Intramolecular rearrangement of α-azidoperoxides: An efficient synthesis of tert-butyl esters

Article abstract of DOI:10.1021/acs.orglett.5b00190

An unprecedented intramolecular rearrangement of α-azidoperoxides, promoted by simple organic base to provide tert-butyl esters, has been presented. Further, a one-pot methodology consisting of in situ generation of the α-azidoperoxides from corresponding aldehydes followed by base-promoted rearrangement to obtain the desired ester has also been executed. Relevant mechanistic studies, to provide the proof for intramolecular alkoxy transfer, are investigated.

Full text of DOI:10.1021/acs.orglett.5b00190

Letter
pubs.acs.org/OrgLett
Intramolecular Rearrangement of α‑Azidoperoxides: An Efficient
Synthesis of tert-Butyl Esters
Suman Pramanik, Reddy Rajasekhar Reddy, and Prasanta Ghorai*
Department of Chemistry, Indian Institute of Science Education and Research Bhopal, Indore By-pass Road, Bhauri, Bhopal 462066,
India
S
* Supporting Information
ABSTRACT: An unprecedented intramolecular rearrangement of α-azidoperoxides, promoted by simple organic base to
provide tert-butyl esters, has been presented. Further, a one-pot methodology consisting of in situ generation of the α-
azidoperoxides from corresponding aldehydes followed by base-promoted rearrangement to obtain the desired ester has also
been executed. Relevant mechanistic studies, to provide the proof for intramolecular alkoxy transfer, are investigated.
tert-Butyl esters are of interest because of their rich
applications across many fields of chemistry. This functionality
has a significant advantage as a protecting group which can be
readily converted to the corresponding acids under mild acidic
conditions.5 Moreover, the steric bulk of this group plays a crucial
role in achieving better selectivity in many asymmetric
processes.6 Traditionally, the synthesis of tert-butyl esters relied
primarily on the reaction of carboxylic acid and its derivatives
with tert-butyl alcohol. However, the preparation of these
hindered esters from carboxylic acids and other precursors is
more complicated than from other esters.7 Considerable
attention has been paid to the synthesis of such esters via
alkoxycarbonylation of aryl halides, and many attractive
processes have been developed.7h,8 However, the use of toxic
carbon monoxide, a crucial raw material in this process, is a
limitation. Further, these reactions are limited to aromatic
substrates only.8
he identification of novel reactivity is not only more
Tchallenging but also increasingly essential to meet the ever-
increasing societal demands on synthetic chemistry. Often, the
discovery of new reactivity has been a consequence of
investigating a hypothesis based on a known reactivity and
intuition, resulting in an unexpected outcome. Kornblum and
DeLaMare reported base-promoted peroxide decomposition for
the synthesis of ketones.1 On the basis of such reactivity, Kelly
and co-workers suggested a synchronous peroxide cleavage and
retro-aldol cleavage of endoperoxides to provide γ-hydroxy
enones.2 Toste et al. developed the enantioselective synthesis of
γ-hydroxyenones by a chiral base-catalyzed Kornblum−DeLaM-
are rearrangement.3 We expected an analogous reactivity of our
recently synthesized new class of α-heteroperoxides A4 to
provide the acyl azide B (Scheme 1). Instead, we observed
unprecedented reactivity that provides the corresponding esters
C through an intramolecular rearrangement of the alkoxy group,
thus unfolding an unrecognized opportunity for the synthesis of
esters.
Recently, oxidative esterification of aldehydes has been
considered as an interesting strategy for the synthesis of esters
(Scheme 2a).9−12 Although large varieties of esters of primary
Scheme 1. Base-Promoted Decomposition of α-H-Containing
Peroxides: (a) Classical Kornblum−DeLaMare
Rearrangement, (b) Unprecedented Rearrangement of α-
Azidoperoxides
Scheme 2. Oxidative Esterification of Aldehydes
Received: January 20, 2015
Published: March 2, 2015
© 2015 American Chemical Society
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DOI: 10.1021/acs.orglett.5b00190
Org. Lett. 2015, 17, 1393−1396

Organic Letters
Letter
and secondary alcohols have been successfully prepared using
these methods, the synthesis of tert-butyl ester still remained a
challenge. In this regard, copper-catalyzed oxidative esterification
of aldehydes with dialkyl peroxides is notable.10 However,
organocatalyzed anodic oxidation11 or Pd-catalyzed hydrogen
transfer12 of aldehydes for the synthesis of esters also failed to
provide the tert-butyl esters. Therefore, the development of a
novel, user-friendly approach for the synthesis of tert-butyl esters
from corresponding aldehydes would be highly useful.
Scheme 3. Scope of Azidoperoxides for tert-Butyl Ester
Synthesis
a,b
We started the investigation of base-promoted decomposition
of α-azidoperoxide to acylazide (3) choosing azido(tert-
butylperoxy)methyl)benzene (1a) as a model substrate and
TMEDA as base in dichloromethane solvent.13 Encouragingly,
the decomposition of α-azidoperoxide gave the formation of tert-
butyl benzoate (2a) as the major product, and benzoylazide (3)
was formed as the minor product. The reaction shows a highly
chemoselective “O−O” bond breaking (over “N−N2” bond),
which drives such rearrangements to occur. We began
optimization of the reaction conditions using different bases
and solvents at 0 °C as shown in Table 1. We found that ethyl
Table 1. Optimization of the Reaction Conditions
a
b
entry
base
solvent
2a (%)
2a:3
1
2
3
4
5
6
7
8
7
8
9
10
TMEDA
TMEDA
TMEDA
NEt3
CH2Cl2
toluene
EtOAc
EtOAc
EtOAc
EtOAc
EtOAc
CH2Cl2
toluene
THF
68
62
71
57
18
1
1:0.21
1:0.21
1:0.16
1:0.17
1:0.40
1:10.0
1:0.12
1:0.34
1:0.12
1:0.12
1:0.59
1:0.08
i-Pr2EtN
pyridine
DBU
a
Azidoperoxide (1, 1.0 mmol) and DBU (1.0 mmol) in EtOAc at 0
c
83 (77)
b
°C, stirred for 15 min. Isolated yield after column chromatography.
DBU
60
72
66
38
72
c
d
Compound has low boiling point.14 Reaction was carried out at
DBU
room temperature for 3 h for the aliphatic α-azidoperoxides 1n−q.
DBU
DBU
CH3CN
1,4-dioxane
(2b−d). Yields of the reaction were not affected when esters
containing electron-withdrawing functional groups like fluoro,
chloro, bromo, or trifluoromethyl were used (2e−h). Azidoper-
oxides prepared from naphthaldehyde and fluorene carboxalde-
hyde reacted even smoothly to furnish the desired esters (2j and
2k, respectively). Esterification of heteroaromatic azidoperoxides
are equally effective for the current process (2l and 2m). Notably,
a wide range of alkyl α-azidoperoxides efficiently undergo such
base-promoted rearrangement under optimized conditions (2n−
q). In contrast to the known method, our metal-free method
provides a novel range of substrates that complements existing
metal-catalyzed methods.
After successful synthesis of tert-butyl esters from azido
peroxides, a one-pot, sequential azidoperoxidation of aldehydes
followed by decomposition was carried out to furnish the tert-
butyl esters (Scheme 4). Aromatic, heteroaromatic, and aliphatic
tert-butyl esters were synthesized at room temperature with
moderate to good yields.
DBU
a
1H NMR yield of the reaction mixture using DMSO as an internal
standard. Ratios were determined using H NMR of the reaction
mixture. Yields (in parentheses) after column chromatography.
b
1
c
acetate was the superior solvent in the presence of TMEDA as
base (entries 1−3). Then several organic bases were used, and
DBU was found to be the best in terms of selectivity as well as
yield of tert-butyl benzoate (2a). All these reactions were found
to be completed within 15 min at 0 °C. We then began carrying
out the reaction in different solvents (entries 7−10), taking DBU
as the suitable base. Changing the solvent to dichloromethane,
toluene, THF, acetonitrile, and 1,4-dioxane led to a decrease in
the yields of the reaction. Finally, the optimum reaction
conditions were determined as the combination of DBU (1
equiv) as base and ethyl acetate as solvent at 0 °C.
Having optimized the reaction conditions, we extended the
esterification to a variety of α-azidoperoxides to synthesize tert-
butyl esters. As shown in Scheme 3, aryl esters (2a−h)
containing electron-donating and electron-withdrawing func-
tional groups were synthesized with excellent yields. Azidoper-
oxides with electron-rich substituents like methyl, tert-butyl, and
methoxy reacted smoothly to provide the corresponding esters
After successful synthesis of tertiary butyl esters, we turned our
attention to investigate the applicability of primary and
secondary alkyl-protected azidoperoxides in this transformation,
and the results are summarized in Scheme 5. The ethyl-protected
peroxide (1r) afforded the corresponding ester (2r) in good
yield. Similarly, the isopropyl ester (2s) was obtained from the
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DOI: 10.1021/acs.orglett.5b00190
Org. Lett. 2015, 17, 1393−1396

Organic Letters
Letter
a,b
Scheme 4. Synthesis of tert-Butyl Esters from Aldehydes
Scheme 6. NMR Study for the Investigation of Reaction
Mechanism
a
t
Step 1: Aldehyde (1.0 mmol), TMSN3 (2.5 equiv), BuOOH (5.5
[M] in decane, 1.0 equiv), and FeCl3 (10 mol %) in anhydrous
dichloromethane at −20 °C stirred for 1 h, then FeCl3 was filtered.
Step 2: Reaction mixture and DBU (1.0 equiv) in EtOAc at 0 °C,
b
stirred for 15 min. Isolated yield after column chromatography.
c
Reaction was carried out at room temperature for 12 h in the second
step for the aliphatic ester 2q.
a
Scheme 5. Synthesis of Primary and Secondary Alkylesters.
a
b
Isolated yield after column chromatography. Compounds have low
boiling point.15 The yields based on the 1H NMR spectroscopy of the
reaction mixture using anisole as an internal standard are shown in
parentheses.
c
Scheme 7. Proposed Reaction Mechanism
corresponding azidoperoxide (1s). The relative lower yields are
assigned due to the volatility of these esters.15
To gain insight into the reaction mechanism and to establish
the intramolecular nature of the reaction, a competitive study was
performed as shown in Scheme 6a. α-Azidoperoxide (1a) was
treated in the presence of 10 equiv of ethanol and 2-propanol in
separate reactions maintaining the standard reaction conditions.
If the reaction is intermolecular, then ethyl benzoate (2r) and
isopropyl benzoate (2s) should be formed through intermo-
lecular alkoxy transfer from ethanol or 2-propanol, respectively.
However, there was no trace of ethyl benzoate or isopropyl
benzoate in the reaction mixture as observed on the basis of the
1H NMR studies of the reaction mixture (see the Supporting
Information). Instead, tertiary benzoate (2a) was obtained in
59% and 70% yields for the respective reactions. These results
indicate an intramolecular 1,2-migration of the alkoxy group in
the α-azidoperoxide (1a).
Further, a crossover experiment was followed to confirm the
intramolecularity of these reactions as shown in Scheme 6b.
Azidoperoxides (1b) bearing tert-butyl peroxide and 1s bearing
isopropyl peroxide were mixed and treated with 1.0 equiv of
DBU. As expected, no cross product (e.g., 2t and 2a,
respectively) was observed in the respective reaction mixture.
Based on the results of our preliminary mechanistic
investigations and recently reported denitrogen of azide,16 we
propose a reaction mechanism as depicted in Scheme 7.
Potentialy, there could be two possible paths for the current
ester synthesis via base-promoted decompostion of α-azidoper-
oxides. Abstraction of α-hydrogen of the azidoperoxide leads to
the direct decomposition of the peroxide bond, which provides
acylazide (3) and alkoxide ion (path a). Further, the exchange of
azide moiety of 3 with alkoxide ion generates the esters. On the
other hand, abstraction of α-hydrogen of the azidoperoxide leads
to a resonance-stabilized intermediate I (path b). Then, an
intramolecular 1,2-alkoxy migration of I, via the peroxide bond
breakage, followed by cleavage of the C−N bond (intermediate
IV) affords the desired ester. However, on the basis of the control
studies, it is probably going through the latter path.
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Organic Letters
Letter
Lett. 2014, 16, 1836−1839. (c) Hong, X.; Wang, H.; Liu, B.; Xu, B.
Chem. Commun. 2014, 50, 14129−14132.
In conclusion, we have developed an unprecedented intra-
molecular rearrangement of α-azidoperoxides for the synthesis of
esters. Esters of primary, secondary, and most importantly
tertiary alcohols can be generated starting from the correspond-
ing α-azidoperoxides. Further, a one-pot methodology for the
synthesis of tert-butyl esters from the corresponding aldehydes
has also been developed. This provides an alternative approach to
the synthesis of tert-butyl ester. Preliminary mechanistic
investigations revealed that intramolecular alkoxy transfer occurs.
Further investigations and applications of these unusual
rearrangements are being actively pursued in our laboratory
and will be reported in due course.
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ASSOCIATED CONTENT
■
S
* Supporting Information
Experimental procedures, characterization data, and copies of
NMR spectra for all products. This material is available free of
charge via the Internet at http://pubs.acs.org.
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500−503.
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°C (3 Torr). See: Olah, G. A.; Narang, S. C.; Salem, G. F.; Gupta, B. G. B.
Synthesis 1981, 142−143.
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: pghorai@iiserb.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work has been supported by BRNS, DAE, India, through a
DAE Young Scientist Research Award Grant. S.P. thanks CSIR,
New Delhi, India, and R.R.R. thanks IISER Bhopal for fellowship.
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