An Unprecedented (Semi)Favorskii rearrangement. evidence for the 2-(Acyloxy)cyclopropanones

Article abstract of DOI:10.1021/acs.orglett.8b00218

Discovery and development of an unprecedented (semi)Favorskii rearrangement has been reported. The intermediacy of structurally singular (acyloxy)cyclopropanones has been unraveled by fruitful control experiments including a crossover experiment. This class of cyclopropanones is found to be inert for classical Favorskii functionalization and preferably undergoes a decycloisomerization (ring-chain valence tautomerism) to α-(acyloxy)enones. A cascade conversion of α,α-diiodo-α′-acetoxyketones to (acyloxy)cyclopropanones via α-iodo-α′-acetoxyketones has been achieved by the synchronous dual basicity (Lewis and Br?nsted) of amines. The overall process is found to be very general for diverse substrates and highly efficient.

Full text of DOI:10.1021/acs.orglett.8b00218

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
An Unprecedented (Semi)Favorskii Rearrangement. Evidence for the
‑(Acyloxy)cyclopropanones
2
Santu Sadhukhan and Beeraiah Baire*
Department of Chemistry, Indian Institute of Technology Madras, Chennai, Tamilnadu 600036, India
*
S Supporting Information
ABSTRACT: Discovery and development of an unprece-
dented (semi)Favorskii rearrangement has been reported. The
intermediacy of structurally singular (acyloxy)cyclopropanones
has been unraveled by fruitful control experiments including a
crossover experiment. This class of cyclopropanones is found
to be inert for classical Favorskii functionalization and
preferably undergoes a decycloisomerization (ring−chain
valence tautomerism) to α-(acyloxy)enones. A cascade conversion of α,α-diiodo-α′-acetoxyketones to (acyloxy)cyclopropanones
via α-iodo-α′-acetoxyketones has been achieved by the synchronous dual basicity (Lewis and Brønsted) of amines. The overall
process is found to be very general for diverse substrates and highly efficient.
1
he classical Favorskii rearrangement is the conversion of
Scheme 2. A New (Semi)Favorskii Rearrangement
T
α-haloketones 1 (possessing α′-protons) to esters or
amides or acids 2 with nucleophilic bases. It involves the
formation of a cyclopropanone 3 as the key intermediate from
the α-haloketone 1. This cyclopropanone 3 upon nucleophilic
addition−ring opening provides the ester/amide/acid 2. On the
other hand, in the presence of a non-nucleophilic base,
cyclopropanones 3 can also be considered equivalents of
oxyallyl cations 4 (a valence tautomer), and their reactivity ha2s
been explored as 1,3-dipoles in organic synthesis (Scheme 1).
Scheme 1. Classical Favorskii Functionalizations
This transformation is unprecedented in organic synthesis, in
terms of (acyloxy)cyclopropanone intermediates and their
reactivity, and for the synchronous dual basicity of 3°-amines.
Recently, we reported a selective monodehalogenation of
α,α-diiodo-α′-acetoxyketones 8 employing water (or alcohols)
as Lewis base for the selective generation of α-iodo-α′-
5
acetoxyketones. In continuation of exploring this process for
various bases (non-nucleophilic) in particular 3°-amines, we
discovered the currently reported transformation.
Our investigation began when a α,α-diiodo-α′-acetoxyketone
Any other type of reactivity of oxyallyl cations is almost
unknown in the literature. Concomitantly, evidence for either
α-hydroxy- or α-(acyloxy)cyclopropanones 5 is scarce. Herein,
9
a was treated with triethylamine (8 equiv) in acetonitrile at 0
3
°C (Table 1, entry 1). After 1 h, a α-iodo-α′-acetoxyketone 10a
was isolated in 80% yield. Increasing the reaction temperature
to rt (∼30 °C) resulted in a 1:1.3 mixture of 10a and a new
compound, α-acetoxyenone 11a, after 30 min. On the other
hand, performing the reaction at rt for 1.5 h (entry 3)
gratifyingly gave the α-acetoxyenone 11a as an exclusive
product in 66% yield. In the case of other amines like pyridine
and diisopropylamine the reaction was not clean and gave poor
yields of 11a (entries 4 and 6). Employing diisopropylethyl-
we report an unprecedented Favorskii rearrangement of α-iodo-
α′-acetoxyketones 6a in the presence of non-nucleophilic base
via structurally singular α-(acyloxy)cyclopropanone intermedi-
ate 5. They (5) are found to be inert for classical Favorskii
functionalization, instead preferably undergoing an unconven-
tional decycloisomerization (ring−chain valence tautomerism)
4
to yield α-(acyloxy)enones 7 (Scheme 2B). In this process, the
synchronous dual basicity (Lewis and Brønsted) of amines has
been utilized for the cascade conversion of α,α-diiodo-α′-
acetoxyketones 8 to the key and unique intermediates
Received: January 22, 2018
(
acyloxy)cyclopropanones 5 via α-iodo-α′-acetoxyketones 6a.
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00218
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Discovery and Optimization
Scheme 3. Scope Study for Aromatic sec-
Acetoxydiiodoketones
a
a
Reaction conditions: 9 (1 equiv), DIPEA (5 equiv), CH Cl , 0 °C,
2
2
5
−10 min.
good yields (Scheme 4). Further, benzyloxy and carbonate
functionalities in place of acyloxy group smoothly underwent
the migration to yield the corresponding products 11t and 11u
in excellent yields.
a
All of the reactions were carried out on a 0.1 mmol scale of 9a in 4
b
c
mL of solvent. Yields after chromatographic purification. Increase in
temperature (50 and 70 °C) gave a complex mixture. Reaction was
sluggish with sec-amines like piperidine and pyrrolidine. Further
d
e
Scheme 4. Extension to Heteroaromatics: Benzyloxy and
a
Carbonate Groups
decrease in equivalents of DIPEA reduced the yields of 11a.
amine (DIPEA, 8 equiv, entry 5) in CH CN at rt resulted in an
3
improved yield (70%) for 11a.
Next various solvents were screened (entries 7−14) against
DIPEA (8 equiv). In dichloromethane (entry 7), the reaction
was very fast (10 min) and efficient to give the product 11a in
a
Reaction conditions: 9 (1 equiv), DIPEA (5 equiv), CH Cl , 0 °C,
−10 min.
2
2
5
85% yield. Since the reaction took only 10 min, next we
performed the reaction with a lower amount (5 equiv) of
DIPEA (entry 8). Delightfully, further improvement of the
yield of 11a (90%) was observed with similar reaction time (10
min). 1,4-Dioxane and acetone resulted in reduced yields (52%
and 57%) of acetoxyenone 11a, whereas THF, EtOAc,
CH NO , and DMSO gave only the monoidodoketone 10a
Surprisingly, substituting the methyl group (9v) in place of
aromatics (Scheme 5) resulted in a sluggish reaction. In this
Scheme 5. Distinct Rates for Aliphatic sec-Acetates Support
Dependency on the α′-H and Its pK Value
a
3
2
in poor yields (30−35%) after 1.5 h at rt.
Therefore, the screening study suggested that DIPEA (5
equiv) in CH Cl at 0 °C is a suitable condition for the direct
2
2
conversion of 9a to 11a. Entries 1−3 (Table 1) revealed that
the monoiodoketone 10a can possibly be one of the
intermediates during the formation of α-acetoxyenone 11a
from α,α-diiodo-α′-acetoxyketone 9a. To further confirm, 10a
was subjected to the standard reaction conditions (Table 1,
entry 8). Fittingly, the α-acetoxyenone 11a was isolated as an
exclusive product (75%) after 5 min.
With the optimized conditions in hand, we turned our
attention to understanding the scope of this novel process. To
begin with, secondary α′-(acyloxy)-α,α-diiodoketones were
studied (Scheme 3). Various functional groups such as
methoxy-, fluoro-, chloro-, bromo-, and dichloro- on the
aromatic ring and at various positions, i.e., ortho-, meta-, and
para-, were well tolerated to provide the corresponding α-
case, formation of monoiodoketone 10v was faster, but
conversion to (acyloxy)ketone 11v was found to be very slow
(11.5 h) at rt yet resulted in a mixture of unidentifiable
products. An increase in temperature (55 °C) reduced the
reaction time (3 h) but did not improve the cleanliness of the
process.
(
acyloxy)enones 11b−p in good yields (62−86%) within short
reaction times (5−10 min). Heteroaromatics such as 2-furanyl-,
-thienyl-, and 3-indolyl-based diiodoketones were also
employed for the synthesis of the respective enones 11q−s in
2
B
DOI: 10.1021/acs.orglett.8b00218
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
On the other hand, with the allylic−propargylic acetates 9w
and 9x, the rate of the reactions (45 min and 6 h) and yields of
the corresponding enone products 11w and 11x (70% and
an intramolecular 1,4-acyl migration to generate the α-
(acyloxy)enone 19.
To provide an evidence for (acyloxy)cyclopropanones and
their decycloisomerization process, we designed a few control
experiments (Scheme 8). At first, a crossover experiment using
4
8%) were comparable with their aromatic counterparts. These
observations suggest that the rate of the conversion of
monoiodoketone to (acyloxy)enone is highly dependent on
the nature of the group attached to α′-carbon. In other words,
Scheme 8. Control Experiments To Study the Proposed
(Semi)Favorskii Rearrangement and
Acyloxycyclopropanone Intermediates
as the acidity of the α′-H increases (or pK of the α′-H
a
6
decreases) among 9a, 9v, and 9w, the rate of the conversion of
monoiodoketones to the corresponding (acyloxy)enones 11a,
1
1v, and 11w also gradually increases. Therefore, we
hypothesized that the α′-H might be involving during the
second step.
To further confirm the role of the α′-H, we next employed
substrates possessing tert-acetates which lack α′-H (Scheme 6).
Scheme 6. Evidence for the Involvement of α′-H Employing
a
tert-Propargylic Acetates (Lacking α′-H)
a
Reaction conditions: 12 (1 equiv), DIPEA (5 equiv), CH Cl , 0 °C
2
2
to rt.
When these α,α-diiodo-α′-acetoxyketones 12a−e were sub-
jected to standard reaction conditions, DIPEA (5 equiv),
CH Cl , 0 °C to rt, only the corresponding monoiodoketones
α-iodo-α′-benzyloxyketone 10u and Ac O was performed
2
(Scheme 8A). Accordingly, 10u was subjected to standard
2
2
reaction conditions but in the presence of Ac O (8 equiv). To
2
1
3a−e were isolated as the sole products. No trace of α-
our delight, it resulted in a (1:0.26) mixture of α-
benzyloxyenone 11u (routine product) and the crossover
product α-(acyloxy)enone 11a along with 43% of α-(acyloxy)-
α′-benzyloxy ketone 20. Isolation of 11a supports the
intermediacy of the benzyloxycyclopropanone 16′ followed
by an intermolecular interception of the isomeric 1,4-dipole 18′
(
acyloxy)enones was detected even after prolonged reaction
times. This observation indicated involvement of the α′-H for
the conversion of monoiodoketones to α-(acyloxy)enones.
On the bais of the above observations (Schemes 5 and 6), we
propose a possible mechanistic pathway (Scheme 7). The
with acylium ion (generated from DIPEA and Ac O).
2
Scheme 7. Proposed Mechanism via a (Semi)Favorskii
Rearrangement to 2-Acyloxycyclopropanones and Their
Decycloisomerization
On the other hand, formation of the α-(acyloxy)-α′-
2
benzyloxy ketone 20 can be possible either via a simple SN
displacement of iodide in 10u with acetate ion (path a) or via a
regioselective ring opening of (benzyloxy)cyclopropanone 16′
by acetate ion (path b). To distinguish between these two
processes, a monoiodoketone 13a (lacks the α′-H there by
possibility for cyclopropanone formation) was subjected to
standard reaction conditions in the presence of Ac O (Scheme
2
8
B). Surprisingly no reaction observed and the iodoketone 13a
was recovered. This experiment manifested the formation of 20
through the ring opening of the benzyloxycyclopropanone
2
N
intermediate 16’ (path b) over a simple S displacement (path
7
,8
a).
Finally, the synthetic utility of derived products was
described by converting the α-(acyloxy)enone 11a to9
corresponding 1,3-diarylpyrazole derivative 21 (Scheme 9).
The enone 11a upon reaction with phenylhydrazine hydro-
1
0
amine initially acts as a Lewis base and transforms the
diiodoketone 14 to the corresponding monoiodoketone 15 via
chloride in ethanol gave the pyrazole 21 in 60% yield.
In conclusion, we discovered and developed an unprece-
dented (semi)Favorskii rearrangement cascade of α-iodo-α′-
a monodeiodination. Next,deprotonation of the α′-H in 15 (by
2
amine as a Brønsted base) followed by an intramolecular S
N
process with α-iodide generates the (acyloxy)cyclopropanone
Scheme 9. Synthesis of 1,3-Diarylpyrazoles
1
6 in a net (semi)Favorskii rearrangement. Since no
nucleophile is present for a classical Favorskii reaction, the
cyclopropanone 16 may undergo a decycloisomeirzation (ring−
chain valence tautomerism) to give oxyallyl cation 17 which is a
resonance structure of 1,4-dipole 18. This 18 further undergoes
C
DOI: 10.1021/acs.orglett.8b00218
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
acetoxyketones. The intermediacy of (acyloxy)cyclopropanones
has been proved by various fruitful control experiments
including a crossover experiment. These cyclopropanones
were found to undergo an unconventional decycloisomerization
to yield α-(acyloxy)enones and were inert for classical Favorskii
functionalizations. During this process, the synchronous dual
basicity (Lewis and Brønsted) of amines was also explored for
the efficient conversion of α,α-diiodo-α′-acetoxyketones to α-
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(
acyloxy)enones via α-iodo-α′-acetoxyketones. This process
was found to be very general for diverse substrates, highly
efficient, and spontaneous.
ASSOCIATED CONTENT
Supporting Information
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1
13
which includes soft copy of each H and C NMR
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AUTHOR INFORMATION
Corresponding Author
■
1
991, 103, 577. (h) Pujanauski, B. G.; Bhanu Prasad, B. A.; Sarpong,
*
E-mail: beeru@iitm.ac.in.
R. J. Am. Chem. Soc. 2006, 128, 6786. (i) Sun, T.; Zhang, X. Adv. Synth.
Catal. 2012, 354, 3211.
ORCID
(
5) (a) Sadhukhan, S.; Baire, B. Chem.Select 2017, 2, 8500.
(b) Sadhukhan, S.; Baire, B. Adv. Synth. Catal. 2018, 360, 298.
6) Clayden, J.; Geeves, N.; Warren, S. Organic Chemistry, 2nd ed.;
Oxford University Press, 2012; pp 193−194. ISBN: 978-0199270293.
7) At this stage we do not have any other strong evidence to rule out
Beeraiah Baire: 0000-0001-8810-1620
Notes
(
The authors declare no competing financial interest.
(
2
the possibility of the SN displacement; hence, we presume that both of
ACKNOWLEDGMENTS
them can contribute to the formation of 20.
■
(
8) We also performed experiments in the presence of various
electrophiles (MeI) or 2π (dimethyacetylene dicarboxylate) and 4π
furan) systems to trap the 1,4-dipoles/1,3-dipoles, respectively. In all
cases, we observed only our regular product α-(acyloxy)enone.
9) Cheung, K.-M. J.; Matthews, T. P.; James, K.; Rowlands, M. G.;
We thank the Indian Institute of Technology Madras, Chennai,
for the infrastructural facility. We thank SERB-INDIA for
financial support through EMR/2016/000041 grant. S.S. thanks
IIT Madras for HTRA fellowship.
(
(
Boxall, K. J.; Sharp, S. Y.; Maloney, A.; Roe, S. M.; Prodromou, C.;
Pearl, L. H.; Aherne, G. W.; McDonald, E.; Workman, P. Bioorg. Med.
Chem. Lett. 2005, 15, 3338.
DEDICATION
■
Dedicated to Prof. S. Sankararaman on the occasion of his 60th
birthday.
(
10) Pu
̈
nner, F.; Sohtome, Y.; Sodeoka, M. Chem. Commun. 2016, 52,
1
4093.
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