoc group did not interfere with reduction. These results suggest that our method can be tailored to retain or reduce N,N-diisopropylamide depending on downstream requirements. This may substantially expand the synthetic possibilities of this traditionally inert functionality. Mechanistic studies. A feasible reaction mechanism was outlined in Scheme 3. Tertiary amide 1 reacts with EtOTf to give imidate 4. The non-nucleophilic base 2,6-DTBMP promotes this step probably by forming the reactive pyridinium intermediate with EtOTf.13g Imidate 4 is reduced by LiAlH(OR)3 to give hemiaminal 5, which in turn hydrolyzes during workup to afford aldehyde 2. Scheme 3. Proposed Reaction Mechanism

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EXPERIMENTAL SECTION

Commercial reagents were used without any purification. All reactions were performed using common anhydrous, inert atmosphere techniques. Reactions were monitored by TLC which was performed 1691



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Figure 1. 1H NMR studies of imidate formation from amide 1a and EtOTf in the presence of 2,6-DTBMP. solution was washed with 1 N HCl. The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by via silica gel flash column chromatography (eluent: petroleum ether/EtOAc) to yield the target amides. Method B. To a solution of a carboxylic acids (1 equiv) in CH2Cl2 or toluene was added SOCl2 (2−4 equiv) slowly. Then DMF (0.05 equiv) was added at room temperature. The mixture was stirred at room temperature or 45 °C for 1−4 h. After concentration in vacuo, the residue was dissolved in CH2Cl2 and cooled to 0 °C. To the solution were added Et3N (1.3 equiv) and diisopropylamine (1.2 equiv) dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for an additional 0.5 h. The reaction was quenched with H2O and extracted with EtOAc or ether. The combined organic extract was washed with satd aq NaCl, dried over MgSO4, and concentrated in vacuo. The residue was purified by via silica gel flash column chromatography (eluent: petroleum ether/ EtOAc) to yield the target amides. Method C. To a solution of a carboxylic acid substrate (1 equiv) in CH2Cl2 at room temperature was added (COCl)2 (2 equiv) slowly. Then DMF (0.05 equiv) was added at room temperature. The mixture was stirred for 2 h. After concentration in vacuo, the residue was dissolved in CH2Cl2 and cooled to 0 °C. To the solution were added Et3N (1.3 equiv) and diisopropylamine (1.2 equiv) dropwise at 0 °C. The resulting mixture was warmed to room temperature and stirred for additional 2 h. Reaction was quenched with H2O and extracted with EtOAc or ether. The combined organic extract was washed with satd aq NaCl, dried over MgSO4, and concentrated in vacuo. The residue was purified by via silica gel flash column chromatography (eluent: petroleum ether/EtOAc) to yield the target amides. Method D. To a solution of TMEDA (1.1 equiv) in anhydrous THF (15 mL) was added s-BuLi (1.0 M in pentane, 1.2 equiv) at −78 °C under Ar atmosphere. The mixture was stirred for 10 min before addition of the solution of benzamide (1.0 equiv) in anhydrous THF (5 mL) via cannula. After the mixture was stirred for 2 h at −78 °C, the electrophile (1.3 equiv) was added dropwise. The resulting mixture was allowed to warm to room temperature with stirring for an additional 2 h. The solvent was removed under reduced pressure. The residue was diluted with water (10 mL), extracted with ether (2 × 15 mL), and washed with satd aq NaCl (15 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (eluent: petroleum ether/EtOAc) to afford the target amides.

Scheme 4. Synthetic Applications

on glass-backed silica plates and visualized using UV, KMnO4 stains, H3PO4·12MoO3/EtOH stains, H2SO4(conc)/anisaldehyde/EtOH stains. Column chromatography was performed using silica gel (200−300 mesh) eluting with EtOAc/petroleum ether. 1H NMR spectra were recorded at 400 MHz (Varian) and 600 MHz (Agilent), and 13C{1H} NMR spectra were recorded at 100 MHz (Varian) and 150 MHz (Agilent) using CDCl3 (except where noted) with TMS as standard. Infrared spectra were obtained using KCl plates on a VECTOR22. High-resolution mass spectral analyses were performed on Waters Q-TOF. CH2Cl2, TMEDA, DMF, (i-Pr)2NH, and Et3N were distilled from CaH2. THF and PhMe were distilled from sodium. All spectral data obtained for new compounds are reported here. General Procedures for Preparation of Amides. Method A. To a solution of amine (1.0 equiv) and Et3N (1.2 equiv) in CH2Cl2 was added commercially available acid chloride (1.0 equiv) slowly at room temperature. The reaction mixture was stirred for 30 min to 3 h at room temperature and then was diluted with CH2Cl2. The resulting 1692



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48.9, 20.8, 14.1; IR (cm−1) 2967, 1617, 1446, 1371, 1328, 1210, 1095, 1029, 811, 708; HRMS (ESI-TOF, m/z) calcd for C12H19NNaOS (M + Na)+ 248.1085, found 248.1082. N,N-Diisopropyl-1-methyl-1H-indole-3-carboxamide (1w). Method B: 1-Methylindole-3-carboxylic acid (0.80 g, 4.5 mmol), SOCl2 (9.0 mmol, 1.10 g), and DMF (0.23 mmol, 16.50 mg) in toluene (15 mL) at 45 °C for 1 h then diisopropylamine (5.40 mmol, 0.55 g) and Et3N (5.70 mmol, 0.58 g) in CH2Cl2 (20 mL) at room temperature for 2 h afforded 1w (0.66 g, 60% yield; mp 156−160 °C) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.50 (d, J = 7.6 Hz, 1H), 7.32 (d, J = 8.0 Hz, 1H), 7.26 (t, J = 6.0 Hz, 1H), 7.17 (t, J = 6.0 Hz, 1H), 3.97 (brs, 2H), 3.80 (s, 3H), 1.39 (d, J = 6.0 Hz, 12H); 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 136.2, 127.9, 126.7, 122.1, 120.5, 120.1, 112.9, 109.2, 48.0, 32.8, 21.2; IR (cm−1) 2965, 1610, 1532, 1471, 1438, 1368, 1301, 1244, 815, 741; HRMS (ESI-TOF, m/z) calcd for C16H22N2NaO (M + Na)+ 281.1630, found 281.1631. 3-Chloro-N,N-diisopropyl-2-methylbenzamide (1r). Method C: 3Chloro-2-methylbenzoic acid (0.85 g, 5.0 mmol), (COCl)2 (10.0 mmol, 1.27 g), and DMF (0.25 mmol, 20.0 mg) in CH2Cl2 (25 mL) at room temperature for 2 h then diisopropylamine (6.0 mmol, 0.61 g) and Et3N (6.50 mmol, 0.66 g) in CH2Cl2 (25 mL) at room temperature for 2 h afforded 1r (0.90 g, 71% yield; mp 106−108 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.26 (d, J = 7.6 Hz, 1H), 7.08 (t, J = 7.6 Hz, 1H), 6.95 (d, J = 7.2 Hz, 1H), 3.53−3.59 (m, 1H), 3.42−3.50 (m, 1H), 2.28 (s, 3H), 1.08 (d, J = 2.8 Hz, 3H), 1.06 (d, J = 2.8 Hz, 3H), 1.02 (d, J = 2.8 Hz, 3H), 1.01 (d, J = 2.8 Hz, 3H);13C{1H} NMR (100 MHz, CDCl3) δ 169.2, 140.2, 135.1, 131.6, 128.6, 126.9, 123.0, 50.7, 45.6, 20.6, 20.4 (2C), 20.2, 16.5; IR (cm−1) 2969, 1629, 1437, 1370, 1336,736; HRMS (ESI-TOF, m/z) calcd for C14H21ClNO (M + H)+ 254.1312, found 254.1306. N,N-Diisopropyl-3-methoxy-2-methylbenzamide (1s). Method C: 3-Methoxy-2-methylbenzoic acid (0.83 g, 5.0 mmol), (COCl)2 (10.0 mmol, 1.27 g) and DMF (0.25 mmol, 20.0 mg) in CH2Cl2 (25 mL) at room temperature for 2 h then diisopropylamine (6.0 mmol, 0.61 g) and Et3N (6.50 mmol, 0.66 g) in CH2Cl2 (25 mL) at room temperature for 2 h afforded 1s (0.70 g, 56% yield; mp 174−179 °C) as a white solid: 1H NMR (600 MHz, CDCl3) δ 7.15 (t, J = 5.2 Hz, 1H), 6.78 (d, J = 5.6 Hz, 1H), 6.70 (d, J = 5.2 Hz, 1H), 3.82 (s, 3H), 3.64−3.68 (m, 1H), 3.46−3.52 (m, 1H), 2.16 (s, 3H), 1.57 (d, J = 3.2 Hz, 3H), 1.56 (d, J = 3.2 Hz, 3H), 1.10 (d, J = 4.4 Hz, 3H), 1.05 (d, J = 4.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.3, 157.8, 139.8, 126.8, 122.2, 116.8, 109.4, 55.3, 50.7, 45.6, 20.8, 20.6 (2C), 20.4, 12.5; IR (cm−1) 2966, 1623, 1464, 1439, 1340, 1261, 1131, 1035,749; HRMS (ESI-TOF, m/z) calcd for C15H23NNaO2 (M + Na)+ 272.1626, found 272.1622. 4-Chloro-N,N-diisopropyl-2-methoxybenzamide (1t). Method C: 4-chloro-2-methoxybenzoic acid (0.93 g, 5.0 mmol), (COCl)2 (10.0 mmol, 1.27 g), and DMF (0.25 mmol, 20.0 mg) in CH2Cl2 (30 mL) at room temperature for 2 h then diisopropylamine (6.0 mmol, 0.61 g) and Et3N (6.50 mmol, 0.66 g) in CH2Cl2 (30 mL) at room temperature for 2 h afforded 1t (1.11 g, 82% yield; mp 127−129 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J = 8.0 Hz, 1H), 6.93 (d, J = 8.0 Hz, 1H), 6.86 (s, 1H), 3.79 (s, 3H), 3.58−3.64 (m, 1H), 3.43−3.52 (m, 1H), 1.50−1.53 (m, 6H), 1.13 (d, J = 6.4 Hz, 3H), 1.02 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.4, 155.7, 134.7, 127.6, 127.0, 120.9, 111.5, 55.6, 50.9, 45.7, 20.7, 20.6, 20.4, 20.3; IR (cm−1) 2967, 1630, 1592, 1439, 1336, 1250, 1033, 878, 764; HRMS (ESI-TOF, m/z) calcd for C14H20ClNNaO2 (M + Na)+ 292.1080, found 292.1075. N,N-Diisopropyl-2-(triethylsilyl)benzamide (1h). Method D: N,NDiisopropylbenzamide (0.40 g, 1.95 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40 mmol), TMEDA (0.25 g, 2.15 mmol), and TESCl (0.39 g, 2.53 mmol) in THF (15 mL) at −78 °C to room temperature for 3 h afforded 1h as a white solid (0.46 g, 74% yield; mp 56−59 °C): 1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 5.6 Hz, 1H), 7.29−7.31 (m, 2H), 7.15 (m, 1H), 3.76−3.78 (m, 1H), 3.48−3.50 (m, 1H), 1.46− 1.72 (m, 6H), 1.14−1.24 (m, 6H), 0.67−0.93 (m, 15H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.1, 144.7, 136.0, 135.0, 128.0, 127.3, 125.3, 50.7, 45.7, 20.5, 7.5, 3.6; IR (cm−1) 2955, 1630, 1424, 1369,

N,N-Diisopropyl-2-(trifluoromethyl)benzamide (1f). Method A: 2(Trifluoromethyl)benzoyl chloride (1.0 g, 4.80 mmol), diisopropylamine (485 mg, 4.80 mmol), and Et3N (582 mg, 5.76 mmol) in CH2Cl2 (20 mL) at room temperature for 3 h afforded 1f (1.23 g, 93% yield; mp 112−114 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.65 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 7.45 (t, J = 7.6 Hz, 1H), 7.25 (t, J = 7.6 Hz, 1H), 3.45−3.56 (m, 2H), 1.55 (d, J = 6.8 Hz, 3H), 1.52 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 167.7, 136.8 (q, 3JC−F = 2.3 Hz), 131.9, 128.3, 126.6 (q, 3JC−F = 4.5 Hz), 126.3, 126.1(q, 2 JC−F = 31.7 Hz), 123.8 (q, 1JC−F = 272.6 Hz), 50.9, 45.8, 20.5, 20.4, 19.7, 19.5; IR (cm−1) 2974, 1628, 1441, 1373, 1343, 1315, 1163, 1117, 1032, 774; HRMS (ESI-TOF, m/z) calcd for C14H18F3NNaO (M + Na)+ 296.1238, found 296.1235. 2-Fluoro-N,N-diisopropylbenzamide (1k). Method A: 2-Fluorobenzoyl chloride (1.0 g, 6.30 mmol), diisopropylamine (697 mg, 6.90 mmol), and Et3N (798 mg, 7.90 mmol) in CH2Cl2 (20 mL) at room temperature for 3 h afforded 1k (1.33 g, 94% yield; mp 100−102 °C) as a pink solid: 1H NMR (400 MHz, CDCl3) δ 7.24−7.29 (m, 1H), 7.21 (t, J = 6.4 Hz, 1H), 7.10 (t, J = 7.2 Hz, 1H), 7.01 (t, J = 8.8 Hz, 1H), 3.64−3.72 (m, 1H), 3.43−3.53 (m, 1H), 1.50 (d, J = 6.8 Hz, 6H), 1.13 (s, 3H), 1.03 (d, J = 4.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 165.6, 157.7 (d, 1JC−F = 244.7 Hz), 129.9 (d, 3JC−F = 7.6 Hz), 127.6 (d, 4JC−F = 4.2 Hz), 126.6 (d, 2JC−F = 19.2 Hz), 124.3 (d, 3 JC−F = 3.4 Hz), 115.0 (d, 2JC−F = 21.3 Hz), 50.9, 45.8, 20.6, 20.4, 20.3, 20.1; IR (cm−1) 2970, 1632, 1453, 1341, 1212, 764; HRMS (ESI-TOF, m/z) calcd for C13H18FNNaO (M + Na)+ 246.1270, found 246.1270. 2,6-Dichloro-N,N-diisopropylbenzamide (1ad). Method A: 2,6Dichlorobenzoyl chloride (1.0 g, 4.77 mmol), diisopropylamine (483 mg, 4.77 mmol), and Et3N (579 mg, 5.72 mmol) in CH2Cl2 (20 mL) at room temperature for 3 h afforded 1ad (0.43 g, 33% yield; mp 141− 146 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.29 (d, J = 8.0 Hz, 2H), 7.19 (t, J = 8.0 Hz, 1H), 3.51−3.60 (m, 2H), 1.59 (d, J = 6.8 Hz, 6H), 1.20 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 164.0, 136.8, 131.6, 129.4, 128.0, 51.6, 46.3, 20.9, 20.2; IR (cm−1) 2980, 1633, 1425, 1335, 793, 753; HRMS (ESI-TOF, m/z) calcd for C13H18Cl2NO (M + H)+ 274.0765, found 274.0769. 4-Acetyl-N,N-diisopropylbenzamide (1am). Method B: 4-Acetylbenzoic acid (2.0 g, 12.2 mmol) and SOCl2 (48.8 mmol, 5.8 g) in CH2Cl2 (40 mL) at 45 °C for 4 h then diisopropylamine (18.3 mmol, 1.85 g) and Et3N (15.3 mmol, 1.54 g) in CH2Cl2 (40 mL) at room temperature for 2 h afforded 1am (1.03 g, 34% yield; mp 104−108 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.97 (d, J = 8.0 Hz, 2H), 7.38 (d, J = 7.6 Hz, 2H), 3.66−3.72 (brs, 1H), 3.52−3.61 (brs, 1H), 2.61 (s, 3H), 1.53−1.58 (m, 6H), 1.13−1.18 (m, 6H); 13 C{1H} NMR (150 MHz, CDCl3) δ 197.4, 169.8, 143.2, 137.0, 128.6, 125.7, 50.9, 46.0, 26.6, 20.6; IR (cm−1) 2969, 1681, 1626, 1440, 1340, 1264, 835, 733; HRMS (ESI-TOF, m/z) calcd for C15H21NNaO2 (M + Na)+ 270.1470, found 270.1469. 4-Formyl-N,N-diisopropylbenzamide (1an). Method B: 4-Formylbenzoic acid (1.0 g, 6.6 mmol) and SOCl2 (26.4 mmol, 3.14 g) in CH2Cl2 (20 mL) at 45 °C for 4 h then diisopropylamine (7.92 mmol, 0.8 g) and Et3N (8.58 mmol, 0.86 g) in CH2Cl2 (20 mL) at room temperature for 2 h afforded 1an (0.6 g, 40% yield; mp 97−100 °C) as a white solid. 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.90(d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.70 (brs, 1H), 3.52 (brs, 1H), 1.40−1.76 (m, 6H), 0.95−1.23 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.5, 169.5, 144.4, 136.1, 130.0, 126.1, 51.0, 46.0, 20.6; IR (cm−1) 2969, 1701, 1625, 1371, 1339, 1206, 1167, 812, 759; HRMS (ESI-TOF, m/z) calcd for C14H19NNaO2 (M + Na)+ 256.1313, found 256.1309. N,N-Diisopropyl-3-methylthiophene-2-carboxamide (1v). Method B: 3-Methylthiophene-2-carboxylic acid (0.65 g, 4.5 mmol), SOCl2 (9.0 mmol, 1.10 g), and DMF (0.23 mmol, 16.50 mg) in toluene (15 mL) at 45 °C for 1 h then diisopropylamine (5.40 mmol, 0.55 g) and Et3N (5.70 mmol, 0.58 g) in CH2Cl2 (20 mL) at room temperature for 2 h afforded 1v (0.69 g, 65% yield; mp 66−70 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.15 (d, J = 4.8 Hz, 1H), 6.79 (d, J = 4.8 Hz, 1H), 3.51−3.95 (m, 2H), 2.22 (s, 3H), 1.24−1.59 (m, 12H); 13 C{1H} NMR (100 MHz, CDCl3) δ 164.8, 135.2, 132.5, 129.3, 123.8, 1693



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N,N-Diethyl-2,6-bis(trimethylsilyl)benzamide (1ai′). Method D: N,N-Diethyl-2-(trimethylsilyl)benzamide (0.50 g, 2.0 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40 mmol), TMEDA (0.26 g, 2.20 mmol), and TMSCl (0.28 g, 2.60 mmol) in THF (10 mL) at −78 °C to room temperature for 3 h afforded 1ai′ (0.32 g, 50% yield) as a colorless oil liquid: 1H NMR (600 MHz, CDCl3) δ 7.56 (d, J = 4.8 Hz, 2H), 7.30 (t, J = 4.8 Hz, 1H), 3.56 (q, J = 4.8 Hz, 2H), 3.06 (q, J = 4.8 Hz, 2H), 1.28 (t, J = 4.8 Hz, 3H), 0.97 (t, J = 4.8 Hz, 3H), 0.27 (s, 18H); 13C{1H} NMR (150 MHz, CDCl3) δ 172.2, 147.6, 135.8, 135.5, 126.4, 43.2, 38.5, 13.2, 12.8, 0.4; IR (cm−1) 2956, 1631, 1245, 1095, 835, 775; HRMS (ESI-TOF, m/z) calcd for C17H31NNaOSi2 (M + Na)+ 344.1842, found 344.1842. Preparation of (E)-N,N-diisopropyl-2-(2-(trimethylsilyl)vinyl)benzamide (1d).30 To a well-stirred suspension of (n-Bu)4NOAc (545 mg, 1.81 mmol) and 4 Å molecularsieves in dry DMF (5 mL) were successively added 2-iodo-N,N-diisopropylbenzamide (300 mg, 0.91 mmol), vinyltrimethylsilane (277 mg, 2.72 mmol), and palladium acetate (25 mg, 0.09 mmol). The reaction mixture was then stirred overnight at 50 °C. The mixture was diluted with Et2O and filtered over Celite. The combined organic layers were concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 200:1 → 20:1) to afford 1d (0.15 g, 55% yield; mp 97−101 °C) as a yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 8.0 Hz, 1H), 7.30 (d, J = 7.2 Hz, 1H), 7.24 (t, J = 7.6 Hz, 1H), 7.12 (d, J = 7.2 Hz, 1H), 6.95 (d, J = 19.2 Hz, 1H), 6.50 (d, J = 19.2 Hz, 1H), 3.46−3.61 (m, 2H), 1.57−1.60 (t, J = 5.6 Hz, 6H), 1.07 (d, J = 6.8 Hz, 3H), 1.03 (d, J = 6.8 Hz, 3H), 0.12 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.1, 140.2, 137.7, 134.2, 131.8, 128.1, 127.9, 125.1, 125.0, 50.9, 45.8, 20.7, 20.6, 20.5, 20.3, 1.3; IR (cm−1) 2959, 1629, 1336, 1032, 865, 755; HRMS (ESI-TOF, m/z) calcd for C18H29NNaOSi (M + Na)+ 326.1916, found 326.1913. Preparation of N,N-Diisopropyl-2-((trimethylsilyl)ethynyl)benzamide (1e).31 To a solution of 1n (400 mg, 1.21 mmol) in Et3N (10 mL) were added DMF (5 mL), bis(triphenylphosphine)palladium(II) dichloride (26 mg, 0.04 mmol), copper iodide (12 mg, 0.06 mmol), and trimethylsilylacetylene (119 mg, 1.21 mmol) at room temperature consecutively, and the reaction mixture was stirred for 6 h at room temperature and then diluted with water and extracted with Et2O (3 × 20 mL). The combined organic layer was washed with 1 N HCl (2 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 200:1 → 10:1) to afford 1e (0.23 g, 52% yield; mp 77−79 °C) as a pale yellow solid: 1H NMR (400 MHz, CDCl3) δ 7.47 (d, J = 7.6 Hz, 1H), 7.24− 7.33 (m, 2H), 7.16 (d, J = 7.2 Hz, 1H), 3.56−3.66 (m, 1H), 3.47−3.54 (m, 1H), 1.58 (t, J = 6.8 Hz, 6H), 1.22 (d, J = 6.8 Hz, 3H), 1.04 (d, J = 6.8 Hz, 3H), 0.20 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 169.0, 141.6, 132.9, 128.7, 127.7, 124.9, 119.3, 102.4, 97.4, 51.2, 45.7, 20.8, 20.7, 20.6, 20.3, 0.2; IR (cm−1) 2964, 1633, 1337, 1135, 865, 757; HRMS (ESI-TOF, m/z) calcd for C18 H27NNaOSi(M + Na)+ 324.1760, found 324.1759. Preparation of 2-((tert-Butyldimethylsilyl)oxy)-N,N-diisopropylbenzamide (1p).32 To a solution of 2-hydroxy-N,N-diisopropylbenzamide (0.44 g, 2.0 mmol), DMAP (30 mg, 0.20 mmol), and imidazole (0.22 g, 3.2 mmol) in CH 2 Cl2 (10 mL) was added tertbutyldimethylsilyl chloride (0.35 g, 2.2 mmol) at 0 °C. The reaction mixture was stirred at room temperature for 12 h. The solution was filtered, and the filtrate was evaporated under reduced pressure. The yellow oil was redissolved in ether and acidified to a pH value of 1.0 with 2% hydrochloric acid. The organic layer was separated and washed with satd aq NaCl (3 × 10 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 200:1 → 20:1) to afford 1p (0.52 g, 77% yield; mp 81−83 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.17 (t, J = 7.6 Hz, 1H), 7.06 (d, J = 7.2 Hz, 1H), 6.92 (t, J = 7.2 Hz, 1H), 6.81 (d, J = 8.0 Hz, 1H), 3.64−3.70 (m, 1H), 3.43−3.49 (m, 1H), 1.52 (t, J = 6.4 Hz, 6H), 1.14 (d, J = 6.4 Hz, 3H), 1.01 (d, J = 6.8 Hz, 3H), 0.97 (s, 9H), 0.22 (s, 3H), 0.21 (s, 3H); 13C {1H} NMR (150 MHz,

1331, 724; HRMS (ESI-TOF, m/z) calcd for C19H33NNaOSi (M + Na)+ 342.2229, found 342.2228. N,N-Diisopropyl-2-(triphenylsilyl)benzamide (1i). Method D: N,NDiisopropylbenzamide (0.40 g, 1.95 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40 mmol), TMEDA (0.25 g, 2.15 mmol), and triphenylsilyl chloride (0.75 g, 2.53 mmol) in THF (15 mL) at −78 °C to room temperature for 3 h afforded 1i as a white solid (0.65 g, 72% yield; mp 129−134 °C): 1H NMR (400 MHz, CDCl3) δ 7.62 (d, J = 6.4 Hz, 6H), 7.56 (d, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 1H), 7.30−7.39 (m, 11H), 3.88 (brs, 1H), 3.16 (brs, 1H), 0.99 (d, J = 6.0 Hz, 12H); 13 C{1H} NMR (150 MHz, CDCl3) δ 170.8, 145.5, 139.4, 136.8, 135.2, 133.3, 129.0, 128.9, 127.6, 127.5, 126.2, 50.6, 45.4, 20.7, 20.2; IR (cm−1) 3376, 2973, 1621, 1427, 1332, 1103, 716, 697; HRMS (ESITOF, m/z) calcd for C31H33NNaOSi (M + Na)+ 486.2229, found 486.2230. N,N-Diisopropyl-2-methoxy-6-methylbenzamide (1af). Method D: N,N-Diisopropyl-2-methoxybenzamide (0.47 g, 2.0 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40 mmol), TMEDA (0.25 g, 2.15 mmol), and MeI (0.85 g, 6.0 mmol) in THF (10 mL) at −78 °C to room temperature for 3 h afforded 1af as a pale yellow solid (0.40 g, 80% yield; mp 138−142 °C): 1H NMR (600 MHz, CDCl3) δ 7.15 (t, J = 5.2 Hz, 1H), 6.78 (d, J = 4.8 Hz, 1H), 6.69 (d, J = 5.6 Hz, 1H), 3.77 (s, 3H), 3.61−3.67 (m, 1H), 3.46−3.51 (m, 1H), 2.27 (s, 3H), 1.59 (d, J = 4.8 Hz, 3H), 1.55 (d, J = 4.4 Hz, 3H), 1.10 (d, J = 4.4 Hz, 3H), 1.07 (d, J = 4.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 168.1, 155.2, 135.4, 128.4, 127.9, 122.5, 107.8, 55.4, 50.9, 45.7, 21.0, 20.7, 20.6, 20.5, 18.6; IR (cm−1) 2997, 1619, 1466, 1434, 1334, 1257, 1092, 784, 764; HRMS (ESI-TOF, m/z) calcd for C15H23NNaO2 (M + Na)+ 272.1626, found 272.1627. N,N-Diisopropyl-2-methoxy-6-(trimethylsilyl)benzamide (1ag). Method D: N,N-Diisopropyl-2-methoxybenzamide (0.58 g, 2.44 mmol), s-BuLi (1.0 M in pentane, 2.90 mL, 2.90 mmol), TMEDA (0.31 g, 2.68 mmol), and TMSCl (0.34 g, 3.17 mmol) in THF (10 mL) at −78 °C to room temperature for 3 h afforded 1ag as a white solid (0.60 g, 80% yield; mp 134−137 °C): 1H NMR (400 MHz, CDCl3) δ 7.26 (t, J = 8.0 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 6.84 (d, J = 8.0 Hz, 1H), 3.75 (s, 3H), 3.59−3.69 (m, 1H), 3.44−3.53 (m, 1H), 1.58 (d, J = 6.8 Hz, 3H), 1.54 (d, J = 6.8 Hz, 3H), 1.12 (d, J = 6.4 Hz, 3H), 1.08 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 169.1, 155.0, 139.0, 133.1, 128.4, 127.0, 111.1, 55.0, 50.6, 45.9, 21.0, 20.9, 20.1, 19.9, 0.4; IR (cm−1) 2935, 1612, 1329, 1265, 1152, 1035, 872, 839, 758; HRMS (ESI-TOF, m/z) calcd for C17H29NNaO2Si (M + Na)+ 330.1865, found 330.1865. N,N-Diisopropyl-2-methyl-6-(trimethylsilyl)benzamide (1ah). Method D: N,N-diisopropyl-2-(trimethylsilyl)benzamide (1.50 g, 5.41 mmol), s-BuLi (1.0 M in pentane, 8.12 mL, 8.12 mmol), TMEDA (0.94 g, 8.12 mmol) and MeI (7.68 g, 54.1 mmol) in THF (40 mL) at −78 °C to room temperature for 3 h afforded 1ah as a yellow solid (1.07 g, 68% yield; mp 58−64 °C). 1H NMR (400 MHz, CDCl3) δ 7.38 (d, J = 7.2 Hz, 1H), 7.19 (d, J = 7.6 Hz, 1H), 7.14 (d, J = 7.6 Hz, 1H), 3.50−3.63 (m, 2H), 2.31 (s, 3H), 1.61 (d, J = 6.8 Hz, 3H), 1.57 (d, J = 6.8 Hz, 3H), 1.10 (d, J = 6.8 Hz, 3H), 1.07 (d, J = 6.8 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.4, 143.0, 136.2, 133.0, 132.6, 130.9, 127.0, 50.4, 46.0, 21.1, 21.0, 20.4, 20.0, 19.4, 0.7; IR (cm−1) 2964, 1626, 1439, 1321, 1031, 878, 837, 773; HRMS (ESITOF, m/z) calcd for C17H29NNaOSi (M + Na)+: 314.1916, found 314.1913. N,N-Diisopropyl-2,6-bis(trimethylsilyl)benzamide (1ai). Method D: N,N-Diisopropyl-2-(trimethylsilyl)benzamide (0.56 g, 2.0 mmol), s-BuLi (1.0 M in pentane, 2.40 mL, 2.40 mmol), TMEDA (0.26 g, 2.20 mmol), and TMSCl (0.28 g, 2.60 mmol) in THF (10 mL) at −78 °C to room temperature for 3 h afforded 1ai (0.60 g, 86% yield) as a colorless oil liquid: 1H NMR (400 MHz, CDCl3) δ 7.56 (d, J = 7.6 Hz, 2H), 7.27(t, J = 7.6 Hz, 1H), 4.08−4.18 (m, 1H), 3.49−3.59 (m, 1H), 1.53 (d, J = 7.2 Hz, 6H), 1.08 (d, J = 6.8 Hz, 6H), 0.31 (s, 18H); 13 C{1H} NMR (150 MHz, CDCl3) δ 172.5, 148.6, 135.9, 135.8, 125.7, 49.8, 46.1, 22.0, 21.5, 1.1; IR (cm−1) 2960, 1629, 1285, 1101, 843, 786; HRMS(ESI-TOF, m/z) calcd for C19H35NNaOSi2 (M + Na)+ 372.2155, found 372.2160. 1694



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CDCl3) δ 168.6, 151.2, 131.3, 128.8, 126.7, 121.1, 119.5, 50.6, 45.5, 25.8, 20.8 (2C), 20.5, 20.4, 18.2; IR (cm−1) 2961, 1636, 1472, 1338, 1252, 907, 837,783; HRMS (ESI-TOF, m/z) calcd for C19H34NO2Si (M + H)+ 336.2359, found 336.2354. Preparation of 2-Bromo-N,N-diisopropyl-6-methylbenzamide (1ae).33 To a solution of 1ah (438 mg, 1.50 mmol) in CH2Cl2 (5.0 mL) was added bromine (360 mg, 2.25 mmol) at 0 °C dropwise. The reaction mixture was stirred at 40 °C for 6 h and then diluted with satd aq Na2SO3 (5 mL) and extracted with CH2Cl2 (3 × 5 mL). The combined organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 100:1 → 10:1) to afford 1ae (0.41 g, 92% yield; mp 156−162 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 7.6 Hz, 1H), 7.11 (d, J = 7.2 Hz, 1H), 7.04 (t, J = 7.6 Hz, 1H), 3.48−3.61 (m, 2H), 2.32 (s, 3H), 1.60 (d, J = 7.2 Hz, 3H), 1.57 (d, J = 7.2 Hz, 3H), 1.23 (d, J = 6.4 Hz, 3H), 1.09 (d, J = 6.4 Hz, 3H); 13 C{1H} NMR (150 MHz, CDCl3) δ 167.7, 139.2, 136.1, 130.0, 129.1, 128.9, 119.2, 51.2, 46.1, 21.2, 20.9, 20.5, 20.1, 19.4; IR (cm−1) 3354, 2932, 1625, 1440, 1369, 1335, 785, 736; HRMS (ESI-TOF, m/z) calcd for C14H20BrNNaO (M + Na)+ 320.0626, found 320.0627. Preparation of N1,N1-Diisopropyl-N4-methoxy-N4-methylterephthalamide (1aw).34 To a solution of methyl 4(diisopropylcarbamoyl)benzoate (263 mg, 1.0 mmol) and Nmethoxymethylamine (151 mg, 1.55 mmol) in THF (2 mL) was added isopropylmagnesium chloride solution (2.0 M in THF, 1.5 mL, 3.0 mmol) at −20 °C. The reaction mixture was stirred for 30 min before being quenched with satd aq NaHCO3 (2 mL) and extracted with Et2O (3 × 5 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 50:1 → 5:1) to afford 1aw (265 mg, 81% yield; mp 130−136 °C) as a white solid: 1HNMR (400 MHz, CDCl3) δ 7.64 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.6 Hz, 2H), 3.67−3.91 (m, 1H), 3.49 (brs, 4H), 3.31 (s, 3H), 1.49 (brs, 6H), 1.08 (brs, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.2, 169.2, 140.8, 134.3, 128.4, 125.2, 61.2, 50.9, 45.8, 33.6, 20.6; IR (cm−1) 2969, 1621, 1440, 1342, 1261, 764; HRMS (ESI-TOF, m/z) calcd for C16H25N2O3 (M + H)+ 293.1865, found 293.1862. Preparation of N1,N1-Diisopropyl-N4-methyl-N4-phenylterephthalamide (1ax).34 To a solution of N-methylaniline (81 mg, 0.75 mmol) in THF (1 mL) was added a solution of isopropylmagnesium chloride lithium chloride complex (1.3 M in THF, 1.1 mL, 1.5 mmol) at room temperature under Ar. After the mixture was stirred for 2 h at room temperature, a solution of methyl 4-(diisopropylcarbamoyl)benzoate (132 mg, 0.5 mmol) in THF (1 mL) was added. The reaction mixture was stirred for 1 h before being quenched with 1 N HCl (2 mL) and extraction with Et2O (3 × 5 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 50:1 → 5:1) to afford 1ax (163 mg, 96% yield; mp 140−145 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.22 (d, J = 8.0 Hz, 2H), 7.11 (t, J = 7.6 Hz, 2H), 7.00−7.04 (m, 3H), 6.93(d, J = 7.6 Hz, 2H), 3.53 (brs, 1H), 3.39 (brs, 4H), 1.38 (brs, 6H), 0.96 (brs, 6H); 13 C{1H} NMR (150 MHz, CDCl3) δ 169.8, 169.6, 144.1, 139.4, 135.9, 128.9, 128.5, 126.5, 126.4, 124.6, 50.5, 45.5, 38.0, 20.2; IR (cm−1) 2967, 1629, 1495, 1369, 1339, 766, 699; HRMS (ESI-TOF, m/z) calcd for C21H27N2O2(M + H)+: 339.2073, found 339.2073. Preparation of tert-Butyl (4-(Diisopropylcarbamoyl)phenyl)carbamate (1ay).35,36 Hydrogen gas was bubbled through the solution of 1aj (1.02 g, 4.6 mmol) and 10% Pd/C (0.20 g, 53% moisture) in ethyl acetate (35 mL) at room temperature. After being stirred for 9 h, the mixture was filtered, and the filtrate was concentrated under reduced pressure to give compound 4-aminoN,N-diisopropylbenzamide 1az (0.78 g, 89%) as a white solid without further purification. To a solution of 1az (0.33 g, 1.5 mmol) in dioxane (6 mL) was added (Boc)2O (0.43 g, 1.95 mmol) at room temperature. After being stirred at 105 °C for 3 h, the reaction mixture was poured into water and extracted with CH2Cl2 (3 × 10 mL). The combined

organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 50:1 → 3:1) to afford 1ay (0.45 g, 94% yield; mp 198−201 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.34 (d, J = 8.4 Hz, 2H), 7.23(d, J = 8.4 Hz, 2H), 6.74 (brs, 1H), 3.69 (brs, 2H), 1.51 (s, 9H), 1.25−1.42 (m, 12H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.8, 152.8, 138.9, 133.1, 126.5, 118.3, 80.5, 50.9, 46.2, 28.3, 20.7; IR (cm−1) 2970, 1724, 1608, 1528, 1342, 1236, 1159, 1051, 850; HRMS (ESITOF, m/z) calcd for C18H29N2O3 (M + H)+ 321.2178, found 321.2175. General Procedures A for Reduction of Amides to Aldehydes. To a solution of amide (1.0 equiv, 0.30 mmol) and 2,6-DTBMP (185 mg, 0.90 mmol) in CH2Cl2 (2 mL) was added EtOTf (80 mg, 0.45 mmol) at room temperature. The mixture was stirred at room temperature or 45 °C for 2−4 h. THF (4 mL) was added into the reaction mixture, and then the mixture was cooled to −78 °C and stirred for 20 min. To the resulting mixture was added LiAlH(O-t-Bu)3 (1.1 M in THF, 0.55 mL, 0.60 mmol). The reaction mixture was stirred for 4 h at −78 °C before being quenched with satd aq C4H4O6KNa·4H2O (2 mL) and extraction with Et2O (3 × 10 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography to afford the corresponding aldehyde. 2-Methylbenzaldehyde (2a): light yellow oil liquid; 33 mg, 92% yield; 1H NMR (400 MHz, CDCl3) δ 10.27 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.49 (t, J = 7.6 Hz, 1H), 7.37 (t, J = 7.6 Hz, 1H), 7.27 (d, J = 7.2 Hz, 1H), 2.68 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 192.8, 140.6, 134.1, 133.6, 132.0, 131.7, 126.3, 19.5. The physical and spectral data were consistent with those previously reported.37 2-Isopropylbenzaldehyde (2b): colorless oil liquid; 42 mg, 95% yield; 1H NMR (400 MHz, CDCl3) δ 10.36 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.45 (d, J = 8.0 Hz, 1H), 7.34 (t, J = 7.2 Hz, 1H), 3.93−4.03 (m, 1H), 1.30 (d, J = 6.8 Hz, 6H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.3, 151.4, 134.0, 132.9, 131.4, 126.1, 126.0, 27.6, 23.8. The physical and spectral data were consistent with those previously reported.38 [1,1′-Biphenyl]-2-carbaldehyde (2c): colorless oil liquid; 49 mg, 91% yield; 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.04 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.45−7.52 (m, 5H), 7.38−7.40 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 192.4, 145.9, 137.7, 133.6, 133.5, 130.7, 130.0, 128.4, 128.1, 127.7, 127.5. The physical and spectral data were consistent with those previously reported.39 (E)-2-(2-(Trimethylsilyl)vinyl)benzaldehyde (2d): yellow oil liquid; 58 mg, 95% yield; 1H NMR (400 MHz, CDCl3) δ 10.32 (s, 1H), 7.82 (d, J = 8.0 Hz, 1H), 7.67 (d, J = 19.2 Hz, 1H), 7.59 (d, J = 7.6 Hz, 1H), 7.55 (d, J = 7.2 Hz, 1H), 7.40 (t, J = 7.2 Hz, 1H), 6.44 (d, J = 19.2 Hz, 1H), 0.19 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.2, 141.8, 139.5, 137.7, 133.6, 132.7, 130.6, 127.8, 127.4, −1.4; IR (cm−1) 2955, 1694, 1246, 838, 756; HRMS (ESI-TOF, m/z) calcd for C12H17OSi (M + H)+ 205.1049, found 205.1048. 2-((Trimethylsilyl)ethynyl)benzaldehyde (2e): colorless oil liquid; 58 mg, 94% yield; 1H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.91 (d, J = 7.6 Hz, 1H), 7.52−7.58 (m, 2H), 7.43 (t, J = 7.6 Hz, 1H), 0.28 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.9, 136.1, 133.7, 133.5, 128.8, 126.8, 126.7, 102.4, 100.0, −0.2; IR (cm−1) 2960, 2157, 1699, 1593, 1250, 865, 842, 760; HRMS (ESI-TOF, m/z) calcd for C12H14NaOSi (M + Na)+ 225.0712, found 225.0723. 2-(Trifluoromethyl)benzaldehyde (2f): colorless oil liquid; 32 mg, 62% yield; 1H NMR (400 MHz, CDCl3) δ 10.41 (s, 1H), 8.13−8.15 (m,1H), 7.79−7.81 (m,1H), 7.71−7.73 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 189.0 (q, 4JC−F = 2.6 Hz), 133.6, 132.3, 131.4 (q, 2 JC−F = 32.2 Hz), 129.1, 126.9 (q, 3JC−F = 5.6 Hz), 126.1 (q, 3JC−F = 5.7 Hz), 123.7 (q, 1JC−F = 273.0 Hz). The physical and spectral data were consistent with those previously reported.40 2-(Trimethylsilyl)benzaldehyde (2g): colorless oil; 48 mg, 90% yield; 1H NMR (400 MHz, CDCl3) δ 10.17 (s, 1H), 7.90 (d, J = 7.6 Hz, 1H), 7.72 (d, J = 7.2 Hz, 1H), 7.53−7.59 (m, 2H), 0.36 (s, 9H); 13 C{1H} NMR (150 MHz, CDCl3) δ 193.5, 142.7, 141.0, 135.6, 133.0, 1695



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10.51 (d, J = 5.6 Hz, 1H), 7.97−7.99 (m, 1H), 7.45−7.52 (m, 2H), 7.27−7.36 (m, 10H), 6.97−7.00 (m, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.6 (d, 3JC−P = 19.2 Hz), 141.1 (d, 1JC−P = 26.3 Hz, 2C), 138.4 (d, 1JC−P = 14.6 Hz), 136.1 (d, 2JC−P = 9.6 Hz),134.0 (d, 2JC−P = 20.3 Hz, 4C), 133.8, 133.6, 130.6 (d, 2JC−P = 4.1 Hz), 129.1 (2C), 128.8, 128.7 (d, 3JC−P = 7.4 Hz, 4C). The physical and spectral data were consistent with those previously reported.37 3-Chloro-2-methylbenzaldehyde (2r): yellow solid; 44 mg, 96% yield; mp 151−157 °C; 1H NMR (400 MHz, CDCl3) δ 10.28 (s, 1H), 7.72 (d, J = 8.0 Hz, 1H), 7.60 (d, J = 8.0 Hz, 1H), 7.31 (t, J = 7.6 Hz, 1H), 2.72 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.7, 138.3, 136.4, 135.7, 134.3, 130.2, 127.0, 15.0. The physical and spectral data were consistent with those previously reported.44 3-Methoxy-2-methylbenzaldehyde (2s): yellow oil liquid; 42 mg, 93% yield; 1H NMR (400 MHz, CDCl3) δ 10.31 (s, 1H), 7.41 (d, J = 7.6 Hz, 1H), 7.30 (t, J = 8.0 Hz, 1H), 7.06 (d, J = 8.0 Hz, 1H), 3.86 (s, 3H), 2.53 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 192.7, 158.0, 135.0, 129.6, 126.5, 122.9, 115.2, 55.8, 10.4; IR (cm−1)2391, 1688, 1583, 1469, 1259, 1242, 782, 705; HRMS (ESI-TOF, m/z) calcd for C9H10NaO2 (M + Na)+ 173.0578, found 173.0578. 4-Chloro-2-methoxybenzaldehyde (2t): yellow solid; 48 mg, 95% yield; mp 67−74 °C; 1H NMR (400 MHz, CDCl3) δ 10.37 (s, 1H), 7.75 (d, J = 5.6 Hz, 1H), 6.99 (d, J = 5.6 Hz, 1H), 6.97 (s, 1H), 3.92 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 188.6, 162.1, 141.9, 129.6, 123.3, 121.2, 112.3, 55.9; IR (cm−1) 2952, 1678, 1590, 1474, 1396, 1243, 1092, 1022, 882, 812; HRMS (ESI-TOF, m/z) calcd for C8H8ClO2 (M + H)+ 171.0213, found 171.0213.The physical and spectral data were consistent with those previously reported.45 1-Naphthaldehyde (2u): colorless oil liquid; 42 mg, 91% yield; 1H NMR (400 MHz, CDCl3) δ 10.40 (s, 1H), 9.26 (d, J = 8.4 Hz, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.99 (d, J = 6.8 Hz, 1H), 7.92 (d, J = 8.0 Hz, 1H), 7.70 (t, J = 7.2 Hz, 1H), 7.58−7.65 (m, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.5, 136.6, 135.2, 133.7, 131.4, 130.5, 129.0, 128.4, 126.9, 124.8 (2C). The physical and spectral data were consistent with those previously reported.46 3-Methylthiophene-2-carbaldehyde (2v): yellow oil liquid; 35 mg, 94% yield; 1H NMR (400 MHz, CDCl3) δ 10.03 (s, 1H), 7.63 (d, J = 4.8 Hz, 1H), 6.97 (d, J = 4.8 Hz, 1H), 2.58 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 182.3, 147.3, 137.6, 134.3, 131.7, 14.2. The physical and spectral data were consistent with those previously reported.47 1-Methyl-1H-indole-3-carbaldehyde (2w): white solid; 43 mg, 90% yield; mp 68−70 °C; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.30 (d, J = 7.2 Hz, 1H), 7.63 (s, 1H), 7.32−7.34 (m, 3H), 3.83 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 184.3, 139.2, 137.8, 125.1, 123.9, 122.8, 121.9, 117.9, 109.8, 33.6. The physical and spectral data were consistent with those previously reported.48 3-Phenylpropiolaldehyde (2x): yellow oil liquid; 32 mg, 82% yield; 1 H NMR (400 MHz, CDCl3) δ 9.42 (s, 1H), 7.61 (d, J = 7.2 Hz, 1H), 7.49 (t, J = 7.2 Hz, 1H), 7.40 (t, J = 7.6 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 176.8, 133.2, 131.3, 128.7, 119.4, 95.1, 88.4. The physical and spectral data were consistent with those previously reported.49 Cinnamaldehyde (2y): yellow oil liquid; 31 mg, 80% yield; 1H NMR (400 MHz, CDCl3) δ 9.72 (d, J = 7.6 Hz, 1H), 7.57−7.59 (m, 2H), 7.49 (d, J = 16.0 Hz, 1H), 7.44−7.45 (m, 3H), 6.73 (dd, J1 = 16.0 Hz, J2 = 7.6 Hz, 1H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.7, 152.8, 134.0, 131.3, 129.1, 128.6, 128.5. The physical and spectral data were consistent with those previously reported.50 Decanal (2z): colorless oil liquid; 30 mg, 65% yield; 1H NMR (400 MHz, CDCl3) δ 9.76 (t, J = 1.6 Hz, 1H), 2.41 (dt, J1 = 6.4 Hz, J2 = 1.6 Hz, 2H), 1.62 (q, J = 6.4 Hz, 2H), 1.26−1.29 (m, 12H), 0.87 (t, J = 6.4 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 203.0, 43.9, 31.8, 29.4, 29.3, 29.2, 29.1, 22.6, 22.1, 14.1. The physical and spectral data were consistent with those previously reported.51 Undec-10-enal (2aa): colorless oil liquid; 34 mg, 68% yield; 1H NMR (400 MHz, CDCl3) δ 9.76 (t, J = 1.6 Hz, 1H), 5.75−5.85 (m, 1H), 4.91−5.00 (m, 2H), 2.41 (dt, J1 = 7.6 Hz, J2 = 1.6 Hz, 2H), 2.03 (m, 2H), 1.61 (m, 2H), 1.25−1.38 (m, 10H); 13C{1H} NMR (150 MHz, CDCl3) δ 202.9, 139.1, 114.1, 43.9, 33.7, 29.3, 29.2, 29.1, 29.0,

132.5, 129.3, 0.1. The physical and spectral data were consistent with those previously reported.41 2-(Triethylsilyl)benzaldehyde (2h): colorless oil; 60 mg, 91% yield; 1 H NMR (400 MHz, CDCl3) δ 10.20 (s, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.67 (d, J = 6.8 Hz, 1H), 7.51−7.58 (m, 2H), 0.92 (s, 15H); 13 C{1H} NMR (150 MHz, CDCl3) δ 193.4, 141.8, 140.4, 136.5, 132.9, 131.0, 129.2, 7.6, 4.4; IR (cm−1) 2953, 1708, 1003, 843, 723; HRMS (ESI-TOF, m/z) calcd for C13H20KOSi (M + K)+ 259.0920, found 259.0919. 2-(Triphenylsilyl)benzaldehyde (2i): white solid; 97 mg, 89% yield; mp 158−162 °C; 1H NMR (400 MHz, CDCl3) δ 10.00 (s, 1H), 8.10 (d, J = 7.6 Hz, 1H), 7.64 (t, J = 7.6 Hz, 1H), 7.53−7.55 (m, 7H), 7.42−7.47 (m, 4H), 7.36−7.39 (m, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 192.5, 141.7, 138.9, 137.4, 136.0, 135.9, 134.4, 133.3, 130.4, 129.7, 128.0; IR (cm−1) 3067, 1694, 1427, 1201, 1107, 698, 506; HRMS (ESI-TOF, m/z) calcd for C25H20NaOSi (M + Na)+ 387.1181, found 387.1176. 2-(Bis(trimethylsilyl)methyl)benzaldehyde (2j): colorless oil; 70 mg, 89% yield; 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 7.69 (d, J = 7.6 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.20 (t, J = 7.2 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 3.41 (s, 1H), 0.03 (s, 18H); 13C{1H} NMR (100 MHz, CDCl3) δ 193.7, 147.8, 134.4, 133.1, 132.8, 130.3, 123.6, 22.8, 0.2; IR (cm−1) 3365, 2954, 1694, 1248, 1210, 835, 751; HRMS (ESITOF, m/z) calcd for C14H24NaOSi2 (M + Na)+ 287.1263, found 287.1267. For gram-scale reaction: 1j (4.36 g, 12.0 mmol), 2,6DTBMP (7.40 g, 36.0 mmol), and EtOTf (3.20 g, 18.0 mmol) in CH2Cl2 (20 mL) at 45 °C for 6 h then THF (20 mL) and LiAlH(O-tBu)3 (1.1 M in THF, 22.0 mL, 24.0 mmol) were added at −78 °C for 8 h to afford 2j as a colorless oil (2.20 g, 70% yield). 2-Fluorobenzaldehyde (2k): colorless oil liquid; 31 mg, 84% yield; 1 H NMR (400 MHz, CDCl3) δ 10.38 (s, 1H), 7.86−7.90 (m, 1H), 7.59−7.64 (m, 1H), 7.27−7.30 (m, 1H), 7.16−7.21 (m, 1H); 13C {1H} NMR (150 MHz, CDCl3) δ 187.2 (d, 3JC−F = 6.8 Hz), 164.7 (d, 1 JC−F = 257.1 Hz), 136.3 (d, 3JC−F = 9.0 Hz), 128.7 (d, 3JC−F = 1.8 Hz), 124.6 (d, 4JC−F = 3.6 Hz), 124.2 (d, 2JC−F = 8.0 Hz), 116.5 (d, 2JC−F = 20.3 Hz). The physical and spectral data were consistent with those previously reported.37 2-Chlorobenzaldehyde (2l): oily liquid; 36 mg, 84% yield; 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 7.92 (d, J = 7.6 Hz, 1H), 7.53 (t, J = 7.2 Hz, 1H), 7.45 (d, J = 7.6 Hz, 1H), 7.38 (t, J = 7.6 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 189.8, 137.9, 135.1, 132.4, 130.6, 129.3, 127.3. The physical and spectral data were consistent with those previously reported.42 2-Bromobenzaldehyde (2m): white solid; 50 mg, 91% yield; 1H NMR (400 MHz, CDCl3) δ 10.35 (s, 1H), 7.90 (d, J = 6.8 Hz, 1H), 7.63−7.65 (m, 1H), 7.40−7.46 (m, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.8, 135.3, 133.8, 133.4, 129.8, 127.8, 127.1. The physical and spectral data were consistent with those previously reported.40 2-Iodobenzaldehyde (2n): white solid; 67 mg, 96% yield; mp 36− 39 °C; 1H NMR (400 MHz, CDCl3) δ 10.06 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H), 7.87 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.2 Hz, 1H), 7.28 (t, J = 7.6 Hz, 1H); 13C{1H} NMR (150 MHz, CDCl3) δ 195.7, 140.6, 135.4, 135.0, 130.2, 128.6, 100.7. The physical and spectral data were consistent with those previously reported.37 2-Methoxybenzaldehyde (2o): light yellow solid; 38 mg, 93% yield; mp 34−39 °C; 1H NMR (400 MHz, CDCl3) δ 10.46 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.54 (t, J = 7.6 Hz, 1H), 6.97−7.03 (m, 2H),3.91 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 189.8, 161.7, 135.9, 128.4, 124.7, 120.6, 111.6, 55.5. The physical and spectral data were consistent with those previously reported.40 2-((tert-Butyldimethylsilyl)oxy)benzaldehyde (2p): yellow oil liquid; 66 mg, 93% yield; 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 7.81 (d, J = 7.6 Hz, 1H), 7.46 (t, J = 7.6 Hz, 1H), 7.03 (t, J = 7.6 Hz, 1H), 6.88 (d, J = 8.0 Hz, 1H), 1.02 (s, 9H), 0.28 (s, 6H); 13C{1H} NMR (150 MHz, CDCl3) δ 190.1, 158.9, 135.7, 128.3, 127.2, 121.4, 120.2, 25.6, 18.3, −4.3. The physical and spectral data were consistent with those previously reported.43 2-(Diphenylphosphino)benzaldehyde (2q): light yellow solid; 68 mg, 78% yield; mp 113−115 °C; 1H NMR (400 MHz, CDCl3) δ 1696



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residue was purified by silica gel flash column chromatography (eluent: petroleum ether/EtOAc) to afford the corresponding aldehyde. Preparation of LiAlH(OEt)3. LiAlH(OEt)3 (1.0 M in THF) was prepared according to the literature55 as described below: To a solution of LiAlH4 (20 mL, 1.0 M in THF) at 0 °C was added ethyl acetate (2.64 g, 3.0 mL) dropwise, the mixture stirred for additional 30 min at 0 °C and used without further purification. 2,4,6-trimethylbenzaldehyde (2ac). colorless oil liquid; 35 mg, 79% yield; 1H NMR (600 MHz, CDCl3) δ 10.56 (s, 1H), 6.90 (s, 2H), 2.58 (s, 6H), 2.32 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 193.0, 143.8, 141.5, 130.5, 129.9, 21.4, 20.5. The physical and spectral data were consistent with those previously reported.56 2,6-dichlorobenzaldehyde (2ad). white solid; 42 mg, 80% yield; mp 67−71 °C; 1H NMR (400 MHz, CDCl3) δ 10.48 (s, 1H), 7.38 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 188.8, 136.8, 133.6, 130.3, 129.7. The physical and spectral data were consistent with those previously reported.57 2-bromo-6-methylbenzaldehyde (2ae). colorless oil liquid; 42 mg, 70% yield; 1H NMR (400 MHz, CDCl3) δ 10.52 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H), 7.26 (t, J = 7.6 Hz, 1H), 7.20 (d, J = 7.6 Hz, 1H), 2.57 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 194.5, 142.6, 133.6, 131.7, 131.6, 131.4, 128.2, 21.2. The physical and spectral data were consistent with those previously reported.58 2-methoxy-6-methylbenzaldehyde (2af). yellow solid; 35 mg, 78% yield; mp 37−39 °C; 1H NMR (400 MHz, CDCl3) δ 10.63 (s, 1H), 7.37 (t, J = 8.0 Hz, 1H), 6.82 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 7.6 Hz, 1H), 3.89 (s, 3H), 2.56 (s, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 192.2, 163.1, 141.9, 134.4, 124.0, 123.3, 109.0, 55.7, 21.4. The physical and spectral data were consistent with those previously reported.59 2-methoxy-6-(trimethylsilyl)benzaldehyde (2ag). colorless oil liquid; 54 mg, 87% yield; 1H NMR (400 MHz, CDCl3) δ 10.59 (s, 1H), 7.52 (t, J = 7.6 Hz, 1H), 7.28 (d, J = 7.2 Hz, 1H), 7.03 (d, J = 8.4 Hz, 1H), 3.92 (s, 3H), 0.20 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.3, 163.0, 144.0, 134.5, 129.0, 127.8, 112.5, 55.6, 0.03; IR (cm−1) 2945, 1682, 1568, 1468, 1394, 1256, 875, 838, 762; HRMS (ESI-TOF, m/z) calcd for C11H16NaO2Si (M + Na)+: 231.0817, found 231.0815. 2-methyl-6-(trimethylsilyl)benzaldehyde (2ah). colorless oil liquid; 43 mg, 75% yield; 1H NMR (400 MHz, CDCl3) δ 10.56 (s, 1H), 7.57 (d, J = 7.2 Hz, 1H), 7.43 (t, J = 7.2 Hz, 1H), 7.27 (d, J = 6.8 Hz, 1H), 2.68 (s, 3H), 0.34 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 193.3, 143.7, 141.3, 138.7, 133.5, 132.7, 132.4, 20.2, 0.5; IR (cm−1) 2955, 1690, 1246, 1145, 879, 836, 756; HRMS (ESI-TOF, m/ z) calcd for C11H17OSi (M + H)+: 193.1049, found 193.1050. 2,6-bis(trimethylsilyl)benzaldehyde (2ai). colorless oil liquid; 48 mg, 64% yield; 1H NMR (400 MHz, CDCl3) δ 10.47 (s, 1H), 7.75 (d, J = 7.6 Hz, 2H), 7.52 (t, J = 7.2 Hz, 1H), 0.38 (s, 18H);13C{1H} NMR (150 MHz, CDCl3) δ 193.8, 145.8, 144.1 (2C), 136.2 (2C), 131.4, 0.7; IR (cm−1) 2956, 1692, 1247, 1025, 859, 757; HRMS (ESI-TOF, m/z) calcd for C13H22NaOSi2(M + Na)+: 273.1107, found 273.1111. Preparation of N,N-diisopropyl-4-methoxybenzamide (7). Using General Method A for the preparation of amide 7: 4-methoxybenzoyl chloride (2.0 g, 11.70 mmol), diisopropylamine (1.20 g, 11.70 mmol), and Et3N (1.43 g, 14.10 mmol) in CH2Cl2 (25 mL) at room temperature for 4 h afforded 7 (2.22 g, 81% yield) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.25 (d, J = 8.4 Hz, 2H), 6.86 (d, J = 8.4 Hz, 2H), 3.79 (s, 3H), 3.50−3.96 (m, 2H), 1.31 (brs, 12H); 13C{1H} NMR (150 MHz, CDCl3) δ 170.8, 159.8, 131.2, 127.3, 113.5, 55.2, 50.4, 46.9, 20.7. The physical and spectral data were consistent with those previously reported.60 Preparation of N,N-diisopropyl-4-methoxy-2-(trimethylsilyl)benzamide (8). Using method D for the preparation of amide 8: amide 7 (0.80 g, 3.40 mmol), s-BuLi (1.0 M in pentane, 4.0 mL, 4.0 mmol), TMEDA (0.44 g, 3.74 mmol) and TMSCl (0.48 g, 4.42 mmol) in THF (15 mL) at −78 °C to room temperature for 3 h afforded 8 (0.62 g, 60% yield; mp 68−76 °C) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.11 (d, J = 8.0 Hz, 2H), 6.80 (dd, J1 = 8.4 Hz, J2 = 2.0 Hz, 1H), 3.86 (brs, 1H), 3.81 (s, 3H), 3.48 (brs, 1H), 1.53 (brs, 6H), 1.15 (brs, 6H), 0.31 (s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 172.2, 158.6, 140.4, 136.5, 126.7, 121.1, 112.4, 55.0, 50.8,

28.9, 22.0. The physical and spectral data were consistent with those previously reported.52 4-Nitrobenzaldehyde (2aj): white solid; 40 mg, 88% yield; 1H NMR (400 MHz, CDCl3) δ 10.16 (s, 1H), 8.39 (d, J = 8.4 Hz, 2H), 8.08 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 190.3, 151.1, 140.0, 130.4, 124.3. The physical and spectral data were consistent with those previously reported.53 4-Cyanobenzaldehyde (2ak): white solid; 36 mg, 92% yield; 1H NMR (400 MHz, CDCl3) δ 10.08 (s, 1H), 7.99 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H); 13C{1H} NMR (100 MHz, CDCl3) δ 190.6, 138.6, 132.8, 129.8, 117.6, 117.5. The physical and spectral data were consistent with those previously reported.53 Methyl 4-formylbenzoate (2al): white solid; 47 mg, 96% yield; mp 60−62 °C; 1H NMR (400 MHz, CDCl3) δ 10.09 (s, 1H), 8.18 (d, J = 5.2 Hz, 2H), 7.94 (d, J = 5.2 Hz, 2H), 3.94 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.6, 166.0, 139.1, 135.0, 130.1, 129.5, 52.6. The physical and spectral data were consistent with those previously reported.54 4-Acetylbenzaldehyde (2am): yellow solid; 14 mg, 93% yield; mp 35−38 °C; 1H NMR (400 MHz, CDCl3) δ 10.11 (s, 1H), 8.10 (d, J = 8.0 Hz, 2H), 7.98 (d, J = 8.4 Hz, 2H); 13C{1H} NMR (150 MHz, CDCl3) δ 197.4, 191.6, 141.2, 139.0, 129.8, 128.8, 27.0. The physical and spectral data were consistent with those previously reported.54 Terephthalaldehyde (2an): white solid; 10 mg, 71% yield; mp 112−116 °C; 1H NMR (400 MHz, CDCl3) δ 10.14 (s, 2H), 8.06 (s, 4H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.5, 140.0, 130.1. The physical and spectral data were consistent with those previously reported.54 4-Formyl-N,N-diisopropylbenzamide (2ao). To a solution of 1aw (33 mg, 0.1 mmol) in THF (0.5 mL) at −78 °C was added DIBAL-H (0.15 mL, 1.0 M solution in hexanes) dropwise, and the reaction mixture was stirred for 2 h at −78 °C before being quenched with satd aq C4H4O6KNa·4H2O (2 mL) and extracted with Et2O (3 × 5 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 100:1 → 10:1) to afford 2ao (19 mg, 82% yield; mp 97−100 °C) as a white solid: 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.90 (d, J = 8.0 Hz, 2H), 7.44 (d, J = 8.0 Hz, 2H), 3.70 (brs, 1H), 3.52 (brs, 1H), 1.40−1.76 (m, 6H), 0.95−1.23 (m, 6H). 2ao and 1an are two identical compounds. The physical and spectral data of 2ao were consistent with those reported for 1an (see the Supporting Information). 4-Formyl-N-methyl-N-phenylbenzamide (2ap): colorless oil liquid; 59 mg, 82% yield; 1H NMR (400 MHz, CDCl3) δ 9.91 (s, 1H), 7.67 (d, J = 8.0 Hz, 2H), 7.42 (d, J = 8.0 Hz, 2H), 7.22 (t, J = 7.2 Hz, 2H), 7.14 (t, J = 7.2 Hz, 1H), 7.02 (d, J = 7.6 Hz, 2H), 3.50 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.5, 169.3, 144.0, 141.6, 136.4, 129.3, 129.1, 129.0, 127.0, 126.9, 38.2; IR (cm−1) 2923, 1697, 1638, 1593, 1494, 1368, 1300, 1205, 1102, 828, 753, 698; HRMS (ESITOF, m/z) calcd for C15H14NO2 (M + H)+ 240.1025, found 240.1026. tert-Butyl (4-formylphenyl)carbamate (2aq): white solid; 62 mg, 94% yield; mp 136−142 °C; 1H NMR (400 MHz, CDCl3) δ 9.89 (s, 1H), 7.82 (d, J = 8.4 Hz, 2H), 7.54 (d, J = 8.4 Hz, 2H), 6.89 (bs, 1H), 1.52(s, 9H); 13C{1H} NMR (100 MHz, CDCl3) δ 191.1, 152.1, 144.3, 131.2, 131.1, 117.8, 81.4, 28.2. The physical and spectral data were consistent with those previously reported.54 General Procedure B for Reduction of Amides to Aldehydes. To a solution of amide (1.0 equiv, 0.30 mmol) in CH2Cl2 (2 mL) was added EtOTf (107 mg, 0.60 mmol). The mixture was stirred at room temperature or 45 °C for 2−4 h. THF (4 mL) was added to the reaction mixture , and then the mixture was cooled to −78 °C and stirred for 20 min. To the resulting mixture was added LiAlH(OEt)3 (1.0 M in THF, 1.20 mL, 1.20 mmol) dropwise. The reaction mixture was stirred for an additional 8 h at −78 or −20 °C before being quenched with satd aq C4H4O6KNa·4H2O (2 mL) and extraction with Et2O (3 × 10 mL). The combined organic layers were then dried over Na2SO4, filtered and concentrated under reduced pressure. The 1697



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45.6, 20.5, 0.02; IR (cm−1) 2962, 1625, 1432, 1332, 1225, 840; HRMS (ESI-TOF, m/z) calcd for C17H30NO2Si (M + H)+: 308.2046, found 308.2043. Preparation of 4-methoxy-2-(trimethylsilyl)benzaldehyde (9). Using method A for reduction of amide 8 to aldehyde 9: amide 8 (277 mg, 0.90 mmol), 2,6-DTBMP (240 mg, 1.35 mmol), and EtOTf (555 mg, 2.70 mmol) in CH2Cl2 (4 mL) at room temperature for 2 h and then THF (6 mL) and LiAlH(O-t-Bu)3 (1.1 M in THF, 0.55 mL, 0.60 mmol) were added at −78 °C for 4 h to afford 9 (172 mg, 92% yield) as a colorless oily liquid: 1H NMR (400 MHz, CDCl3) δ 10.01 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.21(d, J = 2.4 Hz, 1H), 6.99 (dd, J1 = 8.4 Hz, J2 = 2.4 Hz, 1H), 3.89 (s, 3H), 0.35 (s, 9H); 13C{1H} NMR (150 MHz, CDCl3) δ 191.7, 163.1, 145.4, 135.4, 134.4, 122.3, 113.0, 55.4, 0.03; IR (cm−1) 2938, 1690, 1584, 1556, 1229, 837, 765; HRMS (ESI-TOF, m/z) calcd for C11H16NaO2Si (M + Na)+ 231.0817, found 231.0816. Preparation of 1-(2-Allyl-4-methoxyphenyl)pentan-1-ol (10). To a solution of aldehyde 9 (68 mg, 0.33 mmol) in Et2O (0.50 mL) at −78 °C was added n-BuLi (2.5 M in hexane, 0.16 mL, 0.39 mmol) dropwise. After being stirred for 30 min, the resulting solution was added to a mixture of CuI (75 mg, 0.39 mmol) in HMPA/THF (0.50 mL/0.50 mL) via cannula at 0 °C. The resulting solution was warmed to room temperature. After the mixture was stirred for 30 min, allyl bromide (80 μL, 1.0 mmol) in THF (0.50 mL) was added. The mixture was stirred for 2 h at room temperature before being quenched with 1 N HCl (3 mL) and satd aq NH4Cl (3 mL) and extracted with Et2O (3 × 10 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 100:1 → 5:1) to afford 10 (50 mg, 65% yield) as a pale yellow liquid: 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.4 Hz, 1H), 6.80 (dd, J1 = 8.8 Hz, J2 = 2.4 Hz, 1H), 6.70 (d, J = 2.4 Hz, 1H), 5.92−6.02 (m, 1H), 5.08 (d, J = 9.6 Hz, 1H), 5.01 (d, J = 17.2 Hz, 1H), 4.87 (dd, J1 = 7.6 Hz, J2 = 5.6 Hz, 1H), 3.79 (s, 3H), 3.41−3.45 (m, 2H), 1.74−1.83 (m, 1H), 1.64−1.71 (m, 2H), 1.39−1.48 (m, 1H), 1.30−1.37 (m, 2H), 0.90 (t, J = 6.8 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 158.7, 138.1, 137.4, 135.1, 127.0, 116.0, 115.2, 111.9, 70.0, 55.2, 38.0, 36.9, 28.4, 22.6, 14.0; IR (cm−1) 3380, 2954, 1607, 1499, 1251, 1040, 993, 910, 812; HRMS (ESI-TOF, m/z) calcd for C15H22NaO2 (M + Na)+ 257.1517, found 257.1515. Preparation of N,N-Diisopropyl-4′-methyl-[1,1′-biphenyl]-2-carboxamide (12). A mixture of PdCl2 (35.2 mg, 0.20 mmol), AgOTf (102.8 mg, 0.40 mmol), NaOTf (68.8 mg, 0.4 mmol), K2S2O8 (1.10 g, 4.0 mmol), DMA (0.40 mL, 4.0 mmol), and N,N-diisopropylbenzamide (0.41 g, 2.0 mmol) in toluene (12 mL) was heated in a sealed tube at 80 °C for 36 h. The mixture was then cooled to room temperature and purified directly by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 200:1 → 30:1) to afford 12 (295 mg, 50% yield) as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.44 (d, J = 8.0 Hz, 2H), 7.26−7.39 (m, 4H), 7.18 (d, J = 8.0 Hz, 2H), 3.38−3.48 (m, 1H), 3.20−3.28 (m, 1H), 2.37 (s, 3H), 1.52 (d, J = 6.8 Hz, 3H), 1.30 (d, J = 6.8 Hz, 3H), 0.89 (d, J = 6.8 Hz, 3H), 0.35 (d, J = 6.8 Hz, 3H). The physical and spectral data were consistent with those previously reported.61 Preparation of 4′-Methyl-[1,1′-biphenyl]-2-carbaldehyde (13). Using general method A for reduction of amide 12 to aldehyde 13: amide 12 (88 mg, 0.30 mmol), 2,6-DTBMP (185 mg, 0.90 mmol), and EtOTf (80 mg, 0.45 mmol) in CH2Cl2 (2 mL) at room temperature for 2 h, and then THF (4 mL) and LiAlH(O-t-Bu)3 (1.1 M in THF, 0.55 mL, 0.60 mmol) were added at −78 °C for 4 h to afford 13 (50 mg, 86% yield) as a yellow oil liquid: 1H NMR (400 MHz, CDCl3) δ 9.99 (s, 1H), 8.02 (d, J = 7.6 Hz, 1H), 7.63 (t, J = 7.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.44 (d, J = 7.6 Hz, 1H), 7.26−7.28 (m, 4H), 2.44 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 192.6, 146.0, 138.0, 134.8, 133.7, 133.5, 130.8, 130.0, 129.1, 127.5, 21.2. The physical and spectral data were consistent with those previously reported.62 Preparation of 3-Methyl-6H-benzo[c]chromen-6-one (14). To a solution of aldehyde 13 (100 mg, 0.50 mmol) and CuCl (2.40 mg,

0.03 mmol) in DMSO (2.5 mL) was added TBHP (5.5 mol/L in decane, 270 mg, 3.0 mmol) dropwise. Stirring was continued at room temperature for 4 h. The reaction mixture was diluted with water and extracted with ethyl acetate (3 × 20 mL). The combined organic layers were then dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel flash column chromatography (gradient eluent: petroleum ether/EtOAc = 50:1 → 5:1) to afford 14 (48 mg, 46% yield; mp 136−138 °C) as a white solid: 1 H NMR (400 MHz, CDCl3) δ 8.39 (d, J = 8.0 Hz, 1H), 8.09 (d, J = 8.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81 (t, J = 7.6 Hz, 1H), 7.56 (t, J = 7.6 Hz, 1H), 7.15−7.19 (m, 2H), 2.46 (s, 3H); 13C{1H} NMR (150 MHz, CDCl3) δ 161.5, 151.3, 141.3, 135.0, 134.8, 130.6, 128.4, 125.7, 122.5, 121.4, 120.9, 117.9, 115.4, 21.4. The physical and spectral data were consistent with those previously reported.63

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b02868. Attempts to reduce 1a to aldehyde with the previously reported methods; 1H and 13C NMR spectra for all new compounds (PDF)

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AUTHOR INFORMATION

Corresponding Authors

* [email protected]. * [email protected]. ORCID

Zhenlei Song: 0000-0002-7228-1572 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We are grateful for financial support from the National Natural Science Foundation of China (21622202, 21290180, 21502125) and the National Major Scientific and Technological Special Project for “Significant New Drugs Development” during the Thirteenth Five-year Plan Period of China (2017ZX09101003-005-004). We also thank Mr. ZhiXiong in Nanchang University for his invaluable help with measurement of melting points.

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REFERENCES

(1) For the latest reviews, see: (a) Addis, D.; Das, S.; Junge, K.; Beller, M. Angew. Chem., Int. Ed. 2011, 50, 6004. (b) Magano, J.; Dunetz, J. R. Org. Process Res. Dev. 2012, 16, 1156. (c) Smith, A. M.; Whyman, R. Chem. Rev. 2014, 114, 5477. (d) Volkov, A.; Tinnis, F.; Slagbrand, T.; Trillo, P.; Adolfsson, H. Chem. Soc. Rev. 2016, 45, 6685. (2) (a) Homer, R. B.; Johnson, C. D. In Chemistry of Amides; Zabicky, J., Ed.; Interscience: New York, 1970. (b) Seyden-Penne, J. Reductions by the Alumino and Borohydrides in Organic Synthesis, 2nd ed.; Wiley: New York, 1997. (c) The Amide Linkage: Structural Significance in Chemistry, Biochemistry, and Materials Science; Greenberg, A., Breneman, C. M., Liebman, J. F., Eds.; John Wiley & Sons: New York, 2000. (3) For selected works, see: (a) Brown, H. C.; Heim, P. J. Am. Chem. Soc. 1964, 86, 3566. (b) Motoyama, Y.; Mitsui, K.; Ishida, T.; Nagashima, H. J. Am. Chem. Soc. 2005, 127, 13150. (c) Sasakuma, H.; Motoyama, Y.; Nagashima, H. Chem. Commun. 2007, 4916. (d) Hanada, S.; Tsutsumi, E.; Motoyama, Y.; Nagashima, H. J. Am. Chem. Soc. 2009, 131, 15032. (e) Zhou, S. L.; Junge, K.; Addis, D.; Das, S.; Beller, M. Angew. Chem., Int. Ed. 2009, 48, 9507. (f) Sunada, Y.; Kawakami, H.; Imaoka, T.; Motoyama, Y.; Nagashima, H. Angew. Chem., Int. Ed. 2009, 48, 9511. (g) Das, S.; Addis, D.; Zhou, S. L.; Junge, K.; Beller, M. J. Am. Chem. Soc. 2010, 132, 1770. (h) Cheng, C.;

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Chemoselective Reduction of Sterically Demanding N,N

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