Methodology for in Situ Protection of Aldehydes and Ketones Using Trimethylsilyl Trifluoromethanesulfonate and Phosphines: Selective Alkylation and Reduction of Ketones, Esters, Amides, and Nitriles

Abstract

A methodology for selective transformations of ketones, esters, Weinreb amides, and nitriles in the presence of aldehydes has been developed. The use of a combination of PPh₃-trimethylsilyl trifluoromethanesulfonate (TMSOTf) promotes selective transformation of aldehydes to their corresponding, temporarily protected, O,P-acetal type phosphonium salts. Because, hydrolytic work-up following ensuing reactions of other carbonyl moieties in the substrates liberates the aldehyde moiety, a sequence involving aldehyde protection, transformation of other carbonyl groups, and deprotection can be accomplished in a one-pot manner. Furthermore, the use of PEt₃ instead of PPh₃ enables ketones to be converted in situ to their corresponding O,P-ketal type phosphonium salts and, consequently, selective transformations of esters, Weinreb amides, and nitriles in the presence of ketones can be performed. This methodology is applicable to various dicarbonyl compounds, including substrates that possess heteroaromatic skeletons and hydroxyl protecting groups.

From a synthetic perspective, carbonyl groups are among the most important functional groups in organic substances because they participate in simultaneous C–C bond and hydroxyl forming reactions. So they are frequently utilized in organic synthesis and their reactivity is well investigated. It is well known that the reactivity of different types of carbonyl groups towards nucleophiles falls in the following order: aldehydes>ketones>esters>amides and nitriles. By using this reactivity profile, numerous selective transformations of more reactive carbonyl groups in the presence of less reactive counterparts have been developed.¹⁾ In contrast, multiple-step sequences, which include often complicated protection and deprotection steps, are required for selective conversion of less reactive carbonyl groups in substrates that also contain more reactive carbonyl moieties. Moreover, the few methods that have been devised to reverse the reactivity order of carbonyl groups^2–19) have drawbacks that include low substrate scope and reactions that require strict stoichiometry control and use of expensive reagents. Thus, in spite of their ability to simplify preparative sequences, these methods have rarely been used in synthetic organic chemistry.

Previously, we have developed a concise and practical method, which utilizes a combination of trimethylsilyl trifluoromethanesulfonate (TMSOTf) and PPh₃ or PEt₃, for selective transformation of ketones and esters in the presence of aldehydes and ketones²⁰⁾ (Chart 1). Unique advantages of this method, which involves in situ generation of O,P-acetal or -ketal type phosphonium salts, are that commercially available reagents can be utilized and that PPh₃ can be employed to form salts with aldehydes rather than ketones even when it is used in excess. Consequently, the method is simple to execute and no need exists to rigorously control the stoichiometry of reagents even in reactions of substrates that contain both aldehyde and ketone moieties. Below we describe the results of an effort that has expanded the utility of this method by demonstrating that it can be applied to selective transformations of ketones, esters, Weinreb amides and nitriles in the presence of aldehydes, and of esters, Weinreb amides, and nitriles in the presence of ketones.

Chart 1. Selective One-Pot Transformation of a Ketone in the Presence of Aldehyde Group

Results and Discussion

Our initial studies were focused on the reduction of keto-aldehyde 1a with borane (Table 1). In previous work, we observed that acetal-selective deprotection of substrates containing both an acetal and ketal group can be carried out using a combination of 2,4,6-collidine and triethylsilyl trifluoromethansulfonate (TESOTf).^21,22) In this effort, we found that excess amounts of reagents (3 eq of 2,4,6-collidine and 2 eq of TESOTf) are required in order to promote complete reaction. We also observed that acetals can be deprotected using a combination of TESOTf and a phosphine.²³⁾ In the earlier study, we attempted formation of a collidinium salt of the aldehyde group in keto-aldehyde 1a selectively by using TESOTf and 2,4,6-collidine. However, a complex mixture was generated perhaps as a consequence of the basicity of 2,4,6-collidine. In a continuation of these studies, our attention turned to using a phosphine in place of 2,4,6-collidine for the acetal forming process. Indeed, reaction of 1a with the bulky Lewis acid tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) and PPh₃ followed by treatment with borane–tetrahydrofuran (THF) complex and then tetrabutylammonium fluoride (TBAF) led to formation of 2a, arising be selective reduction of the ketone moiety (run 1). The selective reduction could be promoted by using either less bulky TESOTf or TMSOTf in place of TBSOTf (runs 2, 3). Moreover, when TMSOTf was used as the Lewis acid, final treatment of the reaction mixture with TBAF was not required because the O,P-acetal could be cleaved by using saturated aqueous NaHCO₃. In addition, we observed that BF₃·Et₂O could not be employed as a Lewis acid (run 4), that reducing the amount of reagents used did not affect the efficiency of the process (run 5), and that the reaction performed at −40°C takes place in highest yield (run 6). Furthermore, the desired product was not formed when the reaction was conducted in the absence of either PPh₃ or a Lewis acid, but rather the corresponding diol and ketol are produced in respective 20% and 74% yields. Finally, this selective aldehyde protection methodology was also applied to Grignard reaction of 1a at room temperature, which forms the tertiary phenyl-carbinol 2b in high yield (run 8).

Table 1. Conditions for Selective Reactions of Keto-Aldehyde 1a

Run	Lewis acid	PPh3	Reagent	Yielda)
1b)	TBSOTf (2.0 eq)	3.0 eq	BH3·THF (4.0 eq)	94%
2b)	TESOTf (2.0 eq)	3.0 eq	BH3·THF (4.0 eq)	86%
3	TMSOTf (2.0 eq)	3.0 eq	BH3·THF (4.0 eq)	90%
4	BF3·OEt2 (2.0 eq)	3.0 eq	BH3·THF (4.0 eq)	Trace
5c)	TMSOTf (1.2 eq)	1.2 eq	BH3·THF (1.5 eq)	88%
6c,d)	TMSOTf (1.2 eq)	1.2 eq	BH3·THF (1.5 eq)	96%
7e)	—	—	BH3·THF (1.2 eq)	0%
8f)	TMSOTf (1.2 eq)	1.2 eq	PhMgBr (3.0 eq)	93%

a) Isolated yield of 2a and 2b. b) 3.0 eq of TBAF was used for work-up. c) PPh₃ and TMSOTf were at rt. d) Reduction was performed at −40°C. e) The reaction was performed in the absence of Lewis acid and PPh₃. f) Alkylation was performed at room temperature.

Selective Transformation of Carbonyl Groups in the Presence of Aldehydes

The scope of the selective protection methodology described above was explored by using reduction and Grignard addition reactions of a variety of dicarbonyl substrates containing aldehyde group (Table 2). The results show that the in situ protection methodology enabled ketone-selective reduction and alkylation reactions of keto-aldehyde substrates (runs 1–13). In addition, transformations of the 5-oxoaldehyde derivative 1c to 2f and 2g in high yields (runs 6, 7) demonstrated that the method can be utilized in efficient routes for the construction of synthetically useful lactols. Aromatic aldehydes also participated in the selective in situ phosphonium salts protection process (runs 8–13). Moreover, the use of Corey–Bakshi–Shibata (CBS) reagent enabled asymmetric reduction of a ketone in the presence of an aldehyde with good selectivity (run 9). It is notable that the ketone group in the readily enolizable ketone 1e could be selectively reduced in high yield, demonstrating that the protection/deprotection conditions employed in this method are very mild (run 11). Moreover, 1f, which possesses a bulky ketone group, was also selectively converted into the corresponding alcohol 2l when 2 eq of the reductant BH₃–THF were used (run 12). In the case of benzophenone-type ketone 1g, reduction took place to generate the desired product 2m in only moderate yield owing to over reduction of the product that produced 4-benzylbenzaldehyde in 17% yield (run 13). Ester groups in substrates that also contain aldehyde moieties could also be selectively transformed to primary alcohols by diisobutylaluminum hydride (DIBAL-H) reduction and tertiary alcohols by Grignard additions using the in situ protection method (runs 14–18). Finally, DIBAL-H reaction of ester-aldehyde 1h at −78°C, under in situ protection conditions, produced the semi-reduced dialdehyde 2o in good yield (run 15).

Table 2. Selective Transformation of Ketone or Ester in the Presence of Aldehyde

Run	Substrate	Reagent (eq)	Product	Yield
1		BH3·THF (1.5)		96%
2		PhMgBr (3.0)		93%
3		EtMgCl (1.5)		87%
4		allylMgBr (1.5)		75%
5		BH3·THF (1.5)		87%
6		BH3·THF (1.5)		89%
7		MgBr (3.0)		93%
8		BH3·THF (1.5)		96%
9		(S)-CBS (2.0)BH3·THF (2.0)		77%(90% ee)
10		PhMgBr (3.0)		84%
11		BH3·THF (1.5)		87%
12		BH3·THF (2.0)		74%
13		BH3·THF (2.0)		50%
14		DIBAL-H (3.0)		69%
15		DIBAL-H (3.0)		71%
16		MeMgBr (3.0)		69%
17		DIBAL-H (2.2)		80%
18		EtMgCl (3.0)		76%

As can be seen by viewing the results given in Table 3, the in situ protection method enabled selective transformations of amide and nitrile groups in substrates that also contain aldehyde moieties. Reduction and Grignard addition reactions of Weinreb amides took place smoothly to yield the respective dialdehydes and keto-aldehydes (runs 1–5). In addition, the results showed that tert-butyldimethylsilyl (TBS) and methoxymethyl (MOM) groups were shown to tolerate the in situ protection/deperotection conditions (runs 6–9). However, simple, less reactive N,N-dialkyl substituted amides, such as 1n and 1o derived from pyrrolidine and N-butylaniline, were not suitable for this methodology because complicated product mixtures were formed (runs 10, 11). In these cases, long reaction times were required to consume the starting materials and this may enable competitive decomposition of phosphonium protective groups. Although the nitrile groups in nitrile-aldehydes underwent selective reduction using DIBAL-H (runs 12, 14), the yield for formation of the corresponding ketone product was low (run 13).

Table 3. Selective Transformation of Weinreb Amide or Nitrile in the Presence of Aldehyde

Run	Substrate	Reagent (eq)	Product	Yield
1		DIBAL-H (3.0)		76%
2		PhMgBr (3.0)		71%
3		MeMgBr (3.0)		77%
4		DIBAL-H (3.0)		62%
5		MeMgBr (3.0)		62%
6		DIBAL-H (2.0)		66%
7		MeMgBr (3.0)		74%
8		DIBAL-H (1.5)		66%
9		MeMgBr (3.0)		68%
10		DIBAL-H (3.0)		N.D.
11		DIBAL-H (3.0)		N.D.
12		DIBAL-H (3.0)		65%
13a)		PhMgBr (4.0)		50%
14a)		DIBAL-H (3.0)		72%

a) 2 eq of PPh₃ and TMSOTf were used.

NMR analysis was used to demonstrate that phosphonium salt intermediates are selectively formed by treatment of keto-aldehydes under the in situ protection conditions. Inspection of ¹H-NMR spectra (Chart 2) shows that the resonance for the aldehyde proton at 10.1 ppm disappears when a CDCl₃ solution of 1d is treated with PPh₃ (1.2 eq) and TMSOTf (1.2 eq) despite the retention of the signal at 2.7 ppm associated with from acetyl methyl protons. Also, the aromatic proton resonances of 1d are shifted to higher fields owing to the fact that O,P-acetal formation removes the electron-withdrawing aldehyde carbonyl group. Furthermore, the signal derived from O,P-acetal proton is newly observed at 7.14 (1H, d, J_CH-P=5.0 Hz). These results indicated the selective formation of the phosphonium salt intermediates at the aldehyde in the presence of the ketone.

Chart 2. ¹H-NMR Monitoring of the Reaction of 1d with PPh₃ and TMSOTf

Selective Transformation of the Carbonyl Groups in the Presence of Ketone Moieties

Treatment of ketone-containing substrates with even excess amounts of TMSOTf and PPh₃ did not lead to formation of O,P-ketal containing phosphonium salts. We hypothesized that this lack of reactivity is caused by the steric bulkiness and low nucleophilicity of PPh₃. Studies with less bulky phosphines revealed that a combination of PEt₃ and TMSOTf could be employed to form the desired ketone O,P-ketals.

Use of the PEt₃ based in situ ketone protection methodology in ester selective reactions of keto-esters was demonstrated by the results displayed in Table 4. Various keto-esters, including 3c which contains a cyclohexanone moiety, reacted with DIBAL-H and Grignard reagents to furnish the corresponding primary and tertiary alcohols, involving initial formation of ketone protected phosphonium ketals. While the highly enolizable β-keto ester 3e did not participate in this process (run 6), keto-ester substrates containing TBS and MOM protecting groups and pyridine heterocyclic ring underwent selective reactions at their ester centers (runs 7–10).

Table 4. Selective Transformation of Ester in the Presence of Ketone

Run	Substrate	Reagent (eq)	Product	Yield
1		DIBAL-H (3.0)		82%
2		PhMgBr (4.0)		76%
3		DIBAL-H (3.0)		76%
4		DIBAL-H (3.0)		93%
5		MeMgBr (3.0)		83%
6		PhMgBr (3.0)		N.D.
7a)		EtMgCl (3.0)		74%
8a)		EtMgCl (3.0)		80%
9		DIBAL-H (3.0)		62%
10		MeMgBr (3.0)		76%

a) Salt was formed at 0°C.

This methodology was employed to carry out selective reactions of substances that contain ketone moieties along with either Weinreb amide or nitrile groups. The results showed that while Weinreb amide groups generally participated in efficient reduction and alkylation reactions of these substrates, sometimes the reduction processes were attended by low yields (runs 2, 7). In addition, the desired products were not formed at all in the case of the substrates with heteroaromatic ring (runs 6, 9).²⁴⁾ These results may be referred from the reaction of electron deficient aldehydes with highly nucleophilic phosphines.²⁵⁾ The nitrile 3n was also not effective in this reaction and only 32% of desired product was obtained (run 11).

Table 5. Selective Transformation of Weinreb Amide or Nitrile in the Presence of Ketone

Run	Substrate	Reagent (eq)	Product	Yield
1		MeMgBr (3.0)		93%
2		DIBAL-H (3.0)		58%
3		MeMgBr (3.0)		75%
4		DIBAL-H (3.0)		79%
5		MeMgBr (3.0)		84%
6		DIBAL-H (3.0)		N.D.
7		DIBAL-H (3.0)		47%
8		MeMgBr (1.5)		82%
9		DIBAL-H (3.0)		N.D.
10		MeMgBr (3.0)		98%
11		EtMgCl (3.0)		32%

Conclusion

In the study described above, we developed a new, in situ protection methodology that enables selective reduction and alkylation reactions of less reactive carbonyl groups in substrates that also contain more reactive aldehyde and ketone moieties (Chart 3). By using a combination of PPh₃ and TMSOTf, aldehyde groups in substrates of this type are selectively protected in the form of O,P-acetals and, as a result, ketone, ester, Weinreb amide, and nitrile groups undergo selective reactions with a variety of reagents, including BH₃, DIBAL-H, and Grignard reagents as well as CBS reagent. In addition, selective transformations of ester, Weinreb amide and nitrile groups in substrates that also contain ketone moieties can be accomplished by performing preliminary in situ ketone protection using PEt₃ and TMSOTf. These methodologies can be applied to various dicarbonyl substrates including heteroaromatic substrates and substrates having protective groups. The fact that the reagents employed in the processes are commercially available and that no need exists to control reagent stoichiometries, makes the in situ ketone and aldehyde protection methods simple and highly applicable in synthetic organic chemistry.

Chart 3. Reversing the Selectivity of Transformations of Carbonyl Groups by Using the in Situ Protection Methods

Experimental

All reagents were purchased from commercial sources and used without further purification, unless otherwise noted. Reactions were performed under a nitrogen atmosphere using purchased anhydrous solvent. All reactions were monitored by thin-layer chromatography using Merck silica gel 60 F254. The products were purified by column chromatography over silica gel Kieselgel 60 (70–230 mesh ASTM) purchased from Merck or Silica Gel 60N (40–50 µm, spherical neutral) purchased from Kanto Chemical. ¹H- and ¹³C-NMR spectra were recorded at 25°C on a JEOL JNM-AL300 (at 300 MHz and 75 MHz, respectively), a JEOL JNM-ECS 400 (at 400, 100 MHz, respectively) or a JEOL JNM-LA 500 (at 500, 125 MHz, respectively), and the chemical shifts are reported relative to internal tetramethylsilane (TMS) (¹H, δ=0.00) or CD₂HCN (¹H, δ=1.93) and CDCl₃ (¹³C, δ=77.0) or CD₃CN (¹³C, δ=118.2). Data for ¹H-NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s=singlet, d=doublet, t=triplet, q=quartet, quin=quintet, sex=sextet, m=multiplet, br=broad. IR spectra (KBr) were recorded by a SHIMADZU FTIR-8400 or SHIMADZU IRAffinity-1, and are reported in frequency of absorption (cm⁻¹). High-resolution mass spectra (matrix assisted laser desorption/ionization (MALDI)-MS, FAB-MS and electron ionization (EI)-MS) were performed by the Elemental Analysis Section of Graduate School of Pharmaceutical Science in Osaka University. Melting points were determined using a YANAGIMOTO MICRO MELTING POINT APPARATUS and all melting points were uncorrected. Optical rotations were measured on a JASCO P-1020. Enantiomeric excess (ee) was measured by chiral HPLC analysis: Daicel chiralpak AD-H column (4.6 mm×25 cm) using a multiwavelength detector JASCO MD-2010.

General Procedure for the Selective Reduction of Ketones in the Presence of Aldehydes (Table 2, Runs 1, 5, 8, and 11–13)

To a solution of keto-aldehyde (0.200 mmol, 1.0 eq) and PPh₃ (63.0 mg, 0.240 mmol, 1.2 eq) in CH₂Cl₂ (2.0 mL, 0.1 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to −40°C, and BH₃·THF (0.28 mL of 1.08 M in THF, 0.302 mmol, 1.5 eq) was added slowly via syringe. Stirring was continued at −40°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

12-Hydroxytetradecanal²⁰⁾ (2a): ¹H-NMR (400 MHz, CDCl₃) δ: 9.76 (1H, t, J=1.9 Hz), 3.53–3.50 (1H, m), 2.42 (2H, dt, J=1.9, 7.2 Hz), 1.63 (2H, tt, J=7.2, 7.2 Hz), 1.55–1.28 (18H, m), 0.94 (3H, t, J=7.6 Hz).

4-Hydroxycyclohexylacetaldehyde²⁰⁾ (2e): ¹H-NMR (400 MHz, CDCl₃) δ: 9.76 (1H, t, J=2.2 Hz), 3.57 (1H, tt, J=10.8, 4.4 Hz), 2.01–1.97 (2H, m), 1.91–1.79 (3H, m), 1.51 (1H, br s), 1.37–1.27 (2H, m), 1.13–1.03 (2H, m).

6-Phenyl-δ-valerolactol²⁶⁾ (2f): 1 : 1 mixture of diastereoisomers; ¹H-NMR (500 MHz, CDCl₃) δ: 7.38–7.25 (5H, m), 5.43 (0.5H, s), 5.01 (0.5H, dd, J=11.5, 2.5 Hz), 4.85–4.82 (0.5H, m), 4.46 (0.5H, dd, J=12.0, 2.0 Hz), 3.46 (0.5H, d, J=6.0 Hz), 2.99 (0.5H, s), 2.08–1.37 (6H, m).

4-(1-Hydroxyethyl)benzaldehyde²⁷⁾ (2h): ¹H-NMR (400 MHz, CDCl₃) δ: 9.97 (1H, s), 7.85 (2H, d, J=8.4 Hz), 7.53 (2H, d, J=8.4 Hz), 4.98 (1H, q, J=6.5 Hz), 2.50 (1H, br s), 1.51 (3H, d, J=6.5 Hz).

4-(2-Hydroxypropyl)benzaldehyde²⁰⁾ (2k): ¹H-NMR (400 MHz, CDCl₃) δ: 9.96 (1H, s), 7.82 (2H, d, J=8.2 Hz), 7.39 (2H, d, J=8.2 Hz), 4.08 (1H, tq, J=6.3, 6.3 Hz), 2.88–2.78 (2H, m), 1.82 (1H, br s), 1.26 (3H, d, J=6.3 Hz).

4-(1-Hydroxy-2,2-dimethylpropyl)benzaldehyde²⁰⁾ (2l): ¹H-NMR (400 MHz, CDCl₃) δ: 9.98 (1H, s), 7.82 (2H, d, J=8.2 Hz), 7.48 (2H, d, J=8.2 Hz), 4.47 (1H, s), 2.12 (1H, br s), 0.93 (9H, s).

4-(Hydroxyphenylmethyl)benzaldehyde²⁹⁾ (2m): ¹H-NMR (400 MHz, CDCl₃) δ: 9.96 (1H, s), 7.83 (2H, d, J=8.4 Hz), 7.56 (2H, d, J=8.4 Hz), 7.35–7.17 (5H, m), 5.88 (1H, s), 2.30 (1H, br s).

Selective Asymmetric Reduction of Ketone in the Presence of Aldehyde (Table 2, Run 9)

(+)-4-(1-Hydroxyethyl)benzaldehyde (2i): To a solution of 1d (45.3 mg, 0.306 mmol) and PPh₃ (78.6 mg, 0.300 mmol, 1.2 eq) in CH₂Cl₂ (1.0 mL) was added TMSOTf (54 µL, 0.299 mmol) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to −30°C, and the resulted solution was added to a solution of BH₃·THF (0.56 mL of 1.08 M in THF, 0.605 mmol) and (S)-(−)-2-methyl-CBS-oxazaborolidine (160 mg, 0.577 mmol) at −30°C via cannula. Stirring was continued at −30°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (1.0 mL) and MeOH (0.5 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography (hexanes–AcOEt, 2 : 1) to afford 2i (35.3 mg, 0.235 mmol, 77%, 90% ee). The ee value was determined with chiral HPLC analysis (AD-H, 1.0 mL/min, 10% IPA in hexanes) [α]_D²⁶ +34.8 (c=0.979, CHCl₃), (lit.²⁸⁾ [α]_D²⁶ −36.5 (c=1.25, CHCl₃) for (S)-2i).

General Procedure for the Selective Alkylation of Ketone and Ester in the Presence of Aldehyde (Table 2, Runs 2–4, 7, 10, 16, and 18)

To a solution of keto-aldehyde (or ald ester) (0.200 mmol, 1.0 eq) and PPh₃ (63.0 mg, 0.240 mmol, 1.2 eq) in CH₂Cl₂ (2.0 mL, 0.1 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was added slowly to a solution of Grignard reagent (0.600 mmol, 3.0 eq) in THF (or Et₂O) via cannula. Stirring was continued at rt until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and then the resulting solution was stirred for 2 h at 40°C. After being cooled to rt, the aqueous layer was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

12-Hydroxy-12-phenyltetradecanal²⁰⁾ (2b): ¹H-NMR (500 MHz, CD₃CN) δ: 9.66 (1H, t, J=1.9 Hz), 7.36 (2H, d, J=7.5 Hz), 7.30 (2H, t, J=7.5 Hz), 7.18 (1H, t, J=7.5 Hz), 2.71–2.70 (1H, m), 2.36 (2H, dt, J=1.9, 7.2 Hz), 1.83–1.66 (4H, m), 1.54 (2H, tt, J=7.2, 7.2 Hz), 1.24–1.18 (13H, m), 0.94–0.88 (1H, m), 0.67 (3H, t, J=7.3 Hz).

12-Ethyl-12-hydroxytetradecanal²⁰⁾ (2c): ¹H-NMR (400 MHz, CDCl₃) δ: 9.76 (1H, t, J=1.9 Hz), 2.42 (2H, dt, J=1.9, 7.3 Hz), 1.63 (2H, quin, J=7.3 Hz), 1.46 (4H, q, J=7.5 Hz), 1.42–1.38 (2H, m), 1.28 (14H, m), 1.13 (1H, br s), 0.86 (6H, t, J=7.5 Hz).

12-Ethyl-12-hydroxypentadec-14-enal²⁰⁾ (2d): ¹H-NMR (500 MHz, CDCl₃) δ: 9.76 (1H, t, J=1.8 Hz), 5.88–5.80 (1H, m), 5.13–5.09 (2H, m), 2.42 (2H, dt, J=1.8, 7.3 Hz), 2.21 (2H, d, J=7.5 Hz), 1.63 (2H, tt, J=7.3, 7.3 Hz), 1.50–1.45 (2H, m), 1.42–1.40 (3H, m), 1.30–1.28 (14H, m), 0.88 (3H, t, J=7.4 Hz).

6-Phenyl-6-(prop-1-ynyl)-δ-valerolactol²⁰⁾ (2g): ¹H-NMR (400 MHz, CDCl₃) δ: 7.65 (2H, d, J=7.2 Hz), 7.35 (2H, t, J=7.2 Hz), 7.27 (1H, t, J=7.2 Hz), 5.41 (1H, dd, J=9.8, 1.8 Hz), 2.12–1.94 (2H, m), 1.93 (3H, s), 1.88–1.76 (2H, m), 1.68–1.60 (1H, m), 1.44–1.33 (1H, m).

4-(1-Hydroxy-1-phenylethyl)benzaldehyde²⁰⁾ (2j): ¹H-NMR (400 MHz, CDCl₃) δ: 9.95 (1H, s), 7.82–7.79 (2H, m), 7.60–7.57 (2H, m), 7.40 (2H, dt, J=7.3, 1.8 Hz), 7.32 (2H, tt, J=7.3, 1.8 Hz), 7.26 (1H, tt, J=7.3, 1.8 Hz), 1.97 (3H, s).

10-Hydroxy-10-methylundecanal (2p): Collerless oil. TLC (SiO₂): Rf=0.41 (hexanes–EtOAc 2 : 1). IR (KBr) 3394.7, 2929.9, 1854.7, 1722.4, 1465.9, 1375.3, 1149.6, 906.5 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 9.77 (1H, t, J=1.9 Hz), 2.43 (2H, td, J=7.4, 1.9 Hz), 1.65–1.61 (2H, m), 1.48–1.44 (2H, m), 1.36–1.31 (10H, m), 1.21 (6H, s). ¹³C-NMR (MHz, CDCl₃) δ: 202.9, 70.9, 43.9, 43.8, 30.0, 29.3, 29.2 (2×C), 29.1, 24.2, 22.0. HR-MS (FAB) Calcd for C₁₂H₂₄O₂Na [M+Na]⁺: 223.1674, Found 223.1683.

4-(1-Ethyl-1-hydroxypropyl)benzaldehyde (2r)²⁰⁾: ¹H-NMR (400 MHz, CDCl₃) δ: 10.0 (1H, s), 7.88–7.85 (2H, m), 7.58–7.56 (2H, m), 1.96–1.80 (5H, m), 0.76 (6H, t, J=7.6 Hz).

Selective Reduction of Ester to Alcohol in the Presence of Aldehyde (Table 2, Run 14): 10-Hydroxydecanal³⁰⁾ (2n)

To a solution of 1h (40.1 mg, 0.200 mmol) and PPh₃ (63.0 mg, 0.240 mmol) in CH₂Cl₂ (2.0 mL) was added TMSOTf (43 µL, 0.238 mmol) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to 0°C, and DIBAL-H (0.59 mL of 1.02 M in hexane, 0.602 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at 0°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford 2n (23.8 mg, 0.138 mmol, 69%). ¹H-NMR (400 MHz, CDCl₃) δ: 9.77 (1H, t, J=1.8 Hz), 3.64 (2H, t, J=6.6 Hz), 2.42 (2H, td, J=7.3, 1.8 Hz), 1.65–1.56 (4H, m), 1.31–1.25 (10H, m).

General Procedure for the Selective Reduction of Ester and Weinreb Amide in the Presence of Aldehyde (Table 2, Runs 15 and 17; Table 3, Runs 1, 4, 6, and 8)

To a solution of ald ester (or ald amide) (0.200 mmol, 1.0 eq) and PPh₃ (63.0 mg, 0.240 mmol, 1.2 eq) in CH₂Cl₂ (2.0 mL, 0.1 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to −78°C, and DIBAL-H (0.59 mL of 1.02 M in hexane, 0.602 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at −78°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

Decanedial³¹⁾ (2o): ¹H-NMR (400 MHz, CDCl₃) δ: 9.77 (2H, t, J=1.7 Hz), 2.43 (4H, td, J=7.4, 1.7 Hz), 1.65–1.59 (4H, m), 1.41–1.23 (8H, m).

4-Hydroxymethylbenzaldehyde (2q)²⁰⁾: Reduction was conducted with 2.2 eq of DIBAL-H. ¹H-NMR (300 MHz, CDCl₃) δ: 9.99 (1H, s), 7.86 (2H, d, J=8.0 Hz), 7.53 (2H, d, J=8.0 Hz), 4.80 (2H, s), 2.34 (1H, br s).

Benzene-1,4-dicarboxaldehyde³²⁾ (2s): ¹H-NMR (400 MHz, CDCl₃) δ: 10.15 (2H, s), 8.07 (4H, s).

5-(tert-Butyldimethylsilyloxy)isophthalaldehyde³³⁾ (2u): ¹H-NMR (400 MHz, CDCl₃) δ: 10.04 (2H, s), 7.99–7.98 (1H, m), 7.59–7.58 (2H, m), 1.01 (9H, s), 0.27 (6H, s).

5-(Methoxymethoxy)isophthalaldehyde (2w): Colorless oil. TLC (SiO₂): Rf=0.71 (hexanes–EtOAc, 1 : 1). IR (KBr) 3388.9, 2931.8, 2733.1, 2254.8, 1693.5, 1593.2, 1454.3, 1288.5, 1151.5, 912.3, 742.6 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 10.07 (2H, s), 8.03 (1H, t, J=1.6 Hz), 7.80 (2H, d, J=1.6 Hz), 5.30 (2H, s), 3.51 (3H, s). ¹³C-NMR (100 MHz, CDCl₃) δ: 190.7, 158.4, 138.3, 124.7, 121.7, 94.4, 56.4. HR-MS (FAB) Calcd for C₁₀H₁₁O₄N [M+H]⁺: 194.0657, Found 194.0666.

General Procedure for the Selective Alkylation of Weinreb Amide in the Presence of Aldehyde (Table 3, Runs 2, 3, 5, 7, and 9)

To a solution of ald amide (0.200 mmol, 1.0 eq) and PPh₃ (63.0 mg, 0.240 mmol, 1.2 eq) in CH₂Cl₂ (2.0 mL, 0.1 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to 0°C, and a solution of Grignard reagent (0.600 mmol, 3.0 eq) in THF (or Et₂O) was added slowly to the reaction mixture via syringe. Stirring was continued at 0°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and then the resulting solution was stirred for 2 h at 40°C. After being cooled to rt, the aqueous layer was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

4-Benzoylbenzaldehyde³⁴⁾ (1g): ¹H-NMR (400 MHz, CDCl₃) δ: 10.14 (1H, s), 8.02–8.00 (2H, m), 7.94–7.92 (2H, m), 7.83–7.80 (2H, m), 7.66–7.62 (1H, m), 7.54–7.50 (2H, m).

4-Acetylbenzaldehyde²⁰⁾ (1d): ¹H-NMR (400 MHz, CDCl₃) δ: 10.12 (1H, s), 8.11 (2H, d, J=8.2 Hz), 7.99 (2H, d, J=8.2 Hz), 2.68 (3H, s).

10-Oxoundecanal³⁵⁾ (2t): ¹H-NMR (300 MHz, CDCl₃) δ: 9.77 (1H, t, J=2.4 Hz), 2.46–2.40 (4H, m), 2.14 (3H, s), 1.65–1.54 (4H, m), 1.30–1.25 (8H, m).

3-Acetyl-5-(tert-butyldimethylsilyloxy)benzaldehyde (2v): Colorless oil. TLC (SiO₂): Rf=0.37 (EtOAc). IR (KBr) 3369.6, 2955.0, 2731.2, 2254.8, 1693.5, 1591.3, 1454.3, 1311.6, 1255.7, 1217.1, 1147.7, 1024.2, 912.3, 742.6 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 10.02 (1H, s), 8.04 (1H, dd, J=1.3, 1.4 Hz), 7.67 (1H, dd, J=1.3, 2.7 Hz), 7.52 (1H, dd, J=1.4, 2.7 Hz), 2.65 (3H, s), 1.01 (9H, s), 0.26 (6H, s). ¹³C-NMR (100 MHz, CDCl₃) δ: 196.7, 191.2, 156.8, 139.2, 138.0, 125.2, 124.1, 123.0, 26.8, 25.5, 18.2, −4.5. HR-MS (MALDI) Calcd for C₁₅H₂₃O₃Si [M+H]⁺: 279.1416, Found 279.1405.

3-Acetyl-5-(methoxymethoxy)benzaldehyde (2x): Colorless oil. TLC (SiO₂): Rf=0.56 (hexanes–EtOAc, 1 : 1). IR (KBr) 3363.9, 2927.9, 2254.8, 1697.4, 1593.2, 1296.2, 1155.4, 1028.1, 912.3, 742.6 cm⁻¹. ¹H-NMR (400 MHz, CDCl₃) δ: 10.04 (1H, s), 8.08 (1H, dd, J=1.3, 1.4 Hz), 7.87 (1H, dd, J=1.4, 2.5 Hz), 7.74 (1H, dd, J=1.3, 2.5 Hz), 5.29 (2H, s), 3.50 (3H, s), 2.66 (3H, s). ¹³C-NMR (100 MHz, CDCl₃) δ: 196.6, 191.1, 158.0, 139.1, 137.9, 123.2, 121.6, 120.3, 94.4, 56.3, 26.7. HR-MS (FAB) Calcd for C₁₁H₁₃O₄ [M+H]⁺: 209.0814, Found 209.0823.

Selective Reduction of Nitrile of 1p (Table 3, Run 12): Benzene-1,4-dicarboxaldehyde³²⁾ (2s)

To a solution of 1p (26.2 mg, 0.200 mmol) and PPh₃ (63.0 mg, 0.240 mmol) in CH₂Cl₂ (2.0 mL) was added TMSOTf (43 µL, 0.238 mmol) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to 0°C, and DIBAL-H (0.58 mL of 1.03 M in hexane, 0.597 mmol) was added slowly via syringe. Stirring was continued at 0°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography (hexanes–AcOEt, 3 : 1) to afford 2s (17.4 mg, 0.130 mmol, 65%).

Selective Reduction of Nitrile of 1q (Table 3, Run 14): Decanedial³¹⁾ (2o)

To a solution of 1q (45.3 mg, 0.271 mmol) and PPh₃ (143 mg, 0.545 mmol) in CH₂Cl₂ (2.7 mL), was added TMSOTf (98 µL, 0.542 mmol) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to −78°C, and DIBAL-H (0.79 mL of 1.03 M in hexane, 0.814 mmol) was added slowly via syringe. Stirring was continued at −78°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the resulted solution was evaporated and the residue was dissolved with THF (2.0 mL). The solution was acidified with 1 N HCl and stirred for 10 min. The mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography (hexanes–AcOEt, 5 : 1) to afford 2o (33.2 mg, 0.195 mmol, 72%).

Selective Alkylation of Nitrile of 1p (Table 3, Run 13)

4-Benzoylbenzaldehyde³⁴⁾ (1g): To a solution of 1p (65.6 mg, 0.500 mmol) and PPh₃ (262.3 mg, 0.100 mmol) in CH₂Cl₂ (5.0 mL) was added TMSOTf (0.18 mL, 0.996 mmol) dropwise at rt. After being stirred for 1 h at rt, the resulted solution was added to a solution of PhMgBr (1.8 mL of 1.10 M in THF, 1.98 mmol) slowly via cannula. Stirring was continued at rt for 3 h (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (5.0 mL) and MeOH (2.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the resulted solution was evaporated and the residue was dissolved with THF (2.0 mL). The solution was acidified with 1 N HCl and stirred for 15 min. The mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography (hexanes–AcOEt, 7 : 1) to afford 1g (56.4 mg, 0.252 mmol, 50%).

General Procedure for Selective Reduction of Ester in the Presence of Ketone (Table 4, Runs 1, 3, 4, and 9)

To a solution of keto ester (0.200 mmol, 1.0 eq) and PEt₃ (0.18 mL of 20% in toluene, 0.244 mmol, 1.2 eq) in CH₂Cl₂ (0.50 mL, 0.4 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to 0°C, and DIBAL-H (0.58 mL of 1.03 M in hexane, 0.597 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at 0°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

14-Hydroxytetradecan-3-one²⁰⁾ (4a): ¹H-NMR (400 MHz, CDCl₃) δ: 3.64 (2H, t, J=6.8 Hz), 2.44–2.38 (4H, m), 1.59–1.53 (5H, m), 1.36–1.27 (14H, m), 1.05 (3H, t, J=7.3 Hz).

4-(2-Hydroxyethyl)cyclohexanone²⁰⁾ (4c): ¹H-NMR (400 MHz, CDCl₃) δ: 3.75 (2H, t, J=6.6 Hz), 2.41–2.31 (4H, m), 2.13–2.07 (2H, m), 2.00–1.90 (1H, m), 1.69–1.58 (3H, m), 1.49–1.39 (2H, m).

4-Hydroxymethylacetophenone²⁰⁾ (4d): ¹H-NMR (400 MHz, CDCl₃) δ: 7.93 (2H, d, J=8.4 Hz), 7.45 (2H, d, J=8.4 Hz), 4.77 (2H, s), 2.59 (3H, s), 2.39 (1H, brs).

1-(6-(Hydroxymethyl)pyridin-2-yl)ethanone³⁶⁾ (4i): ¹H-NMR (400 MHz, CDCl₃) δ: 7.97 (1H, d, J=7.7 Hz), 7.85 (1H, t, J=7.7 Hz), 7.45 (1H, d, J=7.7 Hz), 4.85 (2H, d, J=4.4 Hz), 3.74 (1H, t, J=4.4 Hz), 2.75 (3H, s).

General Procedure for Selective Alkylation of Ester in the Presence of Ketone (Table 4, Runs 2, 5–8, and 10)

To a solution of keto ester (0.200 mmol, 1.0 eq) and PEt₃ (0.18 mL of 20% in toluene, 0.244 mmol, 1.2 eq) in CH₂Cl₂ (0.50 mL, 0.4 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, Grignard reagent (0.600 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at rt until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

Equilibrium Mixture of 5-Hydroxy-5,5-diphenylpentan-2-one and 2-Methyl-5,5-diphenyltetrahydrofuran-2-ol²⁰⁾ (4b): ¹H-NMR (400 MHz, CDCl₃) δ: 7.45–7.40 (4H, m), 7.32–7.17 (6H, m), 2.87 (0.5H, ddd, J=12.2, 11.9, 7.0 Hz), 2.77 (0.5H, s), 2.66 (0.5H, ddd, J=12.2, 7.2, 3.0 Hz), 2.59 (1H, t, J=6.9 Hz), 2.47 (1H, t, J=6.9 Hz), 2.41 (0.5H, br s), 2.11–2.06 (2H, m), 1.89 (0.5H, ddd, 11.9, 11.9, 7.2 Hz), 1.64 (1.5H, s).

4-(2-Hydroxypropan-2-yl)acetophenone²⁰⁾ (4e): ¹H-NMR (400 MHz, CDCl₃) δ: 7.95–7.91 (2H, m), 7.60–7.57 (2H, m), 2.60 (3H, s), 1.60 (6H, s).

3-(tert-Butyldimethylsilyl)oxy-5-(3-hydroxypentan-3-yl)acetophenone²⁰⁾ (4g): ¹H-NMR (400 MHz, CDCl₃) δ: 7.59–7.58 (1H, m), 7.280–7.276 (1H, m), 7.10–7.09 (1H, m), 2.59 (3H, s), 1.92–1.77 (5H, m), 1.00 (9H, s), 0.76 (6H, t, J=7.6 Hz), 0.22 (6H, s).

3-(Methoxymethoxy)-5-(3-hydroxypentan-3-yl)acetophenone²⁰⁾ (4h): ¹H-NMR (400 MHz, CDCl₃) δ: 7.632–7.626 (1H, m), 7.494–7.488 (1H, m), 7.294–7.285 (1H, m), 5.23 (2H, s), 3.50 (3H, s), 2.61 (3H, s), 1.93–1.78 (4H, m), 0.77 (6H, t, J=7.2 Hz).

1-(6-(2-Hydroxypropan-2-yl)pyridin-2-yl)ethanone (4j): Colorless oil. TLC (SiO₂): Rf=0.45 (hexanes–EtOAc 2 : 1). IR (KBr) 3441.0, 2974.2, 2929.9, 1681.9, 1585.5, 1359.8, 1300.0, 1180.4, 964.4, 819.8, 597.9 cm⁻¹. ¹H-NMR (300 MHz, CDCl₃) δ: 7.96 (1H, dd, J=10.4, 1.8 Hz), 7.88 (1H, t, J=10.4 Hz), 7.61 (1H, dd, J=10.4, 1.8 Hz), 4.78 (1H, s), 2.75 (3H, s), 1.60 (6H, s). ¹³C-NMR (75 MHz, CDCl₃) δ: 199.5, 165.6, 151.3, 138.0, 122.4, 119.8, 71.9, 30.6, 25.8. HR-MS (FAB) Calcd for C₁₀H₁₄NO₂ [M+H]⁺: 180.1025, Found 180.1020.

General Procedure for Selective Reduction of Weinreb Amide in the Presence of Ketone (Table 5, Runs 2, 4, 6, 7, and 9)

To a solution of keto amide (0.200 mmol, 1.0 eq) and PEt₃ (0.18 mL of 20% in toluene, 0.244 mmol, 1.2 eq) in CH₂Cl₂ (0.50 mL, 0.4 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to −78°C, and DIBAL-H (0.58 mL of 1.03 M in hexane, 0.597 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at −78°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

9-Benzoylnonanal³⁷⁾ (4m): ¹H-NMR (400 MHz, CDCl₃) δ: 9.76 (1H, t, J=1.9 Hz), 7.97–7.95 (2H, m), 7.56 (1H, tt, J=7.4, 1.5 Hz), 7.48–7.44 (2H, m), 2.97 (2H, t, J=7.4 Hz), 2.42 (2H, td, J=7.3, 1.9 Hz), 1.77–1.70 (2H, m), 1.64–1.59 (2H, m), 1.40–1.25 (8H, m).

10-Oxoundecanal³⁸⁾ (4p): ¹H-NMR (300 MHz, CDCl₃) δ: 9.77 (1H, t, J=2.4 Hz), 2.46–2.40 (4H, m), 2.14 (3H, s), 1.65–1.54 (4H, m), 1.30–1.25 (8H, m).

General Procedure for Selective Alkylation of Weinreb Amide in the Presence of Ketone (Table 5, Runs 1, 3, 5, 8, and 10)

To a solution of keto amide (0.200 mmol, 1.0 eq) and PEt₃ (0.18 mL of 20% in toluene, 0.244 mmol, 1.2 eq) in CH₂Cl₂ (0.50 mL, 0.4 M) was added TMSOTf (43 µL, 0.238 mmol, 1.2 eq) dropwise at rt. After being stirred for 1 h at rt, the reaction mixture was then cooled to 0°C, and Grignard reagent (0.600 mmol, 3.0 eq) was added slowly via syringe. Stirring was continued at 0°C until the starting material was consumed (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (2.0 mL) and MeOH (1.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography to afford the desired product.

1-(4-Benzoylphenyl)ethanone³⁹⁾ (4k): ¹H-NMR (400 MHz, CDCl₃) δ: 8.08–8.05 (2H, m), 7.88–7.85 (2H, m), 7.82–7.80 (2H, m), 7.65–7.61 (1H, m), 7.54–7.49 (2H, m), 2.68 (3H, s).

1-Phenylundecane-1,10-dione³⁷⁾ (4l): ¹H-NMR (300 MHz, CDCl₃) δ: 7.97–7.94 (2H, m), 7.59–7.53 (1H, m), 7.49–7.44 (2H, m), 2.96 (2H, t, J=9.8 Hz), 2.42 (2H, t, J=10.0 Hz), 2.14 (3H, s), 1.78–1.68 (2H, m), 1.61–1.52 (2H, m), 1.40–1.24 (8H, m).

2,6-Diacetylpyridine⁴⁰⁾ (4n): ¹H-NMR (400 MHz, CDCl₃) δ: 8.22 (2H, d, J=7.6 Hz), 8.00 (1H, t, J=7.6 Hz), 2.80 (6H, s).

Dodecane-2,11-dione⁴¹⁾ (4q): ¹H-NMR (400 MHz, CDCl₃) δ: 2.42 (4H, t, J=7.4 Hz), 2.14 (6H, s), 1.60–1.54 (4H, m), 1.38–1.18 (8H, m).

2,5-Diacetylfuran⁴²⁾ (4s): ¹H-NMR (400 MHz, CDCl₃) δ: 7.23 (2H, s), 2.58 (6H, s).

Selective Alkylation of Nitrile of 3n (Table 5, Run 11): 1-(4-Acetylphenyl)propan-1-one⁴³⁾ (4t)

To a solution of 3n (72.6 mg, 0.500 mmol) and PEt₃ (0.74 mL of 20% in toluene, 1.00 mmol) in CH₂Cl₂ (5.0 mL) was added TMSOTf (0.18 mL, 0.996 mmol) dropwise at rt. After being stirred for 1 h at rt, the resulted solution was added to a solution of PhMgBr (1.4 mL of 1.10 M in THF, 1.54 mmol) slowly via cannula. Stirring was continued at rt for 30 min (TLC analysis was conducted after quenching a small amount of the reaction mixture with a drop of TBAF (1.0 M in THF)). To the mixture were added saturated aqueous NaHCO₃ solution (5.0 mL) and MeOH (2.0 mL), and the resulting solution was then stirred for 2 h at 40°C. After being cooled to rt, the resulted solution was evaporated and the residue was dissolved with THF (2.0 mL). The solution was acidified with 1 N HCl and stirred for 15 min. The mixture was extracted several times with EtOAc (50 mL). The organic layer was dried over Na₂SO₄, filtered, and concentrated under reduced pressure to give a residue. Purification was accomplished by flash column chromatography (hexanes–AcOEt, 5 : 1) to afford 4t (40.4 mg, 0.181 mmol, 36%). ¹H-NMR (400 MHz, CDCl₃) δ: 8.04 (4H, s), 3.05 (2H, q, J=7.2 Hz), 2.65 (3H, s), 1.25 (3H, t, J=7.2 Hz).

Acknowledgment

This work was financially supported by the Hoansha Foundation, the Uehara Memorial Foundation, Takeda Science Foundation, and a Grant-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. Kenzo Yahata is grateful for financial support from the Japan Society for the Promotion of Science Research Fellowship for Young Scientists.

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