1,4-Diketones from Cross-Conjugated Dienones: Potassium Permanganate-Interrupted Nazarov Reaction

Article abstract of DOI:10.1002/anie.201503696

A domino potassium permanganate-interrupted Nazarov reaction to yield syn-2,3-disubstituted 1,4-diketones via a decarbonylative cleavage of the Nazarov oxyallyl intermediate, believed to be without precedent, is presented. This process allows syn substituents to be established stereospecifically on the 2-carbon bridge connecting the ketone carbonyl carbons, and the formation of one carbon-carbon and two carbon-oxygen bonds. Two carbon-carbon bonds are cleaved in this process.

Full text of DOI:10.1002/anie.201503696

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International Edition: DOI: 10.1002/anie.201503696
German Edition: DOI: 10.1002/ange.201503696
Nazarov Reaction
1,4-Diketones from Cross-Conjugated Dienones: Potassium
Permanganate-Interrupted Nazarov Reaction**
Yonghoon Kwon, Devon J. Schatz, and Frederick G. West*
Abstract: A domino potassium permanganate-interrupted
Nazarov reaction to yield syn-2,3-disubstituted 1,4-diketones
via a decarbonylative cleavage of the Nazarov oxyallyl
intermediate, believed to be without precedent, is presented.
This process allows syn substituents to be established stereo-
specifically on the 2-carbon bridge connecting the ketone
carbonyl carbons, and the formation of one carbon–carbon
and two carbon–oxygen bonds. Two carbon–carbon bonds are
cleaved in this process.
T
here has been considerable development in the Nazarov
reaction[1,2] over the past two decades, particularly in the
exploration of alternative substrates,[3] catalytic asymmetric
variants,[4] skeletal rearrangement,[5] and domino/cascade
processes[6] involving the Nazarov intermediate. The latter
approach (interrupted Nazarov reaction) entails trapping the
oxyallyl cation intermediate with a variety of p nucleophiles
such as electron-rich arenes and enol derivatives or s nucle-
ophiles from organoaluminum reagents.[7] Additionally,
[4+3], [3+3], and [2+3] cycloadditions on the Nazarov
intermediates to afford bridged bicyclic ring systems have
been studied.[6a,b,g,h,j] To date, the synthetic utilities of the
Nazarov reaction and the interrupted Nazarov reaction have
been limited to the formation of cyclopentanones and their
derivatives.
Scheme 1. Use of potassium permanganate in the Nazarov cyclization.
With a goal of probing the proposed reactivity of
permanganate in the Nazarov reaction, we embarked on
screening reaction conditions (Table 1). As a control experi-
ment, dienone 1a was treated with KMnO4, and stirred for
18 h in dichloromethane. Direct oxidation of 1a was not
observed in this case and starting material was fully recovered
(entry 1). This result demonstrated that premature oxidation
of the starting dienone could be avoided. In anticipation of
the need for various additives to aid in solubilizing the
KMnO4, moisture sensitive Lewis acids were excluded from
the screening conditions. Initial attempts at using FeCl3·6H2O
resulted in the formation of syn-2,3-disubstituted 1,4-diketone
3a with an 11% isolated yield (entry 2). To the best of our
knowledge, this degradative transformation has no precedent.
The relative configuration of 3a was determined by single-
crystal X-ray diffraction analysis.[11] The syn relative config-
urations of the other diketone products were assigned by
analogy to 3a.
Carbon–carbon bond cleavage is an important process in
synthetic organic chemistry.[8] Along with ozonolysis, a well-
À
known classical C C bond cleaving reaction is potassium
permanganate oxidation of alkenes and oxidative cleavage of
the resulting diols under acidic conditions.[9] Considering the
high oxidizing potential of permanganate, we were curious to
see if permanganate could intercept the intrinsically electro-
philic oxyallyl cation intermediate via a [3+3] cycloaddition.
We envisioned the formation of a,a’-dihydroxycyclopenta-
nones, or further oxidation to the decarbonylated 1,4-
diketone products (Scheme 1). We were particularly inter-
ested in the potential transformation to 1,4 diketones because
they are widely used as synthetic building blocks to construct
heterocyclic 5-membered rings.[10]
Efforts to enhance the dissolution of permanganate in the
reaction mixture and promote higher yields produced two
conditions that were investigated further due to similar yields
of 3a (entries 7 and 9). When methanol was used as the
solvent (entry 7), side products incorporating a methoxide
group were observed by 1H NMR analysis. Therefore, we
decided to further investigate conditions involving dichloro-
methane, FeCl3·6H2O, and
a phase transfer catalyst,
[*] Y. Kwon, D. J. Schatz, Prof. F. G. West
Department of Chemistry, University of Alberta
E3-43 Gunning-Lemieux Chemistry Centre
Edmonton, Alberta, T6G 2G2 (Canada)
E-mail: frederick.west@ualberta.ca
BnNEt3Cl. However, the addition of substoichiometric
amounts of BnNEt3Cl resulted in a reduced yield of 3a
despite full consumption of the starting material 1a
(entry 10). A solvent screening process was then used to
determine if a two-solvent system would be more effective. It
was found that treating 1a with 1.5 equiv FeCl3·6H2O and
2.5 equiv KMnO4 in a 2:1 mixture of CH2Cl2/CH3CN at low
temperature (entry 14) furnished 71% yield of 3a. Addition-
ally, when 18-crown-6 was used as the additive, the solubility
[**] We thank NSERC for support of this work, and Dr. Robert McDonald
(University of Alberta X-ray Crystallography Lab) for obtaining the X-
ray crystal structure of 3a.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201503696.
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cess that has previously been observed with enones.[12] These
Table 1: Screening conditions for the KMnO4-interrupted Nazarov
reaction.[a]
reaction conditions were not applicable to substrate 1e,
containing aliphatic substituents, and no desired product was
formed. Other acid activators (TMSOTf, TiCl4, or HCl) and
exposure to room temperature failed to effect conversion of
1e to 3e.
Unsymmetrically substituted dienones (1 f–1j) did
undergo the permanganate-interrupted Nazarov reaction.
Adding a larger substituent at the C-5 position of dienone
1 f furnished 3 f in 52% yield. Notably, this product was
isolated as a mixture of atropisomers, presumably as a result
of the higher rotational energy barrier. Substrate 1g, differing
from 1a in the substitution of the methyl group with a propyl
group at C-4, provided 3g in good yield (66%). Substrate 1h,
lacking a substituent at the C-1 position, was transformed into
an a-substituted 1,4-diketone 3h in moderate yield (44%). In
this case, cyclopentenone 4h was isolated as a side product in
16% yield. The incompatibility of electron-rich arenes with
these conditions (e.g., entries 3 and 4) is supported by the
lower yield in the conversion of 1j to 3j (entry 10) as
compared with structurally similar 1i!3i, differing only in
the absence of a 4-methoxy group on the arene.
No. Acid
[equiv]
KMnO4 Solvent
[equiv]
Temp.
[8C]
Yield of
3a [%][b]
1
2
3
4
5
6
7
8
9
none
2
2
2
2
2
2
2
2
3
3
3
3
3
CH2Cl2
CH2Cl2
MeOH
MeOH
CH2Cl2
CH3CN
MeOH
CH2Cl2
rt[c]
rt[d]
rt
no rxn
11
1.2 FeCl3·6H2O
1.2 FeCl3·6H2O
0.2 Sc(OTf)3
excess HCl
excess HCl
excess HCl
no rxn
no rxn
NA[e]
NA[e]
28
rt
rt
rt[j]
rt
H2SO4
1.2 FeCl3·6H2O
rt
NA[e]
31
CH2Cl2/additive[f] rt
CH2Cl2/additive[g] rt
CH2Cl2/additive[f] rt
10 1.2 FeCl3·6H2O
11 1.2 FeCl3
12 1.2 FeCl3·6H2O
13 1.2 FeCl3·6H2O
14 1.5 FeCl3·6H2O 2.5
15 1.5 FeCl3·6H2O 2.5
22
NA[e]
trace[h]
49
CH3CN
rt[c]
CH2Cl2/CH3CN[i] rt
CH2Cl2/CH3CN[i] À15 to rt 71
CH2Cl2/additive[k] À15 to rt trace[h]
As this process involves scission of two carbon–carbon
bonds, any mechanistic scheme must involve multiple oxida-
tion events, a postulate supported by the requirement of at
least 2 equiv of KMnO4. In the absence of any relevant
mechanistic precedent for this type of transformation, we
have considered two possible mechanisms, either of which
requires 2 equiv of KMnO4 (Scheme 2). Nucleophilic trap-
ping of the oxyallyl cation intermediate by permanganate
anion after the 4p electrocyclization would afford an electron-
rich enolate intermediate (Mechanism A). The resulting
enolate could then be oxidized by second equivalent of
permanganate to cleave a carbon–carbon bond, resulting in
[a] Standard reaction time was 4 h unless otherwise noted. [b] Isolated
yield. [c] Reaction mixture was stirred 18 h. [d] Reaction mixture was
stirred 14 h. [e] 1a was fully consumed, but 3a was not found in
a complex mixture. [f] BnNEt3Cl (0.2 equiv) was added to dissolve
KMnO4. [g] BnNEt3Cl (0.4 equiv) was added. [h] Starting material was
present with a trace amount of 3a. [i] 2:1 v/v ratio [j] Reaction time was
30 min. [k] 18-crown-6 (0.2 equiv) was added.
of KMnO4 increased in dichloromethane, but only trace
amounts of 3a were observed (entry 15).
To investigate the substrate scope of this reaction, a series
of substituted dienone Nazarov substrates was prepared (in
one step from 3-pentanone or two
steps from the corresponding
Table 2: Synthesis of 1,4-diketones by KMnO4 interruptions of the Nazarov intermediates.[a]
enones via aldol condensations).
First, symmetrical divinyl ketones
were tested using the optimal con-
ditions discovered during the initial
screening process (Table 2). Dien-
one 1b afforded 1,4-diketone 3b in
good yield (60%). Under these
oxidizing conditions, we observed
that 1c, bearing an electron-rich
arene, was converted to 3c with
a reduced yield (26%). Maintaining
the reaction temperature at À158C
was necessary to obtain a higher
yield (45%) in this case. Compound
1d containing heteroaromatic sub-
stituents was converted to 3d in low
yield (17%). Substrates such as 3c,d
bearing electron-rich b substituents
have previously undergone efficient
interrupted Nazarov reaction,[7] so
the low yields in this case are likely
No.
Substrate
R1
R2
R3
R4
Product (yield)[b]
1
2
1a
1b
1c
1d
1e
1 f
1g
1h
1i
Ph
4-Cl-C6H4
4-MeO-C6H4
2-furyl
iPr
Ph
Ph
H
iPr
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
n-Pr
Me
Me
Me
Ph
3a (71%)
3b (60%)
3c (45%)
3d (17%)
NA[e]
4-Cl-C6H4
4-MeO-C6H4
2-furyl
iPr
1-Naph
Ph
3[c]
4[d]
5
6
7
8
9
3 f (52%)[f]
3g (66%)
3h (45%) + 4h (16%)
3i (55%)
Ph
Ph
10
1j
iPr
4-MeO-C6H4
3j (36%)
[a] Standard procedure: KMnO4 was dissolved in a 2:1 mixture of CH2Cl2 and CH3CN for 30 min at room
temperature. To the solution of KMnO4, FeCl3·6H2O was added and the mixture was stirred for 10 min.
The temperature was then lowered to À158C. The dienone was added at À158C and stirred for 3 h,
followed by additional stirring at room temperature for 1 h. [b] Yields are based on isolated product after
chromatography. [c] The reaction mixture was stirred at À158C for 4 h and filtered through silica.
[d] 2.0 equiv FeCl3·6H2O was used. The reaction mixture was stirred for 1 h at À158C and additional 4 h
at 08C. [e] Starting material was recovered from an intractable mixture of minor products. [f] Mixture of
=
due to competing C C oxidative
cleavage by permanganate, a pro- atropisomers.
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Scheme 2. Two proposed mechanisms for the permanganate interruption of the Nazarov reaction.
the loss of MnIII[9] to generate a carboxylate and a ketone.
Experimental Section
Carboxylate addition into the permanganate(VII) species in
equilibrium followed by loss of MnV and carbon dioxide
would afford a decarbonylated 1,4-diketone. The by-product
MnIII could then disproportionate to MnII and MnIV, or the
MnIII and MnV could undergo redox conversion to two MnIV
species.[9]
Representative procedure for the potassium permanganate-inter-
rupted Nazarov reaction (3a): Solvents (dichloromethane and
acetonitrile) were taken directly from fresh bottles without further
purification/drying processes. The reaction was carried out in an open
flask. 2.5 equiv KMnO4 (0.076 g, 0.48 mmol) was dissolved in
a mixture of CH2Cl2:CH3CN (2:1 ratio, 3 mL) and stirred for
30 min at room temperature. 1.5 equiv FeCl3·6H2O (0.077 g,
0.29 mmol) was then added and the mixture was stirred for a further
10 min. The reaction temperature was lowered to À158C and 1a
(solid, 0.050 g, 0.19 mmol) was added in one portion. Stirring at
À158C was continued for 3 h, then the reaction was allowed to warm
to room temperature. After 1 h, the solution was filtered through
a silica gel plug (2 cm thickness), which was then rinsed with 50 mL
ethyl acetate. The organic filtrate was concentrated by a rotary
evaporation and the residue was purified by flash column chroma-
tography (silica gel, 19:1!9:1 hexane:EtOAc) to provide the desired
product 3a (0.036 g, 71%) as a white crystalline solid: Rf 0.24
(hexanes/EtOAc 9:1); mp = 105–1078C; IR (cast film) 3029, 2930,
1708, 1495, 1454 cmÀ1; 1H NMR (400 MHz, CDCl3) d = 7.16–7.09 (m,
6H), 6.97–6.92 (m, 4H), 4.40 (s, 2H), 2.15 ppm (s, 6H); 13C NMR
(125 MHz, CDCl3) d = 208.0, 135.5, 128.7, 128.6, 127.3, 62.0,
29.3 ppm; HRMS (EI, M+) for C18H18O2 calcd. 266.1307, found: m/z
266.1307.
On the other hand, the oxyallyl cation could undergo
a concerted or stepwise [3+3] cycloaddition with permanga-
nate to produce a hypomanganate ester (Mechanism B), in
a homologous process to the [3+2] step that initiates alkene
cleavage. Through equilibrium of the MnV complexes, the a-
oxyanion could react with an additional MnVII, affording
tricyclic manganese complex A. Considering the initial [3+3]
cycloaddition provides syn-a,a’ substituents, the tricyclic
complex A would be a cis,trans-angular structure bearing
significant strain, which may disfavor this pathway. Notably,
in either mechanism the discharge of carbon dioxide rather
than carbon monoxide is proposed. Qualitative analysis via
conversion of Ba(OH)2 to BaCO3 provides support for the
formation of CO2.[13] However, further mechanistic studies
entailing characterization of minor side-products and
attempts to intercept proposed intermediates remain to be
done.
Keywords: 1,4-diketones · electrocyclization · Nazarov reaction ·
oxidative cleavage · potassium permanganate
In summary, we have demonstrated the first oxidative
decarbonylative cleavage of oxyallyl cation species in an
interrupted Nazarov reaction, employing the inexpensive
inorganic oxidant KMnO4. Potassium permanganate-inter-
rupted Nazarov reactions afforded syn-2,3-disubstituted 1,4-
diketones in moderate yield. This new method allows
How to cite: Angew. Chem. Int. Ed. 2015, 54, 9940–9943
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Received: April 22, 2015
Published online: July 3, 2015
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