Cyclohexenynone Precursors: Preparation via Oxidative Dearomatization Strategy and Reactivity

Article abstract of DOI:10.1021/jacs.8b08915

A unique approach toward the preparation of cyclohexenynone equivalents was successfully developed via oxidative dearomatization of aryne precursors, featuring multiple functionalities on the target rings. Upon activation, these in situ formed cyclohexenynone intermediates exhibit good to excellent reactivity with various trapping agents. Moreover, an unprecedented cascade was discovered with aryl allyl sulfoxides, revealing a deeper utilization of the alkyne bond by concomitantly introducing one nucleophile and two electrophiles.

Full text of DOI:10.1021/jacs.8b08915

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Communication
Cyclohexenynone Precursors: Preparation via
Oxidative Dearomatization Strategy and Reactivity
Dachuan Qiu, Jiarong Shi, Qianyu Guo, Qiuxia Xu, Baosheng Li, and Yang Li
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.8b08915 • Publication Date (Web): 04 Oct 2018
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Cyclohexenynone Precursors: Preparation via Oxidative Dearomati-
zation Strategy and Reactivity
Dachuan Qiu,† Jiarong Shi,† Qianyu Guo, Qiuxia Xu, Baosheng Li, Yang Li*
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School of Chemistry and Chemical Engineering, Chongqing University, 174 Shazheng Street, Chongqing, P. R. China,
400030
Supporting Information Placeholder
might perturb both the physical property and chemical reactivity
ABSTRACT: A unique approach towards the preparation of
of a cyclohexyne intermediate. Comparing with those abundant
arene substitution methods ranging from college textbooks to
modern advanced synthesis,13 unfortunately, ways to conveniently
modify those unactivated sites on an aliphatic ring are rare. There-
fore, it is of great interest to develop efficient means to incorpo-
rate various substituents/functional groups on the non-active sites
of a cyclohexyne precursor in, preferentially, chemo- and regiose-
lective manner so as to expand the realm of cyclohexyne.
cyclohexenynone equivalents was successfully developed via
oxidative dearomatization of aryne precursors, featuring multiple
functionalities on the target rings. Upon activation, these in situ
formed cyclohexenynone intermediates exhibit good to excellent
reactivity with various trapping agents. Moreover, an unprece-
dented cascade was discovered with aryl allyl sulfoxides, reveal-
ing a deeper utilization of the alkyne bond by concomitantly in-
troducing one nucleophile and two electrophiles.
Scheme 1. Background and our proposal
Angle-strained cycloalkynes, in which the alkyne bond is em-
bedded into size-restricted rings, belong to a group of reactive
species that have been discovered and investigated since decades
ago.1 The most advantageous aspect of these species resides in
their ease to concomitantly incorporate two functional groups on
both alkyne carbons; whereas no other approaches could provide
comparable solutions. Among them, benzyne gained tremendous
accomplishments in recent years,1a,2 primarily attributed to both
the mild generation conditions developed by Kobayashi3 and
Hoye4 and consequently their compatibility with diverse types of
reactions. As the aliphatic variants of benzyne, either cyclohexyne
or its heteroatom-embedded analogs (Scheme 1a), however, re-
ceived much less attention,1a,2b despite the fact that they possess
great potential as synthons in assembling multisubstituted cyclo-
hexenes. The current underdeveloped situation of cyclohexyne
chemistry can be partly attributed to the low synthetic efficiency
associated with conventional generation methods, i.e. dehydrohal-
ogenation,5 in its early era.1 Until recently, liberation of cyclo-
hexyne analogs adopting Kobayashi’s method from o-silyl triflate
was successfully applied by the Guitian,6 Garg,7 and Danheiser8
groups in a broad scope of transformations. In addition, both the
Along with our study on aryne transformations,14 we recog-
nized that both benzyne and cyclohexyne favor a common mild
generation condition, namely Kobayashi’s method. Can we utilize
readily functionalizable aryne precursors as building blocks in
the preparation of multisubstituted cyclohexyne equivalents? Af-
ter searching for possible ways to reach this goal, we chose to
pursue the oxidative dearomatization strategy of phenols with
hypervalent iodine reagents,15 which would allow the resulting
aliphatic cycles to inherit those latent structural characters em-
bedded in a benzene ring by means of unfolding its aromaticity.
Here, we wish to present our study on a convenient preparation of
cyclohexenynone precursors 1 and 2 via an oxidative dearomati-
zation approach (Scheme 1c). Upon activation, they could gener-
ate the corresponding cyclohex-2-en-4-ynone i and cyclohex-4-
en-2-ynone ii, respectively, which were found efficient cycloal-
kyne building blocks. In addition, a cascade transformation was
also discovered with concomitant introduction of three substitu-
Fujita-Okuyama9 and Carreira10 groups employed
a 1,2-
elimination on iodonium salt for the generation of cyclohexyne,
which also led to an outstanding total synthesis of guana-
castepenes N and O (Scheme 1b).10b Along with these studies,
other methods were also reported by Banert11 and Okano.12 All
these recent achievements unravel an exciting potential of hex-
atomic aliphatic cycloalkynes, whereas more remained unex-
plored and unexploited.
Beyond the triple-bond active site on a cyclohexyne, function-
ality on the other four positions can be equally essential, because
multisubstituted cyclohexane structural motifs commonly exist in
natural products, drugs, and bioactive molecules. Consequently,
not only uncovering new reactivity of the alkyne bond itself, but
also seeking for ready functionalizability of the other sites on the
ring represent notable opportunities associated with the chemistry
of cyclohexyne. Moreover, those additional functional groups
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ents, namely one nucleophile and two electrophiles, onto the triple
bond, revealing a new maneuver for cyclohexyne.
The presence of ketone, olefin, and alkoxy groups on 1 and 2
furnishes an opportunity to further expand the functional group
diversity on these frameworks. As shown in Scheme 4, bromina-
tion of enone 2 with Br2/Et3N afforded compound 9 in 81% yield.
Epoxidation of compound 2 took place selectively on unsubstitut-
ed olefin and gave rise to 10 in 61% yield. When compound 2 was
treated with L-selectride, it was readily converted to 11 in 88%
yield; whereas reduction of 2 with DIBAL-H afforded alcohol 12
in 83% yield. Moreover, alkylation with both MeLi and PhLi took
place efficiently on compound 1a, affording 13 and 14 in 89%
and 76% yields, respectively. Notably, in the presence of
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As shown in Scheme 2, the synthesis of 1 started from 4-methyl
resorcinol (3). After bromination, 2-bromo-4-methyl resorcinol
(4) was obtained in 76% yield. The formation of o-silyl phenyltri-
flate with selective conversion on C1-OH group was achieved in a
one-pot process and gave rise to aryne precursor 5 in 70% overall
yield, in which the TMS migration takes place exclusively from
the sterically less congested C1 position on 4. After optimization,
the best dearomatization conditions for compound 5 was found to
be PhI(TFA)2 in methanol at room temperature, affording pro-
posed compound 1a in 72% yield over two gram-scale. In this
step, the C4-position is the preferred site to accept the incoming
methoxy group. Gratifyingly, both the TMS and OTf groups re-
main untouched under dearomatization conditions. Compound 1a
is a low-melting point pale-yellow solid, the X-ray crystallograph-
ic structure of which confirms the location of the OTf group. By
employing the same protocol, products 1b-1e could be readily
achieved from 5 using different alcohols (Scheme 2).
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BF3 Et2O, both 13 and 14 readily underwent Pinacol-type rear-
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rangement to produce 15 and 16, respectively, with formation of
quaternary carbon centers in highly selective manner. All these
transformations not only unravel the versatile reactivity of olefin,
ketone, and alkoxy moieties on 1 and 2, but also exhibit that both
the TMS and OTf groups are well-tolerated to a wide range of
reaction conditions. Distinctively, the examples in Scheme 4 rein-
force the value of our dearomatization-cyclohexyne protocol, the
reactivity of which toward [4+2] cycloaddition has been examined
as well (see Scheme S1 in SI).
Scheme 2. Synthesis of cyclohexenynone precursors 1
Scheme 4. Further elaboration of 1a and 2
Scheme 3. Synthesis of cyclohexenynone precursor 2
a) 2, Br2/NaHCO3; b) 2, H2O2-K2CO3, MeOH; c) 2, L-selectride,
THF; d) 2, DIBAL-H, THF; e) 1a, MeLi, Et2O; f) 1a, PhLi, Et2O; g)
BF3.Et2O, MeCN, -78oC-rt
With both compounds 1 and 2 in hand, we decided to examine
their potential applications as cyclohexenynone synthons and
study their reaction behavior with different trapping agents. At the
moment, we were aware of the possibility that the presence of
additional groups on the ring might perturb the consequent cyclo-
hexyne reactions in ways of the stability, reactivity, and selectivi-
ty of these highly active intermediate. Satisfyingly, both 1a and 2
were found efficient to generate cyclohexenynones in the pres-
ence of fluoride salts. As shown in Table 1, when trifluoro-
methanesulfonyl (Tf) group-protected aniline was used as nucleo-
phile, both cyclohexenynone precursors could react to produce
single products 17 and 18 in high yields (entry 1). Phenol was
found to be a good nucleophile as well, and its reactions with 1a
and 2 afforded 19 and 20, respectively, in good yields and excel-
lent regioselectivity (entry 2).
Alternatively, in order to examine how the location of OH
group affects dearomatization outcome as well as how the incor-
porated substituents behave during cyclohexyne reactions, com-
pound 2 with a different pattern of functional groups was pro-
posed (Scheme 3). The synthesis commenced with 2-bromo-3-
methylbenzene-1,4-diol (6), the preparation of which has been
reported by Ahmad (see the Supporting Information for detailed
preparation).16 Starting from compound 6, the same one-pot pro-
tocol was employed to prepare 7 in 74% overall yield via inter-
mediate iii. Oxidative dearomatization of 7 over gram-scale could
afford 2 as a pale-yellow solid in 46% yield along with 50% of p-
quinone 8. Although the yield of 2 is not high, p-quinone 8 could
be converted back to 6 with TMSBr in 94% yield,17 giving rise to
an overall good efficiency for this preparation procedure.
Both 1a and 2 were found efficient cyclohexenynone precur-
sors in Diels-Alder reactions and produced compounds 21-24 in
high to excellent yields (entries 3 and 4, Table 1). In addition, N-
tert-butyl-α-phenylnitrone was found to be a distinct trapping
agent to react with both 1a and 2 in excellent regioselectivity,
affording 25 and 26 in 79% and 92% yields, respectively (entry
5).18 Because of the presence of two stereogenic centers on both
25 and 26, they were produced as mixture of diastereoisomers.
The reaction of 1a with benzyl azide furnished 27 in 78% overall
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yield as a mixture of regioisomers in a ratio of 4.6:1 (entry 6).19
Meanwhile, the reaction of 2 with benzyl azide could produce 28
in 58% yield along with 30% of its regioisomer. The reactions of
1a and 2 with 2-phenyliodonio-3-oxobutanoate gave rise to for-
mal [3+2] cycloadducts 29 and 30 in good yields, both of which
were obtained as a single isomer (entry 7).20 The reaction of 1,1-
dimethoxyethene with 1a did not lead to an observable amount of
the desired product. Satisfyingly, [2+2] cycloaddition of 2 with
1,1-dimethoxyethene generated 31 in 62% yield along with 15%
of regioisomer (entry 8).21 Last, the reaction of 1,3-dimethyl-2-
imidazolidinone (DMI) with 1a afforded 32 in 85% yield with the
formation of a [6,7]-fused ring system; whereas no desired prod-
uct was detected from the same reaction with 2 (entry 9).
Conditions unless otherwise stated are slow addition of 1a or 2 (0.3
mmol) in MeCN (5 mL) via a syringe pump over 8 hours to a suspension
of trapping agent (0.6 mmol) and CsF (0.6 mmol) in MeCN (5 mL) at
room temperature. aCsF (0.9 mmol) was used; b1.5 mmol of trapping agent
was used; cKF (0.6 mmol) and 18-c-6 (0.3 mmol) in THF (5 mL) was used
instead of CsF in MeCN; d6 mmol of DMI was used.
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Figure 1 gives the geometry optimizations of both cyclohexen-
ynones i and ii using DFT calculations (B3LYP/6-31G(d)), ex-
pectedly generated from their corresponding precursors 1a and 2,
respectively. Inspired by the Garg-Houk’s distortion-interaction
models for both arynes22 and cyclohexynes,7 we wondered wheth-
er the calculated structures of cyclohexenynones i and ii can ex-
plain their reaction selectivity. As shown in Figure 1, the opti-
mized structure of cyclohex-2-en-4-ynone i indicates that internal
angle x (134.7o) is significantly larger than angle y (121.9o), sug-
gesting that the C1-position of intermediate i is more electro-
philic. This computational prediction on regioselectivity is con-
sistent with our experimental observation on 1a (Table 1), which
can be reasoned by the electron-withdrawing effect of the carbon-
yl group on cyclohexenynone i. In contrast, the calculated cyclo-
hex-4-en-2-ynone ii shows that the difference between internal
angles x (128.0o) and y (128.8o) is not distinct enough to ensure
high regioselectivity. This is the consequence of competing elec-
tron-withdrawing effects on two terminals of the alkyne group,
which counteracts one another. Gratifyingly, steric repulsion ap-
pears to be a dominant tuning factor on cyclohexenynone ii, fur-
nishing good to high selectivity with other trapping agents (Table
1).
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Table 1. Reactions of cyclohexenynone precursors 1a and 2
Figure 1. DFT calculations (B3LYP/6-31G(d)) of cyclohexen-
ynones i and ii with the PCM solvent model for MeCN.
Scheme 5. Reactions with sulfoxides
Along with our study, we noticed that the immediate products
from traditional cyclohexyne are olefins, which are intrinsically
different from those embedded in aromatic systems after aryne
reactions. This might offer us a chance to further elaborate the
resulting nonaromatic olefin in designed cascade processes. As
shown in Scheme 5, when compound 15 was treated with p-tolyl
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Markina, N. A.; Larock, R. C. Org. Biomol. Chem. 2013, 11, 191-
allyl sulfoxide, compound 33a was obtained in 71% yield (see
Table S1 in SI for detailed optimization conditions), the mecha-
nistic pathway of which involves a [2,3]-sigmatropic rearrange-
ment on allyl sulfonium ylide.23,24 In addition, the reactions be-
tween 15 and various aryl allyl sulfoxides afforded 2,2-
disubstituted 1,3-cyclohexadiones 33b-33d in moderate to good
yields. When compounds 16 and 1a were employed, 33e and 33f
could be obtained in high yields, both of which are a mixture of
diastereoisomers.25 To the best of our knowledge, it is the first
example to incorporate three substituents on the alkyne bond of a
cyclohexyne, namely one nucleophile and two electrophiles,
through “onium” ylide,23 allowing a thorough utilization of cyclo-
hexyne. Moreover, both DMSO and sulfinyldibenzene could react
with 1a as well, affording 34 and 35 in 82% and 81% yields, re-
spectively (Scheme 5). In the absence of allyl group on these sul-
foxides, a direct Me/Ph-group migration took place from sulfur to
oxygen.24
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types of cyclohexenynone equivalents, both of which exhibited
good to excellent cycloalkyne reactivity with diverse trapping
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cyclohexyne chemistry in the presence of various substituents as
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Supporting Information. Experimental details for all chemical
reactions and measurements and X-ray single crystallographic
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
y.li@cqu.edu.cn
Author Contributions
†Qiu, D. and Shi, J. contributed equally to this work.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
The authors gratefully acknowledge research support of this work
by Fundamental Research Funds for the Central Universities
(106112017CDJXSYY0001, 2018CDXZ0003), Graduate Scien-
tific Research and Innovation Foundation of Chongqing (Grant
No. CYB17020), and NSFC (21772017).
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(25) In comparison, we tested the reaction between simple
cyclohexyne precursor with p-tolyl allyl sulfoxide. Unexpectedly, no
desired product was observed at all.
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Journal of the American Chemical Society
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ACS Paragon Plus Environment