Iodine(III)-Promoted Ring Contractive Cyanation of Exocyclic β-Enaminones for the Synthesis of Cyanocyclopentanones

Article abstract of DOI:10.1002/adsc.201601208

A highly efficient hypervalent iodine-promoted regiocontrolled ring contractive cyanation (RCC) reaction of exocyclic β-enaminones for the synthesis of cyanocyclopentanone (CCP) was demonstrated at ambient temperature with a wide substrate scope. The meth

Full text of DOI:10.1002/adsc.201601208

Title: Iodine(III) Promoted Ring Contractive Cyanation of Exocyclic β-
enaminones to Cyanocyclopentanones Synthesis
Authors: Dhananjay Bhattacherjee, Vandna Thakur, Saurabh Sharma,
Sandeep Kumar, Richa Bharti, C Bal Reddy, and Pralay Das
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201601208
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10.1002/adsc.201601208
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Iodine(III) Promoted Ring Contractive Cyanation of Exocyclic
β-enaminones to Cyanocyclopentanones Synthesis
Dhananjay Bhattacherjee,a,b Vandna Thakur,a,b Saurabh Sharma,a,b Sandeep Kumar,a,b
Richa Bharti,a,b C. Bal Reddy a,b and Pralay Das*a,b
a
Natural Product Chemistry and Process development division, CSIR- Institute of Himalayan Bioresource Technology,
Palampur-176061, H.P, India, Fax: +91-1894-230433, E-mail: pdas@ihbt.res.in, pdas_nbu@yahoo.com
Academy of Scientific and Innovative Research, New Delhi, India
b
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. A highly efficient hypervalent iodine promoted
regiocontrolled ring contractive cyanation (RCC) reaction
of exocyclic β-enaminones to cyanocyclopentanone (CCP)
synthesis was demonstrated at ambient temperature with
wide substrate scope. The methodology offers a facile
technique to construct amino carbonitrile containing
quaternary stereocenter at the α-position of cyclopentanone
in good yields. The sequence of substrates addition can
facilitate the reaction to follow the different pathways (free
radical/ non radical) to afford the same final product was
critically investigated.
Keywords: hypervalent iodine; cyclopentanone; ring
contraction; β-enaminone; sodium azide
Cyclopentanone derivatives with
a
quaternary
stereocenter serve as basic structural skeletons in
numerous biologically active natural products such as
opaliferin[1], guanacastepene A[2] and estrone.[3]
Traditional methods of cyclopentanone synthesis
includes pyrolysis of adipic acid and its derivatives,[4]
the oxidation of cyclopentenes[5] and ring expansion
reactions.[6] Further, the ring contraction reaction is
an alternative approach for cyclopentanone analogue
Scheme 1: common strategies of ring contractive
cyanation.
cycloperambulatory mechanism.[9]
Tichy et al.
developed nitrile substituted cyclopentadiene from N-
phenyl-3-nitropyridinium ion through vibrationally
excited
singlet
nitrene
formation.[10]
The
synthesis
from
epoxy-/
unsaturated-
thermolytical decomposition of 2-azidopyridine-1-
oxide to 2-cyano-1-hydroxy pyrroles in toluene,[11]
are among the most highlighted protocols for the
RCC reactions. In general, the use of organic azides
as starting materials that led to the formation of
nitrene intermediate under photolytic or thermal
conditions paved the way to ring rearrangement and
simultaneous cyanation reaction.
Recently, hypervalent iodine compounds have
been widely used in different organic transformations
owing to their mild oxidizing nature, excellent
leaving tendency and ability to initiate free radical.[12]
Moreover, hypervalent iodine mediated ring
contraction reactions are limited to glycals,[13] cyclic
ketones and olefins.[12b] To the best of our knowledge,
cyclohexanones.[7]
Among the reported protocols of ring contraction
reactions, the area of ring contractive cyanation
(RCC) remains less explored, which attracted our
attention to work in this area. However, Moore et al.
described a conventional approach for the synthesis
of 2-azetidinones via RCC reaction which is
restricted to 4-azido-2-pyrrolinone compounds at
elevated temperatures.[8a] Moreover, ring contraction
and concurrent cyanation of 2-azido-1,4-quinone via
a zwittazido cleavage mechanism has also been
demonstrated.[8b,8c]
Recently,
flash
vacuum
thermolysis (FVT) has been applied for
cyanocyclopentadiene synthesis from phenyl azide
and isatin at 500-715 oC following
1
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10.1002/adsc.201601208
Advanced Synthesis & Catalysis
there is no available report for the RCC reaction of
exocyclic β-enaminones using hypervalentiodine (III)
(Kosers reagent) in combination with inorganic azide
as the nitrogen source.
Among the different solvents, only chlorinated
solvents were found to be active for the RCC reaction
(Table 1, entries 1-3, 17). Replacement of NaN3 by
TMSN3 did not lead to the formation of desired RCC
product (Table 1, entry 4). Then, various hypervalent
iodine compounds were also screened but no product
formation was observed (Table 1, entry 12-13).
Further changing the reaction temperature or
stoichiometry of the HTIB, no significant changes
were observed in product yields (Table 1, entry 14-
16). The highest yield of the product was obtained by
using 1 equiv. of 1a, 1.2 equiv. of HTIB and 5 equiv.
of NaN3 in 2 mL CH2Cl2 solvent at ambient
temperature under nitrogen atmosphere (Table 1,
entry 17). During optimization we noticed very
interesting role of sequential addition of substrates
(NaN3, HTIB and exocyclic β-enaminones) on their
Over the last few years, we have been working to
develop methodology for new and known classes of
substituted cyclohexane-1,3-dione synthesis and their
applications.[14] In context of our investigation, herein
we
report
synthesis
of
different
cyanocyclopentanones (CCP) from exocyclic β-
enaminones via ring contractive cyanation (RCC)
reaction using hydroxy(tosyloxy)iodobenzene (HTIB)
and NaN3 at ambient temperature. A very interesting
and unusual role of sequential addition of substrates
on the course of reaction mechanism for the final
product formation was critically investigated.
In a trial reaction, we observed a very unusual ring
contraction of exocyclic β-enaminones. With this lead, reactivity. The mechanism of the present reaction
we began our optimization studies choosing 3-
(phenylamino)cyclohex-2-enone 1a as a bench stable
model substrate using HTIB and sodium azide.
could probably follow two different routes depending
on the mode of addition of sodium azide.
On the basis of the above observations and the
precedent literature,[8-9],[15],[17] we propose a plausible
mechanistic pathway for the ring contraction and
concurrent cyanation reaction (Scheme 2). Initially,
the ligand exchange reaction occurs between HTIB
(I) and sodium azide leading to the formation of
intermediate II. Thermal homolytic cleavage of II
Table 1: Optimization studies of RCC reaction for CCP
synthesis[a]
Scheme 2: Proposed mechanism for RCC reaction of
exocyclic β-enaminone on one pot addition of sodium
azide.
may generate the azide radical III which further
trapped by the β-enaminone 1a forming intermediate
IV.[9],[17] The proposal subsequently supported by
separate treatment with (2,2,6,6-tetramethylpiperidin-
1-yl)oxy (TEMPO) and O2 as radical scavenger
which substantially decreased the product formation,
could be an evidence that the reaction may be
following radical pathway (supporting information).
Recently, Hu et al. described the reactivity of vinyl
azide and their participation in carbocyclic
rearrangement reactions.[17a] They suggested that the
[a]
Reaction conditions: 1a (0.5347 mmol), hypervalent
iodine(III) (0.6417 mmol), NaN3 (2.673 mmol) in
dichloromethane (2 mL) for 12 h.; n.d. = not detected,
n.r.
=
no
reaction,
HTIB
=
[hydroxy(tosyloxy)iodo]benzene].
Isolated yield.
NaN3 (1.2 equiv.) was used.
HTIB (0.8 equiv).
Reaction temperature was 40 ºC.
HTIB (2 equiv.).
[b]
[c]
[d]
[e]
[f]
2
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10.1002/adsc.201601208
Advanced Synthesis & Catalysis
intermediate IV was similar to a cyclic vinyl azide
and the ring strain usually inhibited the formation of
bicyclic fused azirine and led to the formation of
zwitterionic intermediate V. Intermediate V favored
the formation of 2a via an electrocyclic ring closing
reaction of VI.[17b] [8b]
[a]
Reaction conditions: 1a (1 mmol.), HTIB (1.2 mmol.)
and sodium azide (5 mmol.) in dichloromethane solvent
(2 mL) for 12 h at room temperature (rt).
Isolated yield.
[b]
[c]
Scheme 3: Proposed mechanism for ring contraction and
concurrent cyanation of exocyclic β-enaminone on
sequential addition of sodium azide.
Reaction carried out at 0 ̊ C.
The optimized reaction conditions were further
applied to explore the substrate diversity of various β-
enaminones by assessing the electronic effect on
amino substituted aryl groups (Table 2). Both the
sequences as stated in Scheme 2 and 3 were followed
to see any effect on the product yield, but no
significant influence was observed for the selected
substrates. Therefore, one pot addition of substrates
was followed for simple and easy access of the
reactions (Scheme 2). Electron deficient groups such
as p-CN, m-NO2, p-CF3, p-COCH3, p-CO2CH3 and p-
CO2CH2CH3 aryl amine substituted β-enaminones
1b-g performed excellently and delivered the
corresponding CCP products 2b-g in 72-81% yields.
Electron rich aryl amine substituted β-enaminones
1h-i gave 64-66% yield of the desired product 2h-i.
Electron pulling effect may stabilized the zwitterionic
intermediate VI and facilitate the formation of final
product. Interestingly, the haloaryl amino substituted
β-enaminones 1j-m participated well in the reaction
and delivered the anticipated cyclopentanones 2j-m
in 72-77% yields. In such cases, electronegativity of
halogen atom might influence the facile
transformation into the product. In addition, 4-vinyl
substituted β-enaminone 1n gave the desired
cyclopentanone 2n in 59% yield. We next targeted β-
enaminones 1o-q for RCC reaction, but unfortunately
no product was detected, possibly due to either
electronic or steric effect which hinders the formation
Interestingly, the reaction probably followed another
route when HTIB was added into a solution of β-
enaminone 1a (step 1) and stirred for 1 h in DCM at
ambient temperature followed by the addition of
NaN3 in step 2 (Scheme 3). In step 1, HTIB
undergoes ligand exchange reaction with β-
enaminone 1a to form intermediate VII, which
participated in conjugation through elimination of
TsOH to give VIII as stable intermediate.[18] The
intermediate VIII was purified, determined by mass
and NMR spectroscopy (supporting information).
Upon prolonged stirring at room temperature,
intermediate VII slowly converted into intermediate
IX, which was also confirmed by mass and NMR
(supporting information). When IX was isolated and
further treated with sodium azide, no conversion to
product was observed, which indicated that the
reaction does not react through intermediate IX. In
step 2, when VIII was treated separately with sodium
azide, the desired CCP product 2a was obtained in
comparable yield, which probably follow the similar
path as that proposed in Scheme 2. Addition of
TEMPO didn’t show significant effect on the
reactivity in this step-wise reaction, which could
indicate the possible non radical pathway (Scheme 3).
Table 2: Electronic effect at the aromatic ring of exocyclic
β-enaminones in RCC reaction.[a][b]
Table 3: Effect of substitution at cyclohexenyl moiety of
exocyclic β-enaminones in RCC reaction.[a][b]
3
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10.1002/adsc.201601208
Advanced Synthesis & Catalysis
addition of sodium azide (Scheme 3) highly
influenced the yields of 3e-l to 56-76%. The reason
may be in case of highly substituted electron rich β-
enaminones 1v-1ac, C-2 carbon behaving as good
nucleophile and participated in the reaction with
HTIB faster and favoured similar intermediates XI
and XII, which afforded high yield of the products
(Scheme 3).
The structure of the products was further
confirmed by single crystal XRD study of compound
2a and 3a (Figure 1) (detailed provided in supporting
information).
O13
C3
N1
C2
C8
C12
C4
C5
C10
C1
N7
C7
C9
C6
C11
[a]
Reaction conditions: 1r-ac (1 equiv.), HTIB (1.2 equiv.)
2a
and NaN3 (5 equiv.) in dichloromethane solvent (2 mL)
for 12 h at room temperature (rt).
Isolated yield.
[b]
[c]
[d]
[e]
Figure 1: X-ray single crystal structures of 2a and 3a.[16]
NaN3 was added in one pot manner.
Diastereomeric mixture was isolated.
NaN3 was added sequentially after 1 h.
In conclusion, we have demonstrated a general
method for ring contractive cyanation (RCC) reaction
of exocyclic β-enaminones to produce CCP products
following a one-pot consecutive approach. The
significant role of HTIB and sodium azide for
product formation and the critical involvement in
mechanistic steps were investigated. Several new
classes of cyclopentanones were synthesized under
this method with wide substrate scope in good yields.
of intermediates (IV, V and VI; Scheme 2) without
aryl substitution at N-atom of β-enaminone.
Moreover, β-enaminones derived from cyclopentane-
1,3-dione and aryl amine did not lead to the
formation of ring contraction product might be due to
its high strain and instability in the reaction media
(Scheme 4, Supporting information).
Next, we evaluated the substitution effect on
cyclohexenone moiety of β-enaminones under
standard reaction conditions.
A series of β-
Experimental Section
enaminones with methyl substitution at various
positions remarkably affect the yield of the
corresponding CCP products (Table 3). Methyl
substitution at C-5 and C-6 position of β-enaminones
afforded desired CCP products 3a-d in 59-64% yields.
It is noteworthy that the compounds 3c and 3d were
isolated as diastereomeric mixture (Table 3). This
result suggests that β-enaminones of electron rich
methyl substituted cyclohexane-1,3-diones may have
largely destabilized transition states V to VI (Scheme
2) and therefore decrease the product yield. Further,
this concept was supported by taking 5,5-dimethyl
substituted β-enaminones 1v-1ac under the standard
reaction condition (Scheme 2) delivered the expected
CCP products, 3e-l only in 38-49% yields.
Surprisingly, we found that the change in the mode of
To an oven dried screw cap reaction vial 3-
(phenylamino)cyclohex-2-enone 1a (100 mg, 0.5347
mmol), HTIB (251.5 mg, 0.6417 mmol), sodium azide
(179 mg, 2.6735 mmol) and dichloromethane (DCM, 2
mL) were added under N2 atmosphere. The reaction
mixture was allowed to stir for 12 h at room temperature
under N2 atmosphere and the progress of reaction was
monitored by TLC. On completion of the reaction, the
reaction mixture was concentrated under reduced pressure
and the crude residue was subjected to column
chromatography on silica gel (mesh 60-120) using
hexane:EtOAc gradient to get the product 2a (74.8 mg,
70%) as white solid; mp: 90.7-92.2 oC. 1H, 13C NMR, GC-
MS, HRMS and FTIR data are provided in supporting
information.
Acknowledgements
4
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10.1002/adsc.201601208
Advanced Synthesis & Catalysis
We are grateful to the Director of CSIR-IHBT for providing the
necessary facilities during the course of this work. The authors
thank CSIR, New Delhi for financial support as part of the XIIth
Five Year Plan programme under title ORIGIN (CSC-0108). We
also thank Mr. Puneet Sood, AMRC, IIT Mandi, for HRMS,
crystal XRD and CIL, PU-Chandigarh for IR analysis. DB, VT,
SS, SK, RB, and CBR thank UGC and CSIR, New Delhi for
awarding fellowships.
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5
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10.1002/adsc.201601208
Advanced Synthesis & Catalysis
COMMUNICATION
Iodine(III) Promoted Ring Contractive Cyanation
of Exocyclic β-enaminones to
Cyanocyclopentanones Synthesis
Adv. Synth. Catal. Year, Volume, Page – Page
Dhananjay Bhattacherjee,Vandna Thakur, Saurabh
Sharma, Sandeep Kumar, Richa Bharti, C. Bal
Reddy and Pralay Das*
6
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