A mild, room-temperature protection of ketones and aldehydes as 1,3-dioxolanes under basic conditions

Article abstract of DOI:10.1055/s-0032-1317529

Protection of ketones or aldehydes as 1,3-dioxolane derivatives proceeds within minutes at room temperature in the presence of N- hydroxybenzenesulfonamide, its O-benzyl derivative, or the tosyl analogue, in the absence of strong protonic acids, and in the presence of base (Et). Acid-sensitive groups such as O-THP, O-TBS, or N-Boc are unaffected. Copyright

Full text of DOI:10.1055/s-0032-1317529

LETTER
▌2773
lAetteMr ild, Room-Temperature Protection of Ketones and Aldehydes as
1,3-Dioxolanes under Basic Conditions
Mild Protection of Ketones and Aldehydes
Alfred Hassner,* Chennakesava Reddy Bandi, Sharad Panchgalle
Department of Chemistry, Bar-Ilan University, Ramat-Gan 52900, Israel
Fax +972(3)7384053; E-mail: hassna@biu.ac.il
Received: 20.09.2012; Accepted after revision: 12.10.2012
we discovered some time ago13 that 1a apparently pro-
motes the formation of dimethyl acetals from aldehydes
and methanol under mild conditions. Neither benzenesul-
fonamide nor phenol (which has a similar pKa to that of
Abstract: Protection of ketones or aldehydes as 1,3-dioxolane de-
rivatives proceeds within minutes at room temperature in the pres-
ence of N-hydroxybenzenesulfonamide, its O-benzyl derivative, or
the tosyl analogue, in the absence of strong protonic acids, and in
the presence of base (Et3N). Acid-sensitive groups such as O-THP, 1a) were effective. However, conversion of benzyl methyl
O-TBS, or N-Boc are unaffected.
ketone into its dimethylketal proceeded in only 33% yield.
Key words: ketals, protecting groups, synthetic methods, ketones,
aldehydes
SO2NHOH
SO2NHOBn
SO2NHOH
Formation of 1,3-dioxolanes is one of the most widely
used methods of protection of ketones or aldehydes.
These cyclic ketals are stable under most alkaline reaction
conditions, as well as to many oxidizing and reducing
agents.1 Furthermore, they can be readily reconverted into
ketones by treatment with aqueous acids. A common way
to achieve the latter is reaction in acetone–water in the
presence of an acid catalyst.
1c
1b
1a
Figure 1 Structures of sulfonamide catalysts 1a–c
In view of the fact that the protection of aldehydes and ke-
tones 2 as dioxolanes 3 is a commonly used reaction that
often requires heating in the presence of strong acids, we
decided to re-examine the effectiveness of 1a as a promot-
er in such reactions. We now report that 1a promotes con-
version of ketones and aldehydes into their 1,3-dioxolanes
in the absence of strong protonic acids and in the presence
of triethylamine at room temperature, within minutes, in
good yield (Scheme 1).
1,3-Dioxolanes are usually prepared from ketones and
1,2-ethanediol in the presence of a strong protonic acid
(such as p-TsOH)2a,2b,2e or Lewis acid (such as BF3,2c
2d
TiCl4 ) catalyst, often with a Dean–Stark trap and azeo-
tropic removal of water to preclude hydrolysis of the
product; sometimes the reaction requires high tempera-
ture, long reaction time, or tedious work up. Usually it is
desirable to avoid the presence of strong acid conditions
during the protection step, not only to prevent ketal hydro-
lysis but also because of the presence of other acid sensi-
tive groups in the molecule such as THP, Boc, or silyl
derivatives. In this context, many mild acid catalysts that
have been reported, including oxalic acid in acetonitrile at
room temperature,3 TsOH-pyridine under reflux,4 acidic
ion-exchange resin5a or clay,5b acidic ionic liquids,6 metal
derivatives such as tin oxide,7 copper(II) salts,8 scandium
triflate with TMSOTf,9 and ZrO2 supported on tungsten
polyacids.10 Furthermore, 1,3-dioxolanes have been pre-
pared by using 1,2-(trimethylsiloxy)ethane with
TMSOTf11 or Bi(OTf)3,12a or with iodine.12b Clearly, neu-
tral or basic conditions would be desirable for ketone/al-
dehyde protection.
N-hydroxybenzenesulfonamide (1a)
O
Et3N
+
O
O
HO
OH
R1
R2
R1
R2
10 min, r.t.
80–90%
2
4
3
Scheme 1
First, we used commercially available 1a as a promoter
and found that even with one equivalent of 1a, the yields
of dioxolane were usually low. When we examined com-
mercial 1a (Pilloti’s acid) in detail, as well as the product
obtained on reaction of PhSO2Cl with NH2OH, we found
it to be composed mainly of a mixture of authentic 1a and
a dimeric salt, as was reported earlier.14 Although both of
these compounds promoted dioxolane formation, the
yields were very low (<30%). As long as the medium re-
mains acidic, the presence of water can reverse the forma-
tion of dioxolane, which is the reason that azeotropic
removal of water is often employed.
In the process of examining the reaction of N-hydroxy-
benzenesulfonamide (1a; Figure 1) with aldehydes in the
presence of base leading to synthesis of hydroxamic acids,
As a plausible pathway for the role of 1a in formation of
3, we considered the pathway shown in Scheme 2, in
which nucleophilic attack of the nitrogen of 1a at the C=O
group leads to formation of a very reactive iminium spe-
cies 7, which rapidly captures the alcohol or diol, ulti-
SYNLETT 2012, 23, 2773–2776
Advanced online publication: 13.11.2012
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0032-1317529; Art ID: ST-2012-B0225-L
© Georg Thieme Verlag Stuttgart · New York

2774
A. Hassner et al.
LETTER
mately leading to the ketal 3 through the conventional alytic amounts (0.1–0.4 equiv) led to much reduced
mechanism. It is known that N–O and N–N compounds yields. Because the promoter 1a is regenerated in step 8
are efficient nucleophiles due to the so-called α-effect.15 → 9 Scheme 2, the reason that 1a is not effective as a cat-
Hence, the first step in the formation of 3 must involve at- alyst is apparently due to a process in which 1a is deplet-
tack of 1a on the carbonyl group of 2. To enhance the nu- ed. In fact, it is known17 that 1a slowly decomposes,
cleophilicity of 1a as well as that of the diol, we added especially in the presence of base, to benzenesulfinic acid
triethylamine, which, by abstracting the acidic H from 1a anions. Indeed, we found that only about 30% of 1a can
in a fast step, should enhance its attack on the carbonyl be recovered from the reaction shown in Scheme 1. Fur-
group of 2. The presence of triethylamine should also aid thermore, reaction of aldehydes and ketones with 1a in the
in the equilibrium formation of alcoholate anion from 4 presence of NaOH is known to lead to hydroxamic acids
and prevent acid-catalyzed hydrolysis of 3 by generated 10 by rearrangement,13,18 thus depleting 1a, albeit in a
water. The presence of base improved the yield of dioxo- slower reaction (Scheme 3). An advantage of using trieth-
lane manyfold, with triethylamine being more effective ylamine in the reaction depicted in Scheme 2 is that, un-
+
than 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) or diiso- like NaOH, it can still act via HNEt3 as a proton donor to
+
propylethylamine. One equivalent of triethylamine was 6, favoring formation of iminium species 7. HNEt3 may
optimal.
also facilitate elimination of 1a from 8 to produce inter-
mediate 9.
For a promoter such as 1a to be effective, it has to incor-
porate two essential features: It must contain a good N-nu-
cleophile that can provide a reactive iminium species 7,
and it must possess a good leaving group enabling forma-
tion of an oxonium species 9 necessary for further reac-
tion (preferably intramolecular) with the second ROH.
The presence of the ArSO2 group is important because it
provides a better leaving group in the subsequent step by
stabilizing a negative charge on the nitrogen. Indeed, p-
TolSO2NHOH (1c; Figure 1), which we prepared accord-
ing to the literature,16 proved to be just as effective as 1a
for dioxolane formation (e.g., from cyclohexanone and
acetophenone). However, N-benzylsulfonamide 5 (Figure
2), a mild acid that is structurally closely related, but lack-
ing the N-OR moiety, was completely inactive in promot-
ing ketalization, indicating that it was not the acidity of
the reagent that was essential but the presence of the
PhSO2N-O grouping.
O
_
O
R1
SO2Ph
O
R1
R1
NaOH
OH
N
N
+
1a
–
– PhSO2
10
R2
R2
R2
OH
2
Scheme 3
Convenient work up by washing and evaporation led to
essentially NMR-pure dioxolanes 3 in good yield. The
yields of pure dioxolanes after chromatography on alumi-
na were in the order of 80–90% for a variety of ketones
and aldehydes (Table 1).
Even hindered ketones such as diisopropyl ketone gave
good results. Functional groups such as OTHP, N-Boc,
methyl (ethyl) ester, and even O-TBS-phenol, which are
sensitive to common acids, remained unaffected (see Ta-
ble 1). Azeotropic removal of water was not necessary.
Dioxolane formation took place within minutes even with
aromatic aldehydes and ketones as well as with the elec-
tron-poor 4-nitrobenzaldehyde, in contrast to reported re-
actions requiring hours,12 especially with electron-poor
aldehydes or ketones.
H+-NEt3
SO2Ph
+
N
R1
O
_
OH
R2
R1
O-H
_
SO2Ph
N
R1
4
Et3N
N
SO2Ph
O
R2
R2
O-H
OH
2
6
7
OH
Et3N
To establish whether hydrogen bonding between the hy-
droxyl group of 1a and the ketone played a major role (see
Figure 2), we also examined the O-benzyl derivative 1b.
In fact, 1b was just as effective as a ketalization catalyst
as 1a (essentially the same yields of 3 from cyclohexa-
none), indicating that the presence of a hydroxyl group
was not essential.
1a
H+-NEt3
SO2Ph
+O
N
R1
R1
R2
OH
O
O
R1
R2
O
R2
– 1a
_
O
HO
3
9
8
In conclusion, we have developed a method that allows
protection of aldehydes or ketones as 1,3-dioxolanes in
Scheme 2 Plausible mechanism
Thus, we settled on the optimal conditions for dioxolane
formation: aldehyde or ketone (1 equiv), ethylene glycol
(2 equiv), 1a (commercial, without purification; 0.7
equiv) and triethylamine (1 equiv) in CH2Cl2, reaction
time 10 min at room temperature.
Ph
H
R1
O
O
SO2Ph
SO2Ph
N
N
R2
O
R3
H
H
H
5
Although 0.7 equiv of 1a worked very efficiently and 1.0
Figure 2 Possible hydrogen bonding between the hydroxyl group of
equiv of 1a improved the yield of 3 only marginally, cat- 1a and the ketone
Synlett 2012, 23, 2773–2776
© Georg Thieme Verlag Stuttgart · New York

LETTER
Mild Protection of Ketones and Aldehydes
2775
Table 1 Reaction of Ketone or Aldehyde 2 with Ethylene Glycol in
the Presence of 1a and Triethylaminea (continued)
the presence of triethylamine as base, proceeding within
minutes at room temperature and using 1a (or its O-benzyl
derivative 1b or tosyl analogue 1c) as promoter.19
Entry Ketone or aldehyde 2
1,3-Dioxolane 3
Yield (%)
Table 1 Reaction of Ketone or Aldehyde 2 with Ethylene Glycol in
the Presence of 1a and Triethylaminea
H
O
O
13
81
O
Entry Ketone or aldehyde 2
1,3-Dioxolane 3
Yield (%)
O
O
O
H
O
O
O
O
O
O
O
1
84
O
O
14
86
O
O
O
O
2
3
4
81
90
83
O
H
15
16
87
82
TBSO
TBSO
O
O
O
O
O
H
H
O
O
THPO
THPO
O
O
H
H
O
O
H
H
17
18
87
82
O
O
TBDPSO
TBDPSO
O
H
5
80
O
O
O
Cl
Cl
H
H
O
O
O
H
6
7
83
80
89
81
89
a Reaction conditions: 2 (1 equiv), ethylene glycol (2 equiv), 1a (0.7
equiv), Et3N (1 equiv), r.t., 10 min.
O2N
O2N
b Reaction performed on a 3 mmol scale.
O
O
O
Acknowledgment
O
O
O
Support of this research by the Marcus Center for Medicinal and
Pharmaceutical Chemistry at Bar-Ilan University is gratefully ack-
nowledged.
8
O
O
References and Notes
O
9
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2005.
O
O
O
10
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O
82b
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O
H
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 2773–2776

2776
A. Hassner et al.
LETTER
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(19) Protection of 2 as 1,3-Dioxolane 3 (Table 1); General
Procedure: A solution of ketone or aldehyde 2 (1 mmol), 1a
(commercial, 121 mg, 0.7 mmol), and ethylene glycol (124
mg, 2 mmol) in CH2Cl2 (4 mL) was stirred at r.t. for 10 min.
The solution was washed with water and brine, and dried
over anhydrous MgSO4 [washing with 2 M NaOH (2 × 10
mL) followed by acidification led to only partial recovery of
1a]. Concentration under vacuum afforded 3. Flash
chromatography (basic alumina; EtOAc–hexane, 1:9) gave
pure 3 in 80–90% yield (Table 1). The analytical data of 1,3-
dioxolanes 3 were in good agreement with those of authentic
compounds.
Synlett 2012, 23, 2773–2776
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