First acid-catalyzed entry to O-alkylated hydroximides from benzylic alcohols

Article abstract of DOI:10.1002/ejoc.201100797

A facile method for the synthesis of O-alkylated hydroximides through the acid-catalyzed alkylation of hydroximides by using benzylic alcohols as alkylating agents is described for the first time. The obtained O-propargylated products offered easy access

Full text of DOI:10.1002/ejoc.201100797

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201100797
First Acid-Catalyzed Entry to O-Alkylated Hydroximides from Benzylic
Alcohols
Chada Raji Reddy,*[a] Laghuvarapu Radhika,[a] Togapur Pavan Kumar,[a] and
Srivari Chandrasekhar[a]
Keywords: Alkylation / Acid catalysis / Heterocycles / Alcohols
A facile method for the synthesis of O-alkylated hydrox-
imides through the acid-catalyzed alkylation of hydroximides
by using benzylic alcohols as alkylating agents is described
for the first time. The obtained O-propargylated products of-
fered easy access to 2,5- and 4,5-dihydroisoxazoles.
Introduction
O-Alkylated hydroximides (hydroxyphthalimides) repre-
sent a versatile class of useful synthons for the synthesis of
several heterocyclic compounds such as dihydroisox-
azoles,[1,2] polysubstituted pyridine N-oxides,[3] and α-
aminoxy acids,[4] as well as other potentially bioactive com-
pounds[5] through O-alkyl hydroxylamine (Figure 1). Gen-
erally, these compounds are obtained by O-alkylation of hy-
droximide by using alkyl halides in the presence of a stoi-
chiometric amount of base[5a,6] or with alcohols under Mit-
sunobu conditions.[1–4,7] The latter method is the most fre-
quently used method, but it suffers from the generation of
phosphane oxide and hydrazine dicarboxylate as byprod-
ucts, which often makes the isolation of pure product in
good yield difficult.[1,8] In addition, a single literature prece-
dence is available on the O-alkylation of N-hydroxyphthal-
imide by using aliphatic tertiary alcohols in the presence of
stoichiometric BF3·OEt2.[9] Alternatively, O-alkylated hy-
droximides are achieved from hydrocarbons through Cu-
catalyzed benzylic and allylic C–H activation[10] or from
carbonates by transition-metal-catalyzed C–O bond forma-
tion.[11] Hence, the development of efficient new methods
for O-alkylation of hydroxamides by using alcohols as alk-
ylating agents is an attractive objective.
Figure 1. Synthesis of N,O-heterocycles from O-propargylated hy-
droxyphthalimide.
bility and high reactivity of benzylic carbocations generated
in the presence of a Lewis or Brønsted acid.[13] The efficacy
of π-activated alcohols in direct nucleophilic SN1-type reac-
tions has been covered by Cozzi and co-workers in a recent
review.[14] Our work on the utility of benzylic alcohols as
carbon electrophiles by treatment with various carbon, oxy-
gen, and nitrogen nucleophiles[15] has encouraged us to fur-
ther explore the scope of benzylic alcohols as alkylating
agents. Herein, we report the first acid-catalyzed O-alk-
ylation of hydroxamides by using benzylic alcohols
(Scheme 1).
In recent years, π-activated alcohols have received con-
siderable attention as alkylating agents towards green and
atom-economic practices, as they generate only water as a
byproduct in the reaction.[12] Among these, benzylic
alcohols are gaining prominence due to the moderate sta-
Scheme 1. Acid-catalyzed access to O-alkylated hydroximides.
[a] Organic Chemistry Division-I (NPL)
Indian Institute of Chemical Technology
Hyderabad 500607, India
Results and Discussion
Fax: +91-40-27160512
Diphenylmethanol (1a) was selected as a model alkyl-
ating agent for the acid-catalyzed O-alkylation of N-hy-
droxyphthalimide (2a). To optimize the reaction conditions,
E-mail: rajireddy@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201100797.
Eur. J. Org. Chem. 2011, 5967–5970
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
5967

Ch. R. Reddy, L. Radhika, T. P. Kumar, S. Chandrasekhar
SHORT COMMUNICATION
we examined different acid catalysts, and the results are Table 2. p-TSA-catalyzed O-alkylation of hydroximides with benz-
ylic alcohols.
summarized in Table 1. At first, the O-alkylation of 2a with
1a was tested by using BF3·OEt2 (5 mol-%) as the catalyst
in CH2Cl2 at room temperature. To our delight, the starting
material was consumed in 30 min and desired O-alkylated
product 3a was obtained in 78% yield (Table 1, Entry 1).
Next, the same reaction was examined with different acid
catalysts (5 mol-%) in CH2Cl2 as solvent to identify the best
catalyst for the O-alkylation of hydroximides. Among the
catalysts used, p-toluenesulfonic acid provided good yield
(86%) of product 3a in 30 min with a clean reaction profile
(based on TLC; Table 1, Entry 3).
Table 1. Optimization of the reaction conditions for the acid-cata-
lyzed O-alkylation of N-hydroxyphthalimide (2a) with benzylic
alcohol (1a).
Entry
Acid
Conditions
Time
[min]
Yield
[%][a]
1
2
3
4
5
BF3·OEt2
ZnCl2
p-TSA
B(C6F5)3
–
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, r.t.
CH2Cl2, reflux
30
40
30
30
2880
78
80
86
82
0[b]
[a] Isolated yield after purification. [b] No reaction.
ZnCl2 and B(C6F5)3 also furnished the product in 80 and
82% yield, respectively (Table 1, Entries 2 and 4). It was
observed that there was no reaction in the absence of a cata-
lyst (Table 1, Entry 5). On the basis of the above results, p-
TSA was chosen for further studies, which was also success-
fully utilized earlier by Sanz et al. and others for the direct
nucleophilic substitution of various benzylic alcohols.[16,17]
To explore the generality of the reaction, a range of
alcohols were studied for the O-alkylation of N-hydroxy-
phthalimide (2a) and N-hydroxysuccinimide (2b) under the
optimized conditions (Table 2). This method is efficient for
the alkylation of 2b with 1a to give 3b in 84% yield (Table 2,
Entry 2). Benzylic alcohols 1b and 1c were treated with
both 2a and 2b under the present reaction conditions to
provide the corresponding O-alkylated products 3c to 3f in
good yields (Table 2, Entries 3 to 6). Next, we sought to
extent the method by using propargylic alcohols as alkyl-
ating agents to obtain O-propargylated hydroxylamines,
which are useful synthons for the preparation of 2,5- and
4,5-dihydroisoxazole derivatives.
Thus, the reaction of propargylic alcohol 1d with 2a and
2b in the presence of p-TSA (5 mol-%) gave the correspond-
ing products 3g and 3h in 82 and 78% yield, respectively
(Table 2, Entries 7 and 8). Similarly, propargylic substrates
1e and 1f were also successful in smooth O-alkylation of 2a
(Table 2, Entries 9 and 10). However, the reaction of pro-
pargylic alcohol 1g with N-hydroxyphthalimide failed to
give the desired O-propargylated product even after 2 h at
room temperature (Table 2, Entry 11). The results from the
above reactions clearly demonstrate that the O-alkylation
1
[a] All the products were characterized by H and 13C NMR spec-
was successful only in the case of propargylic alcohols, ob- troscopy and mass spectrometry. [b] Isolated yield.
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Acid-Catalyzed Entry to O-Alkylated Hydroximides from Benzylic Alcohols
droximide 2a,b (1.2 mmol) and p-TSA (0.05 mmol) at room tem-
tained from aromatic aldehydes and not with the propar-
gylic alcohols generated from aliphatic aldehydes. This may
be due to the formation of more reactive benzylic carbo-
cation from the former alcohols. The reaction of 2a with
primary benzylic alcohol 1h and tertiary benzylic alcohol 1i
also failed to give the product (Table 2, Entries 12 and 13),
which demonstrates that the alkylation was successful only
with secondary benzylic alcohols. On the other hand, 1,1,3-
triphenylpropargyl alcohol (1j) did not react with 2a under
perature, and the mixture was stirred for the given time (see
Table 2). After completion of the reaction (monitored by TLC), the
mixture was quenched by the addition of saturated aq. solution of
sodium hydrogen carbonate (5 mL) and extracted with dichloro-
methane (3ϫ5 mL). The combined organic layer was dried with
anhydrous Na2SO4 and concentrated in vacuo. The residue was
purified by column chromatography on silica gel (EtOAc/hexanes)
to afford O-alkylated hydroximides 3a–j. The products obtained
were characterized by IR, 1H, and 13C NMR spectroscopy and
the present reaction conditions, instead it isomerized into mass spectrometry.
β-phenyl chalcone 3k1 (Meyer–Schuster rearrange-
ment).[17a,18]
Supporting Information (see footnote on the first page of this arti-
cle): Experimental procedures and characterization data of the pre-
pared compounds.
Furthermore, we have demonstrated the utility of O-pro-
pargylated hydroximides in the synthesis of 2,5- and 4,5-
dihydroisoxazole derivatives (Scheme 2).[1] Hence, com-
pound 3j was treated with hydrazine hydrate in CHCl3/
MeOH (1:1) to remove the phthalimide group to obtain
hydroxylamine 4 in 87% yield. N-Tosylation of 4 with tosyl
chloride in the presence of pyridine followed by reaction
with I2/K2CO3 in CH3CN provided 4-iodo-2,5-dihydroisox-
azole 5a in 72% yield (over 2 steps), whereas the reaction
of 4 with 10% AgNO3/SiO2 in CH2Cl2 afforded 4,5-dihy-
droisoxazole 5b in 89% yield.
Acknowledgments
L. R. thanks the University Grants Commission (UGC), New
Delhi and T. P. K. thanks the Council of Scientific and Industrial
Research (CSIR), New Delhi for research fellowships. Authors
thank the referees for their valuable suggestions.
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Ch. R. Reddy, L. Radhika, T. P. Kumar, S. Chandrasekhar
SHORT COMMUNICATION
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Received: June 4, 2011
Published Online: September 14, 2011
5970
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Eur. J. Org. Chem. 2011, 5967–5970