A very mild and selective method for O-benzoylation of hydroxamic acids

Article abstract of DOI:10.1016/j.tetlet.2014.06.009

Selective O-benzoylation of hydroxamic acids is achieved by the treatment of BPO and DABCO. Aliphatic alcohols are not reactive under these conditions. Various radical or oxidation sensitive functional groups are compatible with this protocol, and no anhydrous reagents or solvents are required for the high yields of the benzoylations.

Full text of DOI:10.1016/j.tetlet.2014.06.009

Tetrahedron Letters 55 (2014) 4404–4406
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A very mild and selective method for O-benzoylation of hydroxamic
acids
⇑
Yongsheng Zheng, Muqiong Liu, Yu Yuan
Department of Chemistry, University of Central Florida, 4111 Libra Drive, Orlando, FL 32816-8005, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Selective O-benzoylation of hydroxamic acids is achieved by the treatment of BPO and DABCO. Aliphatic
alcohols are not reactive under these conditions. Various radical or oxidation sensitive functional groups
are compatible with this protocol, and no anhydrous reagents or solvents are required for the high yields
of the benzoylations.
Received 14 May 2014
Revised 4 June 2014
Accepted 4 June 2014
Available online 12 June 2014
Ó 2014 Elsevier Ltd. All rights reserved.
Keywords:
Benzoylation
Hydroxamic acid
Benzoyl peroxide
Nucleophilic attack
O-Acylated hydroxamic acids (HAs) and hydroxyl amines have
found broad applications in organic synthesis. Owing to the unique
nature of the NAO single bond, HA derivatives have served as build-
ing blocks for heterocyclic compound synthesis,1 stoichiometric
oxidants for olefin di-functionalization,2 nitrogen sources for cross
coupling reactions3 and more recently, as precursors for molecular
HNO production.4 Given the nucleophilicity and Lewis basicity of
the heteroatoms, it is not surprising to find that O-acylated HAs also
play important roles in transition metal catalysis: HAs are efficient
nucleophiles for metal catalysed allylic substitution reactions5 and
they are excellent directing groups in aromatic CAH activation.6 In
principle, O-acylated HAs can be prepared by reacting HAs with
various acylation reagents; however, such transformations are typ-
ically carried out at low temperature for prolonged time to avoid
over acylations and other side reactions. In particular, when
multiple hydroxyl groups are present in the same substrate, a pro-
tection–deprotection process is usually necessary for the optimal
yields. To address these problems, we herein disclose an alternative
approach for selective O-benzoylations of HAs by a reagent that is
conveniently prepared from benzoyl peroxide (BPO) and diazabicy-
clo[2,2,2]octane (DABCO).
BPO in MeCN at reflux temperature.7 Although this condition is
suitable for converting phenols as well as primary and secondary
alcohols to the corresponding ester, it is not ideal to acylate HAs
because the benzoate product of HA can undergo a Lossen
rearrangement at high temperature in the presence of a base. We
envisioned that other nitrogen nucleophiles with enhanced
nucleophilicity should be able to cleave the peroxide bond at lower
temperature and the resulting intermediate may exhibit distinct
activities towards different types of hydroxyl groups.
To test the hypothesis, we first used protected hydroxylamine
1a as a model substrate to screen suitable conditions for the
proposed benzoylation (Table 1). When DABCO was added to a
The peroxide bond of BPO is susceptible to reductive cleavage
and the resulting product is capable of transferring the attached
benzoyl group to various alcohols (Scheme 1). Indeed, one of such
protocols has been reported by Nowrouzi et al. for the benzoyla-
tion of alcohols and phenols by reacting 4 equiv imidazole with
⇑
Corresponding author. Tel.: +1 407 823 6367; fax: +1 407 823 2252.
E-mail address: yu.yuan@ucf.edu (Y. Yuan).
Scheme 1. Benzoyl peroxide as an acyl donor for esterification.
http://dx.doi.org/10.1016/j.tetlet.2014.06.009
0040-4039/Ó 2014 Elsevier Ltd. All rights reserved.

Y. Zheng et al. / Tetrahedron Letters 55 (2014) 4404–4406
4405
Table 1
Table 2
Optimization of benzoylation conditionsa
Synthesis of hydroxamic acid benzoate by BPO/DABCOa
Entries
1
Benzoate product
Yieldb (%)
2b
2c
2d
2e
87
92
93
93
Entry
Solvent
Base
Yieldb (%)
2
3
4
1
2
3
MeCN
MeCN
MeCN
MeCN
MeCN
THF
DCM
Toluene
DMF
DABCO
Lutidine
Pyridine
DMAP
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
DABCO
63
0
0
4
56
55
50
46
54
0d
0d
90e
5c
6
7
8
9
10
11
DMSO
MeCN
a
5
6
2f
79
88
Unless specified otherwise, reaction was performed with 0.20 mmol 1a,
1.0 equiv of BPO and 1.0 equiv of DABCO in 1.0 mL solvent for 1 h.
b
Isolated yield.
0.40 mmol of BPO and 0.40 mmol of DABCO were used.
BPO was completely consumed.
Reaction time was 3 h.
c
d
e
2g
reaction mixture containing 1a and BPO in MeCN, the desired
product was rapidly formed within a minute, accompanied by
immediate disappearance of the BPO (Table 1, entry 1). Although
pyridine and lutidine failed to give any benzoylation product
under the same conditions, dimethylaminopyridine (DMAP) did
produce 2a in decent yield, indicating that the nucleophilicity of
the nitrogen atom was one of the determining factors for the
success of benzoylation (Table 1, entries 2–4). The quantity of
BPO and DABCO only had a marginal effect on the acylation, as
the yield of 2a was not improved by 2 equiv of both reagents.
Since the reagent formation involves initial nucleophilic attacks,
we also explore the solvent polarity effects on the benzoylation
(Table 1, entries 6–10). Reactions carried out in common solvents
such as THF, DCM and toluene all gave inferior yields compared
to that in MeCN; polar aprotic solvents, such as DMF and DMSO,
completely shut down the reaction, even though the BPO was
fully consumed in the reaction mixture. The optimal yield was
obtained when the reaction time was extended to 3 h in MeCN
with 1 equiv of BPO and 1 equiv of DABCO. It is worth noting that,
no anhydrous reagents or solvent was necessary for obtaining the
high yield, and the reaction can be performed under an air
atmosphere.
7
8
2h
2i
71
87
9
10
11
2j
81
73
91
2k
2l
12
13
14
2m
2n
2o
73
76
95
With the optimal conditions in hand,8 we evaluated the gener-
ality of this benzoylation reaction with different HAs and the
results are summarized in Table 2. Generally speaking, the
O-benzoylation of protected hydroxyl amines gave good to excel-
lent yields under standard conditions (Table 2, entries 1–9). Even
though BPO can potentially act as an oxidant and radical initiator,
our current method is compatible with a variety of functional
groups including alkenes, alkynes and aromatics with electron-
donating or electron-withdrawing substituents. As expected, HAs
of both aromatic and aliphatic origins were converted to the
corresponding benzoate under the same conditions (Table 2,
entries 10–12). The versatility of the reagent was also demon-
strated by benzoylation of benzylamine- and hexylamine-derived
N-hydroxyurea. We were pleased to find that the additional nitro-
gen atom caused no interference to the acyl transfer reaction and
the BPO/DABCO combination provided the benzoate products in
76% and 95% yields, respectively (Table 2, entries 13 and 14). To
further broaden the substrate scope, we extended the optimized
conditions to N-hydroxysuccinimide and N-hydroxyphthalimide;
15
16
2p
2q
84
91
a
HA 0.20 mmol, 1.0 equiv of BPO and 1.0 equiv of DABCO in 1.0 mL MeCN for 1 h.
Isolated yields.
b
and the reactions proceeded smoothly to afford the desired esters
in excellent yields (Table 2, entries 15 and 16).

4406
Y. Zheng et al. / Tetrahedron Letters 55 (2014) 4404–4406
the oxyanion of HA acts as an acceptor for the benzoyl group in
intermediate I; and DABCO N-oxide II is released as a byproduct.
This mechanistic scheme is supported by the detection of II by
LC–MS and explains the inactivity of pyridine and lutidine in the
benzoylation reaction.
In summary, we have developed a mild and selective method
for the benzoylation of protected hydroxylamines and HAs. The
combination of DABCO and BPO produces a reagent that is capable
of transferring a benzoyl moiety to various N-hydroxyl groups at
room temperature and the rapid consumption of BPO allows radi-
cal and oxidation sensitive functional groups intact during the
acylation process. The reaction conditions are very robust and
require no anhydrous chemicals or inert atmosphere to secure
good yields.
Scheme 2. Selectivity between hydroxamic acid and aliphatic alcohols.
Acknowledgment
The authors acknowledge
University of Central Florida.
a start-up support from the
Supplementary data
Supplementary data associated with this article can be found,
in the online version, at http://dx.doi.org/10.1016/j.tetlet.2014.
06.009.
References and notes
Scheme 3. A plausible mechanism for the benzoylation.
1. Fukumi, H.; Oohata, K.; Takada, K. Heterocycles 1979, 12, 1297–1299.
2. (a) Donohoe, T. J.; Callens, C. K. A.; Thompson, A. L. Org. Lett. 2009, 11,
2305–2307; (b) Donohoe, T. J.; Callens, C. K. A.; Flores, A.; Mesch, S.; Poole, D. L.;
Roslan, I. A. Angew. Chem., Int. Ed. 2011, 50, 10957–10960; (c) Liu, G.-S.; Zhang,
Y.-Q.; Yuan, Y.-A.; Xu, H. J. Am. Chem. Soc. 2013, 135, 3343–3346; (d) Zhang, Y.-
Q.; Yuan, Y.-A.; Liu, G.-S.; Xu, H. Org. Lett. 2013, 15, 3910–3913.
3. Zhang, Z.; Yu, Y.; Liebeskind, L. S. Org. Lett. 2008, 10, 3005–3008.
4. Sutton, A. D.; Williamson, M.; Weismiller, H.; Toscano, J. P. Org. Lett. 2012, 14,
472–475.
A notable advantage of our current protocol is the high selectiv-
ity for HA hydroxyl groups over aliphatic alcohols and phenols:
butanol, benzyl alcohol, menthol and phenol are not reactive under
the optimal conditions. We performed a competition reaction
between equal amount of 1-butanol/phenol and 1b in the presence
of BPO/DABCO (Scheme 2, Eq. 1); and we found that 2b was the
sole product and there was no butyl benzoate or phenol benzoate
formed in the reaction mixture. Such selectivity was retained for
more complex substrate 3, which has a pendant hydroxyl group
and a protected hydroxylamine group within the same molecular
scaffold. The only product isolated from benzoylation reaction
was 4 and no acylation on the aliphatic alcohol was detected. This
observation is attributed to the different pKa of the hydroxyl
groups: the acidic HA hydroxyl proton is readily removed by
DABCO and the resulting oxygen anion is more nucleophilic than
regular aliphatic alcohols.
5. Miyabe, H.; Matsumura, A.; Moriyama, K.; Takemoto, Y. Org. Lett. 2004, 6,
4631–4634.
6. (a) Wang, D. H.; Wasa, M.; Giri, R.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 7190–
7191; (b) Wasa, M.; Yu, J. Q. J. Am. Chem. Soc. 2008, 130, 14058–14059; (c)
Guimond, N.; Fagnou, K. J. Am. Chem. Soc. 2009, 131, 12050–14051; (d) Guimond,
N.; Gorelsky, S. I.; Fagnou, K. J. Am. Chem. Soc. 2011, 133, 6449–6457; (e)
Patureau, F. W.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50, 1977–1979; (f) Ye, B.
H.; Cramer, N. Science 2012, 338, 504–506.
7. Nowrouzi, N.; Alizadeh, S. Z. Tetrahedron Lett. 2013, 54, 2412–2414.
8. A representative procedure for the synthesis of benzoate 2a: To a test tube charged
with a stir bar, 0.20 mmol of 1a and 0.20 mmol of BPO were sequentially added
MeCN 1.0 mL and 0.20 mmol of DABCO. The resulting reaction mixture was
stirred at room temperature for 3 h and diluted by addition of EtOAc, the organic
layer was briefly washed by saturated aqueous sodium bicarbonate solution,
brine and dried over anhydrous sodium sulfate. The bulk solvent was removed
in vacuo, and the residue was purified by silica gel flash chromatography to
afford product 2a 48.8 mg, 90% yield.
A plausible mechanism for the benzoylation of the HAs is
illustrated in Scheme 3. An initial nucleophilic attack by DABCO
generates intermediate I as an acyl donor, which is responsible
for the subsequent esterification reactions. Upon deprotonation,