Unexpected Surprise in the Reactions of Acetals and Trialkylsilyl Chloride (R₃SiCl): Efficient Deprotection of Aromatic Acyclic Acetals

Abstract

The reaction of acetals with trialkylsilyl chloride (R₃SiCl) leads to the deprotection of the acetal group, resulting in the corresponding carbonyl compounds. Notably, aromatic dialkyl acetals yield the corresponding parent aromatic aldehydes and ketones in good yields. The reaction conditions are very mild, allowing many acid-labile functional groups to survive without any problems. Additionally, we clarified the reaction mechanism through an NMR study.

Introduction

Acetals, especially O,O-acetals, are typical protecting groups for carbonyl functional groups and are the most commonly used due to their stability under neutral and basic conditions. Their deprotection is typically achieved through acid catalysis in the presence of water to regenerate the parent carbonyls. However, this method is not suitable for acetals featuring acid-labile structures and/or functional groups. Therefore, considerable efforts have been devoted to developing deprotection methods for acetals that feature acid-labile functionalities.¹⁾ On the other hand, the key reactivity of trialkyl silyl halides for the deprotection of acetals remains less explored. Among these, the method using trimethylsilyl iodide (TMSI) has been known well.²⁾ After that, the method developed by Ukaji et al. employed the more readily available trimethylsilyl chloride (TMSCl) for the deprotection of cyclic ketals and dioxolanes. Although the complex of SmCl₃ and TMSCl in tetrahydrofuran (THF) deprotected acetals in good yields,^3,4) only TMSCl in THF is insufficient. Quite recently, Provot and colleagues have found that TMSCl/NaI in CH₃CN proceeded to deprotect acetals with in situ generated TMSI.⁵⁾ However, to the best of our knowledge, no report has appeared for the deprotection of acetals using standalone TMSCl.

As part of our ongoing studies on the deprotection of O,O-acetals,^6–8) we herein found that trialkylsilyl chlorides (R₃SiCl), including TMSCl, can deprotect aromatic dimethyl acetals to yield aromatic aldehydes in good yields. It was an unexpected and pleasant surprise, as the deprotection of acetals using only R₃SiCl has not been reported, as mentioned above. In this manuscript, these novel results are described in detail.

Results and Discussion

As part of our acetal deprotection studies,^6,7) 4-chlorobenzaldehyde dimethyl acetal 1a⁹⁾ was reacted with laboratory stock (old) TMSCl (1.2 equivalent (equiv.)) in CH₂Cl₂ at room temperature for 15 min.¹⁰⁾ Since the addition of water rendered the resulting mixture acidic, the reaction mixture was quenched by addition into saturated NaHCO₃ aqueous solution to give 4-chlorobenzaldehyde 2a in 62% yield (Table 1, Entry 1). Because TMSCl readily decomposes in the presence of moisture to produce HCl, which acts to deprotect acetals, we next investigated the use of fresh TMSCl¹¹⁾ from various manufacturers (Entries 2–6). First, TMSCl purchased from Nacalai (Kyoto, Japan) was examined, and aldehyde 2a was obtained in high yield (Entry 2). The same trend was observed for all TMSCl purchased from Aldrich (St. Louis, MO, U.S.A.) (Entry 3), Tokyo Chemical Industry Co., Ltd. (Tokyo, Japan) (Entry 4), Kishida (Osaka, Japan) (Entry 5), and Wako (Osaka, Japan) (Entry 6). To confirm that TMSCl itself is the real active species, TMSCl that had been passed through basic alumina to eliminate any acidic impurities (if present) was used, resulting in a yield of 99% (Entry 7). The yield of Nakalai’s old TMSCl, which had 62% in Entry 1, also increased to 74% after passing through basic alumina (Entry 8). The optimal conditions for the reaction were determined by testing the reagent equivalents and temperature using Wako TMSCl. As shown in Entry 9, the reaction at room temperature resulted in a yield of 72%. Furthermore, when 1 equiv. of TMSCl was used, the yield dropped to 78% (Entry 10). As a result, it was concluded that the optimal conditions for the reaction were obtained using 1.2 equiv. of TMSCl in dry CH₂Cl₂ (1 M) at 0°C.

Table 1. The Reaction of 1a with TMSCl in CH₂Cl₂

Entry	Maker, state of TMSCl, yield (%)a)	Entry	Maker, state of TMSCl, yield (%)a)
1	Nakalai, lab-stored, 62%	6	Wako, fresh, 98%
2	Nakalai, fresh, 87%	7	Wako, basic Al2O3 treatment,b) 99%
3	Tokyo Chemical Industry Co., Ltd., fresh, 96%	8	Nakalai, basic Al2O3 treatment,c) 74%
4	Aldrich, fresh, 88%	9d)	Wako, fresh, 72%
5	Kishida, fresh, 99%	10e)	Wako, fresh, 78%

a) ¹H-NMR yield. b) Fresh TMSCl from Wako was passed through basic Al₂O₃ (Merck aluminium oxide 90 active basic [0.063–0.200 mm]) to remove acidic impurities (if present) before use. c) Old TMSCl from Nakalai was passed through basic Al₂O₃ (Merck aluminium oxide 90 active basic [0.063–0.200 mm]) to remove acidic impurities (if present) before use. d) Reaction was performed at room temperature for 5 min. e) TMSCl (1.0 equiv.) for 30 min.

In the subsequent reactions, fresh TMSCl purchased from Kishida was used. The generality of this deprotection method for both acyclic acetal 1a and cyclic acetal 3 was investigated using various R₃SiCl (Table 2). As a result, it was found that TMSCl (Entry 1), TESCl from Aldrich (Entry 2), and TBSCl from Kanto (Entry 3) were all capable of deprotecting 1a in excellent yields; however, TBSCl required a slightly longer reaction time. In contrast, the cyclic acetal 3 was less reactive, and when the reaction was stopped at the same time as for 1a, the yields of the corresponding aldehyde 2a were lower, and the starting dioxirane 3 was recovered (Entries 4–6). Even after 5 h, the reaction of 3 with TMSCl yielded aldehyde 2a in only a 17% isolated yield, leaving 60% of the starting material unreacted.

Table 2. The Reaction of Acyclic or Cyclic Acetal 1a or 3 with R₃SiCl in CH₂Cl₂

Entry	Acetal	R3SiCl	Time (min)	Yield of 2aa) (%)	Recovered acetal (%)a)
1	1a	TMSCl	15	99 (80)b)	—
2	//	TESCl	15	98	—
3	//	TBSCl	30	92	—
4	3	TMSCl	15	20	3 (69%)
5	//	TESCl	15	22	3 (63%)
6	//	TBSCl	30	15	3 (72%)

a) ¹H-NMR yield. b) Isolated yield.

The aliphatic acetal 4 exhibited poor reactivity, yielding the deprotected aldehyde 5 in only a 36% isolated yield after 5 h, while 35% of the acetal 4 was recovered. Extending the reaction time did not improve the conversion (Chart 1).

Chart 1. Reaction of Aliphatic Acetal (4) with TMSCl

To gain a deeper understanding of the reaction mechanism, NMR studies of the aromatic and aliphatic acetals were carried out separately. Although the reaction in CH₂Cl₂ proceeds much faster, Fig. 1 shows the transformation of the aromatic dimethyl acetal 1a observed by ¹H-NMR in CDCl₃ only to understand the reaction mechanism and not the reaction time. The reaction was carried out under the same conditions as in Table 1, except that the solvent was changed from CH₂Cl₂ to CDCl₃. After 2.5 h, ¹H-NMR showed complete consumption of 1a and the new formation of an aldehyde signal (Spectrum 1-D), indicating that the aldehyde was generated in the reaction mixture without adding water. The reaction work-up afforded aldehyde 2a in quantitative yield. Spectrum 1-E shows the ¹H-NMR spectrum of the crude product.

Fig. 1. ¹H-NMR Spectra: Deprotection for Aromatic Acetal 1a

On the other hand, the aliphatic acetal 4 exhibited different results (Fig. 2). Although the reaction progress was very slow, new signals corresponding to the methyl group of Cl-CH-OCH₃ (3.50 ppm), SiOCH₃ (3.41 ppm) from TMSOCH₃, and the hydrogen atom of O-CH-Cl acetal (5.48 ppm) appeared.¹²⁾ Even after 3 d, the starting acetal 4 (-(OCH₃)₂ at 3.30 ppm and -CH- at 4.34 ppm) remained, and no aldehyde signal was observed (Spectra 2-B–2-E). However, after work-up (addition of saturated NaHCO₃ aqueous solution), the new signals mentioned above disappeared, and the crude product contained aldehyde 5 and the starting acetal 4 (Spectrum 2-F). An expanded view of Fig. 2 showing the region from 3.0 to 6.0 ppm can be found in the Supplementary Materials.

Fig. 2. ¹H-NMR Spectra: Deprotection of Aliphatic Acetal 4

From ¹H-NMR experiments, the plausible reaction mechanism for dimethyl acetals was considered as follows (Chart 2). Whether aromatic acetals 1 (Ar is an aromatic ring) or aliphatic acetals 4 (R′ is an alkyl group), the pathway to the oxocarbenium ion intermediate I is the same. First, a lone pair from the acetal oxygen attacks the Si atom of R₃SiCl, removing the chlorine atom as a chloride anion. Then, another oxygen atom assists in the departure of the trialkylsilyl methyl ether, giving the oxocarbenium ion intermediate I along with the chloride anion. In the case of oxocarbenium ion intermediate I from aromatic acetals 1, the aromatic ring can conjugate with the formed aldehyde. That is, the electrophilic ability of the methyl group is increased by the stabilization of the aromatic ring through conjugation with the formed aldehyde. The chloride anion then preferentially attacks the methyl group to generate the corresponding aromatic aldehyde 2 and release MeCl.¹³⁾ However, in the case of oxocarbenium ion I from aliphatic acetals 4, no such stabilization is present. Thus, the chloride anion attacks the electrophilic carbon center to form intermediate II. The chlorine atom is then replaced by a hydroxyl anion upon treatment with aqueous NaHCO₃ to form hemiacetal III, which is subsequently converted to the aliphatic aldehyde 5.

Chart 2. Plausible Reaction Mechanism

The reaction using TMSCl is very mild. Various aromatic dimethyl acetals were next examined to expand the substrate scope (Chart 3). The results presented in this study are based on isolated yields. The reaction of para-chloro benzaldehyde dimethyl acetal 1a gave an 80% isolated yield. Similarly, para-bromo benzaldehyde dimethyl acetal 1b yielded the corresponding aldehyde in 79%. Acid-labile functional groups such as TBS-1d, Tr-1e, and MOM-1f ethers were tolerated under standard conditions, furnishing the corresponding aldehydes 2d–f in excellent yields (90–97%) within 15 min. However, para-nitro benzaldehyde dimethyl acetal 1g, having a very strong electron-withdrawing nitro group, showed poor reactivity, yielding only 56% of the corresponding aldehyde 2g even after 5 h, with 33% of the starting 1g remaining.

Chart 3. Deprotection of Aromatic Dimethyl Acetals with Various Functional Groups

The deprotection of aromatic acetals was extended to other acetals (Chart 4). The reactions of diethyl acetal 1h, diisopropyl acetal 1i, and dimethyl ketal 1j with TMSCl proceeded smoothly to afford the corresponding aldehyde 2a from 1h and 1i, and ketone 2h from 1j, in good isolated yields.

Chart 4. Deprotection of Various Aromatic Acetals

Conclusion

We have developed a new method for the deprotection of acetals, particularly aromatic acyclic acetals, with high efficiency. The major advantages of this method include the involvement of R₃SiCl as the sole deprotecting agent, especially TMSCl, which is a readily available reagent and milder than other alternatives. The achievement of deprotection of acetals, without affecting the tethered acid-labile functional groups, makes this unprecedented operationally simple protocol more appealing.

Experimental

General Information

All reagents were purchased from commercial sources. Reactions were performed under a nitrogen atmosphere using purchased anhydrous solvents. All reactions were monitored by Merck (Darmstadt, Germany) silica gel 60 F254. The products were purified by column chromatography over silica gel Kieselgel 60 (70–230 mesh ASTM) purchased from Merck. ¹H-NMR spectra were recorded at 25°C on a JEOL (Tokyo, Japan) NMR or a Bruker (Billerica, MA, U.S.A.) AVANCE II (¹H-NMR 400 MHz). All compounds except trityl ether dimethyl acetal (1f) are known. Acetals 1b–d and 4 and carbonyl compounds 2a–g, 2h, and 5 are commercially available. Other acetals 1a,¹⁴⁾ 1j,¹⁴⁾ 1f–g,¹⁵⁾ 1h,¹⁶⁾ 1i,¹⁷⁾ 3a,¹⁸⁾ 3b,¹⁹⁾ and 4-(dimethoxymethyl)phenol²⁰⁾ were prepared according to the literature.

Preparation of Trityl Ether Dimethyl Acetal (1e)

To a stirred solution of 4-(dimethoxymethyl)phenol²⁰⁾ (5 mmol) in 1,2-dichloroethane (40 mL), trityl chloride (6 mmol), Et₃N (15 mmol), and N,N-dimethyl-4-aminopyridine (0.5 mmol) were added, and the resulting mixture was stirred at 80°C for 3 h under an N₂ atmosphere. After completion of the reaction, as indicated by TLC, the reaction mixture was diluted with water, and the aqueous suspension was extracted with dichloromethane. The organic layer was dried over anhydrous Na₂SO₄ and concentrated under reduced pressure. The crude product was purified by flash column chromatography using hexane as an eluent to obtain the acetal 1e as a white solid. 1e: 1.108 g, 54% yield, white solid, mp 102–104°C. ¹H-NMR (400 MHz, CDCl₃) δ: 3.21 (s, 6H), 5.21 (s, 1H), 6.66 (d, J = 8.8 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.28–7.18 (m, 9H), 7.44–7.42 (m, 6H); ¹³C-NMR (100 MHz, CDCl₃) δ: 52.6, 90.6, 103.1, 120.7, 126.8, 127.2, 127.8, 129.0, 130.9, 144.2, 156.6; high-resolution mass spectrometry (atmospheric pressure chemical ionization); Calcd for C₂₈H₂₆O₃: m/z [M + Na]⁺ 433.1774. Found 433.1766.

Typical Procedure for Deprotection of Aromatic Acetal

Two hundred and eighty milligrams of acetal 1a (1.5 mmol) was taken in a 30 mL double-neck round-bottom flask with an applied vacuum and connected to an N₂ gas, and then 1.5 mL of anhydrous CH₂Cl₂ was added. Next, 0.23 mL of Kishida’s fresh TMSCl was added slowly to the stirring reaction mixture at 0°C under N₂. The reaction was completed within 15 min as monitored by TLC. The reaction mixture was slowly poured into saturated NaHCO₃ aqueous solution. After 10 min, the mixture was transferred to a separatory funnel and extracted with CH₂Cl₂. The separated organic layer was dried with anhydrous sodium sulfate, followed by the evaporation of CH₂Cl₂ using a rotary evaporator to obtain the crude aldehyde 2a. Finally, compound 2a was purified by column chromatography using an elution system of 1% ethyl acetate in hexane, and 2a was obtained in 80% (168 mg) yield. The other aryl aldehydes 2 were synthesized using the same procedure.

Deprotection of Aliphatic Acetal 4

Two hundred and eighty-two milligrams of acetal 4 (1.5 mmol) was taken in a 30 mL double-neck round-bottom flask with an applied vacuum and connected to an N₂ gas, and then 1.5 mL of anhydrous CH₂Cl₂ was added. Next, 0.23 mL of TMSCl was added slowly to the stirring reaction mixture at 0°C under N₂. After 5 h (prolonging the reaction did not improve the conversion), the reaction mixture was slowly poured into saturated NaHCO₃ aqueous solution. After 10 min, the mixture was transferred to a separatory funnel and extracted with CH₂Cl₂. The separated organic layer was dried by anhydrous sodium sulfate, followed by the evaporation of CH₂Cl₂ using a rotary evaporator to obtain the crude mixture of aldehyde 5 and unreacted acetal 4. Finally, aldehyde 5 and acetal 4 were isolated in 36% (77 mg) and 35% (99 mg), respectively, by column chromatography using an elution system of only hexane.

NMR Analysis

To elucidate the deprotection pathway, NMR spectroscopy (JEOL 400 MHz) was used to monitor the progress of the reaction of acetal with TMSCl in CDCl₃ in place of CH₂Cl₂. The reaction was carried out in the same manner as mentioned above. Samples were taken from the reaction mixture at the times indicated on the NMR graph into NMR tubes, diluted with CDCl₃, and analyzed.

Acknowledgments

This work was supported by JSPS KAKENHI Grant 21K06454.

Conflict of Interest

The authors declare no conflict of interest.

Supplementary Materials

This article contains supplementary materials.

References and Notes

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