Chemoselective deprotection and deprotection with concomitant reduction of 1,3-dioxolanes, acetals and ketals using nickel boride

Article abstract of DOI:10.1039/c4ra15404e

An efficient and mild methodology for the reductive deprotection of 1,3-dioxolanes, acetals and ketals to the corresponding aldehydes/ketones and also deprotection with concomitant reduction to the corresponding alcohols has been achieved in quantitative yields using nickel boride generated in situ from nickel chloride and sodium borohydride in methanol. The reactions are chemoselective as halo, alkoxy and methylenedioxy groups are unaffected.

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Chemoselective Deprotection and Deprotection with concomitant reduction on 1,3-
Dioxolanes, Acetals and Ketals using Nickel Boride
Jitender M. Khurana,* Kiran Dawra and Purnima Sharma
Department of Chemistry, University of Delhi, Delhi-110007, India
*Email: jmkhurana@chemistry.du.ac.in; Fax: 91-11-27666605
Abstract
An efficient and mild methodology for the reductive deprotection of 1,3-dioxolanes, acetals
and ketals to the corresponding aldehydes/ ketones and also deprotection with concomitant
reduction to the corresponding alcohols has been achieved in quantitative yields using
nickel boride generated in situ from nickel chloride and sodium borohydride in methanol.
The reactions are chemoselctive as halo, alkoxy and methylenedioxy groups are unaffected.
Keywords: Nickel boride, acetals, ketals, aldehydes, acetophenones, alcohols
1. Introduction
Protection and deprotection of carbonyl groups are of fundamental importance in the
multistep organic synthesis. Usually deprotection is accomplished by treatment with acids or
Lewis acids but in some cases sensitivity of substrates to acidic media is a severe limiting factor.
Moreover, acetals and ketals tolerate diverse array of nucleophilic and basic reagents.1 Milder
protocols have emerged and reagents such as CAN in neutral or mild conditions,2
CeCl3.7H2O,3 SmCl3/TMSCl,4 FeCl3,5 I2-acetone,6 decaborane in THF,7 cerium triflate in
8
11
CH3NO2, indium triflate9, iodine-acetone10, perchloric acid-SiO2 have been reported for
the deprotection of acetals/ketals. Oxidative cleavage of acetals has been reported.12
Though numerous methods for the deprotection of acetals and ketals are known, newer
1

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efficient and chemoselective processes under mild conditions are always useful. However,
there is only one report on reductive cleavage (hydrogenolysis) of acetals by LiAlH4-
AlCl3.13 Hydrogenolysis of thioacetals to give reduced products (–CH2-) by nickel boride
has been reported.14 Nickel boride generated in situ, has been reported as a reducing agent
which acts both as a catalyst and a source of hydrogen.15 We have investigated its role as a
deprotecting and reducing agent for a variety of acetals and ketals.
2. Results and discussion
We report herein the reductive deprotection and deprotection with concomitant reduction of
a variety of acetals and ketals with nickel boride, generated in situ. This is the first report
on reductive deprotection of acetals and ketals. 2-(4-Tolyl)-1,3-dioxolane (Ia) was chosen
as model substrate. Its reaction with nickel boride using 1:2:2 molar ratio in
tetrahydrofuran, dioxane and acetonitrile were incomplete and showed formation of a
mixture of products while reaction in methanol was also incomplete but showed the
formation of 4-tolualdehyde predominantly besides formation of a small amount of 4-tolyl
alcohol (entries 1-4, table 1). The reaction was repeated under reflux and was found to be
complete after 4 h and yielded 4-tolualdehyde (84%) and 4-tolyl alcohol (10%) (entry 5,
table 1). However, reaction of 2-(4-tolyl)-1,3-dioxolane was complete in 15 min at room
temperature using 1:3:3 molar ratio of Ia: NiCl2: NaBH4 and 87% of 4-tolualdehyde was
obtained after work up (entry 6, table I). A small amount of 4-tolyl alcohol (4%) was also
obtained. The reaction of Ia using higher amounts of nickel boride at room temperature
gave lower yields of 4-tolualdehyde (75%) and higher amount of 4-tolyl alcohol (21%)
(entry 7, table 2). No deprotection of Ia to 4-tolualdehyde was observed when the reaction
was performed with nickel chloride or sodium borohydride separately (entries 8-9, table 1).
2

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Therefore, the deprotection is undoubtedly proceeding due to the in situ formation of nickel
boride.
Table 1: Deprotection of 2-(4-tolyl)-1,3-dioxolane using nickel boride at ambient
temperature.
Entry
Molar ratio
Solvent
Time (h)
Yield (%)
Ia:NiCl2.6H2O:NaBH4
4-CH3C6H4CHO
a
1.
2.
3.
4.
5.
6.
7.
8.
9.
1:2:2
1:2:2
1:2:2
1:2:2
1:2:2
1:3:3
1:4:4
1:2:0
1:0:2
CH3CN
Dioxane
THF
24.0
24.0
24.0
24.0
4.0b
0.25
0.25
24.0
24.0
–
a
–
a
–
a
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
–
84(10)c
87(4)c
75(21)c
d
–
d
–
a Reaction incomplete and a mixture of products was obtained.
b Reaction conducted under reflux.
c Yield in bracket is of corresponding alcohol.
d No reaction was observed.
Subsequently, reactions of different cyclic acetals and ketals (1,3-dioxolanes) have been
investigated with nickel boride in methanol at room temperature. All these compounds (Ib-
r) underwent successful deprotection using variable amounts of substrate: nickel chloride:
sodium borohydride to give high yields of the corresponding aldehydes/ketones (eq 1). All
these results are listed in Table 2.
O
R
R
NiCl2.6H2O, NaBH4
CH3OH, r.t/ reflux
(1)
O
R'
O
R'
R = Alkyl, Aryl; R' = Alkyl,
Aryl, H
I
II
3

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The halo groups (entries 7-10, 17, table 2) and the methoxy groups (entries 4, 6, table 2)
were not affected. Surprisingly, methylene dioxy function (-O-CH2-O-), which is a benzo-
1,3-dixolane moiety, was not affected (entry 5, table 2) making this reductive deprotection
chemoselective. Furthermore, the reaction proceeded very efficiently with aliphatic ketal
(entry 18, table 2). In few cases the reduction of initially formed aldehydes to
corresponding alcohols was significant (entries 4, 21, table 2).
With the successful application of using nickel boride as the unmasking agent of cyclic
acetals and ketals, we turned our attention to acyclic acetals and ketals. 2-
(Dimethoxymethyl)naphthalene (IIIa) was first examined under the optimized reaction
conditions (IIIa:NiCl2.6H2O:NaBH4:: 1:3:3). The reaction regenerated 2-naphthaldehyde in
87% yield within 15 min (entry 19, table 2). A series of other dimethyl acetals and ketals
(IIIb-i) also underwent deprotection using the optimised reaction protocol. High yields of
corresponding aldehyde or ketone were obtained in all these cases (entries 19-27, table 2)
(eq. 2). It was further substantiated that nickel boride is a chemoselective reagent for the
deprotection, since reaction of a mixture of 2-(dimethoxymethyl)naphthalene (IIIa) and 2-
(diethoxymethyl)naphthalene (IIIj) resulted in selective deprotection of IIIa to give 2-
naphthaldehyde. However, this is in contrast to our observation that methoxy group
attached to aryl ring is unaffected. Benzyl methyl ether and 9-flurenyl methyl ether also
remained unaffected under these conditions. To our surprise the diethyl acetals namely, 1-
(diethoxymethyl)-4-methylbenzene
and
2-(diethoxymethyl)naphthalene
remained
unaffected under these conditions and starting materials were recovered quantitatively after
18 h.
4

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R
OCH3
OCH3
R
NiCl2.6H2O, NaBH4
CH3OH, r.t/ reflux
(2)
O
R'
R'
R= Alkyl, Aryl; R'=Alkyl, Aryl, H
II
III
Table 2: Deprotection of cyclic/ acyclic acetals and ketals using nickel boride in
methanol
Entry
R
R’
Molar ratio
S:NiCl2.6H2O:
NaBH4
Time (h) Yield (%)
(II)
1.
2.
4-CH3C6H4 (Ia)
2-Naphthyl (Ib)
1-Naphthyl (Ic)
4-CH3OC6H4 (Id)
3-Piperonyl (Ie)
3,4-(CH3O)2C6H3 (If)
4-ClC6H4 (Ig)
4-BrC6H4 (Ih)
2-ClC6H4 (Ii)
H
1:3:3
0.25
2
87(6)a
90(7)a
86
H
1:3:3
1:3:3b
1:6:6
3.
H
3
4.
H
0.50
0.25
12
1.5
2.5
3
61(25)a
5.
H
1:6:6
86
6.
H
1:6:6b
1:12:12
1:12:12
1:12:12
1:12:12
1:3:3
88
7
H
78
8.
H
81
9.
H
77
10.
11.
12.
13.
3-ClC6H4 (Ij)
H
5
74
90(8)a
C6H5 (Ik)
CH3
C3H7
CH3
CH3
3
C6H5 (Il)
1:3:3b
3.5
3
88
88(10)a
4-CH3C6H4 (Im)
4-CH3OC6H4 (In)
1:8:8
14.
1:8:8
3
89
15.
16.
C6H5 (Io)
C2H5
H
1:8:8b
1:8:8b
5
6
84
90
Fluorenyl (Ip)
4-ClC6H4 (Iq)
CH3
17.
1:12:12
4
77
18.
19.
20.
CH3 (Ir)
C6H13
H
1:6:6
1:3:3
1:3:3b
0.25
0.25
4
82
87(8)a
87
2-Naphthyl (IIIa)
4-CH3C6H4 (IIIb)
1-Naphthyl (IIIc)
H
21.
22.
23.
1:10:10
1:10:10
1:10:10
18
0.5
60(30)a
H
4-BrC6H4 (IIId)
4-ClC6H4 (IIIe)
H
H
75
0.75
78
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3-Piperonyl (IIIf)
C6H5 (IIIg)
H
24.
25.
26.
27.
1:10:10b
3
72
91
90
CH3
1:3:3
1:6:6
1:6:6
0.25
0.25
4
C6H13
CH3
CH3 (IIIh)
92(7)a
4-CH3C6H4 (IIIi)
a Yield in bracket represents the yield of alcohol
b Reaction conducted under reflux
The deprotection is proposed to be proceeding via hydrogenolysis of C–O bond, rather than
a hydrolysis mechanism. The deprotection initially involves the cleavage of C–O bond
leading to the formation of a geminal diol, which undergoes loss of water molecule to
corresponding carbonyl compound. This is in agreement with our observations as no traces
of p-xylene, 2-methylnaphthalene or fluorene were detected in the reactions of Ia, Ib or Ip
with nickel boride. The reaction of 2,2-dimethyl-4,5-diphenyl-1,3-dioxolane yielded only
5% of 1,2-diphenylethane and 95% of starting material was recovered unchanged. Also, in
conformity with the inertness of the methylene dioxy group (Ie), the starting material was
recovered unchanged in the reaction of catechol acetonide, probably because Csp2–O bond
was difficult to cleave.
The activity and selectivity of nickel boride varies dramatically with small variation in the
preparation of nickel boride.16 This coupled with our observations of formation of small
amount of alcohol in a number of reactions, made us to investigate reactions using higher
and by varying molar ratios of substrate to nickel chloride to sodium borohydride reagent.
Treatment of Ia with 1:4:12 molar ratio (Ia:NiCl2.H2O:NaBH4) in methanol gave 2-tolyl
methanol exclusively, in 85% yield within 4 h (entry 1, table 3). Subsequently, various
cyclic as well as acyclic acetals and ketals were treated with nickel boride with indicated
6

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molar ratios in methanol. All theses compounds underwent reduction successfully in 0.25-
18 h at ambient temperature to give the corresponding alcohols in high yields at room
temperature/ reflux (entries 2-18, table 3) (eq. 3). The results are summarized in Table 3.
R
O
R'
O
R
I
NiCl2.6H2O, NaBH4
CH3OH, r.t/ reflux
(3)
OH
R'
IV
OCH3
OCH3
R
R'
III
R= Alkyl, Aryl; R'=Alkyl, Aryl, H
Table 3: Reduction of cyclic/ acyclic acetals and ketals using nickel boride in
methanol
Entry
R
R’
Molar ratio
S:NiCl2.6H2O:NaBH4
1:4:12
Time (h) Yield (%)
(IV)
1.
2.
4-CH3C6H4 (Ia)
2-Naphthyl (Ib)
1-Naphthyl (Ic)
4-CH3OC6H4 (Id)
3-Piperonyl (Ie)
3,4-(CH3O)2C6H3 (If)
C6H5 (Ik)
H
H
4
1
85
85
1:5:15
1:3:9b
3.
H
8
70(25)a
4.
H
1:5:15
1
66
5.
H
1:6:18
0.25
0.25
4
61(28)a
82
6.
H
1:6:18
7.
CH3
C3H7
C6H13
CH3
CH3
1:6:18
1:6:18b
81
8.
C6H5 (Il)
8
85(10)a
9.
CH3 (Ir)
1:6:18
24
0.25
0.25
24
18
2
79
10.
11.
12.
13.
14.
15.
16.
4-CH3C6H4 (Im)
4-CH3OC6H4 (In)
1:6:18
91
1:6:18
1:8:24b
97
C6H5 (Io)
C2H5
H
72
2-Naphthyl (IIIa)
4-CH3C6H4 (IIIb)
1-Naphthyl (IIIc)
C6H5 (IIIg)
1:5:15
80
H
1:3:9
84
H
1:10:15
1:3:9
18
0.25
82
CH3
91
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17.
18.
CH3 (IIIh)
C6H13
CH3
1:6:18
1:6:18
0.5
3
89
90
4-CH3C6H4 (IIIi)
a Yield in bracket refers to yield of corresponding carbonyl compound.
b Reaction conducted under reflux.
The methylene dioxy group was unaffected even with higher molar ratios of substrate to
nickel boride. Also, the chloro and bromo groups were unaffected even under these
conditions. The alcohols are indeed obtained from the corresponding aldehydes which
could be observed distinctly. The reduction of aldehydes/ ketones has already been reported
by us.17
3. Conclusions
In conclusion, we have shown that nickel boride is a useful reagent for the reductive
deprotection of 1,3-dioxolanes, acetals and ketals to give the corresponding
aldehydes/ketones or deprotection with concomitant reduction to the corresponding
alcohols. The conditions are mild, neutral and tolerate a wide range of functionalities,
including methoxy, methylenedioxy and halo groups. The deprotection is believed to be
proceeding via hydrogenolysis.
4. Experimental:
All the melting points (wherever applicable) were recorded on a Tropical Labequip apparatus
and are uncorrected. IR spectra were recorded on Perkin-Elmer FT-IR SPECTRUM-2000.
NMR spectra were recorded on FT-NMR model R-300 Hitachi (300 MHz) with TMS as the
internal standard. All the products are reported compounds and were identified by co-TLC,
m.p, IR and NMR spectra.
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4.1. General procedure for deprotection of cyclic/ acyclic acetals and ketals with NiCl2
and NaBH4
In a typical experiment, 2-(4-tolyl)-1,3-dioxolane (1mmol) and methanol (10 mL) was
placed in a 50 mL round-bottomed flask fitted with a water condenser and mounted over a
magnetic stirrer. Nickel chloride hexahydrate (3 mmol) was added to the flask, followed by
the addition of sodium borohydride (3 mmol) with constant stirring. A vigorous reaction
took place and the reaction mixture turned black due to the in situ formation of nickel
boride. The progress of the reaction was monitored by TLC (petroleum ether: ethyl acetate:
95:5, v/v). After 15 min, the reaction was complete. The reaction mixture was filtered
through a celite pad (~1 inch) and washed with methanol (2 x 10 mL). The combined
extract was then diluted with water (~50 mL) and extracted with dichloromethane (3 x 10
mL). The combined extract was washed with water and dried over anhyd. Na2SO4. After
concentration on a Buchi rotary evaporator, the product was purified by column
chromatography on neutral alumina using petroleum ether: ethyl acetate (97:3, v/v) as
eluent. p-Tolualdehyde was obtained as colourless oil in 87% yield. The product was
identified by IR and NMR spectra.
4.2. General procedure for the reduction of cyclic/ acyclic acetals and ketals with
NiCl2 and NaBH4
In a typical experiment, 2-(4-tolyl)-1,3-dioxolane (1mmol), nickel chloride hexahydrate (4
mmol) and methanol (10 mL) were stirred magnetically in a 50 mL round-bottomed flask
mounted over a magnetic stirrer. Sodium borohydride (12 mmol) was added to the mixture
carefully and the contents were stirred vigorously. The reaction mixture turned black due to
the in situ formation of nickel boride. TLC analyses (petroleum ether: ethyl acetate:: 95:5,
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v/v) showed complete disappearance of the starting material after 4 h and the formation of
a polar product with lower Rf was observed. The reaction mixture was filtered through a
celite pad (~1 inch) and washed with methanol (2 x 10 mL). The filtrate was diluted with
water (~50 mL). It was extracted with CH2Cl2 (3 x 10 mL), washed with water (~10 mL),
dried over anhydride sodium sulphate and concentrated on a Buchi rotavapour. 4-
Tolylmethanol (IIIa) (85 %) was obtained as a white solid. m.p. 60°C (lit. m.p. 60-62°C)
and also identified by IR and NMR spectra.
Acknowledgments
We thank CSIR, New Delhi for providing JRF & SRF to KD and to UGC, New Delhi for
JRF & SRF to PS.
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