Mechanistic pathways in CF3COOH-mediated deacetalization reactions

Article abstract of DOI:10.1021/jo902014z

(Chemical Equation Presented) It has been widely accepted that both the protection of carbonyls and the deprotection of acetals and ketals involve the participation of a water molecule: formation of acetals and ketals is a dehydration process, whereas the deprotection is often referred to as hydrolysis, which, as implied by its name, always requires the presence of water. Herein, we report experimental evidence and mechanistic investigations that provide an alternative view to this process. We have demonstrated that water is not required to convert acetals and ketals to the corresponding carbonyls. The ¹H NMR experimental results revealed that the TFA-mediated transformation of acetal to aldehyde occurs via a hemiacetal TFA ester intermediate, which differentiates itself from the classic acid-catalyzed hydrolysis, where the hemiacetal is the putative intermediate responsible for the formation of the aldehyde. More interestingly, alcohols are not the final byproducts as they are in the classical hydrolysis, rather, the two alcohol molecules are converted to two TFA esters under the reaction conditions. On the basis of theNMRevidence, we have proposed that the two TFA esters are formed in two separate steps via a different mechanism along the reaction pathway. Formation of the TFA esters renders the reaction irreversible. To the best of our knowledge, the cascade reaction pathway presented by the TFA-mediated conversion of acetals and ketals to carbonyls has never been previously postulated.

Full text of DOI:10.1021/jo902014z

[Supporting information]
Mechanistic Pathways in CF3COOH-Mediated
Deacetalization Reactions*
Wei, Li, * Jianchang Li, Yuchuan Wu, Nathan Fuller, and Michelle Markus
Chemical Sciences, Wyeth Research, 200 Cambridge Park Drive, Cambridge,
Massachusetts, 02140, USA
weili@wyeth.com, publications.weili@gmail.com
LIST OF CONTENTS
General experimental
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1H, 13C NMR spectra
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Benzaldehyde (Entry 1, Table 2)
Benzaldehyde (Entry 2, Table 2)
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4-Chlorobenzaldehyde (Entry 3, Table 2)
4-n-Propylbenzaldehyde (Entry 4, Table 2)
4-Methoxybenzaldehyde (Entry 5, Table 2)
3,4,5-Trimethoxybenzaldehyde (Entry 6, Table 2)
3-Bromopropanal (Entry 7, Table 2)
2-Bromoacetaldehyde (Entry 8, Table 2)
Benzaldehyde (Entry 9, Table 2)
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4-bromobenzaldehyde (Entry 10, Table 2)
2-bromobenzaldehyde (Entry 11, Table 2)
*
Dedicated to Professor William von Eggers Doering on the occasion of his 92nd birthday.
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Cyclehexan-1,4-dione (Entry 12, Table 2)
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All common reagents and solvents were purchased and used without further
purification. Chloroform-d was purchased from Cambridge Isotope Laboratories, Inc.
Trifluoroacetic aced was purchased from Sigma-Aldrich. All the acetals and ketals are
commercially available and were used as received after purity check. All products
1
13
were characterized by H and C NMR. NMR spectra were recorded on Bruker-400
instruments using CDCl3 or CD2Cl2 as the solvent for both proton and carbon NMR
unless otherwise indicated. Fluorine-carbon coupling constants are also included in the
13C NMR data for compounds containing fluorine substituents. The following
abbreviations are used to designate the multiplicity: s = singlet, d = doublet, t = triplet, q
= quartet, m = multiplet.
General conditions for TFA-mediated deacetalization: Condition A. To a round-
bottom flask containing the acetal or ketal (10 mmol) in chloroform (20 mL) was slowly
added trifluoroacetic acid (6 equivalents) at ambient temperature. The resulting solution
was allowed to stir for 20 hours, and then the mixture was quenched with water (20 mL)
and extracted with EtOAc (3 x 30 mL). The organic layer was washed with brine (2 x 40
mL) and dried over Mg2SO4. The solvents were removed under reduced pressure to
afford the desired aldehydes (yield as indicated).
Condition B. To a round-bottom flask containing the acetal or ketal (10 mmol) in 20 mL
of chloroform was slowly added trifluoroacetic acid (20 equivalents) at ambient
temperature. The resulting solution was allowed to stir for 5 hours, and then the mixture
was quenched with water (30 mL) and extracted with EtOAc (3 x 40 mL). The organic
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layer was washed with brine (2 x 40 mL) and dried over Mg2SO4. The solvents were
removed under reduced pressure to afford the desired aldehydes (yield as indicated).
Condition C. To a round-bottom flask containing the acetal or ketal (10 mmol) in 20 mL
of chloroform was slowly added trifluoroacetic acid (4 equivalents) at ambient
temperature. The resulting solution was heated at 75 oC for 2 hours and then the mixture
was quenched with water (20 mL) and extracted with EtOAc (3 x 30 mL). The organic
layer was washed with brine (2 x 30 mL) and dried over Mg2SO4. The solvents were
removed under reduced pressure to afford the desired aldehydes (yield as indicated).
Benzaldehyde (Entry 1, Table 2). The known benzaldehyde was obtained as a colorless
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oil (1.0 g, 95%) from the dimethyl acetal 10 following condition B. H NMR δ (400
MHz, DMSO-d6) 10.07 (s, 1 H), 7.95 (d, J = 8.3 Hz, 2 H), 7.74 (t, J = 7.3 Hz, 1 H), 7.63
(t, J = 7.6 Hz, 2 H).
Benzaldehyde (Entry 2, Table 2). The known benzaldehyde was obtained as a colorless
oil (0.10 g, 95%) from the diethyl acetal 11 (1.0 mmol) following condition B.
4-Chlorobenzaldehyde (Entry 3, Table 2). The known 4-chlorobenzaldehyde was
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obtained as a white solid (1.18 g, 84%) from the acetal 12 following condition B. H
NMR (400 MHz, CDCl3) δ 7.50 - 7.55 (m, 2 H), 7.81 - 7.85 (m, 2 H), 9.95 - 10.04 (m, 1
H). 13C NMR (101 MHz, CDCl3) δ 131.4, 132.0, 135.1, 141.4, 191.3.
4-n-Propylbenzaldehyde (Entry 4, Table 2). The reaction was run under both conditions
A and B separately. For condition A, the diethyl acetal 13 (1.01 g, 4.5 mmol) in DCM
(10 mL) was treated with TFA (3.08 g, 27 mmol) at room temperature for 20 h, and the
known 4-n-propylbenzaldehyde was obtained as a colorless crystalline solid (0.554 g,
83%) after column chromatography. 1H NMR (400 MHz, CDCl3) δ 0.96 (t, J = 7.3 Hz, 3
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H), 1.62 - 1.74 (m, 2 H), 2.64 - 2.71 (t, J = 7.3 Hz, 2 H), 7.33 (s, 1 H), 7.35 (s, 1 H), 7.79
- 7.80 (m, 1 H), 7.80 - 7.83 (m, 1 H), 7.82 (d, 1 H). 13C NMR (101 MHz, CDCl3) δ 14.18,
24.62, 38.66, 129.56, 130.30, 134.85, 150.63, 192.47.
4-Methoxybenzaldehyde (Entry 5, Table 2). The reaction was run under both conditions
A and B separately. For condition A, the diethyl acetal 14 (1.0 g, 4.7 mmol) in DCM (10
mL) was treated with TFA (3.25 g, 28.5 mmol) at room temperature for 20 h and the
known 4-methoxybenzaldehyde was obtained as a white solid (0.560 g, 86%) after
column chromatography. 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3 H), 6.98 - 7.04 (m, 2
H), 7.82 - 7.87 (m, 2 H), 9.89 (s, 1 H).
3, 4, 5-Trimethoxybenzaldehyde (Entry 6, Table 2). The reaction was run under both
conditions A and B separately. For condition A, the dimethyl acetal 15 (1.0 g, 4.1 mmol)
in DCM (10 mL) was treated with TFA (2.82 g, 24.7 mmol) at room temperature for 16 h
to yield the known 3,4,5-trimethoxybenzaldehyde (white solid, 0.743 g, 92%) after
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column chromatography. H NMR (400 MHz, CDCl3) δ 3.94 (d, 2 H), 7.14 (s, 2 H), 9.88
(s, 1 H). 13C NMR (101 MHz, CDCl3) δ 55.7, 60.4, 106.1, 131.1, 143.0, 153.1, 190.5.
3-Bromopropanal (Entry 7, Table 2). The reaction was run under both conditions A and
B separately. For condition B, the dimethyl acetal 16 (1.83 g, 10.0 mmol) in DCM (30
mL) was treated with TFA (22.4 g, 200 mmol) at room temperature for 4 h to yield the
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known aldehyde (1.30 g, 95%). H NMR (400 MHz, CDCl3) δ 3.22 (b, 2 H), 3.65 (b,
2H), 9.71 (b, 1 H).
2-Bromoacetaldehyde (Entry 8, Table 2). The reaction was run under both conditions A
and B separately. For condition B, the diethyl acetal 17 (1.97 g, 10.0 mmol) in DCM (30
mL) was treated with TFA (22.4 g, 200 mmol) at room temperature for 6 h to yield the
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known aldehyde (1.23 g, 100%). H NMR (400 MHz, CDCl3) δ 3.97 (b, 2 H), 8.82 (b, 1
H).
Benzaldehyde (Entry 9, Table 2). The reaction was run under both conditions A and B
separately. For condition B, the cyclic acetal 18 (1.50 g, 10.0 mmol) in DCM (20 mL)
was treated with TFA (22.4 g, 200 mmol) at room temperature for 10 h to yield 1.0 g
(95%) of the known benzaldehyde (for analytical data, see Entry 1 & 2).
4-Bromobenzaldehyde (Entry 10, Table 2). The reaction was run under both conditions
A and B separately. For condition A, the cyclic acetal 19 (1.04 g, 4.5 mmol) in DCM (10
mL) was treated with TFA (3.0 g, 26 mmol) at room temperature for 20 h, and the known
4-bromobenzaldehyde was obtained as a white solid (0.730 g, 91%) after
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chromatography. H NMR (400 MHz, CDCl3) δ 7.67 - 7.72 (m, 2 H), 7.73 - 7.79 (m, 2
H), 9.98 (s, 1 H). 13C NMR (101 MHz, CDCl3) δ 128.8, 130.0, 131.5, 134.1, 190.1.
2-Bromobenzaldehyde (Entry 11, Table 2). The reaction was run under both conditions
B and C separately. For condition C, The cyclic acetal 20 (1.03 g, 4.5 mmol) in DCM
o
(15 mL) was treated with TFA (10.2 g, 90 mmol) at 75 C for 4 h and the known 2-
1
bromobenzaldehyde was obtained as a white solid (0.732 g, 88%). H NMR (400 MHz,
CDCl3) δ 7.41 - 7.48 (m, 2 H), 7.64 - 7.68 (m, 1 H), 7.90 - 7.94 (m, 1 H), 10.37 (s, 1 H).
13C NMR (101 MHz, CDCl3) δ 127.1 , 127.9, 129.9, 133.5, 133.9, 135.4, 191.9.
Cyclohexane-1,4-dione (Entry 12, Table 2). The reaction was run under both conditions
A and B separately. For condition B, the cyclic ketal 21 (1.56 g, 10.0 mmol) in DCM (20
mL) was treated with TFA (22.8 g, 200 mmol) at room temperature for 12 h and the
known cyclohexane-1,4-dione was obtained as a white solid (1.01 g, 90%). 1H NMR
(400 MHz, CDCl3) δ 2.72 (s, 8 H).
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Benzaldehyde (Entry1 & 2, Table 2)
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4-Chlorobenzaldehyde (Entry 3, Table 2)
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4-n-Propylbenzaldehyde (Entry 4, Table 2)
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4-Methoxybenzaldehyde (Entry 5, Table 2)
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3,4,5-Trimethoxybenzaldehyde (Entry 6, Table 2)
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3,4,5-Trimethoxybenzaldehyde (Entry 6, Table 2)
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3-bromopropanal (Entry 7, Table 2)
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2-Bromoacetaldehyde (Entry 8, Table 2)
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Benzaldehyde (Entry 9, Table 2, see Entry 1, Table 2)
4-bromobenzaldehyde (Entry 10, Table 2)
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4-bromobenzaldehyde (Entry 10, Table 2)
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2-bromobenzaldehyde (Entry 11, Table 2)
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2-bromobenzaldehyde (Entry 11, Table 2)
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Cyclohexane-1,4-dione (Entry 12, Table 2)
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