Diverse acetals from stoichiometric amounts of aldehydes and alcohols under very mild conditions: a new twist to PPh₃–CCl₄ reagent combination

Abstract

The most frequently utilized method for the preparation of acetals is the reaction of alcohols and aldehydes or ketones, but it suffers from a number of shortcomings: bad thermodynamics, the presence of an acid catalyst and occasionally a complicated reaction workup. Frequently, PPh₃ in combination with CCl₄ has been successfully used in the Appel reaction and for the preparation of esters and amides as a chlorinating and/or dehydrating agent. In this work, the possible use of PPh₃–CCl₄ reagent in the synthesis of acetals from aldehydes and alcohols was studied. By varying the ratio of reactants and reaction conditions (temperature, reaction time, solvent), the reaction yield was optimized, while side products were reduced to a minimum. The best results were attained when a near stoichiometric ratio (1 : 2.2 : 1.1 = aldehyde/alcohol/PPh₃) of the reactants was used and the reaction was conducted at room temperature in CCl₄. This reagent ratio also resulted in reaction mixtures that besides OPPh₃, residual reactants and the acetal, contained no more than 10% of side products, with respect to the acetal. Chromatography-free acetal isolation/purification was readily accomplished using a pentane–acetonitrile partition. In this way we obtained 100 acetals out of which 30 acetals represented new compounds which were fully spectrally (1D-, 2D-NMR, MS, IR, UV) characterized. The reaction mechanism behind this newly developed synthetic procedure was elucidated and discussed.

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Introduction

The acetal moiety is widespread in both natural and synthetic organic compounds. The conversion of aldehydes to the corresponding acyclic or cyclic acetals is an important synthetic transformation that has received a lot of attention from organic chemists.^1,2 In most cases acetals represent a protecting group,^1–5 but they can also be converted to a variety of other functional groups and hence serve as useful intermediates in synthesis. For example, acetals can be reduced (removing one alcohol moiety),⁶ allylated,⁷ undergo substitution⁸ and other transformations.^6,9–12

Aldehydes are typically acetalized by a protic or Lewis acid-catalyzed treatment with a large excess of an alcohol, in the presence of (at least) stoichiometric amounts of a water scavenger. TsOH,¹³ HCl,¹ HBF₄,¹⁴ and silica-supported HClO₄ ¹⁵ are just few examples of the employed protic acids, while metal triflates,^16–18 and chlorides^19–21 are the commonly used Lewis acids. Most successful methods for the formation of dimethyl/diethyl acetals are based on the reaction of an orthoformate, as both the water scavenger and the source of the alcohol, with an aldehyde, in the presence of a catalyst, usually using the corresponding alcohol as the solvent. Acetals can also be prepared starting from geminal dihalides and alkoxides,⁶ or in the alkyl-de-alkoxy-substitution reaction of orthoesters with Grignard reagents.⁶ Various acetals could be produced in transetherification (transacetalization) reactions, usually by removing the more volatile alcohol from the reaction mixture.⁶

A combination of triphenylphosphine and carbon tetrachloride is a reagent mixture capable of performing a number of chlorinations and dehydrations,²² in which CCl₄ plays a role of both reagent and solvent. The reaction kinetics are solvent-dependent, with MeCN providing the fastest rates,²² while the thermodynamics are favorable due to the formation of OPPh₃. This reagent is employed in the well-known Appel reaction^6,23,24 by which alcohols are converted to alkyl chlorides (SP-5, Scheme 1). Aldehydes also react with PPh₃–CCl₄ reagent yielding an equimolar mixture of a Wittig-type product (1,1-dichloroalkene, SP-4, Scheme 1) and gem-dichloro derivative (SP-3, Scheme 1) of the employed aldehyde.²⁵ Due to low rates at ambient temperature, most of the reactions performed with this reagent are conducted at reflux temperatures.²²

Scheme 1 The reaction of PPh₃–CCl₄ with alcohols and aldehydes under reflux. Appel reaction mechanism and the plausible mechanism for the formation of dichloroalkene.

At first, it seemed to us that PPh₃–CCl₄ reagent could also be used as a source of CCl₃⁻ ion, as this chemical species appears in the first step of the Appel reaction mechanism (Scheme 1). In order to test this hypothesis, we assumed that if we introduced a suitable electrophile, such as an aromatic aldehyde (2-chlorobenzaldehyde and cinnamaldehyde), into the reagent mixture, under the Appel conditions (refluxing CCl₄), we would obtain 2,2,2-trichloro-1-arylethanol (SP-1, Scheme 1) as one of the products. Although, the reaction mixture, refluxed for one hour, contained a small amount of this product, it was another, unexpected, minor product that drew our attention to a possible, completely different application of this reagent.

Namely, a detailed analysis of the reaction mixture revealed that, along with the expected major geminal dichloride of the aldehyde and dichloroalkene, a 1-chloro-1-alkoxy derivative (hemiacetal-chloride) formed under these conditions (SP-2, Scheme 1). This 1-chloro-1-ethoxymethylarene was probably the result of the reaction of residual ethanol, a stabilizer, present in the used commercial CCl₄, and the chlorinating-dehydrating effect of PPh₃–CCl₄ reagent. This prompted us to further study this interesting transformation – the formation of an acetal related compound under apparently neutral conditions. This investigation resulted in the development of a new synthetic methodology for the synthesis of acetals from aldehydes using PPh₃–CCl₄ reagent and stoichiometric amounts of various alcohols, under very mild conditions (room temperature, no acid added), which we report on herein.

Results and discussion

Initially, the products obtained in a reaction similar to these mentioned in the introduction section (the reaction of 3-nitrobenzaldehyde with 1 equivalent of PPh₃ in refluxing CCl₄, devoid of the precipitated OPPh₃; Table 1, entry 1; see table legend), were further subjected to the reaction conditions with excess of ethanol (4 equivalents) in a fresh quantity of CCl₄ without the addition of new amounts of PPh₃. After 1 h of reflux, the mixture was shown to contain 41% of the diethyl acetal of 3-nitrobenzaldehyde (Table 1, entry 2) together with an almost equal amount of β,β-dichloro-3-nitrostyrene. The acetal appeared to have formed from the geminal dichloride judged from its reduced amount in the resulting mixture. Encouraged by these results, we tried to perform the transformation (aldehyde to acetal) in a one-pot manner by mixing the reactants all at once.

Table 1 The reaction of an aldehyde/ketone, alcohol, PPh₃ and CCl₄. The effect of varying reaction conditions on the yield (%) of the acetal and other reaction products

Entry	Carbonyl	Alcohol (ROH)	Aldehyde : alcohol : PPh3	Reaction time and temperature	Acetal	β,β-Dichloro-styrene	Benzal-chloride	Unreacted aldehyde	RCl	Unreacted ROH
a No reagent added or no product detected.b The yield (%) of the product. The formed acetal, styrene, benzal chloride and unreacted aldehyde make up 100%.c Lower alcohols (ethanol, 1-propanol and 1-pentanol) and alkyl chlorides derived from them (chloroethane, 1-chloropropane and 1-chloropentane), the oxirane, aliphatic aldehydes and products derived from them, were completely or partially lost during the workup due to their volatility.d The reaction mixture from entry 1 treated with pentane was further subjected to conditions under entry 2. The starting pentane solution from entry 1 contained the aldehyde, styrene and benzal chloride in the ratio 5 : 49 : 46 (GC-MS).e r.t. – room temperature.f The obtained acetal is a new compound. It was fully spectrally characterized (IR, UV, MS, and ^1H and ^13C NMR) and their ^1H and ^13C NMR spectra assigned through detailed analyses of 1D- (including selective homodecoupling experiments) and 2D-NMR spectra. All NMR spectral data for the new compounds are reproduced in the ESI.g The yield of the alkyl chloride relative to the amount of the starting alcohol (based on ^1H NMR).h The percentage of the unreacted alcohol relative to the starting amount (based on ^1H NMR).i Cyclohexanone, cyclopentanone, 2-pentanone and acetophenone were used in entries 16–19.j 140 mg (1 mmol) of K2CO3 were added into the reaction mixture.k Two equivalents of ethylene glycol and PPh3 were used because of the expected oxirane formation.
1	3-NO2–C6H4CHO	—^a	1 : 0 : 1	1 h, reflux	—	16^b	17	76	—^c	—
2	Entry 1 products^d	Ethanol	1 : 4 : 0	1 h, reflux	41	49	5	5	—	—
3	3-NO2–C6H4CHO	Ethanol	1 : 1 : 1	1 h, reflux	26	11	5	58	—	—
4–6	3-NO2–C6H4CHO	Ethanol	1 : (2–10) : 1	1 h, reflux	46–66	11	1–3	39–22	—	—
7–9	3-NO2–C6H4CHO	1-Alkanol (C3, C5, C7)	1 : 5 : 1	1 h, reflux	64–67	12	1	23–20	—	—
10	3-NO2–C6H4CHO	1-Heptanol	1 : 2 : 1	48 h, r.t.^e	47^f	1	0	52	3^g	50^h
11	3-Cl–C6H4CHO	1-Heptanol	1 : 2 : 1	48 h, r.t.	38^f	1	1	60	3	59
12	4-OMe–C6H4CHO	1-Heptanol	1 : 2 : 1	48 h, r.t.	7^f	2	1	90	6	87
13	4-NMe2–C6H4CHO	1-Heptanol	1 : 2 : 1	48 h, r.t.	≈0	≈0	≈0	≈99	7	93
14–15	3-NO2–C6H4CHO and 4-NMe2–C6H4CHO or acetophenone	1-Heptanol	(1 + 1) : 2.2 : 1.1	48 h, r.t.	54	1	1	44	2	49
					0	0	0	≈100
16–19	Various ketones^i	1-Heptanol	1 : 2 : 1	48 h, r.t.	≈0	≈0	≈0	≈99	6	94
20	Hexanal	1-Heptanol	1 : 2.2 : 1.1	48 h, r.t.	51^f	—	—	—	3	51
21	3-Methylbutanal	1-Heptanol	1 : 2.2 : 1.1	48 h, r.t.	46	—	—	—	3	55
22	2-Methylpentanal	1-Heptanol	1 : 2.2 : 1.1	48 h, r.t.	40^f	—	—	—	4	60
23	3-NO2–C6H4CHO	3-Methyl-1-butanol	1 : 2.2 : 1.1	48 h, r.t.	53	1	1	45	—	—
24	3-NO2–C6H4CHO	2-Methyl-1-butanol	1 : 2.2 : 1.1	48 h, r.t.	47	1	1	51	—	—
25	3-NO2–C6H4CHO	2-Butanol	1 : 2.2 : 1.1	48 h, r.t.	22^f	1	2	75	—	—
26	3-NO2–C6H4CHO	2-Methyl-2-propanol	1 : 2.2 : 1.1	48 h, r.t.	≈0	1	2	97	—	—
27–29	3-NO2–, 3-Cl-, 4-OMe–C6H4CHO	Ethylene glycol	1 : 2 : 2^k	48 h, r.t.	17–3	1	0	82–96	—	—
30–32	3-NO2–C6H4CHO	1-Heptanol	1 : 2.2 : (1.1–3)	48 h, r.t.	55–60	1	1	43–38	2–5	48–40
33	3-NO2–C6H4CHO^j	1-Heptanol	1 : 2.2 : 1.1	48 h, r.t.	52	1	1	46	3	50
34–35	—	1-Heptanol	0 : (1–2) : 1	48 h, r.t.	—	—	—	—	7–11	93–89
36–37	—	1-Heptanol	0 : (1–2) : 1	5 h, reflux	—	—	—	—	37–71	63–29

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Thus, the following reactions were conducted with mixtures of the aldehyde, alcohol and PPh₃ in differing ratios (Table 1, entries 3–6) in refluxing CCl₄ at millimolar scale. Surprisingly, only the acetal was formed, with only trace amounts of the hemiacetal-chloride even when the ratio of the reactants was 1 : 1 : 1 (Table 1, entry 3). All of the reaction mixtures contained the dichloroalkene in approximately equal amount and varying amounts of the geminal dichloride which was found to decrease with the increasing amount of the used alcohol. The yield of the acetal naturally increased with the amount of the added ethanol; however, the obtained contaminated acetal required additional steps of elaborate purification (distillation or chromatography on special stationary phases).

The next step was to ascertain whether the reaction will be applicable to alcohols other than ethanol. Additional three n-alcohols (1-propanol, 1-pentanol and 1-heptanol, Table 1, entries 7–9) demonstrated similar conduct when subjected to the reaction conditions described for ethanol. The yield of the formed acetals was higher or comparable to that of the diethyl acetal. The identity of the alcohol used did not significantly affect the amount of the formed dichlorostyrene. Also, the reaction mixture obtained when 1-heptanol was used for the reaction contained appreciable amounts of 1-chloroheptane (Table 1, entry 9). This chloroalkane must have formed in the Appel reaction under these conditions and its formation negatively influenced the yield of the acetal.

In order to determine the optimal reaction conditions and with an aim of lowering/eliminating the formation of side products, the time dependence of product formation in two sets of reactions (3-nitrobenzaldehyde : 1-heptanol : PPh₃ = 1 : 2 : 1) was tracked at reflux and room temperatures (Fig. 1 and 2). Additionally, the reactions without the aldehyde and without the alcohol were performed in parallel. As expected, the room temperature reaction was much slower; however, only very small amounts of the dichloroalkene were detected. The formation of 1-chloroheptane and other side products was also much slower at room temperature. Although, it took ca. 25 times longer to reach the same yield of the acetal at room temperature, when compared to the reaction conducted under reflux conditions, the obtained product contained at least a two times lower quantity of the side products. Thus, the side reactions (Appel and the formation of the dichloroalkene and geminal dichloride) showed a more significant temperature dependence in comparison to the acetal-forming reaction. We decided to exploit this, and, all further experiments were done at room temperature (Table 1, entries 10–33). The duration of the acetal forming reaction was inferred from the second set of experiments, where at least two days were necessary to attain a yield of ca. 50%.

Fig. 1 Dependence of yield on reaction time at reflux temperature: acetalization (aldehyde : alcohol : PPh₃ = 1 : 2 : 1; solid lines), Appel reaction (alcohol : PPh₃ = 1 : 1; dotted lines), and dichoroalkene-gem-dichloride (side) reaction (aldehyde : PPh₃ = 1 : 1; dotted lines).

Fig. 2 Dependence of yield on reaction time at reflux temperature: acetalization (aldehyde : alcohol : PPh₃ = 1 : 2 : 1; solid lines), Appel reaction (alcohol : PPh₃ = 1 : 1; dotted lines), and dichoroalkene-gem-dichloride (side) reaction (aldehyde : PPh₃ = 1 : 1; dotted lines).

The scope of the reaction was further explored by reacting aldehydes of different electrophilicity with 1-heptanol. Opposite to the standard acid-catalyzed acetalization,² it was shown that the yield and the reaction rate positively correlated with the increasing electrophilicity of the used aldehydes (Table 1, entries 10–13). In the case of benzaldehyde derivatives with highly electron-donating substituents (for example, entry 13) the reaction did not take place at all or only trace amounts of the acetals were detected. Experiments with a mixture of two carbonyl compounds (two aldehydes, and an aldehyde and a ketone) showed that the acetalization of the more electrophilic of carbonyl compound could be achieved selectively under these conditions (entries 14 and 15). In the series of regioisomeric nitrobenzaldehydes (Table 2, entries 1–3) when this π-electron-withdrawing substituent was either ortho or para to CHO group the reaction proceeded in better yield than when a meta NO₂ was in place. In the case of chloro- and fluoro-substituted PhCHO (Table 2, entries 4–9), the yield was lower than for all nitrobenzaldehydes, and decreased as the halogen atom became more distant from the aldehyde group, most probably due to the decreasing σ-electron-withdrawing effect.

Table 2 The reaction of an aldehyde/ketone, 1-heptanol, PPh₃ and CCl₄. The effect of varying reaction conditions on the yield (%) of the acetal

Entry	Carbonyl	Yield of diheptyl acetal (%)
		48 h, r.t.^a	7 d,^b r.t.	2 h, reflux	5 h, reflux
a r.t. – room temperature.b d – day.c The obtained acetal is a new compound. It was fully spectrally characterized (IR, UV, MS, and ^1H and ^13C NMR) and their ^1H and ^13C NMR spectra were assigned through detailed analyses of 1D- and 2D-NMR spectra. All NMR spectral data for the new compounds are reproduced in the ESI.d No data. The reaction was not conducted.
1	2-NO2–C6H4CHO	67^c	—^d	—	—
2	3-NO2–C6H4CHO	55^c	—	62	—
3	4-NO2–C6H4CHO	61^c	—	—	—
4	2-F–C6H4CHO	53^c	—	45	—
5	3-F–C6H4CHO	50	—	56	—
6	4-F–C6H4CHO	25	—	—	—
7	2-Cl–C6H4CHO	53^c	—	47	—
8	3-Cl–C6H4CHO	48^c	—	—	—
9	4-Cl–C6H4CHO	15	—	—	—
10	PhCHO	14	—	—	—
11	4-OMe–C6H4CHO	3^c	17	—	—
12	4-Me–C6H4CHO	3^c	13	—	3
13	4-NMe2–C6H4CHO	0	0	0	0
14	3,4-DiOMe–C6H3CHO	2	—	—	—
15	3,4,5-TriOMe–C6H2CHO	2^c	9	—	4
16	Acetophenone	0	0	0	1
17	Cyclohexanone	1^c	3	—	6
18	Hexanal	52^c	—	60	—
19	Octanal	51^c	—	57
20	Nonanal	51	—	—	—
21	3-Methylbutanal	46	—	—	—
22	2-Methylpentanal	39^c	—	—	—

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Among the aliphatic carbonyls, the aldehydes were expectedly more reactive, while cyclohexanone, cyclopentanone and 2-pentanone (Table 1, entries 16–18, Table 2, entry 17) gave only trace amounts of the corresponding acetals. Acetophenone was likewise unreactive (Table 1, entry 19/Table 2, entry 16). The position of a methyl branch in aliphatic aldehydes strongly influenced the outcome of the acetalization. Steric hindrance imposed by the branch supposedly should be responsible for this (Table 1, entries 20–22; Table 2, entries 18–22).

The existence of branching in the structure of the used alcohols also exerted a negative effect on the yield of the acetalization (Table 1, entries 23–26), but to a lesser extent when compared to the same steric interference observed for the aldehydes. Compared to primary alcohols, racemic 2-butanol gave a significantly lower yield of the corresponding diastereoisomeric acetals (Table 1, entry 25), whereas a tertiary alcohol, tert-butanol was completely unreactive (Table 1, entry 26). Diastereoselectivity of formation of the acetals of 2-butanol was close to the statistical one (meso-1 : meso-2 : enantiomeric pair ≈ 21 : 29 : 50) as inferred from GC-MS and NMR analyses. When the reaction was applied to the synthesis of cyclic acetals with ethylene glycol (1,3-dioxolanes), probably due to an intramolecular side reaction leading to epoxide,²⁶ the desired products were obtained in low yields (up to 20%; Table 1, entries 27–29).

It appears that the acetalization with PPh₃–CCl₄ proceeds with the stoichiometry represented by the equation given in Scheme 2. In general, an increase in the yield of the acetalization was noted when an excess of 10 mol% of both the alcohol and PPh₃ was used instead of the stoichiometric amounts (Table 1, entry 30). Since any further increase of the amount of the alcohol would lead to the formation of increased amounts of side products, as noted above, and the unwanted consumption of PPh₃, we decided to leave the amount of the used alcohol to 2.2 equivalents and to vary the amount of PPh₃ used. However, a further increase to 1.5 or 3 equivalents of PPh₃ (Table 1, entries 31 and 32) gave no satisfactory result on the yield while making the purification of the product more difficult.

Scheme 2 The overall reaction stoichiometry of the acetalization using PPh₃–CCl₄.

Due to an expected stabilizing effect of polar solvents on transition states with developing charges,²⁷ as could be anticipated for our reaction, addition of a more polar (than CCl₄), aprotic, and unreactive co-solvent (such as THF or MeCN) is likely to produce a desirable acceleration of the acetalization. Based on this, a number of experiments corresponding to entry 10 (Table 1) with variable amounts of THF or MeCN, as the co-solvents, were conducted, while keeping the total volume of the solvents constant. And indeed, a considerable increase in rate was observed (Fig. 3); while an acceptable yield (ca. 44%) of the acetal of 3-nitrobenzaldehyde and 1-heptanol was reached only after two days at room temperature in CCl₄, 2 times less was needed to obtain a similar yield (ca. 42%) in a mixture of MeCN and CCl₄ in the ratio 85 : 15, v/v (here, ca. 5 equivalents of CCl₄ were present with respect to the amount of the used aldehyde). Any further reduction of the quantity of CCl₄ (Fig. 3) or a corresponding dilution with a stoichiometric excess of CCl₄ resulted in a decrease of the yield. However, this acceleration came at a price; the rate of side reactions also increased significantly (Fig. 3), resulting in either a contaminated acetal (especially when THF was utilized), or in the more pronounced consumption of PPh₃ making it a limiting reagent (observed for MeCN–CCl₄ mixtures). Although commercial dry solvents (CCl₄, THF and MeCN) gave satisfactory results, repeatability was maintained by storing the solvents over molecular sieves and additionally drying/neutralizing them by passing the needed amount of the solvent through a small column of anhydrous K₂CO₃ immediately before the commencement of the reaction.

Fig. 3 The yields of the acetal (black lines) and side products (grey lines) depending on the reaction media (solvent mixture); conditions: 3-nitrobenzaldehyde : 1-heptanol : PPh₃ = 1 : 2 : 1, at room temperature, 24 h or 48 h.

Although, in general, all of the abovementioned reactions were conducted under a protective atmosphere of nitrogen, a number of representative runs (Table 2, entries 5, 8, 10–12) were repeated under air, but with a CaCl₂-guard tube present. This was done to ascertain the impact of atmospheric O₂ on the reaction outcome and to verify whether the inert atmosphere was necessary to begin with. In the case of reactions run in CCl₄, no significant effect was noted; however, when the reaction medium consisted of THF and CCl₄, an autooxidation of THF took place, due to long reaction times, leading to higher amounts of side products; as for the reactions run in MeCN (plus the necessary CCl₄), the consumption of PPh₃ in side reactions was much more pronounced (usually no PPh₃ could be detected in the resulting reaction mixtures). Hence, if the reaction time is not a limiting factor, it is recommended to conduct the reaction in pure CCl₄ (Fig. 3).

The existing well-known procedures for the synthesis of non-cyclic acetals are usually limited to dimethyl and diethyl acetals (i.e. the availability of the corresponding orthoesters limits their applicability). For this reason, we decided to apply our synthetic procedure for the preparation of acetals of alcohols other than methanol or ethanol. In this way, among the 100 prepared acetals, we obtained 30 new compounds and the results of these runs are presented partially in Tables 1 and 2, while the remaining new compounds are summarized in Table 3. All of the synthesized acetals were fully spectrally characterized (IR, UV, MS, and ¹H and ¹³C NMR) and their ¹H and ¹³C NMR spectra assigned through detailed analyses of 1D- (including a series of selective ¹H homodecoupling experiments) and 2D-NMR spectra. All NMR spectral data for the new compounds are reproduced in the ESI.†

Table 3 Newly prepared acetals using PPh₃ (1.1 eq.)–CCl₄ reagent and the corresponding alcohol (2.2 eq.), together with their yields

Entry	Aldehyde	Alcohol (ROH)	Product	Yield (%)
a Due to the volatility of the used alcohol reaction the mixtures were closed with a stopper.
1				65
2				67
3				53
4				56
5				53
6				47 (meso-1 : enant. pair : meso-2 = 1 : 2 : 1)
7				26 (meso-1 : enant. pair : meso-2 = 29 : 50 : 21)
8				57
9				54
10				53
11				47
12				44
13				51
14				51
15				47

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In addition to the sensitivity of acetals towards acid-catalyzed hydrolysis, we encountered another well-known purification problem frequently met in reactions that include the formation of OPPh₃. Usually the oxide precipitates from the reaction mixture and this is further induced by the addition of cold n-pentane. Unfortunately, even if the precipitation is repeated several times, a portion of OPPh₃ remains in the pentane solution. Sometimes unreacted PPh₃ can be even more troublesome. All of this provoked us to search for a better method for the purification of acetals.

An acetonitrile–pentane partition met all of the conditions. It proved to be a quick and reliable separation method for all herein prepared acetals. It was particularly suitable for dipentyl, dihexyl and diheptyl acetals: only the acetals remained in the pentane layer, while the alcohols, alkyl chlorides and other side products were taken up by MeCN (ESI, Fig. S1†). The excess of PPh₃ and the residual part of the formed OPPh₃ were completely removed from the pentane layer after 2–3 additional partitions (reextraction of MeCN with pentane). The reason behind the success of this partition probably lies in the lipophilicity of the synthesized acetals bearing (long) alkyl chains. Interestingly, probably due to their higher miscibility, MeCN–hexane mixtures did not prove to be so efficient in the isolation of acetals from such reaction mixtures.

Mechanistic considerations

To verify the direct participation of PPh₃ in the transformation, acetalization was carried out in CCl₄ but without PPh₃, and in 48 h only trace amounts of the acetal could be detected in the reaction mixture. The formation of an acetal directly from an aldehyde and alcohol requires the presence of an acid catalyst. This was evidenced when unpurified CCl₄ (HCl or other acidic impurities were not removed by K₂CO₃) was used as a medium for acetalization in the absence of PPh₃. In this case a yield of ca. 10% of the acetal was obtained (analogues to Table 1, entry 35, unpurified CCl₄ used). Thus, PPh₃ played a crucial role in the onset of the reaction as a true reagent or by generating an acid catalyst (for example an equivalent of HCl is formed during this reaction based on the equation given in Scheme 2). The latter was easily ruled out by introducing anhydrous potassium carbonate, as an acid quencher, in the reaction mixture (Table 1, entry 33). The presence of K₂CO₃ did not influence the outcome, in turns of either the yield of the acetal or the rate of the reaction.

It could be that the PPh₃–CCl₄ reagent simply removes one equivalent of water formed in the reaction of an aldehyde and two equivalents of an alcohol. If this were the case, the potentially formed water (RCHO + 2 R¹OH = RCH(OR¹)₂ + H₂O) and the unreacted alcohol would be expected to be of similar reactivity towards ⁺PPh₃Cl (Int 1, Scheme 1) under these conditions. As no more than 10% of the starting alcohol was ever consumed in a side reaction of the Appel-type (SP-5, Scheme 1), this does not seem to be very likely. Even when the Appel reaction (1 eq. PPh₃ + 2 eq. ROH, also at room temperature) was allowed to proceed (therefore in the absence of the aldehyde, entry 34/Fig. 1), the conversion of the alcohol to alkyl chloride reached only 7% after 48 h.

Based on the obtained results and the general understanding of the reactions of carbonyl compounds and the behavior of PPh₃ in combination with CCl₄, we wish to propose a plausible mechanism for the acetal-forming reaction intervened by PPh₃–CCl₄ at room temperature. We propose that chlorotriphenylphosphonium cation (Int 1, known to form under the conditions of the Appel reaction, Scheme 1) reacts with a carbonyl compound in the same manner as an alcohol reacts with this cation in the Appel reaction, giving (alkylideneoxonio)triphenylphosphonium cation, a more electrophilic chemical species than the starting aldehyde (Int 2, Scheme 3). Int 2 can subsequently react more readily with the alcohol, generating a tetrahedral intermediate Int 3, which would collapse to a familiar intermediate (Int 4), with a release of OPPh₃, as an excellent leaving group.²⁸ An alternative route to Int 4, via Int 3, could involve the reaction of a preformed hemiacetal with Int 1 (Scheme 3). The highly electrophilic Int 4 reacts with the second equivalent of the alcohol yielding the final acetal.

Scheme 3 A proposed mechanism for the PPh₃–CCl₄ mediated acetalization.

The proposed mechanism can also provide a logical pathway to the formation of the geminal dichloride from an aldehyde and PPh₃–CCl₄. The only difference from the above-stated mechanism would be that instead of the alcohol, the role of the nucleophiles attacking Int 2 and an intermediate analogous to Int 4, is played by chloride ions (counter ion of Int 1).

The effect of temperature on the reaction outcome (cf. Fig. 1 and 2) can straightforwardly be explained by the known instability of the conjugated base of chloroform at higher temperatures,²⁹ formed initially in the reaction of PPh₃ and CCl₄ (Scheme 1). α-Elimination of Cl⁻ from this anion leads to dichlorocarbene which hampers the acetalization by consuming PPh₃ and the aldehyde (Scheme 1).

As already stated, the yield, and indirectly the reaction rate, increased with the increasing electrophilicity of the used aromatic aldehydes. It is known that in regular acetalization reactions (acid catalyzed reaction of aldehydes and alcohols), the rate-determining step is the expulsion of water from a protonated hemiacetal intermediate.² It therefore follows that more electron-donating, i.e. less electrophilic, aldehydes are expected to form acetals faster.² This is in obvious contradiction with the reactivity trend observed in our acetalization reactions. We believe that this can be easily rationalized by considering that the rate-determining step in our reaction is not the same, and that the nucleophilic addition of the alcohol to one of the intermediates Int 2 or Int 4 (Scheme 2) is the slowest (rate-determining) step of the reaction. When compared to Int 4, the evident higher steric hindrance present in Int 2, caused by three phenyl groups near the electrophilic carbon, probably retards the nucleophilic attack. However, this assumption needs additional experimental support.

Conclusions

Herein, a new, very mild and simple method for the preparation of acetals of aromatic and aliphatic aldehydes was described and applied in the synthesis of over 100 acetals. An advantage of this method over known ones is that it requires only stoichiometric amounts of both aldehyde and alcohol. It may be successfully applied to the synthesis of structurally diverse acetals, in both the alcohol and aldehyde moieties, allowing the focus of the acetal functionality to shift from a protecting group to either a useful synthetic intermediate or a target molecule. The driving force behind the acetalization was provided by PPh₃–CCl₄ reagent combination. Mechanistically, this reagent opened a new route to acetals and delivered the necessary favorable thermodynamic grounds. The kinetics of the PPh₃–CCl₄ mediated acetalization differed from the classic, acid-catalyzed acetal formation (more electrophilic aldehydes gave acetals faster, while the reverse is true for the classic reaction).

The fact that this reaction takes place at room temperature and does not require the addition of an acid catalyst also represents a great advantage. Instead of an acid, in situ generated reactive intermediate, chlorotriphenylphosphonium cation, plays a roll of the activator and reagent. If the reaction time does not represent an obstacle (typically two days), the herein developed synthetic methodology is ideal for the preparation of acetals from aliphatic and highly electrophilic aromatic aldehydes. This feature of the reaction also allows selective acetalization, i.e. a discernment of aldehydes and ketones, as well as aldehydes of differing electrophilicity. The reaction can also be successfully performed in other solvents (THF, MeCN), while supplying CCl₄ in only stoichiometric quantities (5 equivalents); however, the application of these solvents suffers from more demanding pre/post-reaction procedures, although significantly shortening the reaction time. Fast and simple, chromatography-free isolation/purification method was also proposed for the work-up of this reaction.

Experimental

Materials and methods

All herein used reagents (aldehydes, ketones, alcohols, PPh₃) and solvents (CCl₄, acetonitrile, pentane, tetrahydrofuran, hexane) were obtained from commercial sources (Sigma-Aldrich, St. Louis, MO, USA; Merck, Darmstadt, Germany; Carl Roth, Karlsruhe, Germany) and used as received, except that the solvents were additionally dried (molecular sieves). CCl₄ was also passed through a small column of anhydrous K₂CO₃ immediately before the commencement of the reaction.

Gas chromatography/mass spectrometry (GC-MS) analyses were repeated three times for each sample using an HP 6890N gas chromatograph coupled with an HP 5975B mass-selective detector (Hewlett-Packard, Palo Alto, CA, USA). Details regarding the GC-MS analyses are provided in the ESI.† UV spectra (in acetonitrile) were measured using a UV-1800 Shimadzu spectrophotometer (Tokyo, Japan). Infrared (IR) measurements (attenuated total reflectance) were carried out using a Thermo Nicolet 6700 FTIR spectrometer (Thermo Fisher Scientific, Waltham, MA, USA). Microanalysis of carbon, hydrogen and nitrogen were carried out on a Carlo Erba 1106 microanalyzer (Carlo Erba Strumentazione, Italy); their results agreed favorably with the calculated values. The ¹H and ¹³C NMR spectra were recorded on a Bruker Avance III 400 MHz NMR spectrometer (Fällanden, Switzerland; ¹H at 400 MHz, ¹³C at 100.6 MHz), equipped with a 5 mm dual ¹³C/¹H probe head. All NMR spectra were recorded at 20 °C in deuterated chloroform with TMS as internal standard. Chemical shifts (δ) are reported in parts per million and referenced to TMS (δ_H = 0.00 ppm) in ¹H and to the (residual) solvent signal in ¹³C NMR and heteronuclear 2D spectra (residual CHCl₃ δ_H = 7.26 ppm and ¹³CDCl₃ δ_C = 77.16 ppm). Scalar couplings are reported in Hertz (Hz). Samples (ca. 20–30 mg of the acetals) were dissolved in 1 mL of deuterated chloroform, and 0.7 mL of the solution transferred into a 5 mm Wilmad, 528-TR-7 NMR tube. Details regarding the measurement of NMR spectra are provided in the ESI.†

General procedure for the synthesis of acetals (1)

A 10 mL round-bottom flask was charged with a solution of the appropriate aldehyde (1 mmol), alcohol (2.2 mmol), triphenylphosphine (288 mg, 1.1 mmol) and the dried carbon tetrachloride (3 mL, 30.95 mmol). The reaction vessel was closed with a CaCl₂-drying tube or just a stopper and the mixture magnetically stirred for 48 h. After removing the excess CCl₄ on a rotary vacuum evaporator at 40 °C, the residue was taken up by pentane (2 × 5 mL). The dissolution was effectuated by exposing the contents of the flask to ultrasonic waves for 30–60 s, whereupon the pentane solution was transferred into a small separating funnel (a Pasteur pipette and a test tube can equally efficiently be used for this purpose; see ESI, Fig. S2†). Three consecutive partitions between the pentane layer and MeCN (2 mL) were performed; MeCN layers were washed with a fresh amount (2 mL) of pentane; prior to the next partition, the two pentane layers were combined. The pentane layer, after the removal of the solvent, afforded (up to 70%) the pure acetal (>98%, confirmed by GC-MS and ¹H and ¹³C NMR spectroscopy). A scale up to 0.1 mol worked particularly well.

General procedure for the synthesis of acetals from benzaldehydes containing electron-donating substituents (2)

The procedure differed from the above-stated only in the duration of the reaction. Instead of 48 h, the reaction mixture was stirred for 7 days.

Spectral data of the newly prepared acetals

Copies of ¹H- and ¹³C-NMR and EI-MS spectra of all new acetals can be found in the ESI.† In addition, the file also contains tables with the assigned NMR chemical shifts of ¹H and ¹³C and an interpretation of the observed couplings in ¹H NMR spectra. HMBC and NOESY interactions are also summarized in tables, and the key ones used during the assignation are presented on appropriate schemes. The number (1 or 2) written in superscript after the yield refers to the procedure employed.

1-(Diisobutoxymethyl)-2-nitrobenzene. Colorless oily liquid (149 mg, 53%¹). Found: C, 63.9; H, 8.1; N, 5.0; O, 22.9%. Calc. for C₁₅H₂₃NO₄: C, 64.0; H, 8.2; N, 5.0; O, 22.75%. UV λ_max (CH₃CN)/nm 258 (log ε 4.2). FTIR (neat) ν_max/cm⁻¹: 2955.9, 2910.2, 2871.5, 1529.8, 1470.3, 1360.4, 1108.2, 1052.3, 1037.7, 832.2, 724.7, 694.6. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.84 (1H, dd, J = 7.8, 1.5 Hz), 7.80 (1H, dd, J = 8.0, 1.2 Hz), 7.59 (1H, pseudo td, J = 7.8, 7.5, 1.2 Hz), 7.45 (1H, pseudo td, J = 8.0, 7.5, 1.5 Hz), 6.04 (1H, s), 3.38 (2H, dd, J = 8.9, 6.5 Hz), 3.29 (2H, dd, J = 8.9, 6.6 Hz), 1.87 (2H, pseudo nonuplet, J = 6.7 Hz), 0.92 (12H, two overlapped d, J = 6.7 Hz); δ_C (100.6 MHz, CDCl₃) 149.1 (1C), 133.8 (1C), 132.5 (1C), 129.2 (1C), 128.3 (1C), 124.3 (1C), 98.5 (1C), 74.4 (2C), 28.7 (2C), 19.6 (4C). EIMS m/z 208 (50), 153 (8); 152 (100), 151 (17), 135 (16), 121 (9), 104 (17), 77 (9), 57 (36), 41 (19).

3-Methyl-1,1-dipropoxybutane. Colorless oily liquid (87 mg, 46%¹). Found: C, 70.1; H, 12.7; O, 17.2%. Calc. for C₁₁H₂₄O₂: C, 70.2; H, 12.85; O, 17.0%. FTIR (neat) ν_max/cm⁻¹: 2956.7, 2923.4, 2855.8, 1464.6, 1435.4, 1377.7, 1118.4, 1067.8, 742.5, 722.3, 695.1. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 4.56 (1H, t, J = 6.0 Hz), 3.54 (2H, dt, J = 9.3, 6.7 Hz), 3.38 (2H, dt, J = 9.3, 6.8 Hz), 1.73 (1H, pseudo nonuplet, J = 7.0, 6.7 Hz), 1.59 (4H, pseudo sextuplet, J = 7.4, 6.8, 6.7 Hz), 1.50 (2H, dd, J = 7.0, 6.0 Hz), 0.93 (6H, t, J = 7.4 Hz), 0.92 (6H, d, J = 6.7 Hz); δ_C (100.6 MHz, CDCl₃) 101.9 (1C), 67.2 (2C), 42.4 (1C), 24.5 (1C), 23.3 (1C), 22.9 (2C), 10.9 (2C). EIMS m/z 131 (67), 129 (87), 113 (15), 89 (80), 87 (52), 71 (76), 69 (71), 43 (100), 41 (52), 39 (17).

1-(Di-sec-butoxymethyl)-3-nitrobenzene (mixture of diastereomers, r-meso : enantiomeric pair : s-meso = 29 : 50 : 21). Colorless oily liquid (76 mg, 27%¹). Found: C, 63.8; H, 8.2; N, 5.0; O, 22.9. Calc. for C₁₅H₂₃NO₄: C, 64.0; H, 8.2; N, 5.0; O, 22.75. UV λ_max (CH₃CN)/nm 259 (log ε 4.3); FTIR (neat) ν_max/cm⁻¹: 2955.4, 2925.3, 2853.2, 1531.1, 1467.1, 1347.8, 1207.1, 1104.4, 1042.9, 806.1, 720.1, 695.8, 675.

1-(Di((R)-sec-butoxy)methyl)-3-nitrobenzene and 1-(di((S)-sec-butoxy)methyl)-3-nitrobenzene (assigned from NMR spectra of a mixture of diastereoisomers). NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.34 (1H, pseudo t, J = 2.3, 1.5 Hz), 8.18 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.83 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.54 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.60 (1H, s), 3.75 (1H, pseudo sextuplet, J = 6.4 Hz), 3.68 (1H, pseudo sextuplet, J = 6.4 Hz), 1.67–1.53 (2H, overlapped signals), 1.57–1.43 (2H, overlapped signals), 1.21 (3H, d, J = 6.1), 1.14 (3H, d, J = 6.2 Hz), 0.95 (3H, t, J = 7.5), 0.86 (3H, t, J = 7.5). δ_C (100.6 MHz, CDCl₃) 148.09 (1C), 143.03 (1C), 132.96 (1C), 129.14 (1C), 123.20 (1C), 121.87 (1C), 98.75 (1C), 74.31 (1C), 73.73 (1C), 29.86 (1C), 29.23 (1C), 20.03 (1C), 19.66 (1C), 9.84 (1C), 9.49 (1C). EIMS m/z 209 (3), 208 (24), 153 (8), 152 (100), 136 (3), 106 (3), 105 (6), 77 (5), 57 (15), 41 (8).

1-((r)-(R)-sec-Butoxy((S)-sec-butoxy)methyl)-3-nitrobenzene. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.34 (1H, pseudo t, J = 2.3, 1.5 Hz), 8.18 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.83 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.54 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.61 (1H, s), 3.75 (2H, pseudo sextuplet, J = 6.4 Hz), 1.67–1.53 (2H, overlapped signals), 1.57–1.43 (2H, overlapped signals), 1.14 (6H, d, J = 6.2 Hz), 0.94 (6H, t, J = 7.5). δ_C (100.6 MHz, CDCl₃) 148.09 (1C), 143.25 (1C), 132.97 (1C), 129.12 (1C), 123.16 (1C), 121.89 (1C), 98.16 (1C), 73.93 (2C), 29.88 (2C), 19.62 (2C), 9.85 (2C). EIMS m/z 209 (3), 208 (26), 153 (8), 152 (100), 136 (3), 106 (3), 105 (6), 77 (4), 57 (14), 41 (7).

1-((s)-(R)-sec-Butoxy((S)-sec-butoxy)methyl)-3-nitrobenzene. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.34 (1H, pseudo t, J = 2.3, 1.5 Hz), 8.18 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.83 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.54 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.58 (1H, s), 3.68 (2H, pseudo sextuplet, J = 6.4 Hz), 1.67–1.53 (2H, overlapped signals), 1.57–1.43 (2H, overlapped signals), 1.21 (6H, d, J = 6.2 Hz), 0.86 (6H, t, J = 7.5). δ_C (100.6 MHz, CDCl₃) 148.09 (1C), 142.86 (1C), 132.95 (1C), 129.16 (1C), 123.23 (1C), 121.85 (1C), 99.45 (1C), 74.29 (2C), 29.25 (2C), 20.06 (2C), 9.51 (2C). EIMS m/z 209 (3), 208 (24), 153 (9), 152 (100), 136 (3), 106 (3), 105 (6), 77 (4), 57 (16), 41 (8).

1-(Bis(heptyloxy)methyl)-2-chlorobenzene. Colorless oily liquid (188 mg, 53%¹). Found: C, 70.9; H, 9.9. Calc. for C₂₁H₃₅ClO₂: C, 71.1; H, 9.9; Cl, 10.0; O, 9.0%. UV λ_max (CH₃CN)/nm 264 (log ε 2.8). FTIR (neat) ν_max/cm⁻¹: 2953.4, 2925.0, 2855.6, 1466.9, 1442.4, 1377.3, 1357.2, 1267.1, 1200.2, 1106.1, 1033.9, 754.3, 724.2, 706.6. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.66 (1H, m), 7.34 (1H, m), 7.27 (1H, m), 7.25 (1H, m), 5.72 (1H, s), 3.57 (2H, dt, J = 9.3, 6.7 Hz), 3.49 (2H, dt, J = 9.3, 6.6 Hz), 1.61 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.42–1.23 (16H, m), 0.87 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 136.6 (1C), 133.3 (1C), 129.6 (2C), 128.3 (1C), 126.7 (1C), 99.5 (1C), 66.9 (2C), 32.0 (2C), 29.9 (2C), 29.2 (2C), 26.3 (2C), 22.8 (2C), 14.2 (2C). EIMS m/z 241 (30), 240 (14), 239 (87), 143 (33), 142 (9), 141 (100), 139 (10), 57 (16), 43 (8), 41 (8).

1-(Dipropoxymethyl)-2-nitrobenzene. Colorless oily liquid (164 mg, 65%¹). Found: C, 61.5; H, 7.5; N, 5.5, O, 25.5%. Calc. for C₁₃H₁₉NO₄: C, 61.6; H, 7.6; N, 5.5, O, 25.3%. UV λ_max (CH₃CN)/nm 256 (log ε 4.0). FTIR (neat) ν_max/cm⁻¹: 2954.5, 2925.2, 2856.7, 1532.0, 1465.1, 1359.9, 1258.1, 1197.3, 1108.5, 1054.8, 1031.9, 783.6, 739.2, 723.2, 622.4. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.84 (1H, ddd, J = 7.6, 1.5, 0.5 Hz), 7.81 (1H, dd, J = 7.5, 1.3 Hz), 7.59 (1H, pseudo td, J = 7.9, 7.6, 1.3 Hz), 7.45 (1H, pseudo td, J = 7.9, 7.5, 1.5 Hz), 6.04 (1H, s), 3.60 (2H, dt, J = 9.2, 6.6 Hz), 3.49 (2H, dt, J = 9.2, 6.7 Hz), 1.63 (4H, pseudo sextuplet, J = 7.4, 6.7, 6.6 Hz), 0.94 (6H, t, J = 7.4 Hz); δ_C (100.6 MHz, CDCl₃) δ 149.1 (1C), 133.9 (1C), 132.6 (1C), 129.2 (1C), 128.2 (1C), 124.3 (1C), 98.6 (1C), 69.7 (2C), 23.1 (2C), 10.8 (2C). EIMS m/z 194 (59), 152 (100), 151 (9), 135 (18), 134 (17), 121 (13), 104 (29), 105 (11), 77 (11), 43 (10).

1-(Bis((2-methylpentyl)oxy)methyl)-3-nitrobenzene (mixture of diastereomers r-meso : enantiomeric pair : s-meso ≈ 1 : 2 : 1). Colorless oily liquid (159 mg, 47%¹). Found: C, 67.5; H, 9.2; N, 4.2; O, 19.0. Calc. for C₁₉H₃₁NO₄: C, 67.6; H, 9.3; N, 4.15; O, 19.0. UV λ_max (CH₃CN)/nm 263 (log ε 4.4). FTIR (neat) ν_max/cm⁻¹: 2956.2, 2926.0, 2871.4, 1530.6, 1466.0, 1346.5, 1205.5, 1103.6, 1045.7, 805.0, 719.8, 695.5, 675.5. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.35 (1H, pseudo t, J = 2.3, 1.5 Hz), 8.19 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.81 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.55 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.58/5.57 (1H, s), 3.39/3.37 (2H, dd, J = 9.4, 5.8 Hz), 3.29/3.26 (2H, dd, J = 9.4, 6.8 Hz), 1.77 (4H, pseudo octuplet, J = 6.8, 6.7, 6.4, 5.8 Hz), 1.45–1.06 (8H, m), 0.95 (6H, d, J = 6.4 Hz), 0.90/0.89 (6H, t, J = 7.1 Hz); δ_C (100.6 MHz, CDCl₃) 148.4 (1C), 141.6 (1C), 133.1 (1C), 129.2 (1C), 123.3 (1C), 122.1 (1C), 100.4/100.2/100.1 (1C), 71.1/70.9 (2C), 36.0 (2C), 33.3 (2C), 20.2 (2C), 17.4 (2C), 14.4 (2C). EIMS m/z, 237 (10), 236 (71), 153 (8), 152 (84), 105 (7), 85 (100), 57 (10), 55 (7), 43 (54), 41 (14).

5-(Bis(heptyloxy)methyl)-1,2,3-trimethoxybenzene. Colorless oily liquid (37 mg, 9%²). Found: C, 70.1; H, 10.3; O, 19.6%. Calc. for C₂₄H₄₂O₅: C, 70.2; H, 10.3; O, 19.5%. UV λ_max (CH₃CN)/nm 285 (log ε 4.5). FTIR (neat) ν_max/cm⁻¹: 2953.7, 2925.0, 2854.7, 1598.2, 1578.2, 1459.3, 1259.6, 1252.6, 1159.2, 1030.5, 832.1, 721.9, 606.9. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 6.71 (2H, s), 5.42 (1H, s), 3.87 (6H, s), 3.84 (3H, s), 3.57 (2H, dt, J = 9.4, 6.7 Hz), 3.49 (2H, dt, J = 9.4, 6.6 Hz), 1.57 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.42–1.23 (16H, m), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 153.2 (1C), 137.7 (2C), 135.0 (1C), 103.5 (2C), 101.8 (1C), 65.9 (2C), 61.0 (2C), 56.1 (2C), 32.0 (2C), 29.9 (2C), 29.3 (2C), 26.4 (2C), 22.8 (2C), 14.2 (2C). EIMS m/z 410 (10), 296 (31), 295 (100), 197 (62), 196 (16), 181 (10), 169 (34), 57 (18), 54 (10), 43 (10).

1-(Bis(hexyloxy)methyl)-2-fluorobenzene. Colorless oily liquid (161 mg, 52%¹). Found: C, 73.4; H, 10.0. Calc. for C₁₉H₃₁FO₂: C, 73.5; H, 10.1; F, 6.1; O, 10.3. UV λ_max (CH₃CN)/nm 259 (log ε 2.7). FTIR (neat) ν_max/cm⁻¹: 2954.7, 2927.4, 2857.9, 1487.8, 1457.2, 1228.9, 1114.8, 1063.4, 1027.8, 809.7, 756.8, 724.5. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.60 (1H, pseudo td, J = 7.5, 7.1, 1.8 Hz), 7.29 (1H, dddd, J = 8.2, 7.3, 5.3, 1.8 Hz), 7.14 (1H, pseudo td, J = 7.5, 7.3, 1.0 Hz), 7.03 (1H, ddd, J = 10.2, 8.2, 1.0 Hz), 5.7 (1H, s), 3.58 (2H, dt, J = 9.3, 6.7 Hz), 3.49 (2H, dt, J = 9.3, 6.6 Hz), 1.60 (4H, pseudo quintet, J = 6.7, Hz), 1.40–1.22 (12H, m), 0.87 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 160.6 (1C, d, J = 248.1 Hz), 130.0 (1C, d, J = 8.2 Hz), 128.2 (1C, d, J = 4.0 Hz), 126.6 (1C, d, J = 12.7 Hz), 123.9 (1C, d, J = 3.6 Hz), 115.4 (1C, d, J = 21.6 Hz), 97.0 (1C, d, J = 3.4 Hz), 66.7 (2C, s), 31.8 (2C, s), 29.8 (2C, s), 26.0 (2C, s), 22.7 (2C, s), 14.2 (2C, s). EIMS m/z 210 (8), 209 (59), 126 (8), 125 (100), 123 (10), 97 (6), 85 (4), 55 (4), 43 (13), 41 (6).

1-(Dipropoxymethyl)-3-fluorobenzene. Colorless oily liquid (109 mg, 48%¹). Found: C, 68.9; H, 8.4%. Calc. for C₁₃H₁₉FO₂: C, 69.0; H, 8.5; F, 8.4; O, 14.1%. UV λ_max (CH₃CN)/nm 259 (log ε 2.8). FTIR (neat) ν_max/cm⁻¹: 2953.7, 2922.5, 2854.3, 1457.8, 1260.0, 1116.1, 1091.4, 1036.4, 804.9, 758.2, 722.7. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.32 (1H, pseudo td, J = 8.4, 7.7, 5.7 Hz), 7.25 (1H, pseudo dt, J = 7.7, 1.4, 1.0 Hz), 7.20 (1H, br ddd, J = 9.8, 2.6, 1.4 Hz), 7.00 (1H, dddd, J = 9.0, 8.4, 2.6, 1.0 Hz), 5.50 (1H, s), 3.50 (2H, dt, J = 9.4, 6.7 Hz), 3.43 (2H, dt, J = 9.4, 6.7 Hz), 1.64 (4H, pseudo sextuplet, J = 7.4, 6.7 Hz), 0.95 (6H, t, J = 7.4 Hz); δ_C (100.6 MHz, CDCl₃) 163.0 (1C, d, J = 245.5 Hz), 142.0 (1C, d, J = 6.8 Hz), 129.8 (1C, d, J = 8.3 Hz), 122.5 (1C, d, J = 2.8 Hz), 115.2 (1C, d, J = 21.3 Hz), 113.9 (1C, d, J = 22.2 Hz), 100.7 (1C, d, J = 2.0 Hz), 67.3 (2C, s), 23.1 (2C, s), 10.9 (2C, s). EIMS m/z 168 (10), 167 (70), 126 (8), 125 (100), 124 (4), 123 (14), 97 (24), 95 (8), 43 (12), 41 (6).

1-(Bis(heptyloxy)methyl)-3-nitrobenzene. Colorless oily liquid (190 mg, 52%¹). Found: C, 68.9; H, 9.6; N, 3.8; O, 17.6%. Calc. for C₂₁H₃₅NO₄: C, 69.0; H, 9.65; N, 3.8; O, 17.5%. UV λ_max (CH₃CN)/nm 263 (log ε 4.3). FTIR (neat) ν_max/cm⁻¹: 2955.7, 2925.5, 2855.8, 1530.3, 1466.4, 1346.4, 1205.5, 1108.4, 1040.6, 805.8, 719.0, 695.5, 675.1. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.34 (1H, pseudo t, J = 2.3, 1.5 Hz), 8.18 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.81 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.54 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.57 (1H, s), 3.53 (2H, dt, J = 9.4, 6.7 Hz), 3.49 (2H, dt, J = 9.4, 6.6 Hz), 1.62 (4H, pseudo quintet, J = 6.9, 6.7, 6.6), 1.42–1.23 (16H, m), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 148.4 (1C), 141.6 (1C), 133.0 (1C), 129.3 (1C), 123.4 (1C), 122.1 (1C), 100.2 (1C), 65.9 (2C), 31.9 (2C), 29.8 (2C), 29.2 (2C), 26.3 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 251 (18), 250 (100), 153 (9), 152 (82), 136 (6), 99 (13), 57 (79), 55 (9), 43 (17), 41 (16).

1-(Bis(heptyloxy)methyl)-4-methoxybenzene. Colorless oily liquid (59 mg, 17%²). Found: C, 75.3; H, 11.0; O, 13.7%. Calc. for C₂₂H₃₈O₃: C, 75.4; H, 10.9; O, 13.7%. UV λ_max (CH₃CN)/nm 271 (log ε 4.4). FTIR (neat) ν_max/cm⁻¹: 2954.1, 2925.0, 2854.9, 1599.2, 1578.1, 1459.5, 1259.6, 1159.4, 1030.3, 832.2, 722.7, 607.5. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.38 (2H, m), 6.88 (2H, m), 5.46 (1H, s), 3.80 (3H, s), 3.51 (2H, dt, J = 9.4, 6.7 Hz), 3.43 (2H, dt, J = 9.4, 6.6 Hz), 1.60 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.40–1.23 (16H, m), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 159.6 (1C), 131.6 (1C), 128.0 (2C), 113.5 (2C), 101.5 (1C), 65.4 (2C), 55.3 (1C), 32.0 (2C), 29.9 (2C), 29.3 (2C), 26.4 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 235 (100), 236 (17), 138 (8), 137 (87), 136 (8), 135 (14), 109 (6), 57 (7), 43 (5), 41 (5).

1-(Bis(pentyloxy)methyl)-3-nitrobenzene. Colorless oily liquid (167 mg, 54%¹). Found: C, 65.9; H, 8.7; N, 4.5; O, 20.9%. Calc. for C₁₇H₂₇NO₄: C, 66.0; H, 8.8; N, 4.5; O, 20.7%. UV λ_max (CH₃CN)/nm 262 (log ε 4.3). FTIR (neat) ν_max/cm⁻¹: 2955.2, 2930.7, 2870.3, 1529.4, 1466.2, 1347.4, 1203.0, 1106.4, 1053.2, 806.4, 718.9, 696.1, 675.5. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.35 (1H, pseudo t, J = 2.3, 1.5 Hz), 8.19 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.82 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.55 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.58 (1H, s), 3.53 (2H, dt, J = 9.3, 6.7 Hz), 3.49 (2H, dt, J = 9.3, 6.6 Hz), 1.64 (4H, pseudo quintet, J = 6.7 Hz), 1.29–1.42 (8H, m), 0.91 (6H, t, J = 7.1 Hz); δ_C (100.6 MHz, CDCl₃) 148.3 (1C), 141.5 (1C), 133.0 (1C), 129.3 (1C), 123.3 (1C), 122.1 (1C), 00.1 (1C), 65.8 (2C), 29.5 (2C), 28.5 (2C), 22.6 (2C), 14.1 (2C). EIMS m/z 223 (9), 222 (68), 153 (9), 152 (100), 105 (6), 77 (5), 71 (30), 55 (6), 43 (35), 41 (10).

1-(Bis(heptyloxy)methyl)-3-chlorobenzene. Colorless oily liquid (170 mg, 48%¹). Found: C, 71.0; H, 9.8. Calc. for C₂₁H₃₅ClO₂: C, 71.1; H, 9.9; Cl, 10.0; O, 9.0%. UV λ_max (CH₃CN)/nm 263 (log ε 3.1). FTIR (neat) ν_max/cm⁻¹: 2953.8, 2925.2, 2855.7, 1466.7, 1337.7, 1260.9, 1200.2, 1108.2, 1038.9, 785.9, 747.3, 723.7, 684.5. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.47 (1H, m), 7.34 (1H, m), 7.28 (2H, overlapped signals), 5.47 (1H, s), 3.51 (2H, dt, J = 9.4, 6.7 Hz), 3.44 (2H, dt, J = 9.4, 6.6 Hz), 1.60 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.43–1.21 (16H, overlapped signals), 0.88 (6H, t, J = 6.7 Hz); δ_C (100.6 MHz, CDCl₃) 141.4 (1C), 134.5 (1C), 129.6 (1C), 128.5 (1C), 127.1 (1C), 125.1 (1C), 100.7 (1C), 65.6 (2C), 32.0 (2C), 29.8 (2C), 29.3 (2C), 26.4 (2C), 22.8 (2C), 14.2 (2C). EIMS m/z 241 (26), 240 (12), 239 (76), 143 (32), 142 (9), 141 (100), 139 (10), 57 (23), 43 (10), 41 (10).

1,1-Dipropoxyhexane. Colorless oily liquid (103 mg, 51%¹). Found: C, 71.1; H, 13.0; O, 15.9%. Calc. for C₁₂H₂₆O₂: C, 71.2; H, 12.95; O, 15.8%. FTIR (neat) ν_max/cm⁻¹: 2953.8, 2922.8, 2854.4, 1465.2, 1377.7, 1347.3, 1115.3, 1067.7, 723.0. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 4.48 (1H, t, J = 5.8 Hz), 3.54 (2H, dt, J = 9.3, 6.7 Hz), 3.38 (2H, dt, J = 9.3, 6.8 Hz), 1.65–1.54 (6H, overlapped signals), 1.43–1.25 (6H, overlapped signals), 0.94 (6H, t, J = 7.4 Hz), 0.89 (3H, t, J = 6.8 Hz); δ_C (100.6 MHz, CDCl₃) 103.3 (1C), 67.2 (2C), 33.6 (1C), 31.8 (1C), 24.6 (1C), 23.3 (2C), 22.7 (1C), 14.2 (1C), 10.9 (2C). EIMS m/z 143 (99), 131 (100), 101 (46), 89 (89), 83 (76), 57 (12), 55 (33), 44 (10), 43 (76), 41 (33).

1-(Dipropoxymethyl)-2-chlorobenzene. Colorless oily liquid (114 mg, 47%¹). Found: C, 64.2; H, 7.9. Calc. for C₁₃H₁₉ClO₂: C, 64.3; H, 7.9; Cl, 14.6; O, 13.2%. UV λ_max (CH₃CN)/nm 264 (log ε 2.8). FTIR (neat) ν_max/cm⁻¹: 2953.3, 2925.2, 2853.6, 1462.4, 1443.1, 1377.2, 1356.1, 1267.7, 1199.4, 1107.6, 1034.2, 754.6, 723.6, 705.2. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.66 (1H, m), 7.35 (1H, m), 7.28 (1H, m), 7.25 (1H, m), 5.72 (1H, s), 3.57 (2H, dt, J = 9.2, 6.7 Hz), 3.49 (2H, dt, J = 9.2, 6.7 Hz), 1.63 (4H, pseudo sextuplet, J = 7.4, 6.7 Hz), 0.94 (6H, t, J = 7.4 Hz); δ_C (100.6 MHz, CDCl₃) 136.5 (1C), 133.3 (1C), 129.64 (1C), 129.60 (1C), 128.2 (1C), 126.7 (1C), 99.4 (1C), 68.5 (2C), 23.1 (2C), 10.9 (2C). EIMS m/z 185 (22), 184 (7), 183 (66), 143 (31), 142 (8), 141 (100), 139 (14), 113 (10), 77 (18), 43 (8).

1-(Bis(isopentyloxy)methyl)-4-nitrobenzene. Colorless oily liquid (176 mg, 57%¹). Found: C, 65.9; H, 8.8; N, 4.5; O, 20.8%. Calc. for C₁₇H₂₇NO₄: C, 66.0; H, 8.8; N, 4.5; O, 20.7%. UV λ_max (CH₃CN)/nm 268 (log ε 4.5). FTIR (neat) ν_max/cm⁻¹: 2954.8, 2927.3, 2869.6, 1608.3, 1522.8, 1465.3, 1342.0, 1201.3, 1098.8, 1062.4, 1014.9, 855.6, 834.3, 746.7, 717.2. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.22 (2H, m), 7.65 (2H, m), 5.57 (1H, s), 3.54 (2H, dt, J = 9.4, 6.6 Hz), 3.51 (2H, dt, J = 9.4, 6.6 Hz), 1.74 (2H, pseudo nonuplet, J = 6.9, 6.6 Hz), 1.51 (4H, pseudo q, J = 6.9, 6.6 Hz), 0.91 (6H, d, J = 6.6 Hz), 0.90 (6H, d, J = 6.6 Hz); δ_C (100.6 MHz, CDCl₃) 148.0 (1C), 146.3 (1C), 127.9 (2C), 123.5 (2C), 100.4 (1C), 64.2 (2C), 38.6 (2C), 25.2 (2C), 22.8 (2C), 22.7 (2C). EIMS m/z 223 (13), 222 (91), 152 (11), 150 (6), 77 (5), 72 (5), 71 (100), 55 (8), 43 (54), 41 (11).

1-(Bis(heptyloxy)methyl)-4-methylbenzene. Colorless oily liquid (43 mg, 13%²). Found: C, 78.9; H, 11.4; O, 9.7%. Calc. for C₂₂H₃₈O₂: C, 79.0; H, 11.45; O, 9.6%. UV λ_max (CH₃CN)/nm 262 (log ε 3.5). FTIR (neat) ν_max/cm⁻¹: 2954.3, 2925.5, 2854.6, 1598.2, 1579.3, 1459.7, 1259.1, 1157.4, 1031.2, 832.4, 722.4, 607.6. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.35 (2H, m), 7.16 (2H, m), 5.48 (1H, s), 3.52 (2H, dt, J = 9.4, 6.7 Hz), 3.44 (2H, dt, J = 9.4, 6.6 Hz), 2.35 (3H, s), 1.60 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.40–1.23 (16H, overlapped signals), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 138.0 (1C), 136.3 (1C), 128.9 (2C), 126.7 (2C), 101.6 (1C), 65.4 (2C), 32.0 (2C), 29.9 (2C), 29.3 (2C), 26.4 (2C), 22.8 (2C), 14.2 (2C). EIMS m/z 220 (14), 219 (88), 122 (9), 121 (100), 119 (12), 93 (10), 91 (8), 57 (12), 43 (6), 41 (6).

1,1-Dipropoxyoctane. Colorless oily liquid (118 mg, 51%¹). Found: 72.9; H, 13.1; O, 13.95%. Calc. for C₁₄H₃₀O₂: C, 73.0; H, 13.1; O, 13.9%. FTIR (neat) ν_max/cm⁻¹: 2954.6, 2923.1, 2855.5, 1463.6, 1435.0, 1377.7, 1118.5, 1067.9, 742.4, 722.2, 695.0. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 4.48 (1H, t, J = 5.8 Hz), 3.54 (2H, dt, J = 9.2, 6.7 Hz), 3.38 (2H, dt, J = 9.2, 6.8 Hz), 1.65–1.54 (6H, overlapped signals), 1.40–1.20 (10H, overlapped signals), 0.94 (6H, t, J = 7.4 Hz), 0.88 (3H, t, J = 6.7 Hz); δ_C (100.6 MHz, CDCl₃) 103.3 (1C), 67.2 (2C), 33.6 (1C), 31.9 (1C), 29.6 (1C), 29.4 (1C), 24.9 (1C), 23.3 (2C), 22.8 (1C), 14.2 (1C), 10.9 (2C). EIMS m/z 171 (37), 170 (20), 131 (56), 99 (40), 89 (48), 69 (38), 57 (100), 55 (21), 43 (66), 41 (47).

1-(Bis(hexyloxy)methyl)-2-nitrobenzene. Colorless oily liquid (226 mg, 67%¹). Found: C, 67.5; H, 9.2; N, 4.2; O, 19.1%. Calc. for C₁₉H₃₁NO₄: C, 67.6; H, 9.3; N, 4.15; O, 19.0%. UV λ_max (CH₃CN)/nm 257 (log ε 4.0). FTIR (neat) ν_max/cm⁻¹: 2954.1, 2925.4, 2856.0, 1532.0, 1466.0, 1359.5, 1259.3, 1196.8, 1108.5, 1057.2, 1030.8, 784.2, 738.8, 723.3, 621.3. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.83 (1H, dd, J = 7.7, 1.5 Hz), 7.80 (1H, dd, J = 7.5, 1.2 Hz), 7.59 (1H, pseudo td, J = 7.9, 7.7, 1.2 Hz), 7.45 (1H, pseudo td, J = 7.9, 7.5, 1.5 Hz), 6.02 (1H, s), 3.62 (2H, dt, J = 9.2, 6.6 Hz), 3.52 (2H, dt, J = 9.2, 6.7 Hz), 1.60 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.40–1.22 (12H, overlapped signals), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 149.2 (1C), 133.9 (1C), 132.5 (1C), 129.2 (1C), 128.2 (1C), 124.2 (1C), 98.6 (1C), 68.0 (2C), 31.7 (2C), 29.8 (2C), 25.9 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 236 (62), 153 (10), 152 (100), 135 (43), 134 (9), 104 (12), 85 (13), 55 (9), 43 (29), 41 (12).

1-(Bis(heptyloxy)methyl)-2-fluorobenzene. Colorless oily liquid (176 mg, 52%¹). Found: C, 74.4; H, 10.4. Calc. for C₂₁H₃₅FO₂: C, 74.5; H, 10.4; F, 5.6; O, 9.45%. UV λ_max (CH₃CN)/nm 259 (log ε 2.7). FTIR (neat) ν_max/cm⁻¹: 2954.7, 2927.4, 2858.1, 1488.3, 1456.8, 1229.6, 1114.1, 1062.9, 1027.6, 809.5, 756.7, 724.8. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.59 (1H, pseudo td, J = 7.5, 7.1, 1.8 Hz), 7.29 (1H, dddd, J = 8.1, 7.3, 5.4, 1.8 Hz), 7.14 (1H, pseudo td, J = 7.5, 7.3, 1.2 Hz), 7.03 (1H, ddd, J = 10.2, 8.1, 1.2 Hz), 5.71 (1H, s), 3.55 (2H, dt, J = 9.4, 6.7 Hz), 3.47 (2H, dt, J = 9.4, 6.6 Hz), 1.57 (4H, pseudo quintet, J = 6.7 Hz), 1.43–1.23 (16H, overlapped signals), 0.87 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 160.6 (1C, d, J = 248.1 Hz), 130.0 (1C, d, J = 8.4 Hz), 128.2 (1C, d, J = 3.9 Hz), 126.6 (1C, d, J = 12.8 Hz), 123.9 (1C, d, J = 3.5 Hz), 115.4 (1C, d, J = 21.4 Hz), 97.0 (1C, d, J = 3.5 Hz), 66.7 (2C, s), 32.0 (2C, s), 29.8 (2C, s), 29.2 (2C, s), 26.3 (2C, s), 22.8 (2C, s), 14.2 (2C, s). EIMS m/z 224 (11), 223 (70), 126 (9), 125 (100), 123 (8), 97 (5), 57 (16), 55 (4), 43 (6), 41 (6).

1-(Bis(heptyloxy)methyl)-2-nitrobenzene. Colorless oily liquid (245 mg, 67%¹). Found: 68.9; H, 9.7; N, 3.8; O, 17.6%. Calc. for C₂₁H₃₅NO₄: 69.0; H, 9.65; N, 3.8; O, 17.5%. UV λ_max (CH₃CN)/nm 267 (log ε 4.0). FTIR (neat) ν_max/cm⁻¹: 2954.2, 2925.3, 2856.2, 1532.4, 1466.3, 1359.8, 1258.3, 1197.5, 1108.5, 1058.4, 1031.2, 781.1, 738.5, 722.8, 622.4. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.82 (1H, dd, J = 7.7, 1.5 Hz), 7.80 (1H, dd, J = 7.5, 1.2 Hz), 7.59 (1H, pseudo td, J = 7.9, 7.7, 1.2 Hz), 7.45 (1H, pseudo td, J = 7.9, 7.5, 1.5 Hz), 6.02 (1H, s), 3.62 (2H, dt, J = 9.2, 6.6 Hz), 3.51 (2H, dt, J = 9.2, 6.7 Hz), 1.60 (4H, pseudo quintet, J = 6.7 Hz), 1.40–1.20 (16H, 1.40–1.22) (16H, overlapped signals), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 149.2 (1C), 133.9 (1C), 132.5 (1C), 129.2 (1C), 128.2 (1C), 124.3 (1C), 98.6 (1C), 68.1 (2C), 31.9 (2C), 29.8 (2C), 29.2 (2C), 26.2 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 236 (61), 153 (10), 152 (100), 135 (44), 104 (12), 85 (14), 55 (10), 43 (31), 41 (13), 34 (9).

1,1-Diheptoxyhexane. Colorless oily liquid (164 mg, 52%¹). Found: C, 76.3; H, 13.5; O, 10.2%. Calc. for C₂₀H₄₂O₂: C, 76.4; H, 13.5; O, 10.2%. FTIR (neat) ν_max/cm⁻¹: 2953.8, 2922.4, 2854.9, 1465.4, 1377.6, 1346.9, 1115.3, 1067.7, 723.0. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 4.46 (1H, t, J = 5.8 Hz), 3.56 (2H, dt, J = 9.3, 6.6 Hz), 3.40 (2H, dt, J = 9.3, 6.7 Hz), 1.63–1.52 (6H, overlapped signals), 1.40–1.24 (22H, overlapped signals), 0.92–0.85 (9H, overlapped signals); δ_C (100.6 MHz, CDCl₃) 103.29 (1C), 65.56 (2C), 33.58 (1C), 31.99 (2C), 31.84 (1C), 30.08 (2C), 29.29 (2C), 26.40 (2C), 24.63 (1C), 22.76 (2C), 22.75 (1C), 14.20 (2C), 14.13 (1C). EIMS m/z 198 (11), 83 (16), 82 (26), 70 (19), 69 (13), 57 (100), 56 (19), 55 (28), 43 (25), 41 (34).

4-(Bis(hexyloxy)methyl)benzonitrile. Colorless oily liquid (140 mg, 44%¹). Found: C, 75.6; H, 9.7; N, 4.4; O, 10.2%. Calc. for C₂₀H₃₁NO₂: C, 75.7; H, 9.8; N, 4.4; O, 10.1%. UV λ_max (CH₃CN)/nm 258 (log ε 2.8). FTIR (neat) ν_max/cm⁻¹: 2954.8, 2926.7, 2855.7, 2235.1, 1611.2, 1523.4, 1461.9, 1342.7, 1202.7, 1102.4, 1040.3, 1015.8, 8548.2, 825.1, 743.8, 715.4, 696.5. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 7.66 (2H, m), 7.59 (2H, m), 5.52 (1H, s), 3.50 (2H, dt, J = 9.4, 6.7 Hz), 3.46 (2H, dt, J = 9.4, 6.6 Hz), 1.60 (4H, pseudo quintet, J = 6.7, 6.6 Hz), 1.42–1.22 (12H, overlapped signals), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 144.4 (1C), 132.2 (2C), 127.7 (2C), 118.9 (1C), 112.2 (1C), 100.4 (1C), 65.8 (2C), 31.8 (2C), 29.8 (2C), 26.0 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 217 (14), 216 (75), 133 (10), 132 (100), 130 (8), 104 (6), 85 (20), 57 (6), 43 (29), 41 (12).

1,1-Diheptoxyoctane. Colorless oily liquid (175 mg, 51%¹). Found: C, 77.0; H, 13.5; O, 9.4%. Calc. for C₂₂H₄₆O₂: C, 77.1; H, 13.5; O, 9.3%. FTIR (neat) ν_max/cm⁻¹: 2953.8, 2922.4, 2854.9, 1465.4, 1377.6, 1346.9, 1115.3, 1067.7, 723.0. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 4.46 (1H, t, J = 5.8 Hz), 3.56 (2H, dt, J = 9.3, 6.7 Hz), 3.40 (2H, dt, J = 9.3, 6.7 Hz), 1.63–1.52 (6H, overlapped signals), 1.40–1.24 (26H, overlapped signals), 0.91–0.85 (9H, overlapped signals); δ_C (100.6 MHz, CDCl₃) 103.30 (1C), 65.58 (2C), 33.62 (1C), 32.00 (2C), 31.95 (1C), 30.08 (2C), 29.60 (1C), 29.39 (1C), 29.30 (2C), 26.40 (2C), 24.96 (1C), 22.79 (1C), 22.77 (2C), 14.22 (2C), 14.22 (1C). EIMS m/z 227 (15), 111 (12), 99 (199), 70 (15), 69 (21), 57 (100), 56 (14), 55 (24), 43 (25), 41 (29).

1-(Bis(heptyloxy)methyl)-4-nitrobenzene. Colorless oily liquid (223 mg, 61%¹). Found: 68.9; H, 9.6; N, 3.85; O, 17.6%. Calc. for C₂₁H₃₅NO₄: 69.0; H, 9.65; N, 3.8; O, 17.5%. UV λ_max (CH₃CN)/nm 262 (log ε 4.5). FTIR (neat) ν_max/cm⁻¹: 2954.8, 2926.7, 2855.7, 1608.2, 1523.7, 1465.9, 1341.7, 1201.4, 1100.4, 1039.9, 1015.6, 854.3, 824.4, 743.2, 715.8, 696.4. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.22 (2H, m), 7.65 (2H, m), 5.57 (1H, s), 3.51 (2H, dt, J = 9.4, 6.6 Hz), 3.48 (2H, dt, J = 9.4, 6.7 Hz), 1.60 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.43–1.23 (16H, overlapped signals), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 148.0 (1C), 146.3 (1C), 127.9 (2C), 123.5 (2C), 100.3 (1C), 65.8 (2C), 31.9 (2C), 29.8 (2C), 29.2 (2C), 26.3 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 251 (22), 250 (100), 153 (8), 152 (69), 136 (3), 99 (4), 57 (44), 55 (6), 43 (11), 41 (11).

1-(Bis(decyloxy)methyl)-3-nitrobenzene. Colorless oily liquid (238 mg, 53%¹). Found: C, 72.0; H, 10.5; N, 3.1; O, 14.3%. Calc. for C₂₇H₄₇NO₄: C, 72.1; H, 10.5; N, 3.1; O, 14.2%. UV λ_max (CH₃CN)/nm 263 (log ε 4.3). FTIR (neat) ν_max/cm⁻¹: 2953.1, 2921.6, 2852.7, 1532.6, 1465.6, 1347.3, 1205.5, 1111.6, 1038.5, 805.5, 719.4, 675.1. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.34 (1H, pseudo td, J = 2.3, 1.5, 0.6 Hz), 8.18 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.81 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.54 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.57 (1H, s), 3.53 (2H, dt, J = 9.4, 6.7 Hz), 3.48 (2H, dt, J = 9.4, 6.6 Hz), 1.62 (4H, pseudo quintet, J = 6.9, 6.7, 6.6 Hz), 1.42–1.23 (28H, overlapped signals), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 148.4 (1C), 141.6 (1C), 133.0 (1C), 129.3 (1C), 123.4 (1C), 122.1 (1C), 100.2 (1C), 65.9 (2C), 32.0 (2C), 29.8 (2C), 29.73 (2C), 29.72 (2C), 29.57 (2C), 29.5 (2C), 26.4 (2C), 22.8 (2C), 14.2 (2C). EIMS m/z 293 (25), 292 (100), 152 (44), 99 (14), 85 (52), 71 (46), 57 (57), 55 (24), 43 (42), 41 (24).

1-(Bis(hexyloxy)methyl)-3-nitrobenzene. Colorless oily liquid (189 mg, 56%¹). Found C, 67.5; H, 9.2; N, 4.1; O, 19.1%. Calc. for C₁₉H₃₁NO₄: C, 67.6; H, 9.3; N, 4.15; O, 19.0%. UV λ_max (CH₃CN)/nm 263 (log ε 4.3). FTIR (neat) ν_max/cm⁻¹: 2955.1, 2925.5, 2854.7, 1530.6, 1466.2, 1346.4, 1205.5, 1108.4, 1040.6, 805.8, 719.0, 695.5, 675. NMR: δ_H (400 MHz, CDCl₃, Me₄Si) 8.34 (1H, pseudo td, J = 2.3, 1.5, 0.6 Hz), 8.18 (1H, ddd, J = 8.2, 2.3, 1.0 Hz), 7.81 (1H, pseudo dt, J = 7.7, 1.5, 1.0 Hz), 7.54 (1H, pseudo t, J = 8.2, 7.7 Hz), 5.57 (1H, s), 3.53 (2H, dt, J = 9.4, 6.7 Hz), 3.49 (2H, dt, J = 9.4, 6.6 Hz), 1.62 (4H, pseudo quintet, J = 6.7 Hz), 1.26–1.45 (12H, m), 0.88 (6H, t, J = 6.9 Hz); δ_C (100.6 MHz, CDCl₃) 148.4 (1C), 141.6 (1C), 133.0 (1C), 129.3 (1C), 123.4 (1C), 122.1 (1C), 100.2 (1C), 65.9 (2C), 31.8 (2C), 29.8 (2C), 26.1 (2C), 22.7 (2C), 14.2 (2C). EIMS m/z 237 (12), 236 (74), 152 (100), 85 (59), 77 (11), 57 (15), 56 (19), 55 (19), 43 (76), 41 (26).

MS spectra of 1-chloro-1-ethoxy derivatives obtained in the reactions of cinnamaldehyde/2-chlorobenzaldehyde under Appel conditions (the reaction mixture which contained an aldehyde, PPh₃ and traces of ethanol (stabilizer) was refluxed for one hour in CCl₄).

(E)-(3-Chloro-3-ethoxyprop-1-en-1-yl)benzene. EIMS m/z 161 (100), 115 (76), 133 (49), 77 (19), 105 (17), 89 (13), 55 (13), 91 (12), 162 (12), 116 (11).

1-Chloro-2-(chloro(ethoxy)methyl)benzene. EIMS m/z 169 (100), 141 (86), 77 (33), 171 (29), 139 (26), 159 (21), 143 (20), 113 (17), 111 (14), 140 (12), 161 (9).

Acknowledgements

The authors are grateful to the Ministry of Education, Science and Technological Development of the Republic of Serbia (Project 172061) for the financial support of this work. This study is a part of the PhD thesis of Milan S. Nešić under the supervision of Niko S. Radulović.

References

1. T. Greene and P. Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, Inc, Hoboken, New Jersey, 4th edn, 2002.
2. E. Schmitz and I. Eichhorn, in The Chemistry of the Ether Linkage, ed. S. Patai, John Wiley & Sons Ltd, London, New York, Sidney, 1967, vol. 7, pp. 310–345.
3. B. Trost and W. Tang, J. Am. Chem. Soc., 2002, 124, 14542.
4. S. Danishefsky, J. Masters, W. Young, J. Link, L. Snyder, T. Magee, D. Jung, R. Isaacs, W. Bornmann, C. Alaimo, C. Coburn and M. Di Grandi, J. Am. Chem. Soc., 1996, 118, 2843.
5. E. Corey, M. Ohno, P. Vatakencherry and R. Mitra, J. Am. Chem. Soc., 1961, 83, 1251.
6. M. Smith and J. March, March's advanced organic chemistry, John Wiley & Sons, Inc, Hoboken, New Jersey, 6th edn, 2007.
7. M. Barbero, S. Bazzi, S. Cadamuro, S. Dughera and C. Piccinini, Synthesis, 2010, 315.
8. H. Fujioka, T. Okitsu, T. Ohnaka, R. Li, O. Kubo, K. Okamoto, Y. Sawama and Y. Kita, J. Org. Chem., 2007, 72, 7898.
9. C. Vo, T. Mitchell and J. Bode, J. Am. Chem. Soc., 2011, 133, 14082.
10. S. Yoshioka, M. Oshita, M. Tobisu and N. Chatani, Org. Lett., 2005, 7, 3697.
11. L. Lemiègre, R. Stevens, J. Combret and J. Maddaluno, Org. Biomol. Chem., 2005, 3, 1308.
12. L. Li, S. Das and S. Sinha, Org. Lett., 2004, 6, 127.
13. H. Mansilla and D. Regás, Synth. Commun., 2006, 36, 2195.
14. D. Kumar, R. Kumar and A. Chakraborti, Synthesis, 2008, 8, 1249.
15. R. Kumar, D. Kumar and A. Chakraborti, Synthesis, 2007, 2, 299.
16. C. Chen, S. Weng, J. Kao, C. Lin and M. Jan, Org. Lett., 2005, 7, 3343.
17. N. Leonard, M. Oswald, D. Freiberg, B. Nattier, R. Smith and R. Mohan, J. Org. Chem., 2002, 67, 5202.
18. D. Bradley, G. Williams and M. Lawton, Green Chem., 2008, 10, 914.
19. A. Roy, M. Rahman, S. Das, D. Kundu, S. Kundu, A. Majee and A. Hajra, Synth. Commun., 2009, 39, 590.
20. H. Firouzabadi, N. Iranpoor and B. Karimi, Synlett, 1999, 321.
21. S. Velusamy and T. Punniyamurthy, Tetrahedron Lett., 2004, 45, 4917.
22. M. Taschner, in Encyclopedia of Reagents for Organic Synthesis, ed. P. Fucks, et al., John Wiley & Sons Inc, 2001.
23. I. Downie, J. Lee and M. Matough, Chem. Commun., 1968, 1350.
24. R. Appel, Angew. Chem., Int. Ed., 1975, 14, 801.
25. R. Rabinowitz and R. Marcus, J. Am. Chem. Soc., 1962, 84, 1312.
26. C. Barry and S. Evans, J. Org. Chem., 1981, 46, 3361.
27. C. Reichardt, Solvents and Solvent Effects in Organic Chemistry (3rd), Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, 2003, pp. 147, 173, 187.
28. S. Fletcher, Org. Chem. Front., 2015, 2, 739.
29. H. Weinberg and E. Meijer, in Organic Reactions, vol. 28, ed. W. Dauben, et al., John Wiley & Sons Inc, Hoboken, New Jersey, 1982, vol. 1, pp. 2–22.

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Footnote

† Electronic supplementary information (ESI) available: Copies of ¹H- and ¹³C-NMR and EI-MS spectra of all new acetals can be found in the supplementary data file. In addition, the file also contains tables with the assigned NMR chemical shifts of ¹H and ¹³C and an interpretation of the observed couplings in ¹H NMR spectra. HMBC and NOESY interactions are also summarized in tables, and the key ones used during the assignation are presented on appropriate schemes. See DOI: 10.1039/c6ra19980a

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