Synthesis of pinacol acetals catalyzed by (2-carboxyphenyl)diphenylphosphonium bromide

Article abstract of DOI:10.1080/00397911.2017.1368082

(2-Carboxyphenyl)diphenylphosphonium bromide that is readily prepared from commercial 2-(diphenylphosphino)benzoic acid and HBr is an efficient catalyst for the synthesis of pinacol acetals from a variety of aldehydes at room temperature.

Full text of DOI:10.1080/00397911.2017.1368082

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: http://www.tandfonline.com/loi/lsyc20
Synthesis of pinacol acetals catalyzed by (2-
carboxyphenyl)diphenylphosphonium bromide
Wenhua Huang & Ning Xu
To cite this article: Wenhua Huang & Ning Xu (2017): Synthesis of pinacol acetals catalyzed
by (2-carboxyphenyl)diphenylphosphonium bromide, Synthetic Communications, DOI:
10.1080/00397911.2017.1368082
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1368082
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Date: 30 September 2017, At: 18:20

Synthesis of pinacol acetals catalyzed by (2-
carboxyphenyl)diphenylphosphonium bromide
Wenhua Huang
Department of Chemistry, Tianjin University, Tianjin, P. R. China
Ning Xu
Department of Chemistry, Tianjin University, Tianjin, P. R. China
Address correspondence to Wenhua Huang, Department of Chemistry, Tianjin University, 135
Yaguan Road, Tianjin 300354, P. R. China. E-mail: huangwh@tju.edu.cn
Full experimental detail, 1H and 13Cꢀ NMR spectra. This material can be found via the
“Supplementary Content” section of this article’s webpage.
ABSTRACT
(2-Carboxyphenyl)diphenylphosphonium bromide that is readily prepared from
commercial 2-(diphenylphosphino)benzoic acid and HBr is an efficient catalyst for the synthesis
of pinacol acetals from a variety of aldehydes at room temperature.
GRAPHICAL ABSTRACT
1

KEYWORDS: acetal; aldehyde; Brønsted acid; phosphonium salt; pinacol
Introduction
Pinacol acetals have been widely applied as robust protective groups[1–8] for aldehydes and
as heterocyclic reactants[9–15] inꢀ organic synthesis. Although a number of methods have been used
for the synthesis of pinacol acetals,[10],[16],[17] the most commonly used method is the reaction of
aldehydes with pinacol catalyzed by TsOH with concomitant removal of the water by azetropic
distillation.[1],[2],[4–6],[18],[19] This classic method is simple but suffers from high temperatures and
the use of strong acid. Ph3PHBr has been used as a mild, crystalline source of anhydrous HBr for
the glycosidation[20],[21] of glycals, tetrahydropyranylation[22] of tertiary alcohols, and cleavage[23]
of benzyl ethers, and as a source of both Ph3P and HBr for the preparation of
alkyltriphenylphosphonium bromides directly from primary alcohols[24] or acetals.[25] Ph3PHBF4,
which is also a non-hygroscopic crystalline material, has been utilized as a source of both Ph3P
and HBF4inꢀ the preparation of alkyltriphenylphosphonium tetrafluoroborates.[26–29] Recently we
used both Ph3PHBr and Ph3PHBF4 as mild sources of HBr and HBF4, respectively, for the
preparation of cyclic -alkoxyphosphonium salts.[30] Herein, we report an efficient synthesis of
pinacol acetals catalyzed by phosphonium salt 2 at room temperature, as shown in Scheme 1.
2

Results and Discussion
When a mixture of p-chlorobenzaldehyde (1a), pinacol (pinacol:1a = 1:1), and Ph3PHBF4
1
(2a) (10molꢀ%) was stirred at room temperature overnight, H-NMR analysis of the resulting
mixture showed acetal 3a formed in a 57% yield (Table 1, entry 1). Increasing the usage of pinacol
to 1.5 and 2.0 equiv led to increased yields of 3a to 89% and 94%, respectively (entries 2 and 3).
Further increasing the usage of pinacol to 3.0 equiv gave 3a in the same yield of 94% as with 2.0
equiv. When the usage of 2a was reduced to 2molꢀ%, the yield of 3a drastically decreased to 29%
(entries 4 and 5). Other phosphonium salts, such as Ph3PHBr (2b) and tricyclohexylphosphonium
tetrafluoroborate (2c), also gave 3a in 87% and 76% yields in entries 6 and 7, respectively.
Phosphonium salt 2d, which was readily prepared from 2-(diphenylphosphino)benzoic acid (2e)
and HBr, afforded 3a in a quantitative yield, whereas no 3a was detected in a control experiment
using 2e (entries 8 and 9). Therefore, we chose 2d as the catalyst (10molꢀ%) and the ratio 2:1 of
pinacol to aldehyde as the optimized reaction conditions.
We next examined a variety of aldehydes under the optimized reaction conditions, and the
results are summarized in Table 2. For benzaldehydes 1a–1e, with an electron-withdrawing group
at the para position of the benzene ring, acetals 3a–3e were isolated in good to excellent yields
(entries 1–5). It is noteworthy that the isolated yield of 3a was lower than the NMR yield of 3a,
probably due to the volatility of 3a. For m-nitrobenzaldehyde (1f), acetal 3f was obtained in 88%
yield; but for o-nitrobenzaldehyde (1gꢀ), acetal 3gꢀ was obtained in only 26% yield (entries 6 and
3

7). This is possibly due to steric hindrance from the ortho-position nitro group. For benzaldehyde
(1hꢀ), cinnamaldehyde (1i), and 1-naphthaldehyde (1j), the corresponding acetals 3hꢀ–3j were
obtained in high yields (entries 8–10). For benzaldehydes with an electron-donating group at the
para position of benzene ring, p-tolualdehyde (1k) gave 3k in 80% yield (entry 11) and p-
anisaldehyde (1l) gave 3l in nearly quantitative yield (entry 12). However, p-
(dimethylamino)benzaldehyde (11mmꢀꢀ) gave 33mmꢀꢀ in only 9% yield (entry 13), possibly
because the basicity of the dimethylamino group interferes with the reaction. For salicylaldehyde
(1n), acetal 3n was obtained in a reasonable yield (entry 14). Finally, for heterocyclic aldehyde 1o
and aliphatic aldehyde 1p, acetals 3o and 3p were also obtained in good yields (entries 15 and 16).
Attempts to synthesize pinacol ketals and glycol acetals using 2d as a catalyst were unsuccessful.
These above results can be explained by postulating the dissociation of phosphonium salt
2 into a phosphine, an anion, and a proton that subsequently protonates aldehyde 1 to trigger the
formation of pinacol acetals, as shown in Scheme 2. When using phosphonium salt 2a, we found
the isolated acetal 3a was contaminated with a trace of Ph3P, probably from the dissociation of 2a
because Ph3P has a similar polarity to acetal 3a. This problem could be overcome by using
phosphonium salt 2d because the dissociated phosphine 2e has a carboxyl group; and thus, is much
more polar than pinacol acetals. In this case, it was very convenient to isolate pinacol acetals
through a short silica gel column with a low polarity eluate. In addition, the catalytic efficiency of
phosphonium salt 2 seems to be dependent on its acidity, which in turn is related to both the
4

basicity of its phosphine component and the acidity of its Brønsted acid component: the stronger
the basicity of the phosphine, the weaker the acidity of 2; the stronger the acidity of the Brønsted
acid, the stronger the acidity of 2. The yield of 3a was higher using 2a than 2c (Table 1, entries 3
and 7), probably due to the stronger acidity of 2a (pKa of HP + Ph3 = 2.7)[31] than 2c (pKa of HP +
Cy3 = 9.7).[31] Using 2d gave a higher yield of 3a than using 2b (Table 1, entries 6 and 8), possibly
because the phosphine component of 2e has weaker basicity than that of Ph3P due to the existence
of an electron-withdrawing carboxylic group at the ortho position of benzene ring. The failure to
give 3a using 2e (Table 1, entry 9) was probably due to the weak acidity of the carboxylic acid
compared with HBr and HBF4.
Conclusions
In conclusion, using phosphonium salts as a catalyst, we have developed a method for the
synthesis of pinacol acetals from a variety of aldehydes at room temperature. Among the tested
phosphonium salts, (2-carboxyphenyl)diphenylphosphonium bromide, which can be readily
prepared from 2-(diphenylphosphino)benzoic acid and HBr, is not only the most efficient catalyst
but also helpful for the isolation of pinacol acetals. With mild reaction conditions and easy catalyst
handling, this methodology provides facile access to pinacol acetals.
Experimental
Melting points were uncorrected and measured on a melting point apparatus with a
microscope and a hot stage. 1H and 13Cꢀ NMR spectra were recorded on a Bruker Avance 400 or
5

600 NMR spectrometer. IR spectra were recorded on a Thermo Nicolet Avatar 360 IR
spectrometer. HRMS spectra were recorded on a Varian 7.0Tꢀ FTMS. THF (SuperDry) was
purchased from a local company and used as received. MTBE = Methyl t-butylether. PE =
Petroleum ether, bp 60–90 C. All pinacol acetals are known compounds. Phosphonium salts 2a–
2c and 2e were purchased from a local company.
Typical procedure for the synthesis of pinacol acetals using 2d as a catalyst
To a round-bottom flask (25mLꢀ), pinacol (431.3mgꢀ, 3.65 mmol), p-chlorobenzaldehyde
(1a) (256.5mgꢀ, 1.82 mmol), (2-carboxyphenyl)diphenylphosphonium bromide (2d) (70.5mgꢀ,
0.18 mmol), and THF (5mLꢀ) were added. After stirring at room temperature overnight, the
reaction mixture was evaporated under reduced pressure to remove THF and the residue was
separated by a short silica gel column (eluent: PE:EtOAc (30:1)) to afford the acetal (3a)[32]
(378.0mgꢀ) in 86% yield as a colorless oil. 1H-NMR (600MHzꢀ, DMSO-d6)  1.18 (s, 6 H), 1.25
(s, 6 H), 5.89 (s, 1 H), 7.43 (d, 2 H, J = 8.7Hzꢀ), 7.45 (d, 2 H, J = 8.7Hzꢀ); 13Cꢀ-NMR (150MHzꢀ,
DMSO-d6)  21.9, 24.0, 82.3, 98.3, 128.1, 128.2, 133.1, 138.8.
Acknowledgements
We thank the National Natural Science Foundation of China for their financial support of
our program (Grant No. 21272170).
References
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8

Table 1. Optimization of pinacol acetal synthesis catalyzed by phosphonium salts.a
Entry
1
2
pinacol: 1a: 2b
Yield (%)c of 3a
Ph3PHBF4 2a
1: 1: 0.1
57
2
2a
2a
2a
2a
1.5: 1: 0.1
89
94
94
29
87
76
100
3
4
5
6
7
8
2.0: 1: 0.1
3.0: 1: 0.1
2.0: 1: 0.02
2.0: 1: 0.1
2.0: 1: 0.1
2.0: 1: 0.1
Ph3PHBr 2b
d
9
2.0: 1: 0.1
–
aReaction conditions: 1a (0.38 mmol), pinacol, 2, THF (1mLꢀ), rt, overnight. bMolar ratios. cThe yield determined by 1H NMR.
dNot detected.
9

Table 2. Synthesis of pinacol acetals catalyzed by phosphonium salt 2d.a
Entry
1
1
3, yieldb
Entry
9
1
3, yieldb
2
10
3
4
5
6
7
8
11
12
13
14
15
16
aReaction conditions: 1, pinacol (2.0 equiv), 2 (10molꢀ%), THF, rt, overnight. Isolated yield.
10

Scheme 1. Methods for the synthesis of pinacol acetals.
11

Scheme 2. Proposed mechanism for pinacol acetal formation catalyzed by phosphonium salts.
12