Chloral hydrate as a water carrier for the efficient deprotection of acetals, dithioacetals, and tetrahydropyranyl ethers in organic solvents

Article abstract of DOI:10.1080/00397911.2013.876652

The efficient deprotection of several acetals, dithioacetals, and tetrahydropyranyl (THP) ethers under ambient conditions, using chloral hydrate in hexane, is described. Excellent yields were realized for a wide range of both aliphatic and aromatic substrates. The method is characterized by mild conditions (room temperatures or below), simple workup, and the ready availability of chloral hydrate. High chemoselectivity was also observed in the deprotection, acetonides, esters, and amides being unaffected under the reaction conditions. Products were generally purified chromatographically and identified spectrally. These results constitute a novel addition to current methodology involving a widely employed deprotection tactic in organic synthesis. It seems likely that the mechanism of the reaction involves adsorption of the substrate on the surface of the sparingly soluble chloral hydrate.

Full text of DOI:10.1080/00397911.2013.876652

This article was downloaded by: [Fordham University]
On: 02 September 2014, At: 10:11
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
Chloral Hydrate as a Water Carrier for
the Efficient Deprotection of Acetals,
Dithioacetals, and Tetrahydropyranyl
Ethers in Organic Solvents
Sosale Chandrasekhar a & Annadka Shrinidhi a
a Department of Organic Chemistry , Indian Institute of Science ,
Bangalore , India
Accepted author version posted online: 03 Apr 2014.Published
online: 29 May 2014.
To cite this article: Sosale Chandrasekhar & Annadka Shrinidhi (2014) Chloral Hydrate as a Water
Carrier for the Efficient Deprotection of Acetals, Dithioacetals, and Tetrahydropyranyl Ethers in
Organic Solvents, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 44:13, 1904-1913, DOI: 10.1080/00397911.2013.876652
To link to this article: http://dx.doi.org/10.1080/00397911.2013.876652
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 44: 1904–1913, 2014
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.876652
CHLORAL HYDRATE AS A WATER CARRIER FOR THE
EFFICIENT DEPROTECTION OF ACETALS,
DITHIOACETALS, AND TETRAHYDROPYRANYL
ETHERS IN ORGANIC SOLVENTS
Sosale Chandrasekhar and Annadka Shrinidhi
Department of Organic Chemistry, Indian Institute of Science,
Bangalore, India
GRAPHICAL ABSTRACT
Abstract The efficient deprotection of several acetals, dithioacetals, and tetrahydropyranyl
(THP) ethers under ambient conditions, using chloral hydrate in hexane, is described. Excel-
lent yields were realized for a wide range of both aliphatic and aromatic substrates. The
method is characterized by mild conditions (room temperatures or below), simple workup,
and the ready availability of chloral hydrate. High chemoselectivity was also observed in
the deprotection, acetonides, esters, and amides being unaffected under the reaction con-
ditions. Products were generally purified chromatographically and identified spectrally.
These results constitute a novel addition to current methodology involving a widely employed
deprotection tactic in organic synthesis. It seems likely that the mechanism of the reaction
involves adsorption of the substrate on the surface of the sparingly soluble chloral hydrate.
Keywords Acetals; chemoselective; deprotection; hydrolysis; nonaqueous
INTRODUCTION
Acetals, dithioacetals, and tetrahydropyranyl (THP) ethers are widely used as
carbonyl protecting groups, often in multistep organic syntheses.[1–5] Even though
many methods have been developed for regenerating the carbonyl functionality from
Received November 6, 2013.
Address correspondence to Sosale Chandrasekhar, Department of Organic Chemistry, Indian
Institute of Science, Bangalore 560 012, India. E-mail: sosale@orgchem.iisc.ernet.in
1904

CHLORAL HYDRATE AS WATER CARRIER
1905
Scheme 1. Chloral hydrate (1) facilitated hydrolysis of acetals and thioacetals (2) and of THP ethers (4),
with the corresponding main products (3 and 5 respectively).
these acetals, most of them employ aqueous acidic conditions. Thus, acetals can be
cleaved by acid-catalyzed exchange dioxolanation, acid-catalyzed hydrolysis, and
oxidation;[2] THP ethers can be removed either by acid hydrolysis to furnish the
original alcohol or by oxidative deprotection.[3] However, most methods employ
relatively strong acids in the case of acetals[2] and THP ethers,[3] and hazardous
mercury salts or expensive silver salts in the case of dithioacetals,[4] under aqueous
conditions.
In protection–deprotection chemistry it is very important that after the step
involving the necessary transformation is complete, the protective group be selectively
removed, in good yield and under mild conditions. Even when a substrate is protected
and deprotected efficiently, the final products must be isolated from the reaction mix-
ture and purified by appropriate methods. Hydrolysis is a straightforward deprotec-
tion tactic, in the cases of both base-sensitive and acid-sensitive groups. Therefore, the
importance of efficient, mild, and selective deprotection procedures cannot be over-
stated. We report herein the deprotection of acetals, thioacetals, and THP ethers to
corresponding carbonyl compounds and alcohols in hexane, a nonaqueous and
nonpolar reaction medium, with chloral hydrate as the reagent (Scheme 1).
Chloral hydrate (1) is a colorless crystalline solid, which is inexpensive and read-
ily available. In 1 a molecule of water is covalently bound to chloral in a gem-diol
unit. Compound 1 is also weakly acidic with pKa 9.66.[6] Essentially, the present
method employs 1 as a means to deliver a molecule of water to the substrate molecule.
DISCUSSION
Deprotection of Acetals and Dithioacetals
Exploratory and optimization studies were initially carried out with 1,4-
dioxaspiro[4.5]decane (2a) as a model substrate. The hydrolysis of 2a was very slow
in several polar organic solvents, even when excess 1 (1:3 molar ratio) was employed.
In the absence of solvent, the hydrolysis was incomplete (<15%), as even after
heating at 70 ꢀC for 12 h only 43% of product ketone was observed.
However, satisfactory results were obtained when the solvent was changed
to hexane. It was also observed that any solvent that dissolved 1 decreased the
reactivity of 1. When the nonpolar hexane was used as solvent, 1 did not dissolve
completely in the reaction medium, although the acetal hydrolyzed to the extent

1906
S. CHANDRASEKHAR AND A. SHRINIDHI
of 78% in 1 h. An optimum volume of hexane was also indicated (ꢁ1 ml), above
which the reaction did not go to completion.
A catalytic amount of 1 in hexane was insufficient to hydrolyze 2a completely.
Stoichiometric quantities of 1 were needed to catalyze the reaction and the rate (in
terms of percentage yield at 1 h) increased with the amount of 1 added. Once the
ratio of 1 to reactant reached ꢂ4, there was no effect of 1 concentration on the rate
of the reaction.
Table 1. Hydrolysis of acetals and thioacetals
Cl3CCH(OH)2
(equiv)
Entry
Substrate (2a–h)
Product (3a–h)
Time (h) Yield (%)
Alicyclic dioxolanes
1
1.5
0.5
83
2
3
3.0
1.5
3.0
2.0
0.5
1.0
78
84
76
4
Aliphatic dioxolanes
5
6
3.0
3.0
5.0
3.0
98
97
7
8
1.5
1.5
0.5
0.5
>99
>99
(Continued )

CHLORAL HYDRATE AS WATER CARRIER
1907
Table 1. Continued
Cl3CCH(OH)2
(equiv)
Entry
Substrate (2i–u)
Product (3i–u)
Time (h)
0.5
Yield (%)
Aromatic dioxolanes
9
1.5
98
10
11
3.0
1.0
96
1.5
1.5
1.0
2.0
99
98
12
Acyclic acetals
13
3.0
1.5
4.5
1.5
82
83
14
Cyclic acetals
15
16
2.0
3.5
86
2.0
1.5
4.5
1.5
92
98
17
Dithioacetals
18
6.0
12.0
64
(Continued )

1908
S. CHANDRASEKHAR AND A. SHRINIDHI
Table 1. Continued
Cl3CCH(OH)2
(equiv)
Entry
Substrate (2i–u)
Product (3i–u)
Time (h)
Yield (%)
19
20
6.0
6.0
12.0
12.0
97
76
21
6.0
12.0
—
The reaction furnished good yields of product at rt, but at both low and high
temperatures the yields were very poor. At low temperature, the reactivity of acetal
with 1 would, of course, decrease. At high temperatures, the decomposition of 1 is
the likely reason for incomplete hydrolysis.
From these studies, it was apparent that the presence of 1 in the solid state in
the reaction medium was important for the hydrolysis reaction to occur. It
appeared that the reaction occurs at the surface of 1 and that the solvent should
remove the product from the surface efficiently for the reaction to go to
completion.
A series of acetals and dithioacetals were subjected to hydrolysis under the
optimized reaction conditions, with the results being summarized in Table 1.
The cyclic acetals derived from alicyclic ketones (2a–d), aliphatic ketones (2e–h),
aromatic ketones (2i–l), alicyclic acetals (2 m and n), cyclic acetals (2o–q), and dithioa-
cetals (2r–t) were converted to corresponding ketones or aldehydes often in quantitat-
ive yields. Of the ketals 2a–d, 2b and 2d were difficult to hydrolyze as compared to 2a
and 2c, perhaps because of the greater stability of the cyclohexanone acetal relative to
cyclopentanone or cycloheptanone acetals. Dithioacetals (2r–t) were less reactive
toward 1 and required more equivalents (6 equiv) of 1 for hydrolysis.
Deprotection of Tetrahydropyranyl (THP) Ethers
The reaction conditions employed for the hydrolysis of these substrates also
effected the hydrolysis of THP-protected alcohols. When various THP-protected
primary and secondary alcohols (aliphatic, aromatic, and heterocyclic) were
subjected to hydrolysis using 1 in hexane, quantitative yields of the corresponding
alcohols were obtained. The results of these reactions are summarized in Table 2.
Note that the nitro alcohol (5k) is very sensitive toward aqueous acidic or basic
conditions, and hence deprotection of 4k under the usual aqueous conditions can
lead to further degradation of the product. Under such circumstances, 1 can be used
for deprotection to yield nearly quantitative yields of the nitro alcohol.

CHLORAL HYDRATE AS WATER CARRIER
1909
Table 2. Hydrolysis of THP ethers
Cl3CCH(OH)2
(equiv)
Time
(h)
Yield
(%)
Entry
Substrate (4a–k)
Product (5a–k)
THP protected 1 ꢀ alcohols
1
1.5
1.5
0.5
0.5
95
2
3
95
1.5
1.5
0.5
0.5
98
98
4
THP protected 2 ꢀ alcohols
5
6
3.0
3.0
2.5
4.0
93
88
7
3.0
6.0
84
8
9
3.0
3.0
3.5
5.0
98
87
10
3.0
1.5
2.0
1.5
98
98
THP protected 2-nitro alcohols
11

1910
S. CHANDRASEKHAR AND A. SHRINIDHI
Table 3. Chemoselectivity in deprotection
Cl3CCH(OH)2 Time Yield
(equiv)
Entry
Substrate (6a–b)
Product (7a–b)
(h)
(%)
1
2
3.0
1.5
99
1.5
1.5
92
Functional Group Tolerance
Under the standardized reaction conditions, esters generally remained unreactive
(Table 3 and Scheme 2). Heating the reaction mixture and increasing the equivalents of 1
did not hydrolyze the esters studied. Several labile esters such as methyl 4-nitrobenzoate,
4-nitrophenyl 4-nitrobenzoate, and 2,4,6-trinitrophenyl 4-nitrobenzoate also did not
react under the reaction conditions. Thus, the reaction may be employed for the selective
hydrolysis of acetals and THP ethers in the presence of esters (Table 3).
We have observed that the acid-sensitive protective groups of ketone, alcohol,
amine, acid, and amide in the compounds shown in Scheme 2 were also not hydro-
lyzed by 1. Therefore, 1 can be used for the selective hydrolysis of acetals or THP
ethers in a compound bearing other functional groups shown in Scheme 2.
Possible Mechanism of the Reaction
The fact that the reaction is strongly accelerated in a nonpolar medium
(hexane) in which 1 is very sparingly soluble indicates that the reaction likely occurs
Scheme 2. Substrates unreactive toward 1.

CHLORAL HYDRATE AS WATER CARRIER
1911
Scheme 3. Possible mechanism of acetal cleavage by chloral hydrate.
at the solid–liquid interface. A pKavalue of 9.66 for 1[6] indicates the presence of
weakly protic sites on the surface of crystalline 1. This, combined with dissociated
water present nearby, is the likely reason for the observed hydrolysis reaction. A ten-
tative mechanistic scheme for the observed hydrolysis reaction is shown in Scheme 3
(for the case of 2).
In this, two molecules of 1 lead to the formation of H3Oþ. This may be envi-
saged to occur via dissociation of a molecule of 1 to chloral (I) and water. The latter
is protonated by the acid dissociation of the other chloral hydrate molecule, via the
complex II, leading to the formation of III and H3Oþ. The H3Oþ thus generated at
the surface of 1 reacts with the acetal (2), hydrolyzing it to carbonyl compound (3)
and the alcohol constituents. Interestingly, the fact that the reaction is incomplete in
the absence of solvent indicates that the products need to be removed from the
surface sites for the reaction to occur continuously.
CONCLUSIONS
We have developed a novel method for the selective deprotection of acetals,
dithioacetals, and THP ethers by chloral hydrate, under mild, nonaqueous, neutral
conditions at room temperature. The scope of the methodology is large, involving
both aliphatic and aromatic substrates. Reaction apparently occurs at the surface
of the solid 1 in hexane, and excellent yields of products were obtained after purifi-
cation. Furthermore, it is established that chloral hydrate can be used for the selec-
tive hydrolysis of acetals, dithioacetals, and THP ethers in the presence of acetonide
linkages, esters, and amides.
EXPERIMENTAL
Typical Deprotection Procedure for Acetals and Thioacetals
A stirred solution of the acetal (2, 3.5 mmol) in dry hexane (5 ml), under dry
nitrogen at 25 ꢀC, was treated with 1 (1.7 g, 10.6 mmol). The mixture was stirred
for 2 h, treated with water, and extracted with dichloromethane (10 ml). The extracts
were washed with brine solution, dried (Na2SO4), and concentrated in vacuo. The
resulting residue was purified by column chromatography on neutral alumina
(50–325 mesh, eluent: 2.5:97.5 ethyl acetate–hexane), to obtain the corresponding

1912
S. CHANDRASEKHAR AND A. SHRINIDHI
carbonyl compound (3). The purity was estimated to be >98% by 1H and 13C NMR
spectroscopic analysis.
In the case of solid acetals, 0.5 ml of dichloromethane along with hexane was
added for added solubility; in the case of thioacetals, 21.2 mmol of 1 was used for
effective deprotection.
Typical Deprotection Procedure for THP Ethers
To a stirred solution of the THP ether (4, 2.6 mmol) in sodium-dried hexane
(5 ml) under nitrogen at 0–5 ꢀC was added 1 (0.65 g, 3.9 mmol). The mixture was
stirred for 0.5 h and treated with water. The reaction mixture was extracted with
dichloromethane (10 ml), and the organic layer was washed with brine solution,
dried (Na2SO4), and concentrated in vacuo. The resulting residue was purified by
column chromatography on neutral alumina (50–325 mesh, eluent: 10:90 ethyl
acetate–hexane). The purity of the resulting product (5) was estimated to be >98%
1
by H and 13C NMR spectroscopic analysis.
FUNDING
A.S. thanks the Council of Scientific and Industrial Research (New Delhi) for
generous fellowship support.
SUPPORTING INFORMATION
Synthetic procedures and spectral characterization data can be accessed on the
publisher’s website.
REFERENCES
´
1. (a) Kocienski, P. J. Protecting Groups; Thieme: New York, 2005; (b) Wuts, P. G. M.;
Greene, T. W. Greene’s Protective Groups in Organic Synthesis; John Wiley: Hoboken,
NJ, 2007; (c) Kunz, H.; Waldmann, H. In Comprehensive Organic Synthesis; B. M. Trost
and I. Fleming (Eds.); Pergamon: Oxford, 1991; pp. 631–701.
2. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis; John Wiley:
Hoboken, 2007; pp. 435–476.
3. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis; John
Wiley: Hoboken, 2007; pp. 59–68.
4. Wuts, P. G. M.; Greene, T. W. Greene’s Protective Groups in Organic Synthesis; John Wiley:
Hoboken, 2007; pp. 482–501.
5. (a) Bailey, A. D.; Cherney, S. M.; Anzalone, P. W.; Anderson, E. D.; Ernat, J. J.; Mohan,
R. S. Synlett 2006, 215–218; (b) Isakov, V. E.; Kulinkovich, O. G. Tetrahedron Lett. 2008,
49, 6959–6961; (c) Williams, D. B. G.; Simelane, S. B.; Lawton, M.; Kinfe, H. H. Tetra-
hedron 2010, 66, 4573–4576; (d) Bockman, M. R.; Angeles, V. V.; Martino, J. M.; Vagadia,
P. P.; Mohan, R. S. Tetrahedron Lett. 2011, 52, 6939–6941; (e) Jin, Y.-S.; Zhang, W.;
Zhang, D.-Z.; Qiao, L.-M.; Wu, Q.-Y.; Chen, H.-S. Asian J. Chem. 2011, 23, 1117–1119;
(f) Poon, P. S.; Banerjee, A. K.; Bedoya, L.; Sanchez, J.; Laya, M. S. J. Chem. Res.
2011, 35, 477–479; (g) Thevenet, D.; Neier, R. Helv. Chim. Acta 2011, 94, 331–346; (h)
Kirihara, M.; Noguchi, T.; Okajima, N.; Naito, S.; Ishizuka, Y.; Harano, A.; Tsukiji,

CHLORAL HYDRATE AS WATER CARRIER
1913
H.; Takizawa, R. Tetrahedron 2012, 68, 1515–1520; (i) Madabhushi, S.; Mallu, K. K. R.;
Chinthala, N.; Beeram, C. R.; Vangipuram, V. S. Tetrahedron Lett. 2012, 53, 697–701;
(j) Vicente-Soler, J. J.; Arcas Garcia, A.; Julia Hernandez, F. Spanish Patent ES 2 372
´ ´
457 A1, Jan 20, 2012; (k) Yuan, C.; Yang, L.; Yue, G.; Yu, T.; Zhong, W.; Liu, B. Tetra-
hedron Lett. 2012, 53, 6972–6976; (l) Kirihara, M.; Suzuki, S.; Ishizuka, Y.; Yamazaki, K.;
Matsushima, R.; Suzuki, T.; Iwai, T. Tetrahedron Lett. 2013, 54, 5477–5480.
6. Gawron, O.; Draus, F. J. Am. Chem. Soc. 1958, 80, 5392–5394.