Method for the selective formation of dimethyl acetals in the presence of hydroxylamine

Article abstract of DOI:10.1080/00397911.2010.523156

An inexpensive and mild method for the formation of dimethyl acetals from the corresponding aldehydes is achieved using hydroxylamine and methanol under neutral conditions at room temperature. Notably, the reaction is selective for aldehydes in the presence of ketones, rendering this an example of a chemoselective acetalization. For saturated, sterically accessible aldehydes, catalytic amounts of hydroxylamine may be employed to attain the corresponding dimethyl acetal as the sole product in good to excellent yield. Unsaturated and hindered aldehydes required stoichiometric amounts of hydroxylamine but provided dimethyl acetals as the major product in typically excellent yield. In some cases, the corresponding oxime was also observed but may be separated from the acetal by flash column chromatography or distillation. The involvement of an intermediate oxime compound is postulated. Supplemental materials are available for this article. Go to the publisher's online edition of Synthetic Communications to view the free supplemental file. Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397911.2010.523156

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Method for the Selective Formation of
Dimethyl Acetals in the Presence of
Hydroxylamine
Ky J. Mickelsen a , Chelsea M. Tajc a , Kevin R. Greenwood a & Cindy
C. Browder a
a Department of Chemistry and Biochemistry , Northern Arizona
University , Flagstaff , Arizona , USA
Accepted author version posted online: 26 Jul 2011.Published
online: 14 Sep 2011.
To cite this article: Ky J. Mickelsen , Chelsea M. Tajc , Kevin R. Greenwood & Cindy C. Browder
(2012) Method for the Selective Formation of Dimethyl Acetals in the Presence of Hydroxylamine,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 42:2, 186-194, DOI: 10.1080/00397911.2010.523156
To link to this article: http://dx.doi.org/10.1080/00397911.2010.523156
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Synthetic Communications1, 42: 186–194, 2012
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2010.523156
METHOD FOR THE SELECTIVE FORMATION OF
DIMETHYL ACETALS IN THE PRESENCE OF
HYDROXYLAMINE
Ky J. Mickelsen, Chelsea M. Tajc, Kevin R. Greenwood, and
Cindy C. Browder
Department of Chemistry and Biochemistry, Northern Arizona University,
Flagstaff, Arizona, USA
GRAPHICAL ABSTRACT
Abstract An inexpensive and mild method for the formation of dimethyl acetals from the
corresponding aldehydes is achieved using hydroxylamine and methanol under neutral con-
ditions at room temperature. Notably, the reaction is selective for aldehydes in the presence
of ketones, rendering this an example of a chemoselective acetalization. For saturated, steri-
cally accessible aldehydes, catalytic amounts of hydroxylamine may be employed to attain
the corresponding dimethyl acetal as the sole product in good to excellent yield. Unsatu-
rated and hindered aldehydes required stoichiometric amounts of hydroxylamine but pro-
vided dimethyl acetals as the major product in typically excellent yield. In some cases,
the corresponding oxime was also observed but may be separated from the acetal by flash
column chromatography or distillation. The involvement of an intermediate oxime
compound is postulated.
Supplemental materials are available for this article. Go to the publisher’s online edition
of Synthetic Communications1 to view the free supplemental file.
Keywords Acetal; hydroxylamine; oxime; selective acetalization
INTRODUCTION
Acetals are among the most common protecting groups for the aldehyde func-
tionality and are typically formed using Lewis or Brønsted acids.[1] The availability
of basic or neutral acetalization conditions is desirable, as such conditions provide
an improved range of functional group tolerance. To that end, a number of reports
describe basic or otherwise very mild acetalization conditions,[2] many of which are
Received June 18, 2010.
Address correspondence to Cindy C. Browder, Department of Chemistry and Biochemistry,
Northern Arizona University, P.O. Box 5698, Flagstaff, AZ 86011, USA. E-mail: cindy.browder@nau.edu
186

SYNTHESIS OF DIMETHYL ACETALS USING HYDROXYLAMINE
187
selective for aldehydes in the presence of ketones.[3] However, few are general in
their substrate scope, and virtually none employ common off-the-shelf, inexpensive
reagents.
We report herein an acetalization procedure that is (a) chemically neutral, (b)
selective for aldehydes in the presence of ketones, and (c) catalytic in many cases.
Hydroxylamine, which is inexpensive and widely commercially available as the
hydrochloride salt, is the putative reagent that facilitates this reaction. In addition
to demonstrating the scope of this reaction, we propose that an intermediate oxime
is responsible for the selectivity of this process.
RESULTS
In the process of synthesizing oximes from various carbonyls in our laboratory,
we were successful in generating ketoximes from saturated and unsaturated ketones
using 1.5 equivalents each of hydroxylamine hydrochloride and lithium carbonate in
methanol. However, we noted that aldehydes 1 resulted in the corresponding
dimethyl acetals 2 under the intended hydroxylamine condensation conditions.
While a similar reaction was previously observed by Sasaki and Yoshioka, only vinyl
and aryl aldehydes were described in that report.[4] We have found the reaction to be
far more general under our conditions, and several examples are provided in Table 1.
While acetals were the major product for a number of the aldehydes we screened, in
substrates containing a,b-unsaturated aldehydes (entries 6 and 7), a mixture of acetal
2 and oxime 3 was observed.
Intrigued by this discovery, we explored the reaction further. Specifically, we
were curious as to the mechanism of this reaction and why aldehydes behaved
remarkably differently from ketones. Suspecting an intermediate oxime was respon-
sible for this process, we proceeded to explore the effect of variations of the amounts
of reagents on the reaction outcome. As shown in Table 2, entry 1, benzaldehyde
treated with 1.5 equivalents each of hydroxylamine hydrochloride and lithium car-
bonate using methanol as the solvent resulted in benzaldehyde dimethyl acetal 2a
as the sole product in good yields. Similarly, use of 0.1 mol equivalent of hydroxyla-
mine from a 1:1 ratio of hydroxylamine hydrochloride and lithium carbonate in cata-
lytic amounts also led acetal 2a as the only observed product (entry 2). We quickly
found that longer reaction times were required for the catalytic reaction at room
temperature, with most reactions ceasing to progress after 18–20 h. When hydroxy-
lamine hydrochloride was omitted from the reaction in entry 3, unreacted aldehyde
dominated the product mixture. Omission of the base in entry 4 resulted in only
recovered starting aldehyde. Interestingly, stirring the aldehyde in methanol alone
(entry 5) provided a 1:1 mixture of aldehyde and acetal.
Additional studies included using ethanol in place of methanol as the solvent,
which provided poor yields and incomplete conversion of aldehydes to the corre-
sponding diethyl acetal. Ketones, including 3-pentanone, 4-phenyl-3-butan-2-one,
and 4-phenyl-3-buten-2-one, provided only recovered starting materials in catalytic
reaction conditions. Furthermore, we found that sodium hydroxide was a viable base
for this reaction.
Interested in the potential for the development of a catalytic reaction, as
indicated by the results of Table 2, entry 2, we explored the scope of the reaction with

188
K. J. MICKELSEN ET AL.
Table 1. Hydroxylamine condensation of aldehydes in methanol results in formation of dimethyl acetals
Entry
1
Substrate
Yield 2 (%)
Yield 3 (%)
80
0
2
47
0
3
4
5
64
50
52
0
0
0
6
7
50
45
17
28
8
9
25
12
43
38
a range of aldehyde substrates. Although Hassner previously reported a related pro-
cess employing catalytic amounts of N-phenyl hydroxylamine for the preparation of
acetals or ketals,[5] our conditions have the potential to be selective for aldehydes in
the presence of ketones. As shown in Table 3, a number of aldehydes were treated
with 0.1 mol equivalents each of hydroxylamine hydrochloride and sodium hydrox-
ide (powder). The catalytic acetalization reaction was most successful for saturated

SYNTHESIS OF DIMETHYL ACETALS USING HYDROXYLAMINE
189
Table 2. Examination of conditions for formation of dimethyl acetal
Entry
H2NOH . HCl (equiv.)
Li2CO3 (equiv.)
Time (h)
Ratio 1a:2a:3a
Yield (%)
1
2
3
4
5
1.5
0.1
0
1.5
0.1
0.1
0
0.5
18
18
18
18
0:1:0
0:1:0
4:1:0
1:0:0
1:1:0
78–83
70
50 (by mass)
50 (by mass)
90 (by mass)
0.1
0
0
Table 3. Catalytic amounts of hydroxylamine allow for preferential formation of dimethyl acetals
Entry
Substrate
Yield 2 (%)
1
70
2
3
4
68
57
88
5
6
76
99
7
99

190
K. J. MICKELSEN ET AL.
and unhindered aldehydes; other aldehydes (for example, substrates 1b, 1f, 1g, and
1h) resulted in copious amounts of unreacted aldehyde dominating the product mix-
ture. However, for the substrates shown in Table 3, entries 1–4 had improved yields
under catalytic reaction conditions relative to the stoichiometric conditions reported
in Table 1. Additional substrates shown in entries 5–7 also provided acetals in
excellent yields under catalytic conditions.
In our preliminary studies, the catalytic reaction provided acetals from alde-
hydes and only recovered starting material for ketones. Hence, the potential for
development of a chemoselective acetalization was apparent. A competition experi-
ment was carried out to demonstrate the selectivity of the catalytic reaction, wherein
a 1:1 mixture of aldehyde 1m and related ketone 1n were treated with 0.1 equivalents
each of hydroxylamine hydrochloride and sodium hydroxide (Fig. 1a). For this
1
experiment, two H NMR spectra were obtained. The spectrum in Fig. 1b was
obtained for the reaction mixture prior to the addition of hydroxylamine hydro-
chloride and sodium hydroxide and shows the 1:1 mixture of aldehyde and ketone
at the start of the reaction. The spectrum in Fig. 1c was obtained for the crude
Figure 1. (a) Competition reaction equation. (b) 1H NMR spectrum of starting reaction mixture. (c) 1H
NMR spectrum of crude product. The starting aldehyde was consumed completely and converted to
the corresponding dimethyl acetal. The ketone remains in the reaction mixture unchanged.

SYNTHESIS OF DIMETHYL ACETALS USING HYDROXYLAMINE
191
product mixture following workup. The crude product mixture contained a 1:1 mix-
ture of acetal 2m and recovered 1n. As shown in these spectra, the aldehyde was con-
sumed in the reaction process and the ketone remained unreacted. These results
indicate that the catalytic variant of this reaction will be selective for aldehydes
in the presence of ketones, which is an improvement over previous
hydroxylamine-induced acetalization processes.[4,5]
DISCUSSION
From the exploration of reaction conditions summarized in Table 2, it
appeared that free hydroxylamine was responsible for the clean conversion of alde-
hydes to dimethyl acetals. Because the nonnucleophilic hydrochloride salt was inef-
ficient in this conversion and base alone resulted in no reaction, it was logical to
conclude that the nucleophilic hydroxylamine played a key role in the reaction.
We propose the mechanism outlined in Scheme 1 to explain both the stoichiometric
and catalytic versions of this acetalization. The process includes formation of an oxi-
minium intermediate III that is either deprotonated to form oximes 3 or behaves as
an electrophile to undergo further reaction, resulting in acetals 2.
Logically, reactions of oximes should mechanistically parallel those of imines.
There are a variety of reactions with intermediate nucleophilic imines including the
Mannich reaction, the aza-Henry reaction, the Strecker synthesis, the Petasis reac-
tion, and the Kabachnik–Fields reaction. While oximes are occasionally used as syn-
thetic intermediates, their occurrence in the literature is relatively limited. The
Griesbaum coozonolysis employs O-methyl oximes as dipolarophiles in a 1,3-dipolar
cycloaddition with ozone,[6] and Nanjundaswamy and Pasha have described the
preparation of hydrazones from oximes rather than the usual carbonyl precursors.[7]
Scheme 1. Proposed mechanism for hydroxylamine-induced acetalization.

192
K. J. MICKELSEN ET AL.
Likewise, invocation of oxime reactive intermediates is rare, with only Hassner et al.’s
1970 report suggesting such a process.[5]
It is well understood that oximes are less electrophilic relative to their imine
counterparts, as is evidenced by retarded hydrolysis rates for oximes compared to
imines.[8] This difference can be attributed to the a-effect, wherein the N-oxygen
donates electron density to the nitrogen and increases the highest occupied molecular
orbital (HOMO) energy relative to imines. Consequently, the oxime nitrogen has
increased nucleophilicity relative to an imine nitrogen. This corollary to the a effect
is key to our proposed mechanism (Scheme 1), wherein oximinium intermediate III is
possible because of the basicity of the oxime nitrogen. A comparable intermediate
would not likely form in an imine-mediated pathway. This crucial intermediate is
rendered electrophilic, which facilitates the addition of methanol. Following this
addition, formation of the acetal is favorable. Notably, this mechanism parallels that
proposed by Hassner et al., where N-phenyl hydroxylamine was found to act as a
catalyst for acetalziation.[5]
The mechanism shown in Scheme 1 also explains the formation of oximes
rather than dimethyl ketals when ketones are subjected to the same reaction con-
ditions that generate acetals from aldehydes. Ketoximiniums analogous to III likely
experience steric hinderance to nucleophilic addition, precluding formation of a
tetrahedral intermediate similar to IV. Hence deprotonation is a more viable path-
way, and oximation products 3 dominate. Correspondingly, sterically hindered
aldehydes will generate some amount of oxime product.
The limitations of the catalytic version of this reaction also become evident
within this mechanistic scheme. For aldehydes with decreased electrophilicity (such
as a,b-unstaturated aldehydes 1f–g or aldehyde 1h), intermediate III is likely to be
deprotonated to form product 3 rather than undergo nucleophilic addition and
generate intermediate IV.
SUMMARY
The results reported herein demonstrate a new method for generation of
dimethyl acetals in the presence of ketones, which is selective in its catalytic form.
Inexpensive and widely available hydroxylamine is a key reagent for this reaction,
and the mechanism likely proceeds via an oxime intermediate. Studies are ongoing
in our laboratory to expand the scope of the catalytic version of this reaction and
further probe the mechanism of this process.
EXPERIMENTAL
Stoichiometric Acetalization Procedure
Hydroxylamine hydrochloride (2.25 mmol) and lithium carbonate (2.25 mmol)
were added, in that order, to a mixture of the carbonyl compound (1.5 mmol) in
MeOH (HPLC grade, 5 mL). The reaction was stirred for 30 min, and then 3 mL
of saturated NH4Cl and 3 mL of H2O were added. The mixture was extracted with
diethyl ether (3 ꢀ 10 mL); the combined organic layers were washed with brine
(10 mL), dried (MgSO4), and concentrated by rotary evaporation.

SYNTHESIS OF DIMETHYL ACETALS USING HYDROXYLAMINE
193
Catalytic Acetalization Procedure
Hydroxylamine hydrochloride (0.15 mmol) and powdered sodium hydroxide
(0.15 mmol) were added, in that order, to a mixture of the carbonyl compound
(1.5 mmol) in MeOH (HPLC grade, 5 mL). The reaction was stirred for 18 h, and
then 3 mL of saturated NH4Cl and 3 mL of H2O were added. The mixture was
extracted with diethyl ether (3 ꢀ 10 mL); the combined organic layers were washed
with brine (10 mL), dried (MgSO4), and concentrated by rotary evaporation.
Supporting Information Available
Detailed experimental procedures and characterization of dimethyl acetals 2a–
2l and oximes 3f–3i are available online.
ACKNOWLEDGMENT
The authors are grateful to Northern Arizona University for support of this
project.
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