Nickel boride mediated chemoselective deprotection of 1,1-diacetates to aldehydes and deprotection with concomitant reduction to alcohols at ambient temperature

Article abstract of DOI:10.1080/00397911.2017.1390687

A variety of 1,1-diacetates have been chemoselectively and efficiently deprotected to the corresponding aldehydes as well as deprotected and concomitantly reduced to the corresponding alcohols in high yields at ambient temperature with nickel boride generated in situ using different molar ratios of sodium borohydride and nickel (II) chloride in methanol at room temperature. Deprotection and reduction of a variety of aromatic, aliphatic and heterocyclic acylals have been achieved efficiently. Mild reaction conditions, easy work-up, high yields and chemoselectivity demonstrate the efficiency of this new method.

Full text of DOI:10.1080/00397911.2017.1390687

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
Nickel boride mediated chemoselective
deprotection of 1,1-diacetates to aldehydes and
deprotection with concomitant reduction to
alcohols at ambient temperature
Gaurav Bartwal, Mohit Saroha & Jitender M. Khurana
To cite this article: Gaurav Bartwal, Mohit Saroha & Jitender M. Khurana (2017): Nickel boride
mediated chemoselective deprotection of 1,1-diacetates to aldehydes and deprotection with
concomitant reduction to alcohols at ambient temperature, Synthetic Communications, DOI:
10.1080/00397911.2017.1390687
To link to this article: http://dx.doi.org/10.1080/00397911.2017.1390687
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Date: 01 November 2017, At: 08:40

Nickel boride mediated chemoselective deprotection of 1,1-
diacetates to aldehydes and deprotection with concomitant
reduction to alcohols at ambient temperature
Gaurav Bartwal
Department of Chemistry, University of Delhi, New Delhi, India
Mohit Saroha
Department of Chemistry, University of Delhi, New Delhi, India
Jitender M. Khurana
Department of Chemistry, University of Delhi, New Delhi, India
*Address correspondence to Jitender M. Khurana. Tel.: +91 11 2766772; fax: +91 11 27667624.
E-mail: jmkhurana1@yahoo.co.in; jmkhurana@chemistry.du.ac.in
ABSTRACT
A variety of 1,1-diacetates have been chemoselectively and efficiently deprotected to the
corresponding aldehydes as well as deprotected and concomitantly reduced to the corresponding
alcohols in high yields at ambient temperature with nickel boride generated in situ using different
molar ratios of sodium borohydride and nickel (II) chloride in methanol at room temperature.
Deprotection and reduction of a variety of aromatic, aliphatic and heterocyclic acylals have been
1

achieved efficiently. Mild reaction conditions, easy work-up, high yields and chemoselectivity
demonstrate the efficiency of this new method.
GRAPHICAL ABSTRACT
KEYWORDS: 1,1-diacetates, alcohol, aldehyde, deprotection, nickel boride, reduction
Introduction
The selective protection and deprotection of functional groups is of vital importance in
synthetic organic chemistry. 1,1-Diacetates have been employed as suitable protecting groups for
aldehydes[1] as they show remarkable stability in neutral, basic[2a] as well as acidic media.[2b] They
can also be chemoselectively synthesized in presence of ketonic group and serve as important
precursors for the synthesis of valuable intermediates of Diels-Alder reaction.[3,4] Different
methodologies have been developed for the deprotection of acylals to corresponding aldehydes.
These include the use of sulphuric acid,[5] hydrochloric acid,[6] expensive graphite,[7] zeolite,[8]
2

montomorillonite clays,[9] layered zirconiumsulfophenyl phosphonate,[10] Envirocat EPZG,[11]
boron triiodide-N,N-diethylaniline complex,[12] ceric ammonium nitrate coated on silica gel,[13]
neutral alumina under microwave irradiation,[14] CeCl3.7H2O/NaI,[15] CBr4,[16] [NO+-Crown
-
H(NO3)2 ],[17]
AlCl3,[18]
zirconium(IV)
chloride,[19]
BiCl3,[20]
Sc(OTf)3,[21]
2,6-
dicarboxypyridiniumchlorochromate.[22] Some of the methods suffer from one or more drawbacks
such as long reaction time, tiresome work up procedures, long reaction time for catalyst
preparation, large amount of solid supports, lack of selectivity, expensive reagents or requirement
of a microwave oven.
Nickel boride can be generated in situ from nickel(II) chloride and sodium borohydride in
different solvents and has been used as an efficient reagent in various organic reactions. It is
superior to many other metal catalysts due to its low cost, ease of preparation and handling, non-
pyrophoric nature and easy removal. It is used as a reducing agent without need of any external
hydrogen source as it contains adsorbed hydrogen.[23] Our research group has reported a number
of transformations with nickel boride.[24] Recently, we had reported chemoselective deprotection
and deprotection with concominant reduction of 1,3-dioxolanes, acetals and ketals using nickel
boride.[25] Therefore, we decided to investigate the reactions of 1,1-dacetates (acylals) which are
also employed as protecting groups of aldehydes with nickel boride.
Result and Discussion
In this paper, we report a simple, rapid and convenient procedure for the deprotection of a
variety of 1,1-diacetates to the corresponding aldehydes (eq. 1) and also deprotection with
concomitant reduction of 1,1-diacetates to the corresponding alcohols (eq. 2) with nickel boride
generated in situ using different molar ratios of nickel (II) chloride and sodium borohydride. The
3

appropriate conditions for chemoselective deprotecion of 1,1-diacetates were investigated using
4-chlorobenzaldiacetate (1a) as the model substrate. The activity of nickel boride is known to
depend on the method of its preparation, source of metal used, solvents etc.[23] Therefore,
parameters had to be set out by carrying out reactions of 1a with nickel boride generated in situ by
changing molar ratios of nickel chloride and sodium borohydride and solvents.
Initially, reactions of 1a were carried out with NiCl2.6H2O and NaBH4 in 1:3:9 and 1:4:12
molar ratio of 1a: nickel chloride: sodium borohydride in THF at room temperature. There was no
reaction at all (entries 1-2, Table 1). Similarily, there was no reaction in DMF using 1:4:12 ratio
of 1a: nickel chloride: sodium borohydride (entry 3, Table 1) whereas reactions carried out in
CH3CN and DCM using 1:5:15 molar ratio of 1a: NiCl2.6H2O: NaBH4 were incomplete and
mixtures of products was formed (entries 4-5, Table 1). The reaction carried out using 1:4:12
molar ratio of 1a: NiCl2.6H2O: NaBH4 in methanol at ambient temperature showed formation of
two products which were seperated after 4 h and identified as 4-chlorobenzaldehyde 2a (34%) and
4-chlorobenzyl alcohol 3a (56%) (entry 6, Table 1). The above reaction was repeated using 1:3:9
molar ratio (1a: NiCl2.6H2O: NaBH4) in methanol and was complete in 2 h. After work up, 88%
of 4-chlorobenzaldehyde (entry 7, Table 1) was obtained. Reaction carried out with still lower
ratio 1:2:6 of 1a: NiCl2.6H2O: NaBH4 was incomplete even after 4 h and gave only 51% of 4-
chlorobenzaldehyde (entry 8, Table 1). The reaction of 1a with only sodium borohydride in 1:9
molar ratio in methanol at ambient temperature was incomplete even after 12 h (entry 9, Table 1)
whereas 1a was left unreacted when treated with NiCl2.6H2O in 1:3 molar ratio in methanol even
after 12 h (entry 10, Table 1). Therefore, it can be inferred that the reduction was proceeding due
to in situ formation of nickel boride.
4

Subsequently, reactions of different 1,1-diacetates were carried out with nickel chloride
and sodium borohydride in methanol at room temperature. All the reactions were complete in 2-3
h by changing the molar ratios and gave the corresponding aldehydes (eq. 1) in high yields (entries
1-14, Table 2). The results are listed in Table 2.
It can be inferred from above results that 1,1-diacetaes showed remarkable selectivity to
give the corresponding aldehydes. It is also clear that halo groups (entries 1 and 5-6, Table 2),
methoxy group (entries 3-4, Table 2) and heterocyclic moieties (entries 9-10, Table 2) remained
unaffected under these conditions. Aliphatic 1,1-diacetaes could also be deprotected under these
conditions (entries 12-14, Table 2).
The reaction of 1a was then attempted using higher molar ratio 1:5:15 of 1a: NiCl2.6H2O:
NaBH4. The reaction was complete in 3 h and gave 90% of 4-chlorobenzyl alcohol (3a). When the
progress of the above reaction was monitored, formation of 4-chlorobenzaldehyde was distinctly
observed. Therefore, it can be inferred that 4-chlorobenzal diacetate is undergoing deprotection
with concomitant reduction using higher molar ratio of substrate: NiCl2.6H2O: NaBH4.
Subsequently, reactions of a variety of 1,1-diacetates were carried out using 1:5:15 molar ratio in
methanol at room temperature. All the reactions were complete in 2-4 h and gave the corresponding
alcohols (eq. 2) in high yields. The results are summarized in Table 3.
The halo substituents as well as hetroaryl groups remained unaffected under these
conditions. A probable mechanism has been given in Scheme 1.
5

The reaction involves initial coordination of acetoxy group with nickel boride followed by
hydrogenolysis of O-CO bond to give a gem-diol which loses water to give the aldehyde. Aldehyde
undergoes subsequent reduction to alcohols using higher molar ratios of substrate to nickel boride.
The nickel boride generated in situ is reported to contain absorbed hydrogen.[26] The mechanism
is in agreement with our observations as no traces of 4-xylene or 4-trifluromethyl toluene were
detected in the reactions of substrate 1f and 1g (entries 6-7, Table 3) with nickel boride. The
aldehyde formed undergoes subsequent reduction to give corresponding alcohols when the
reaction was carried out in higher molar ratios.
Conclusion
In conclusion, we have reported an efficient procedure for the deprotection of various 1,1-
diacetaes to corresponding aldehydes and deprotection with concomitant reduction to
corresponding alcohols. Nickel boride generated in situ under non-acidic and protic conditions at
room temperature afforded products in excellent yields. Chemoselective reaction, easy workup
and no undesirable side-products are the advantages of this methodology.
Experimental
All chemicals were of analytical grade. HPLC grade methanol (S.D. Fine) was used for the
reactions. Sodium borohydride (S.D. Fine) and nickel chloride hexahydrate (S.D. Fine) were used
as such. All 1,1-diacetaes were prepared by standard synthetic methods.[27] Melting points were
recorded on a Tropical Labequip apparatus and are uncorrected. IR spectra were recorded on
6

Perkin Elmer FT-IR SPECTRUM-2000. NMR spectra were recorded on JEOL at 400 MHz using
TMS as internal standard. All products are reported compounds and were identified by co-TLC
with authentic samples wherever applicable, and by m.p., IR and 1H NMR spectra.
General Procedure for chemoselective reduction of 1,1-diacetaes to
corresponding aldehydes
In a typical experiment 4-chlorobenzaldiacetate (2.0 mmol, 0.5 g), methanol (10 mL) and
NiCl2.6H2O (6.0 mmol, 1.469 g) were placed in a 100 mL round-bottomed flask fitted with a reflux
condenser, a CaCl2 guard tube and mounted over a magnetic stirrer. NaBH4 (9.0 mmol, 0.7 g) was
added cautiously and formation of black precipitate of nickel boride was observed immediately.
The reaction mixture was stirred vigorously at room temperature and its progress was monitored
by TLC using ethyl acetate: petroleum ether (10: 90) as eluent. TLC showed complete
disappearance of the starting material after 2 h. The reaction mixture was quenched with methanol
(20 mL) and filtered through a celite pad (~1 inch). The celite residue was washed with methanol
(2 x 5 mL). The filtrate was concentrated to nearly half volume on rotavapor and diluted with water
(20 mL). It was extracted with diethyl ether (3 x 10 mL). The combined ether extract was dried
over anhyd. MgSO4 and concentrated on a Buchi rotavapor to give 4-chlorobenzaldehyde (2a) as
a pale yellow solid in 88% yield, m.p. 45 °C (lit.[28] m.p. 47 °C) and was also identified by IR and
1H NMR spectra.
General procedure for chemoselective reduction of 1,1-diacetaes to
corresponding benzyl alcohols
In a typical experiment, 4-chlorobenzaldicetate (2.0 mmol, 0.5 g), methanol (10 mL) and
NiCl2.6H2O (10.0 mmol, 2.440 g) were placed in a 100 mL round-bottomed flask fitted with a
7

reflux condenser, a CaCl2 guard tube and mounted over a magnetic stirrer. NaBH4 (30.0 mmol,
1.169 g) was added cautiously and formation of black precipitate of nickel boride was observed
immediately. The reaction mixture was stirred vigorously at room temperature and its progress
was monitored by TLC using ethyl acetate: petroleum ether (10: 90) as eluent. TLC showed
complete disappearance of the starting material after 3 h. The reaction mixture was quenched with
methanol (20 mL) and filtered through a celite pad (~1 inch). The celite residue was washed with
methanol (2 x 5 mL). The filtrate was concentrated to nearly half volume on rotavapor and diluted
with water (20 mL) and extracted with diethyl ether (3 x 10 mL). The combined ether extract was
dried over anhyd. MgSO4 and concentrated on a Buchi rotavapor to give 4-chlorobenzyl alcohol
(3a) as white crystalline solid in 90% yield, m.p. 74 °C (lit.[28] m.p. 75 °C) and was also identified
by IR and 1H NMR spectra.
Acknowledgement
G.B. and M.S. thank CSIR, New Delhi, India for the grant of JRF and SPM fellowships,
respectively.
References
[1] Greene, T. W.; Wuts, P. G. M. Protective groups in organic synthesis, 3rd ed.; John Wiley and
Sons: New York, 1999; 306.
[2] (a) Gregory, M. J. J. Chem. Soc. B 1970, 0, 1201; (b) Kochhar, K. S.; Bal, B. S.; Deshpande,
R. P.; Rajadhyksha, S. R.; Pinnick, H. W. J. Org. Chem. 1983, 48, 1765.
[3] Banks, R. E.; Miller, J. A.; Nunn, M. J.; Stanley, P.; Weakley, T. J. R.; Ulah, Z. J. Chem. Soc.
Perkin. Trans. I 1981, 0, 1096.
[4] Snider; Amin, S. G. Synth. Commun. 1978, 8, 117.
[5] Lieberman, S. V.; Cannon, R. Org. Synth. 1951, 3, 441.
[6] Tsaug, S. M.; Wood, E. H.; Johnson, J. R. Org. Synth. 1955, 3, 141.
[7] Jin, T.-S.; Ma, Y. R.; Zhang, Z. H.; Li, T. S. Synth. Commun. 1997, 27, 3379.
[8] Ballini, R.; Bordoni, M.; Bosica, G.; Maggi, R.; Sartori, G. Tetrahedron Lett. 1998, 39, 7580.
8

[9] (a) Li, T.-S.; Zhang, Z.-H.; Fu, C.-G. Tetrahedron Lett. 1997, 38, 3285; (b) Villemin, D.;
Martin, B. J. Chem. Res. (S) 1994; (c) Perez, E. R.; Marrero, A. L.; Perez, R.; Autie, M. A.
Tetrahedron Lett. 1995, 36, 1779.
[10] Curini, M.; Epifano, F.; Marcotullio, M. C.; Rosati, O.; Nocchetti, M. Tetrahedron Lett. 2002,
43, 2709.
[11] Bandgar, B. P.; Kasture, S. P.; Tidke, K.; Makone, S. S. Green. Chem. 2000, 2, 152.
[12] Narayana, C.; Padmanabhan, S.; Kabalka, G. W. Tetrahedron Lett. 1990, 31, 6977.
[13] Cotelle, P.; Catteau, J. P. Tetrahedron Lett. 1992, 33, 3855.
[14] Varma, R. S.; Chatterjee, A. K.; Varma, M. Tetrahedron Lett. 1993, 34, 3207.
[15] Reddy, G. S.; Radhika, R.; Neelakantan, P.; Iyengar, D. S. Indian J. Chem. 2002, 41B, 863.
[16] Ramalingam, T.; Srinivas, R.; Reddy, B. V. S.; Yadav, J. S. Synth. Commun. 2001, 31, 1091.
[17] Zolifgol, M. A.; Zebarjadian, M. H.; MohammadpoorBaltork, I.; Shamsipur, M. Synth.
Commun. 2002, 32, 2803.
[18] Mohammadpoor-Baltork, I.; Aliyan, H. J. Chem. Res. (S) 1999, 0, 272.
[19] Smitha, G.; Reddy, S. Tetrahedron 2003, 59, 9571.
[20] Mohammadpoor-Baltork, I.; Aliyan, H. Synth. Commun. 1999, 29, 2741.
[21] Aggarwal, V. K., Fonquerna, S.; Vennall, G. P. Synlett 1998, 849.
[22] Hosseinzadeh, R.; Tajbakhsh, M.; Shakoori, A.; Niaki, M. Y. Monatsh. Chem. 2004, 135,
1243.
[23] (a) Ganem, B.; Osby, J. O. Chem. Rev. 1986, 86, 763; (b) Khurana, J. M.; Gogia, A. Org.
Prep. Proced. Int. 1997, 29, 1–32.
[24] (a) Khurana, J. M.; Kukreja, G.; Bansal, G. J. Chem. Soc., Perkin Trans. 1, 2002, 2520; (b)
Khurana, J. M.; Kukreja, G. J. Heterocycl. Chem. 2003, 40, 677; (c) Khurana, J. M.;
Agrawal, A.; Kukreja, G. Heterocycles 2006, 68, 1885; (d) Khurana, J. M.; Arora, R.;
Satija, S. Heterocycles 2007, 71, 2709; (e) Khurana, J. M.; Sharma, V. Chem. Heterocycl.
Compd. 2008, 44, 309; (f) Khurana, J. M.; Kumar, S.; Nand, B. Can J. Chem. 2008, 86,
1052; (g) Khurana, J. M.; Magoo, D. Synth. Commun. 2010, 40, 2908; (h) Khurana, J. M.;
Magoo, D.; Dawra, K. Monatsh Chem. 2016, 147, 1113.
[25] Khurana, J.M.; Dawra, K.; Sharma, P. RSC Adv. 2015, 5, 12048.
[26] Maybury, P. C.; Mitchell, R.W.; Hawthorne, M. F. Chem. Commun. 1974, 534.
[27] (a) Roy, S. C.; Banerjee, B. Synlett 2002, 10, 1677; (b) Zheng, Y.; Li, J.; Lu, J.; Jia, Y.; Li, B.
Gaodeng Xuexiao Huaxue Xuebao, 2013, 34, 2738.
[28] Furniss, B. S.; Hannaford, A. J.; Smith, P. W. G.; Tatchell, A. R. Vogel's Textbook of Practical
Organic Chemistry, 5th ed.; Wiley: New York, 1989; 1334. (b) Buckingham, J. Dictionary
of Organic Compounds, 5th ed; Chapman and Hall: New York, 1982.
9

Table 1. Optimization of reaction conditions for deprotection of 4-benzachlorodiacet ate (1a)
asmodel substrate.
S.No.
Solvent
THF
1a:NiCl2.6H2O:NaBH4
Time (h)
Yield (%) (2a)
a
1.
1:3:9
1:4:12
1:5:15
1:5:15
1:5:15
1:4:12
1:3:9
4
4
-
a
2.
THF
-
a
3.
DMF
4
-
b
4.
CH3CN
DCM
4
-
b
5.
8
-
6.
MeOH
MeOH
MeOH
MeOH
MeOH
4
34(56)c
88d
7.
2
8.
1:2:6
4
51
b
9.
1:0:9
12
12
-
a
10.
1:3:0
-
aNo reaction.
bIncomplete reaction and mixture of products.
cYield in bracket is of 4-chloro benzyl alcohol.
dAverage isolated yield of two runs.
10

Table 2. Chemoselective deprotection of 1,1-diacetates to corresponding aldehyde using nickel
boride in methanol at ambient temperature.
S.No.
R
a: NiCl2.6H2O: NaBH4 Time (h) Producta
Yield
(%)
1.
2.
4-ClC6H4 (1a)
C6H5 (1b)
1:3:9
1:4:12
1:4:12
1:4:12
1:3:9
2
2.5
2
2a
2b
2c
2d
2e
2f
88
84
86
90
87
84
82
86
88
90
80
78
3.
4-(OCH3)C6H4 (1c)
3,5-(OCH3)2C6H3 (1d)
4-BrC6H4 (1e)
4.
2
5.
2.5
2.5
2
6.
2,4-Cl2C6H3 (1f)
4-(CH3)C6H4 (1g)
4-(C2H5)C6H4 (1h)
2-Thienyl (1i)
1:3:9
7.
1:4:12
1:4:12
1:3:9
2g
2h
2i
8.
2.5
2.5
2
9.
10.
11.
12.
2-Furanyl (1j)
1:3:9
2j
PhCH2 (1k)
1:3:9
3
2k
2l
2-(CH3)2CHCH2CH2
(1l)
1:4:12
3
11

13.
14.
n-CH3(CH2)4 (1m)
n- CH3(CH2)6 (1n)
1:3:9
3
2m
2n
84
86
1:4:12
3.5
aYield of isolated products.
12

Table 3. Chemoselective reduction of substituted 1,1-diacetate to corresponding alcohols using
nickel boride in methanol at ambient temperature.
S.No.
R
1a: NiCl2.6H2O:
NaBH4
Time (h) Producta Yield (%)
1.
2.
4-ClC6H4 (1a)
C6H5 (1b)
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:5:15
1:4:12
1:5:15
1:5:15
1:4:12
1:4:12
3
3
3a
3b
3c
3d
3e
3f
90b
84
86
84
88
84
90
88
78
80
80
80
84
86
88
86
3.
4-(OCH3)C6H4 (1c)
4-BrC6H4 (1d)
3.5
2
4.
5.
2,4-(Cl)2C6H3 (1e)
4-(CH3)C6H4 (1f)
4-(CF3)C6H4 (1g)
3,4,5-(OCH3)3C6H2 (1h)
3,4-(CH3)2C6H3 (1i)
4-(C2H5)C6H4 (1j)
PhCH2 (1k)
2
6.
3
7.
3
3g
3h
3i
8.
2.5
3
9.
10.
11.
12.
13.
14.
15.
16.
3
3j
4
3k
3l
(CH3)2CH(1l)
3.5
3
n-CH3(CH2)4 (1m)
n-CH3(CH2)6 (1n)
2-Thienyl (1o)
3m
3n
3o
3p
3.5
4
2-Furanyl (1p)
4
aYield of isolated product.
bThe progress of the reaction was monitored by TLC which showed the formation of 4-chlorobenzaldehyde during the course of
reaction.
13

Scheme 1. Probable mechanism for nickel boride deprotection of 1,1-diacetates into aldehydes
and alcohols.
14