Oxidation-Initiated Cyclizations of Pentadienyl Ethers: An Alternative Entry to the Nazarov Reaction

Article abstract of DOI:10.1002/anie.201701748

Oxidation-initiated Nazarov reactions of 1,4-pentadien-3-yl ethers take place in the presence of DDQ. Termination by regioselective elimination preserves both stereocenters created during electrocyclization, providing cyclopentanone products bearing an ex

Full text of DOI:10.1002/anie.201701748

Angewandte
Communications
Chemie
International Edition: DOI: 10.1002/anie.201701748
German Edition: DOI: 10.1002/ange.201701748
Synthetic Methods
Oxidation-Initiated Cyclizations of Pentadienyl Ethers: An Alternative
Entry to the Nazarov Reaction
Ryan J. Fradette, Minkyu Kang, and F. G. West*
Abstract: Oxidation-initiated Nazarov reactions of 1,4-penta-
dien-3-yl ethers take place in the presence of DDQ. Termi-
nation by regioselective elimination preserves both stereocen-
ters created during electrocyclization, providing cyclopenta-
none products bearing an exocyclic methylene unit. Use of
catalytic DDQ with MnO2 as terminal oxidant is also
described.
Scheme 1. Proposed oxidation-initiated Nazarov cyclization.
and report here a general and mild route to alkylidene
cyclopentenyl ethers via oxidative cyclization.
As a test reaction, substrate 1a was stirred with 1.5 equiv-
alents of DDQ in dichloromethane at room temperature for
4 h, resulting in consumption of the starting material and
clean formation of a single new product 2a (Figure 1).
I
n its classical form, the Nazarov reaction involves cyclization
of 1,4-dien-3-ones, either as starting materials or generated in
situ, to form cyclopentenones.[1] Contemporary studies have
revealed alternative methods to generate the key pentadienyl
cation intermediates needed for electrocyclization, reducing
the necessity for strong and often harsh acid initiators and
allowing broader latitude in substrate design.[2a–e] Recent
examples of alternative Nazarov reactions where substrates
maintain oxygenation at the 3-position include Brønsted acid
activation of alkoxy trienes[3a–c] and vinylsiloxyallenes.[4] In
both cases, activation occurs by protonation of an electron-
rich p bond to form the reactive 3-oxidopentadienyl cation
intermediate. AgI salts promote 2p electrocyclic opening of
dichlorocyclopropanol derivatives, leading to chlorocyclo-
pentenones.[5a,b] 1-Ethynyl-2-propenyl pivaloates have been
used in AuI-catalyzed cyclizations,[6] and a recent example of
allene oxide opening leading to Nazarov cyclization has been
reported.[7]
Figure 1. The DDQ-initiated Nazarov reaction of pentadienyl ether 1a.
Notably, the product proved to be an enol ether in contrast
to the enones typically formed in the Nazarov reaction. In
addition, eliminative termination in this case surprisingly
afforded exclusively an exocyclic olefin. As a consequence,
the two stereocenters generated stereospecifically in the
electrocyclization step were both preserved.[12] Following
optimization,[13] we found that 1.2 equiv of DDQ was
sufficient to drive the reaction to completion.
This cyclization likely proceeds via single electron transfer
from the p-system of bis(allylic) ether 1a, leading to radical
cation I (Scheme 2). Pentadienyl cation III is generated by
hydrogen atom abstraction by radical anion II, followed by 4p
electrocylization to give the 2-alkoxycyclopentenyl cation V.
A regioselective elimination follows, with exclusive deproto-
nation at the methyl group. While the benzylic methine is
presumably more acidic, this termination appears to be
influenced by steric demand and the likely close proximity
of the hydroquinone anion to the methyl group following
hydrogen abstraction.
Skipped dienes bearing an ether moiety at the doubly
allylic C-3 position can be viewed as precursors to 3-oxy-
genated pentadienyl cations by an oxidative path. We
anticipated that the ether could undergo formal loss of
hydride to form an oxocarbenium cation able to undergo
Nazarov cyclization (Scheme 1). There is ample precedent for
single electron oxidation of benzyl and allyl ethers. Benzo-
quinones, particularly DDQ, are used for deprotection of p-
methoxybenzyl ethers,[8] and to a lesser degree, allyl ethers.[9]
Additionally, domino and cascade processes have been
initiated by oxidative oxocarbenium ion formation from
benzyl ethers,[10a–h] allyl ethers,[10e] and styryl ethers,[11a–c]
followed by trapping with a variety of nucleophiles. Consid-
ering these precedents, we examined the use of DDQ to
initiate Nazarov cyclization of pentadienyl ether substrates,
We sought to expand the scope of this reaction beyond
substrate 1a, with an initial focus on what range of ether
substituents could be tolerated, as well as the effect of
electronic perturbation of the cinnamyl group (Table 1).
Substrates were prepared by etherification of the correspond-
ing dienols with the appropriate alkyl halides.[13] We initially
examined ether substituents containing functional groups that
would be unlikely to be oxidized in the presence of the
[*] Dr. R. J. Fradette, M. Kang, Prof. F. G. West
Department of Chemistry, University of Alberta
E3-43 Gunning-Lemieux Chemistry Centre
Edmonton, AB, T6G 2G2 (Canada)
E-mail: frederick.west@ualberta.ca
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.201701748.
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In a series of benzyl ether derivatives, unsubstituted
benzyl ether 1e underwent cyclization without complication
(entry 5). The electron-withdrawing 4-bromobenzyl moiety of
1 f and mildly electron-donating p-methylbenzyl group in 1g
were expected to have greater oxidation potentials than the
bis(allylic) ether, and were expected to undergo the desired
Nazarov cyclization (entries 6 and 7). In the event, 4-
bromobenzyl substrate 1 f gave cyclopentenyl ether 2 f as
the exclusive product. However, while the 4-methylbenzyl
substrate 1g gave a moderate yield of the Nazarov product
2g, traces of 4-tolualdehyde and dienol 1o were observed in
the crude 1H NMR spectrum, resulting from competing
oxidative cleavage of the 4-methylbenzyl group. We also
tested the 4-methoxybenzyl derivative 1h with the expect-
ation that the reaction conditions were likely to remove the 4-
methoxybenzyl ether, given the low oxidation potential of 4-
methoxybenzyl alcohol (Eox8 = 1.22 V)[15] and ample prece-
dent for DDQ-mediated deprotection of 4-methoxybenzyl
ethers.[8] This reaction led to a complex mixture of products
Scheme 2. Proposed DDQ-initiated oxidative Nazarov mechanism.
DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone.
1
bis(allylic) ether based on the reported oxidation potential of
a comparable compound (cinnamyl alcohol Eox8 = 1.36 V).[14]
Ether 1b, the n-butyl homologue of the methyl ether test
substrate underwent clean and high yielding oxidative
Nazarov cyclization using the optimized conditions. Next,
we investigated the allyl ether- bearing substrate 1c; based on
the observations of Lund,[14] the oxidation potential of allyl
alcohol is greater than 2.0 V, persuading us that the DDQ
oxidation would be regioselective to furnish the desired
pentadienyl cation. In practice, the reaction generating 1c was
high yielding with no evidence of allyl ether cleavage.
Similarly, propargyl ether 1d was successfully converted to
2d.
with H NMR resonances corresponding to 4-anisaldehyde,
dienol 1o, dibenzylidiene-3-pentanone 3a, unreacted bis-
(allylic) ether 1h, and signals characteristic of the exocyclic
olefin observed for previous enol ether products 2a–2g
(entry 8). Unfortunately, attempts to isolate pure enol ether
2h were unsuccessful.
We prepared ethers 1i and 1j, bearing 3-methoxybenzyl
and 3-methoxyphenyl ether moieties to evaluate the potential
for an interrupted Nazarov process in which electron-rich aryl
groups might intercept the intermediate 2-alkoxycyclopen-
tenyl cations.[2b] Using the optimized reaction conditions we
observed clean conversion to cyclized products 2i and 2j with
no evidence of additional bond formation (entries 9, 10).
Table 1: DDQ-initiated Nazarov cyclization of symmetrical bis(allylic) ethers.
Entry
Ether
R1
R2/R5
Time [h]
Product
Yield [%][a]
Substrate
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1 f
1g
1h
1i
1j
1k
1l
1m
1n
1o
Me
Bu
CH2CH CH2
CH2CCH
Bn
CH2(4-BrC6H4)
CH2(4-MeC6H4)
CH2(4-OMeC6H4)
CH2(3-OMeC6H4)
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
4.0
3.0
2.5
1.0
8.0
8.0
2.0
2a
2b
2c
2d
2e
2 f
2g
–
92
88
85
90
82
89
67[b]
=
[c,d]
–
9
Ph
Ph
2i
2j
86
81
93
86
89
84
94
10
11
12
13
14
15
3-OMeC6H4
Bn
Me
Bn
Me
H
4-OMeC6H4
4-OMeC6H4
4-ClC6H4
4-ClC6H4
Ph
2k
2l
2m
2n
3a
[a] Yields given are for isolated product after purification. [b] Traces of alcohol 1o, ketone 3a, and p-tolualdehyde were observed in the crude 1H NMR
spectra. [c] Traces of alcohol 1o, ketone 3a, and p-anisaldehyde were observed in the crude 1H NMR spectra. [d] Characteristic signals consistent with
1
the desired oxidative Nazarov product 2h were observed in the crude H NMR spectra; however, pure product could not be isolated.
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Lowered reaction temperatures served only to decrease the
oxidant. Both HNO3[17] and FeCl3[18] are known to regenerate
rate of reaction.
DDQ from its hydroquinone form; however, one goal of this
approach to the Nazarov reaction was avoidance of strong
Brønsted or Lewis acids. Guided by reports from Liu and
Floreancig[19] and Helquist and co-workers[20] describing the
use of MnO2 and Mn(OAc)3 respectively as terminal oxidants
for DDQ, we applied these reagents to the oxidation-initiated
Nazarov process. In theory, one equivalent of MnO2 or two
equivalents of Mn(OAc)3 should suffice for complete oxida-
tion of the ether substrate via regeneration of catalytic DDQ.
However, in practice a larger excess of terminal oxidant was
found to be necessary to consume 1a in an experimentally
convenient timeframe (Figure 2). While these reactions
Aromatic substitution on the styryl moieties had only
minor effects on the reaction (entries 11–14). Methoxy-
substituted substrates 1k and 1l underwent successful Naz-
arov reaction in 2.5 and 1.0 hours, respectively, while 4-
chlorophenyl bearing substrates 1m and 1n gave the expected
products in 8 hours. These results suggest that the DDQ
oxidation step is rate limiting. Regardless of ether substitution
or terminal arene, all Nazarov cyclization products 2a–
n possessed an exocyclic methylene moiety resulting from
exclusive elimination with complete regioselectivity. Finally,
the presence of an unprotected alcohol was not tolerated, as
only ketone oxidation product 3a was obtained (entry 15).
We turned to unsymmetrical substrates to probe the
regioselectivity of the eliminative step (Scheme 3). Substrates
Figure 2. The use of catalytic DDQ with a MnIV or MnIII terminal
oxidant.
occurred in comparable yield to those using stoichiometric
quantities of DDQ, the time to completion was noticeably
greater, indicating that other co-oxidants may merit exami-
nation.
We have demonstrated the first oxidation-initiated Naz-
arov reactions of pentadienyl ethers, using DDQ to convert
a wide range of 3-alkoxy-1,4-pentadienes to pentadienyl
cations subject to standard Nazarov 4p electrocyclization.
The products are enol ethers bearing an exo methylene, the
result of a highly regioselective elimination step. Notably, the
exo-selective elimination leaves the two stereocenters gen-
erated in the electrocyclization intact. The oxidative Nazarov
cyclization permits the use of a new class of alternative
substrates, a mild method of activation, affords a new type of
dienol ether Nazarov products, and can be carried out with
substoichiometric quantities of the quinone oxidant.
Scheme 3. DDQ-initiated Nazarov cyclization products derived from
unsymmetrical substrates.
1p and 1q differentially substituted with aryl and isopropyl
groups at the termini underwent oxidative Nazarov cycliza-
tion in high yield to afford 2p and a pair of regioisomeric
dienol ethers 2q and iso-2q.[15] In both cases, high or complete
selectivity for elimination at the methyl group adjacent to the
isopropyl substituent was observed, which may arise from
lower steric demand by the isopropyl group.
Experimental Section
Representative procedure: Conversion of 1a to 2a via oxidative
Nazarov cyclization. Bis(allylic) ether 1a (56 mg, 0.20 mmol) was
dissolved in CH2Cl2, 2,3-dichloro-4,5-dicyano-1,4-benzoquinone
(55 mg, 0.24 mmol) was added, and the reaction mixture immediately
turned a deep purple color. The reaction was stirred at RT until
starting material was consumed as observed by TLC (4 h). The
reaction mixture was then filtered through a silica gel plug and eluted
with CH2Cl2 (50 mL). The filtrate was concentrated, and further
purification by flash chromatography gave 51 mg (92%) of enol ether
2a as a colorless oil.
Unsymmetrical substitution at the 2- and 4-positions of
the pentadienyl scaffold was also probed. Complete removal
of one methyl group (substrates 1r and 1s) did not affect the
overall efficiency of the oxidative Nazarov cyclization. More-
over, no evidence of competing endocyclic elimination was
observed, and only exo-methylene products 2r and 2s were
isolated. Substrates 1t and 1u, bearing methyl and n-propyl at
the 2- and 4-positions, showed high selectivity for elimination
from the more sterically accessible methyl group, affording 2t
exclusively and a 10:1 ratio of 2u and iso-2u as an inseparable
mixture.
Rf 0.51 (10:1 Hexane : EtOAc); IR (film): 3084, 3061, 3027, 2922,
1
2851, 1634, 1492, 1453, 1140 cmÀ1; H NMR (500 MHz, CDCl3): d =
7.32–7.27 (m, 4H), 7.25–7.20 (m, 2H), 7.14–7.09 (m, 4H), 5.08 (m,
1H), 4.54 (m, 1H), 3.87 (s, 3H), 3.66 (m, 1H), 3.57 (m, 1H), 1.67 ppm
(m, 3H); 13C NMR (125 MHz, CDCl3): d = 154.4, 150.7, 144.9, 143.9,
129.2, 128.6, 128.5, 127.8, 127.6, 126.6, 126.4, 101.6, 60.4, 59.7, 56.2,
11.9 ppm; HRMS calcꢀd for C20H20O (M+) 276.1514; found 276.1512.
The moderate toxicity of DDQ[16] and the potential for
HCN liberation in the presence of moisture prompted us to
consider use of catalytic DDQ with a stoichiometric terminal
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Conflict of interest
The authors declare no conflict of interest.
Keywords: electrocyclic reactions · Nazarov cyclization ·
oxidation · quinones · synthetic methods
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Manuscript received: February 16, 2017
Final Article published: && &&, &&&&
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Synthetic Methods
R. J. Fradette, M. Kang,
F. G. West*
&&&& — &&&&
Oxidation-Initiated Cyclizations of
Pentadienyl Ethers: An Alternative Entry
to the Nazarov Reaction
Dehydrogenative Nazarov reaction: 1,4-
Pentadien-3-yl ethers undergo oxidative
conversion to the corresponding 3-alk-
oxypentadienyl cations followed by clean
Nazarov cyclization and regioselective
exocyclic elimination to furnish alkylidene
cyclopentenol ethers with the net loss of
H2. This method provides mild, Lewis
acid-free access to Nazarov products in
which the stereogenic centers formed in
the electrocyclization are preserved.
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