Phenyl sulphonyl acetaldehyde diethyl acetal: A new robust 1,2-diol protective group

Article abstract of DOI:10.1081/SCC-120016347

A simple preparation of a novel resilient protective group for 1,2-diols is described herein which is remarkably stable in the presence of extremely harsh basic conditions as well as acidic media. The title reagent's versatility is detailed with numerous examples.

Full text of DOI:10.1081/SCC-120016347

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Phenyl Sulphonyl Acetaldehyde Diethyl Acetal: A New
Robust 1,2-Diol Protective Group
Dr. S. Chandrasekhar a , Ch. Srinivas a & P. Srihari a
a Indian Institute of Chemical Technology , Hyderabad, India
Published online: 17 Aug 2006.
To cite this article: Dr. S. Chandrasekhar , Ch. Srinivas & P. Srihari (2003) Phenyl Sulphonyl Acetaldehyde Diethyl Acetal:
A New Robust 1,2-Diol Protective Group, Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 33:6, 895-902, DOI: 10.1081/SCC-120016347
To link to this article: http://dx.doi.org/10.1081/SCC-120016347
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SYNTHETIC COMMUNICATIONSÕ
Vol. 33, No. 6, pp. 895–902, 2003
Phenyl Sulphonyl Acetaldehyde Diethyl
Acetal: A New Robust 1,2-Diol
Protective Group#
*
S.Chandrasekhar, Ch.Srinivas, and P.Srihari
Indian Institute of Chemical Technology,
Hyderabad, India
ABSTRACT
A simple preparation of a novel resilient protective group for 1,2-
diols is described herein which is remarkably stable in the presence of
extremely harsh basic conditions as well as acidic media. The title
reagent’s versatility is detailed with numerous examples.
Key Words: 1,2-Diols; Acetals; Robust.
#IICT Communication No.: 4583.
*Correspondence: Dr. S. Chandrasekhar, Indian Institute of Chemical
Technology, Hyderabad 500007, India; Fax: 91-040-27160512; E-mail: srivaric@
iict.ap.nic.in.
895
DOI: 10.1081/SCC-120016347
Copyright & 2003 by Marcel Dekker, Inc.
0039-7911 (Print); 1532-2432 (Online)
www.dekker.com

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896
Chandrasekhar, Srinivas, and Srihari
INTRODUCTION
The 1,2-diol group is a commonly encountred functionality especially
in the polyol class of natural products. Like any other functionality, this
too demands special protective groups, which would mask it efficiently
during a long synthetic scheme. Several protective groups[1] have been
documented in the literature for existing functionalities, which could also
be cleaved under essentially mild conditions. Often, synthetic chemistry
requires a protection tool, which is robust and stable to various drastic
reagents. Acetal classes of protective groups with appendage are limited
and no systematic study has been carried out in detail.[2] Notmuch work
has been reported in this direction.
RESULTS AND DISCUSSION
Herein we report the utility of a-phenyl sulfonyl acetaldehyde diethyl
acetal as a novel, robust protective group for 1,2-diols (Sch. 1).
Interestingly, this protective group is stable to 60% AcOH,[3] 6M-HCl
and 0.1 M H2SO4 as well.
The reagent, phenyl sulfonyl acetaldehyde diethyl acetal,[4] prepared
from sodium phenyl sulfinate[5] and bromoacetaldehyde diethyl acetal
was treated with cyclooctane diol and AmberlystÕ 15 in dry toluene
(reflux) to furnish the protected diol 1b. This was treated with the non-
nucleophilic base DBU to check if deprotection could be achieved
through b-elimination.[6] Surprisingly however, after several hours of
stirring with excess of DBU, the protection was intact. Intrigued by
this, the action of a few other bases such as NaOH, NaOMe, NaH and
LDA was attempted without any success. This protective group was
however successfully cleaved when exposed to LiNH2 in liquid NH3
at ꢀ33ꢁC as well as by n-butyl lithium at 35ꢁC (Table 1). The interesting
robustness of this new protective group prompted us to study
Scheme 1.

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New Robust 1,2-Diol Protective Group
Table 1.
897
Entry
Acid/base employeda
Result
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
DBU/anhydrous DCM/r.t./12 h
DBU/anhydrous DCM/reflux/8 h
DBU/H2O/DCM/PTC/r.t./6 h
DBU/H2O/DCM/PTC/reflux/8 h
SmI2/anhydrous THF/r.t./6 h
NaOMe/anhydrous MeOH/r.t./12 h
Bu3SnH/AIBN/anhydrous benzene/reflux/6 h
LDA/anhydrous THF/ꢀ78ꢁC/6 h
NaH/anhydrous DMF/sonication/4 h
aqueous NaOH/sonication/6 h
DBU/anhydrous DCM/sonication/6 h
NaOMe/anhydrous MeOH/sonication/4 h
NaH/anhydrous DMF/r.t./8 h
Na-Naphthalenide/ꢀ78ꢁC/4 h
n BuLi/r.t./2 h
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Stable
Cleaved
Cleaved
Cleaved
Stable
Stable
Stable
LiNH2, liquid NH3/4 h
60% AcOH, r.t./8 h
0.1 N H2SO4, MeOH, r.t./8 h
6 N HCl, THF/6 h
aEntries 1, 2, 8 and 10 of Table 2 were subjected to these conditions.
a few other substrates (Table 2). The p-fluorophenol derivative (Entry 2)
was protected and subjected to cleavage to recover the parent diol in 84%
isolated yield. Similarly, the benzyloxy derivative of undecanediol also
behaved well during protection (87%) as well as deprotection (73%).
Various other diol derivatives were subjected to the above-mentioned
protocol to prove the consistency of the present reaction conditions.
To check the acid stability of this novel protective group an equimolar
mixture of the isopropylidene derivative of cyclooctanediol and 1b (Sch. 2)
was stirred in 60% AcOH, as well as 0.1 M H2SO4 in MeOH to observe
clean recovery of 1b whereas the isopropylidene derivative was
hydrolyzed back to 1a.
CONCLUSION
We have demonstrated the unique robustness of phenyl sulfonyl
acetaldehyde diethyl acetal as a protective reagent for 1,2-diols which
is not only stable to harsh basic conditions but also maintains its

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898
Chandrasekhar, Srinivas, and Srihari
Table 2.
Protection Deprotection
yield (%)a
Entry
1
Diol substrate
Protected diol
yield (%)a
71
75
2
74
84
3
4
78
87
74
73
5
6
75
79
74
76
7
82
86
8
9
76
69
72
79
10
85
76
aYields calculated after column chromatography of the products.

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New Robust 1,2-Diol Protective Group
899
Scheme 2.
resilience in an acidic environment(60% AcOH, 0.1 M H SO4, MeOH;
2
6 M HCl, THF). This protocol would find applications in polyol
chemistry.
EXPERIMENTAL SECTION
General Methods: Crude products were purified by column chroma-
tography on silica gel of 60–120 mesh. 1H NMR were obtained in CDCl3 at
200 MHz. Chemical shifts are given in ppm with respect to internal TMS,
and J values are quoted in Hz. Infrared spectra were obtained neat, and
only the most significant absorptions in cmꢀ1 are indicated. Toluene was
distilled over P2O5 and stored over sodium. All reactions were carried out
under an atmosphere of nitrogen using dry glassware.
Procedure for the preparation of Reagent: An equimolar mixture of
sodium phenylsulphinate (5 g, 30.4 mmol) and bromoacetaldehyde
diethyl acetal (5.97 g, 30.4 mmol) in dry DMF (25 mL) was stirred
at70 ꢁC for 12 h. The reaction mixture was extracted with ether
(3 ꢂ 50 mL). The organic layer was washed with water (10 mL), brine
(10 mL) and dried over anhydrous Na2SO4. The volatiles were removed
on a rotary evaporator to give the crude reagent. Purification by
chromatography (silica gel, n-hexane:ethyl acetate, 30:1) to yield colour-
less liquid (6.2 g, 79%).1H NMR (CDCl3): ꢀ 7.85 (d, 2H, J ¼ 5.7 Hz),
7.65–7.45 (m, 3H), 4.87 (t, 1H, J ¼ 4.5 Hz), 3.50–3.30 (m, 6H), 1.00
(t, 6H, J ¼ 6.8 Hz). ꢀ 13C NMR (CDCl3): ꢀ 139.96, 133.22, 128.67,
127.82, 97.30, 61.73, 59.47, 14.58. MS (Mꢀ): 258.
General Procedure for the protection of diol as described for 1a: To
diol 1a (1 g, 6.9 mmol) in dry toluene (15 mL) was added phenyl sulfonyl
acetaldehyde diethyl acetal (1.79 g, 6.9 mmol), AmberlystÕ15 (0.01 g), and
refluxed for 12 h. The resin was then filtered off and the volatiles removed
under reduced pressure. The residue was dissolved in ethyl acetate (50 mL)
and washed with water (25 mL), brine (25 mL) and dried over anhydrous

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900
Chandrasekhar, Srinivas, and Srihari
Na2SO4. The volatiles were removed in vacuo to afford crude 1b.
Purification by silica gel chromatography (hexane:ethylacetate, 15:1),
yielded 1b (1.323 g, 71%).
General procedure for deprotection of protected diol as described for 1b
using Lithium amide: To a stirred solution of lithium amide (0.1 g,
4.3 mmol) in liq. NH3 (10 mL), was added 1b (0.5 g, 1.6 mmol) in
dry THF (10 mL) and stirred for 10 min after which the excess
of liq NH3 was allowed to evaporate. The liberated diol was isolated
by quenching with saturated NH4Cl solution and extracting with diethyl
ether. The organic layer was washed with water (5 mL), brine (5 mL) and
dried over anhydrous Na2SO4. The volatiles were removed under vacuum
to afford parent diol 1a (0.174 g, 75%).
General procedure for deprotection of protected diol using nBuLi: To
ꢁ
a stirred solution of 1b (0.5 g, 1.6 mmol) in dry THF (10 mL) at0 C was
added butyl lithium 2.5 M in Hexane (1.62 mL, 4.03 mmol) allowing the
reaction mixture to warm to room temperature and stirred for 2 h. After
monitoring by TLC the diol was isolated by quenching with saturated
NH4Cl solution and extracting with diethyl ether. The organic layer
was washed with water (5 mL), brine (5 mL) and dried over anhydrous
Na2SO4. The volatiles were removed under vacuum to afford parent
diol 1a (0.162 g, 70%).
1
Compound 1b: Colourless liquid. H NMR (CDCl3): ꢀ 7.90 (d, 2H,
J ¼ 7.6 Hz), 7.65–7.45 (m, 3H), 5.3(t, 1H, J ¼ 5.1 Hz), 3.75–3.55(m, 2H),
3.35(d, 2H, J ¼ 5.1 Hz), 1.85–1.65(m, 4H), 1.45–1.10(m, 8H); IR (neat):
1083, 1130, 1309 cmꢀ1. MS (Mþ): 310; HRMS (Mþþ1) Calcd. for
C16H22SO4: 311.1317 found 311.1318.
1
2b: Colourless liquid. H NMR (CDCl3): ꢀ 7.90 (d, 2H, J ¼ 7.0 Hz),
7.65–7.47 (m, 3H), 7.0–6.85 (m, 2H), 6.77–6.67 (m, 2H), 5.35 (t, 1H,
J ¼ 5.8 Hz), 4.40–4.27 (m, 1H), 4.0–3.68 (m, 4H), 3.40 (d, 2H,
J ¼ 5.8 Hz); IR (neat): 1041, 1083, 1134, 1210, 1506 cmꢀ1. MS (Mþ):
352; HRMS (Mþþ1) Calcd. for C17H17SO5F: 353.0858 found 353.0857.
1
3b: Colourless liquid. H NMR (CDCl3): ꢀ 7.90 (d, 2H, J ¼ 6.9 Hz),
7.65–7.45 (m, 3H), 7.35–7.15 (m, 5H), 5.35 (t, 1H, J ¼ 5.5 Hz), 4.40
(s, 2H), 4.20–3.65 (m, 5H), 3.40 (d, 2H, J ¼ 5.5 Hz); IR (neat): 1151,
1249, 1309, 1450, 2927 cmꢀ1. MS (Mþ): 348; HRMS (Mþþ1) Calcd.
for C18H20SO5: 349.1109 found 349.1110.
4b: Colourless viscous liquid. 1H NMR (CDCl3): ꢀ 7.95 (d, 2H,
J ¼ 7.0 Hz), 7.70–7.50 (m, 3H), 7.35–7.25 (m, 5H), 5.35 (t, 1H,
J ¼ 4.7 Hz), 4.50 (s, 2H), 4.02–3.85 (m, 2H), 3.50–3.34 (m, 5H),
1.65–1.15 (m, 16H); IR (neat): 1083.8, 1126, 1152, 1310, 2930 cmꢀ1
.
MS (Mþ): 460; HRMS (Mþþ1) Calcd. for C26H36SO5: 461.2361
found 461.2360.

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New Robust 1,2-Diol Protective Group
901
1
5b: Colourless liquid. H NMR (CDCl3): ꢀ 7.90 (d, 2H, J ¼ 8.1 Hz),
7.70–7.45 (m, 3H), 5.30 (t, 1H, J ¼ 4.6 Hz), 4.55 (t, 1H, J ¼ 2.3 Hz),
3.95–3.70 (m, 7H), 3.40 (d, 2H, J ¼ 4.6 Hz), 1.65–1.15 (m, 22H); IR
(neat): 1079, 1132, 125, 1308, 1438, 2926 cmꢀ1. MS (Mþ): 454.
6b: Colourless viscous liquid. 1H NMR (CDCl3): ꢀ 7.95 (d, 2H,
J ¼ 7.5 Hz), 7.70–7.50 (m, 3H), 7.30–7.17 (m, 2H), 6.9–6.8 (m, 2H),
5.30 (t, 1H, J ¼ 5.0 Hz), 4.40 (s, 2H), 4.10–3.80 (m, 5H), 3.80 (s, 3H),
3.40 (d, 2H, J ¼ 5.0 Hz), 1.65–1.15 (m, 16H); IR (neat): 1085, 1150, 1252,
1312, 1448, 2922 cmꢀ1. MS (Mþ): 490.
1
7b: Colourless liquid. H NMR (CDCl3): ꢀ 7.95 (d, 2H, J ¼ 7.6 Hz),
7.65–7.45 (m, 3H), 7.35–7.15 (m, 3H), 7.12–7.0 (m, 2H), 5.45 (t, 1H,
J ¼ 5.1 Hz), 4.95 (t, 1H, J ¼ 7.6 Hz), 4.10 (d, 2H, J ¼ 5.1 Hz), 3.5 (d,
2H, J ¼ 6.2 Hz); IR (neat): 1083, 1150, 1310, 2928 cmꢀ1. MS (Mþ): 304.
1
8b: Colourless liquid. H NMR (CDCl3): ꢀ 7.90 (d, 2H, J ¼ 7.0 Hz),
7.70–7.50 (m, 3H), 5.55 (s, 2H), 5.20 (t, 1H, J ¼ 4.7 Hz), 3.60 (d, 2H,
J ¼ 4.7 Hz), 3.45 (d, 2H, J ¼ 4.7 Hz), 3.35 (d, 2H, J ¼ 4.7 Hz), 2.15–1.85
(m, 6H); IR (neat): 997, 1083, 1131, 1149, 1308, 2901 cmꢀ1. MS (Mþ):
308; HRMS (Mþþ1) Calcd. for C16H20SO4: 309.1160 found 309.1160.
9b: Colourless viscous liquid. 1H NMR (CDCl3): ꢀ 7.95 (d, 2H,
J ¼ 7.0 Hz), 7.65–7.45 (m, 3H), 7.40–7.15 (m, 10H), 5.70 (t, 1H,
J ¼ 4.7 Hz), 4.85 (d, 1H, J ¼ 8.2 Hz), 4.55 (d, 2H, J ¼ 7.0 Hz), 4.02–3.82
(m, 1H), 3.65 (d, 2H, J ¼ 4.7 Hz), 3.55 (d, 2H, J ¼ 4.7 Hz); IR (neat):
1024, 1083, 1151, 1309, 2929 cmꢀ1. MS (Mþ): 425; HRMS (Mþ) Calcd.
for C24H24SO5: 425.1422 found 425.1421.
10b: Colourless liquid. 1H NMR (CDCl3): ꢀ 7.90 (d, 2H, J ¼ 7.1 Hz),
7.65–7.45 (m, 3H), 7.35–7.15 (m, 5H), 5.40 (t, 1H, J ¼ 4.8 Hz), 4.40 (s,
2H), 3.90 (s, 2H), 3.50 (s, 2H), 3.35 (d, 2H, J ¼ 4.8 Hz), 1.25 (s, 3H); IR
(neat): 1043, 1083, 1123, 1150, 1309 cmꢀ1. MS (Mþ): 362.
ACKNOWLEDGMENT
Two of us (ChS., PSH) thank CSIR, New Delhi, for financial
assistance.
REFERENCES
1. (a) Greene, T.W.; Wuts, P.G.M. In Protective Groups in Organic
Synthesis; Wiley: N.Y. 1991, 2nd Ed.; (b) Kocienski, P.J. Protecting
Groups; Thieme: Stuttgart, 1994.

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902
Chandrasekhar, Srinivas, and Srihari
2. Chery, F.; Rollin, P.; De Lucchi, O.; Cossu, S. Tetrahedron Lett.
2000, 41, 2357.
3. Lewbart, M.L.; Schneider, J.J. J. Org. Chem. 1969, 34, 3505.
4. See experimental section for the preparation of reagent.
5. Furniss, B.S.; Hannaford, A.J.; Smith, P.W.G.; Tatchell, A.R.
Vogel’s Text book of Practical Organic Chemistry; 5th Ed.; 1989, 888.
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Received in the USA February 24, 2002