Utilization of hexabromoacetone for protection of alcohols and aldehydes and deprotection of acetals, ketals, and oximes under UV irradiation

Article abstract of DOI:10.1007/s11164-017-3168-0

Hexabromoacetone (HBA) was efficiently used for the protection of alcohols and aldehydes and deprotection of benzaldehyde dimethyl acetal, solketal, and other acetals and ketals. In only 10?min, the protection of glycerol yielded 90% of solketal and protection of benzaldehyde gave 95% of benzaldehyde dimethyl acetal. The deprotection of benzaldehyde dimethyl acetal under UV irradiation gave over 90% yield of benzaldehyde within 15?s using only 2.5?mol% of HBA. HBA was also successfully used for deoximation. Solvent was found to play an important role in the efficiency of HBA for these reactions.

Full text of DOI:10.1007/s11164-017-3168-0

Res Chem Intermed
DOI 10.1007/s11164-017-3168-0
Utilization of hexabromoacetone for protection
of alcohols and aldehydes and deprotection of acetals,
ketals, and oximes under UV irradiation
2
1
Kittichai Chaiseeda1 Ladawan Chantharadet Warinthorn Chavasiri
•
•
Received: 21 April 2017 / Accepted: 6 October 2017
Ó Springer Science+Business Media B.V. 2017
Abstract Hexabromoacetone (HBA) was efficiently used for the protection of
alcohols and aldehydes and deprotection of benzaldehyde dimethyl acetal, solketal,
and other acetals and ketals. In only 10 min, the protection of glycerol yielded 90%
of solketal and protection of benzaldehyde gave 95% of benzaldehyde dimethyl
acetal. The deprotection of benzaldehyde dimethyl acetal under UV irradiation gave
over 90% yield of benzaldehyde within 15 s using only 2.5 mol% of HBA. HBA
was also successfully used for deoximation. Solvent was found to play an important
role in the efficiency of HBA for these reactions.
Keywords Hexabromoacetone Á Glycerol Á Solketal Á Diol Á Aldehyde Á Ketal Á
Acetal Á Protection Á Deprotection Á Oxime
Introduction
Conversion from one functional group to another is not always straightforward.
Occasionally, when there are two or more functional groups in the same molecule,
protection of one or more functional groups may be necessary in order to
chemoselectively perform a reaction at the desired part of the molecule. The process
does add additional steps to the synthesis, and even though there have been attempts
to avoid protection and subsequent deprotection steps [1–4], it is arguably still the
method that is more commonly used. Despite having many established methods for
&
Warinthorn Chavasiri
warinthorn.c@chula.ac.th
1
2
Center of Excellence in Natural Products Chemistry, Department of Chemistry, Faculty of
Science, Chulalongkorn University, Bangkok 10330, Thailand
Program in Petrochemistry and Polymer Science, Faculty of Science, Chulalongkorn
University, Bangkok 10330, Thailand
123

K. Chaiseeda et al.
protection and deprotection [5], researchers still try to find a more selective,
convenient, rapid, and economical method. Depending on the reaction performed,
functional groups that are normally required to protect are hydroxyl, amine,
carbonyl, carboxylic acid, phosphate, and terminal alkyne. Hydroxyl and carbonyl
compounds are the main focus here.
When the compound that is being worked on has a hydroxyl group and there is a
need to carry out a transformation on another functional group in the molecule, such
as oxidation, acylation, halogenation with phosphorus or hydrogen halides, and
dehydration, then this hydroxyl group likely requires to be protected [5]. Hydroxyl
compounds are normally protected by converting them to ethers or esters, while 1,2-
and 1,3-diols can be protected by making cyclic acetals and ketals. Among various
cyclic acetals and ketals that have been reported, the formation of acetonide
(isopropylidene ketal) is the most commonly used protection for 1,2- and 1,3-diols.
The use of acetone, which is cheap, readily available and easy to remove, and other
small molecules also makes this method attractive as a protective group. Because of
its advantages and popularity, 33 preparative methods using various reagents and
catalysts were listed in the latest edition of Greene’s Protective Groups in Organic
Synthesis, while the classical method is the reaction of diol with acetone using an
acid as a catalyst [5].
Acetalization is not only for protection of hydroxyl group but it can also be used
for producing fine chemicals. For instance, with the recent popularity of biodiesel,
large excess glycerol byproduct is being produced, and one way to convert this
excess glycerol to a fine chemical is to make its ketal, called solketal, as shown in
Scheme 1. Solketal is a valuable chemical and being utilized as a solvent,
plasticizer, surfactant, flavor enhancer, pharmaceutical intermediate, and fuel
additive [6]. Latest examples of publications on the production of solketal from
glycerol include the use of Lu(OTf)3 [7], a batch process using sulfonic ion
exchange resin Lewatit GF101 [8], metal-containing TUD-1 mesoporous silicates as
solid acid catalysts [9], b and Y zeolites and KU-2 and Amberlyst 70 cation-
exchange resins [10], M-AlPO4/xAlPO4 (x = Zn, Cu, Ni, or Co) solid acid catalysts
[11], various types of Brønsted solid acid catalysts including various forms of
zeolites, Amberlyst-15, cesium salt of phosphotungstic acid (CsHPW), montmoril-
lonite K-10, molybdenum oxide supported on silica (MoO3/SiO2) [12], SnCl2 [13],
aluminum triflate-grafted MCM-41 [14], and organic–inorganic hybrid catalysts
from organic ammonium salt and heteropoly acid [15].
For aldehydes and ketones, they are normally converted to an acetal or ketal
[5, 16]. A classical method for making acetals or ketals uses an acid to catalyze, and
the mechanism is generally well known. The use of acid is sometimes not
compatible with the intended substrate and the reaction generally requires the use of
the Dean–Stark apparatus to remove water and shift the equilibrium toward the
Scheme 1 Conversion of glycerol to solketal
123

Utilization of hexabromoacetone for protection of…
product. Many methods have been reported for the preparation of acetals and ketals.
Some recent examples are the use of (bromodimethyl)sulfonium bromide [17],
various Brønsted acidic imidazolium salts [18, 19], and metal organic frameworks
(MOFs) as solid heterogeneous catalysts [20, 21].
After protection of the susceptible group and transformation of the desired group,
the next step is deprotection. Traditionally, deprotection of acetal uses acid as a
catalyst. Other reagents or catalysts that can be used for the deprotection of acetals
and ketals include CF3COOH [22], PTSA [23], LiBF4 [24], HCO2H [25],
Amberlyst-15 [26], Me2BBr [27], I2 [28], hollow mesoporous aluminosilica spheres
[29], mesoporous silica-supported Er(III) catalyst [30], zeolite ZSM-5 embedded in
the walls of hollow fibers [31], chloral hydrate [32], TiF4 [33], and silica sulfuric
acid and wet SiO2 [34]. In another interesting example, Williams et al. [35] reported
that various aliphatic and aromatic dimethyl and diethyl acetals and dketals can be
hydrolyzed when heated at 80 °C in neat water or aqueous medium without a
catalyst or additive. Recently, there has been growing interest in multistep cascade
reactions, and the conversion of acetal to aldehyde has been a part of several
multistep cascade reactions [36–50].
Formation of oximes is another way to protect carbonyl compounds, even though
it is not very popular because it still possesses an acidic hydrogen and a quite
reactive C=N [5]. They can then be cleaved by oxidation, reduction, or hydrolysis in
the presence of another carbonyl compound [5, 51]. Many methods have been
reported, and over 60 methods were summarized in Greene’s Protective Groups in
Organic Synthesis [5]. It should be noted that carbonyl compounds are also
byproducts for Beckmann rearrangement by various catalysts [52–55]. The latest
discoveries that have been reported are the use of NaClO2 in water [56], ruthenium
trichloride and p-toluenesulfonic acid (PTSA) in a mixture of dimethylacetamide
and water for deoximation [57], sodium bromate in the presence of acidic ionic
liquid [bmim]HSO4 [58], p-chloroperbenzoic acid [59], mixed iron and copper
hexacyanocolbatate [60], sym-collidinium chlorochromate (S-COCC) [61], nano-
manganese-catalyst and N-hydroxyphthalimide (2-hydroxy-1H-isoindole-1,3-dione)
under oxygen pressure [62], and anhydrous AlCl3 supported on nano-silica [63].
Even though hexabromoacetone (HBA) was first reported hundreds of years ago
[64], there have been a few reports on its applications. Recently, it has been used for
the bromination of alcohols [65–67], as a tribromoacetylating agent for the
preparation of tribromoacetamide [68–70], as a mediator in the conversion of
carboxylic acids into amides [70], and as a catalyst for the chemoselective N-tert-
butyloxycarbonylation of amines [71]. To explore its potential applications, HBA
was tested for the protection of alcohols, aldehydes, and ketones and deprotection of
various acetals and ketals, and it could catalyze the reactions quickly and efficiently.
In addition, it was also used for the conversion of oximes back to their
corresponding carbonyl compounds.
123

K. Chaiseeda et al.
Experimental
General
Chemicals and solvents were purchased from standard suppliers and were used
without further purification. HBA was both synthesized [72] and obtained from
1
Sigma–Aldrich. Oximes were prepared according to the literature [73]. H and 13C
NMR spectra were recorded on a Bruker Ultrashield 400 Plus NMR spectrometer or
a Varian Mercury NMR spectrometer with an Oxford YH400 magnet operating at
400 MHz for 1H and 100 MHz for 13C. GC analysis was performed using a Varian
CP-3800 Gas Chromatograph equipped with SGE BP1 or BP21 column. A home-
made UV reactor consisted of eight UV lamps (6 W, 254 nm, Sylvania G6 W T5)
and a fan for ventilation. A magnetic stirrer was placed underneath the UV reactor
for stirring the reaction. The reactions under UV irradiation were performed in
custom-made quartz tubes for maximum UV transmission. The tubes were placed in
the middle of the UV reactor at approximately 7 cm from the nearest UV lamp.
General procedure for preparation of dioxolane derivatives
To a 250-mL round-bottomed flask was added the corresponding carboxylic acid
(25 mmol), trichloroacetamide (8.12 g, 50 mmol), triphenylphosphine (13.11 g,
50 mmol), and dichloromethane (100 mL) to give a colorless solution. The mixture
was stirred and heated at reflux for 1 h. Then, solketal (3.11 mL, 25 mmol) and
pyridine (6.04 mL, 75 mmol) were added to the resulting acid chloride solution and
the reaction mixture was heated at reflux until completion as indicated by TLC
(approximately 4 h). After completion, the solution was extracted with 10% HCl
and sat. aq. NaHCO3, dried over Na2SO4 and evaporated. The crude product was
purified with a silica gel column eluting with 5% EtOAc/hexane (Scheme 2).
General procedure for protection of glycerol and diols with acetone
To a 25-mL quartz tube was added 1 mmol of glycerol or diol, 0.025 mmol (13 mg)
of HBA, and 1 or 2 mL of acetone. The reaction mixture was stirred and irradiated
by a home-made UV reactor for the desired time at room temperature. To quantify
the product using GC, 1 mmol of naphthalene or biphenyl was added as an internal
standard. The sample was diluted with acetone and injected into the GC equipped
with a SGE BP21 or BP5 column.
Scheme 2 Procedure for preparation of dioxolane derivatives
123

Utilization of hexabromoacetone for protection of…
General procedure for protection of diols with benzaldehyde
To a 25-mL quartz tube was added 1 mmol of a diol, 2.5 mmol benzaldehyde,
0.025 mmol (13 mg) of HBA, and 2 mL of dichloromethane. The reaction mixture
was stirred and irradiated by a home-made UV reactor for 60 min at room
temperature. To quantify the product using GC, 1 mmol (128 mg) of naphthalene
was added as an internal standard. The sample was diluted with dichloromethane
and injected into the GC equipped with a SGE BP5 column.
Representative procedure for protection of benzaldehyde with methanol
To a 25-mL quartz tube was added 1 mmol (106 mg) of benzaldehyde, 0.025 mmol
(13 mg) of HBA, and 1 mL of methanol. The reaction mixture was stirred and
irradiated by a home-made UV reactor for 10 min at room temperature. To quantify
the product using GC, 1 mmol (154 mg) of biphenyl was added as an internal
standard. The sample was diluted with methanol and injected into the GC equipped
with a SGE BP1 column.
General procedure for protection of other aldehydes and ketones
with methanol
To a 25-mL quartz tube was added 1 mmol of an aldehyde or ketone, 0.025 mmol
(13 mg) of HBA, and 8 mL of methanol. The reaction mixture was stirred and
irradiated by a home-made UV reactor for the desired time at room temperature. To
quantify the product using GC, 1 mmol of naphthalene or biphenyl was added as an
internal standard. The sample was diluted with methanol and injected into the GC
equipped with a SGE BP5 column.
General procedure for protection of other aldehydes with ethylene glycol
To a 25-mL quartz tube was added 1 mmol of an aldehyde, 1.5 mmol ethylene
glycol, 0.025 mmol (13 mg) of HBA, and 2 mL of dichloromethane. The reaction
mixture was stirred and irradiated by a home-made UV reactor for 30 min at room
temperature. To quantify the product using GC, 1 mmol of naphthalene or biphenyl
was added as an internal standard. The sample was diluted with dichloromethane
and injected into the GC equipped with a SGE BP5 column.
Representative procedure for deprotection of acetals and ketals
To a 25-mL quartz tube was added 1 mmol (152 mg) of benzaldehyde dimethyl
acetal, 0.025 mmol (13 mg) of HBA, and 5 mL of solvent. The reaction mixture
was stirred and irradiated by a home-made UV reactor for 1 min at room
temperature. To quantify the product using GC, 1 mmol (154 mg) of biphenyl was
added as an internal standard. The sample was diluted with methanol and injected
into the GC equipped with a SGE BP1 column. To obtain an isolated yield, the
solvent was evaporated and the crude product was purified using a silica gel column.
123

K. Chaiseeda et al.
Representative procedure for conversion of oximes to ketones
To a 25-mL quartz tube was added 1 mmol (113 mg) of cyclohexanone oxime,
0.2 mmol (106 mg) of HBA, 4 mL of CH3CN, and 1 mL of water. The reaction
mixture was stirred and irradiated by a home-made UV reactor for 2 min at room
temperature. To quantify the product using GC, 1 mmol (154 mg) of biphenyl was
added as an internal standard. The sample was diluted with methanol and injected
into the GC equipped with a SGE BP21 column.
Results and discussion
Protection of glycerol with acetone
For the protection of glycerol with acetone to prepare solketal (Table 1) using
2.5 mol% of HBA as a catalyst under UV irradiation, the yield of solketal was 75%
after only 1 min (entry 1) and 87% after 5 min (entry 2). Note that, for the reactions
under UV irradiation, quartz test tubes were used in order to maximize the UV light
transmitted to the reaction mixture. Increasing the reaction time to 10 and 30 min,
Table 1 Conversion of glycerol to solketal by HBA
Entry
Time (min)
Remaining glycerol (%)a
Yield of solketal (%)a
1
1
5
15
8
75
87
88
85
86
86
90
1
2
3
10
30
10
10
10
10
10
10
10
10
12
14
5
4
5b
6c
7d
8e
9f
10e,f
99
100
100
0
0
Reaction conditions: 1 mmol glycerol, 1 mL acetone, 0.025 mmol (2.5 mol%) HBA, room temperature
aDetermined by GC and SGE BP21 column using naphthalene as an internal standard
b50 mg of molecular sieves type 4A was added to the reaction mixture
c0.050 mmol (5 mol%) HBA was used
d2 mL acetone was used
eWithout HBA
fWithout UV irradiation
123

Utilization of hexabromoacetone for protection of…
the yields did not change much (entries 3, 4). Reaction conditions were then
changed to improve the product yield. Since the formation of acetal generally
generates water, to drive equilibrium to the solketal product, a drying agent can be
added to absorb water. However, in this case, when 50 mg of molecular sieves type
4A was added to the reaction mixture, the yield of solketal did not improve (entry
5). Doubling the amount of HBA still did not increase the product yield (entry 6)
while doubling the amount of acetone only slightly increased the product yield
(entry 7). It should be noted that, under UV irradiation and without HBA (entry 8),
with HBA and without UV irradiation (entry 9), and without HBA and UV
irradiation (entry 10), only trace amounts or no solketal was detected by GC.
Overall, HBA was successfully used to catalyze the conversion of glycerol with
acetone to solketal and only 2.5 mol% of HBA was used. Using higher amounts of
acetone would give higher amounts of solketal product. The results here are much
faster than those reported in the literature. For example, a catalyst based on
mesostructured cellular foams gave only 72% conversion after 180 min [6],
Ln(OTf)3 produced 100% conversion and selectivity but took 1–3 h [7], and SnCl2
gave a yield under 80% after 250 min at 60 °C [13].
Protection of diols
This protection method was then applied for the protection of 1,2-hexanediol and
1,2-decanediol using either acetone or benzaldehyde (Table 2). Protection of both
diols with acetone proceeded quickly and the yields were 100% for both diols in
10 min (entries 1, 3). Benzaldehyde acetals of these two diols were also prepared,
and after 60 min the yields were 74 and 63% for 1,2-hexanediol and 1,2-decanediol,
respectively (entries 2, 4).
Table 2 Protection of other diols by HBA
Protecting
agent
Time Yield
(min) (%) a
Entry
1b
Reagent
Product
Acetone
10
100
2c
Benzaldehyde
60
74
3b
4c
Acetone
10
60
100
63
Benzaldehyde
Reaction conditions: 1 mmol reagent, 0.025 mmol (2.5 mol%) HBA, under UV irradiation, room
temperature
aDetermined by GC and SGE BP5 column using naphthalene or biphenyl as an internal standard
b2 mL acetone
c2.5 mmol benzaldehyde, 2 mL CH2Cl2
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K. Chaiseeda et al.
Protection of benzaldehyde with methanol
The effect of the amount of methanol for protection of benzaldehyde with methanol
The amount of methanol was varied for the protection of benzaldehyde using HBA
as a catalyst. Since this reaction is generally reversible, increasing the amount of
methanol should shift the reaction toward the product. As shown in Table 3, when
the amount of methanol increased from 0.5 to 16 mL, the amount of benzaldehyde
dimethyl acetal did increase. The amount of the product reached a plateau of about
95% after 8 mL of methanol was used. The reactions were performed under UV
irradiation for 10 min.
The effect of the amount of HBA for protection of benzaldehyde with methanol
The amount of HBA was also varied from 0.63 to 5 mol% in order to find the
optimal amount (Table 4). The reactions were performed under UV irradiation for
10 min using 8 mL of methanol. At 0.63 mol%, only 66% of benzaldehyde
dimethyl acetal was formed, indicating that this was too small an amount (entry 1).
When the amount of HBA was raised to 1.25–5 mol%, the yields increased to above
90%, but were not over 95% (entries 2–4). This means that using between 1.25 and
2.5 mol% of HBA should be sufficient for this reaction. In addition, for control
experiments, when the reactions were performed either without HBA or UV
irradiation (entries 5–7), there was no acetal produced at all. This indicates that both
HBA and UV irradiation are required.
In summary, protection of benzaldehyde with methanol by HBA produced very
high yields of the acetal product in very short times. Higher amounts of methanol
used will result in higher yields of the product. The amount of HBA can be reduced
Table 3 The effect of the amount of methanol for protection of benzaldehyde with methanol
Entry
MeOH (mL)
Remaining aldehyde (%)a
Yield of acetal (%)a
1
2
3
4
5
6
0.5
1
29
15
12
10
4
71
84
88
89
95
95
2
4
8
16
5
Reaction conditions: 1 mmol benzaldehyde, 0.025 mmol (2.5 mol%) HBA, 10 min UV irradiation, room
temperature
aDetermined by GC and SGE BP1 column using biphenyl as an internal standard
123

Utilization of hexabromoacetone for protection of…
Table 4 The effect of the amount of HBA for protection of benzaldehyde with methanol
Entry
HBA (mol%)
Remaining aldehyde (%)a
Yield of acetal (%)a
1
0.63
1.25
2.5
5.0
2.5
0
33
9
66
91
95
90
0
2
3
4
4
5b
10
100
100
100
6
7b
0
0
0
Reaction conditions: 1 mmol benzaldehyde, 8 mL MeOH, 10 min UV irradiation, room temperature
aDetermined by GC and SGE BP1 column using biphenyl as an internal standard
bWithout UV irradiation
to as low as 1.25 mol% and the reaction can still produce high yields of the product.
HBA-catalyzed protection of benzaldehyde with methanol is much faster than other
recent methods in the literature. For instance, when Brønsted acidic imidazolium
salts were used, it took 24 h to obtain yields of 98% [18] while MOFs-catalyzed
reaction also took 24 h to produce 94% yield [20].
Protection of other aldehydes and ketones
This method was subsequently applied for the protection of other aldehydes and
ketones using either methanol or ethylene glycol as a protecting agent into the
corresponding dimethyl acetals or ketals (Table 5). Protection of an aliphatic
aldehyde 2-ethylbutyraldehyde with methanol produced 95% of the acetal product
in 10 min (entry 1), while protection with ethylene glycol (1.5 equivalent) in 2 mL
dichloromethane took a longer time and gave 89% of the corresponding product in
30 min (entry 2). While the protection of benzaldehyde with methanol explained
above gave up to 95% of product in 10 min, protection with ethylene glycol
produced the lower yield at 60% in 30 min (entry 3). 2-Furaldehyde was readily
protected with methanol and the yield was 97% in just 10 min (entry 4). However,
with ethylene glycol, the yield was surprisingly low at 39% in 30 min (entry 5). The
other two aldehydes tested were 1-naphthaldehyde and 2-hydroxybenzaldehyde, and
protection with methanol gave the corresponding acetals at 83 and 76% in 60 min,
respectively (entries 6, 7). This method was also tested with ketones, and for a
cyclic aliphatic ketone, cyclohexanone, protection with methanol gave 68% of the
ketal product in 10 min (entry 8). Protection of aromatic ketones were much more
difficult and the yields for the protection of acetophenone and propiophenone with
methanol were only 11 and 10% in 60 min, respectively. Therefore, more
optimization is needed to provide better yields for the protection of ketones.
123

K. Chaiseeda et al.
Table 5 Protection of other aldehydes and ketones by HBA
Protecting
Time
(min)
Yield
(%) a
Entry
1b
Reagent
Product
agent
CH3OH
10
95
2c
3c
4b
5c
HOCH2CH2OH
HOCH2CH2OH
CH3OH
30
30
10
30
89
60
97
39
HOCH2CH2OH
6b
CH3OH
60
83
7b
8b
CH3OH
CH3OH
60
10
76
68
9b
CH3OH
CH3OH
60
60
11
10
10b
Reaction conditions: 1 mmol reagent, 0.025 mmol (2.5 mol%) HBA, under UV irradiation, room
temperature
aDetermined by GC and SGE BP5 column using naphthalene or biphenyl as an internal standard
b8 mL MeOH
c1.5 mmol HOCH2CH2OH, 2 mL CH2Cl2
Deprotection of acetals and ketals
To demonstrate that HBA can deprotect acetals or ketals and is truly responsible for
the deprotection and to investigate reaction parameters including the reaction time,
molar ratio of HBA to substrate, and the amount of solvent (reaction concentration),
various experiments were performed using the commercially available benzalde-
hyde dimethyl acetal as a model compound. Benzaldehyde dimethyl acetal was
converted to benzaldehyde only when HBA was present under UV irradiation
123

Utilization of hexabromoacetone for protection of…
Table 6 Controlled experiments for the deprotection of benzaldehyde dimethyl acetal by HBA
Entry HBA (mmol) UV irradiation (min) Remaining acetal (%)a Yield of Benzaldehyde (%)a
1b
2
3b
0
0
5
0
5
100
101
100
3
0
0
0
0.025
0.025
0
4
97
Reaction conditions: 1 mmol benzaldehyde dimethyl acetal, 0.025 mmol (2.5 mol%) HBA (if applica-
ble), 5 mL CH3CN, 5 min reaction time
aDetermined by GC and SGE BP1 column using biphenyl as an internal standard
bThe reaction tube was wrapped with aluminum foil
(Table 6). The protection of benzaldehyde dimethyl acetal was found to be very
fast. To investigate this, the reaction was quenched with sat.aq. NaHCO3 after 0.25,
0.5, 1, and 5 min, and the amounts of benzaldehyde dimethyl acetal and
benzaldehyde were quantified by GC. Within 15 s, the yield was already over
90% (Fig. 1), which is remarkably much faster than other methods. For example,
when silica sulfuric acid and wet SiO2 was used, the reaction time was 60 min and
must perform at 60–70 °C [34] and, in the case of I2, it took 5–45 min [28].
Reaction conditions: 1 mmol benzaldehyde dimethyl acetal, 0.025 mmol
(2.5 mol%) HBA, 5 mL CH3CN, under UV irradiation. The amounts of the
100
90
80
70
60
Remaining Acetal (%)
50
Yield of Benzaldehyde (%)
40
30
20
10
0
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
Time (min)
Fig. 1 Time-course investigation of the deprotection of benzaldehyde dimethyl acetal by HBA
123

K. Chaiseeda et al.
substrate and product were determined by GC and SGE BP1 column using biphenyl
as an internal standard.
In addition, HBA is also very efficient in the deprotection of benzaldehyde
dimethyl acetal. When the amount of HBA was reduced to 1 mol%, the yield of
benzaldehyde was 92% in 1 min. However, in 15 s, the yield of benzaldehyde was
only 9%. Therefore, there is a tradeoff between the amount of HBA used and the
reaction time. Higher amounts of HBA would take less time and vice versa. The
effect of the amount of solvent, however, is more pronounced. Increasing the
volume of CH3CN also increases the yield of the product (Fig. 2). This could be
because methanol produced from the reaction is more diluted in higher amounts of
solvent and, therefore, the competing reverse reaction is much slower, giving higher
amounts of product.
Reaction conditions: 1 mmol benzaldehyde dimethyl acetal, 0.0125 mmol
(1.25 mol%) HBA, 1 min UV irradiation. The amounts of the substrate and product
were determined by GC and SGE BP1 column using biphenyl as an internal
standard.
Changing the solvent used in the reaction also changed the effectiveness of HBA
as shown in Table 7. Chlorinated solvents gave the highest yields of benzaldehyde
(entries 1, 2). Further investigation found that benzaldehyde dimethyl acetal is not
very stable in this type of solvent. Upon irradiation under UV light in either 1,2-
dichloroethane (DCE) or CH2Cl2 without HBA, benzaldehyde dimethyl acetal was
converted to benzaldehyde, though at a lower rate than with HBA (62, 35% yield of
benzaldehyde in 1,2-dichloroethane and CH2Cl2, respectively, after 5 min). Without
UV irradiation, 11% of benzaldehyde was formed in 1,2-dichloroethane and a trace
amount of benzaldehyde was formed in CH2Cl2 after 5 min. Acetonitrile was also a
good solvent, giving 94% of benzaldehyde (entry 3). Acetone, THF, diethyl ether,
100
90
80
70
60
Remaining Acetal (%)
50
Yield of Benzaldehyde (%)
40
30
20
10
0
0
1
2
3
4
5
6
7
8
Solvent Volume (mL)
Fig. 2 The effect of the amount of solvent on the deprotection of benzaldehyde dimethyl acetal by HBA
123

Utilization of hexabromoacetone for protection of…
Table 7 The effect of solvent on the deprotection of benzaldehyde dimethyl acetal by HBA
Entry
Solvent
Acetal (%)a
Yield (%)a
1
DCE
0
1
98
97
94
88
86
63
63
58
0
2
CH2Cl2
CH3CN
Acetone
THF
3
6
4
11
1
5
6
Et2O
13
30
21
95
2
7
Benzene
Hexane
MeOH
EtOH
8
9
10b
17
Reaction conditions: 1 mmol benzaldehyde dimethyl acetal, 0.025 mmol (2.5 mol%) HBA, 5 mL sol-
vent, 1 min UV irradiation, room temperature
aDetermined by GC and SGE BP1 column using biphenyl as an internal standard
bMajor product was benzaldehyde diethyl acetal at 80% yield
benzene, and hexane gave less yield of benzaldehyde (entries 4–8). Using methanol
as a solvent, no benzaldehyde product was formed (entry 9), indicating that the
reverse reaction was dominating. In addition, when ethanol was used as a solvent
(entry 10), transetherification occurred and benzaldehyde diethyl acetal was
obtained as a major product (80%). In summary, reactions performed in solvents
with higher relative polarity produced higher yields than solvents with lower
relative polarity.
To further explore the potential of HBA for the deprotection of acetals and ketals,
HBA was also successfully used to deprotect other acetals and ketals as shown in
Table 8. For the deprotection of solketal, the reaction tooka much longer time than
that of benzaldehyde dimethyl acetal. Methanol was found to be the best solvent. At
first, several modifications of the reaction conditions were tried including raising the
amount of HBA, variation of the amount of solvent, and increasing reaction time,
but the yield of glycerol did not improve. When the product was prepared for
1
verification using H NMR, evaporation under reduced pressure was needed to
evaporate the solvent. It was found that there was no solketal left. Sun et al. [28]
also stated that, because of equilibrium between the substrate and the product, they
had to raise the temperature to complete the reaction. However, in this case, after
simple evaporation under reduced pressure, a quantitative yield of glycerol was
obtained (entry 1). HBA could also cleave solketal that had been esterified to
1-naphthoic acid, benzoic acid, and nonanoic acid giving the corresponding product
in high yields (entries 2–4). In addition, 1-naphthoic acid was not detected from the
123

K. Chaiseeda et al.
Table 8 Deprotection of acetals and ketals by HBA
Entry
1
Reagent
Product
Yield (%)
100a
2
3
96b
90b
4
5
98b
–
No reactionc
Reaction conditions: 1 mmol substrate, 10 mol% HBA, 5 mL MeOH, 30 min UV irradiation, room
temperature, and followed by evaporation under reduced pressure
a2.5 mol% HBA, determined by GC and SGE BP21 column using naphthalene as an internal standard
bIsolated yield
cChecked by 1H NMR spectroscopy
reaction indicating that the ester bond was not cleaved. However, dioxolanes of
safrole was not cleaved (entry 5) and bromine addition products were not detected.
Conversion of oximes to ketones
To investigate the scope of substrates that can be deprotected by HBA, this reagent
was tested for deoximation. Like the reactions above, in addition to HBA, the
solvent also plays an important role. In the conversion of cyclohexanone oxime to
cyclohexanone, when CH3CN, 1,2-dichloroethane, diethyl ether, and methanol were
used, only a trace amount of cyclohexanone was detected. When water is used
together with CH3CN, the yield was much better. Several publications also used
water in combination with other solvents and found that it is a crucial factor
[74–77]. It was also found that, for this reaction, the reaction time is much longer
and the amount of HBA required is more than that of the deprotection of acetals and
ketals. After varying the ratio of CH3CN and water, 4 mL CH3CN and 1 mL water
was a suitable ratio. As shown in Table 9, when 20 mol% of HBA was used, the
yield of cyclohexanone was 51% after 2 h (entry 1). Increasing the reaction time did
not improve the yield by much (entries 2, 3). However, when the amount of
substrate is lower (lower substrate concentration), the yield is much higher (entry 4),
but raising the amount of HBA did not improve the yield (entry 5). It appeared that
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Utilization of hexabromoacetone for protection of…
Table 9 Conversion of cyclohexanone oxime to cyclohexanone by HBA
Entry
Oxime (mmol)
HBA (mol%)
UV irradiation time (h)
Oxime (%)a
Yield (%)a
1
1
20
2
32
39
27
13
7
51
60
59
87
78
91
6
2
1
20
4
3
1
20
14
4
0.25
0.25
0.20
1
20
4
5
6b
80
2
20 9 2
–
1 9 2
5
7
2
91
Reaction conditions: 4 mL CH3CN, 1 mL H2O, room temperature
aDetermined by GC and SGE BP21 column using biphenyl as an internal standard
bHBA was added in 2 portions at the specified amount and the reaction was stirred for 1 h for each portion
Table 10 Conversion of oximes to ketones by HBA
Oxime
Entry
1
Reagent
Product
Yield (%)a
92
(%)a
2
2
3
13
9
87
91
4
88
12
Reaction conditions: 0.40 mmol oxime, 20 mol% HBA added twice (total 40 mol%, second addition
after 1 h stirring), UV irradiation, room temperature, 2 h total, 8 mL CH3CN and 2 mL H2O
aDetermined by GC and SGE BP1 column using naphthalene as an internal standard
HBA became ineffective after some period of time. Therefore, HBA was added in 2
portions and the yield of cyclohexanone dramatically increased to 91% (entry 6). As
a controlled reaction, cyclohexanone oxime was irradiated for 2 h without HBA and
only 6% of ketone was formed. In comparison to some recently reported methods
123

K. Chaiseeda et al.
Scheme 3 Using TEMPO as a radical trap for the deprotection of benzaldehyde dimethyl acetal by HBA
for the oxidation of oxime into ketone [60, 62, 78, 79], our method produces the
ketone product in very high yield in a short time, uses relatively mild condition, and
is also metal-free.
In addition to cyclohexanone oxime, HBA was tested for the conversion of other
oximes using the above method, as shown in Table 10. HBA could effectively
convert 3-pentanone oxime, 2-hexanone oxime, and 2-ethylbutyraldehyde oxime to
the corresponding carbonyl compounds (entries 1–3). However, for a-tetralone
oxime, only a small amount of product was obtained (entry 4).
Mechanism investigation
Since UV irradiation was required for the reactions, they were expected to take
place via radical intermediates. 2,2,6,6-Tetramethylpiperidine-1-oxyl (TEMPO)
radical was used as a radical trap for the reaction in Scheme 3. While the reaction
without TEMPO was nearly complete within 5 min, when TEMPO was added, only
Scheme 4 TEMPO captures the radicals generated from HBA
123

Utilization of hexabromoacetone for protection of…
Scheme 5 Proposed mechanism for deprotection of benzaldehyde dimethyl acetal
6% of benzaldehyde product was formed, reaffirming that radical intermediates
were formed after UV irradiation and trapped by TEMPO, inhibiting the reaction
(Scheme 4). In Table 1, molecular sieves were added to the reaction, but the yield
did not improve at all. Therefore, it is possible that water is not generated by this
method. Based on all this information, we proposed the mechanism for deprotection
of benzaldehyde dimethyl acetal in Scheme 5.
Conclusions
In summary, HBA was efficiently used for the protection of glycerol, diols, and
aldehydes and it was also effective as a deprotecting agent of benzaldehyde
dimethyl acetal, solketal, and some other acetals and ketals. In most cases, the
reaction was very fast and a very small amount of HBA was needed. HBA was also
effectively used for deoximation. The solvent was found to have an impact on the
efficiency of HBA, and it is crucial to choose the right solvent or solvent
combination for each type of substrate and reaction.
Acknowledgements This work was supported by the 90th Year Chulalongkorn Scholarship and the
Graduate School, Chulalongkorn University, Thailand.
123

K. Chaiseeda et al.
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