Transition metal-free cyclobutene rearrangement in fused naphthalen-1-ones: Controlled access to functionalized quinones

Article abstract of DOI:10.1039/c9cc08628e

The controlled synthesis of 1,4-naphthoquinones and tetraphene-7,12-diones, which bear the ABCD-ring of landomycins, has been accomplished directly through oxidative rearrangement of common stable precursors, namely, previously non-isolable cyclobuta[a]naphthalen-4(2H)-ones.

Full text of DOI:10.1039/c9cc08628e

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Transition metal-free cyclobutene rearrangement in fused
naphthalen-1-ones: Controlled access to functionalized
quinones†‡
Received 00th January 20xx,
Accepted 00th January 20xx
Fernando Herrera,a Amparo Luna,a Israel Fernández,b and Pedro Almendros*c
DOI: 10.1039/x0xx00000x
www.rsc.org/
periodinane (DMP) to introduce the carbonyl moiety gives rise
directly to cyclobutene-fused naphthalen-1-ones 3a–k (Scheme 2). It
was found that the best results were systematically obtained in the
presence of DMP. Because of the great reactivity imparted by the
highly conjugated system in the initially formed non-isolable
allenynones, [2+2] cycloaddition reactions take place
The controlled synthesis of 1,4-naphthoquinones and tetraphene-
7,12-diones, which bear the ABCD-ring of landomycins, has been
accomplished directly through oxidative rearrangement of
common stable precursors, namely, previously non-isolable
cyclobuta[a]naphthalen-4(2H)-ones.
spontaneously.6 Tricyclic cyclobutenes
complete chemo- and regioselectivity in good yields.
3 were obtained with
The ubiquity of the quinone moiety in natural products and organic
materials justifies the continued interest in the synthesis of
molecules containing this framework.1 The widespread occurrence
of the cyclobutene nucleus in natural products and bioactive
compounds, coupled to the use of this strained carbocycle as a
building block in organic synthesis, triggered a renewed activity in
the synthesis of cyclobutenes.2 However, the preparation of the
quinone core from cyclobutenes has remained unexplored. Jiang and
co-workers have recently communicated the cyclization reactions of
allenynones toward naphthols using DABSO [DABCO·(SO2)2] and
arenediazonium salts (Scheme 1a),3 or either in presence of alkynes
(Scheme 1b),4 or β-ketonitriles (Scheme 1c),5 involving the generation
of tricyclic cyclobutene intermediates. Aiming to extend the utility of
allenynones, we planned to use allenyne precursors bearing
substituents at the internal allene double bond. Worthy of note, the
presence of the extra-substituent (R3 = Me, Ar) did allow for the
isolation of previously unstable and non-isolable tricyclic
cyclobutenes (R3 = H). Herein, we present a convenient method for
the divergent synthesis of 1,4-naphthoquinones and tetraphene-
7,12-diones through the oxidative reorganization of cyclobutene-
fused naphthalen-1-ones (Scheme 1d).
H
•
H
•
H
O
O
ArN2
R1
R1
R1
R1
Ar
N
(a)
previous
work
[DABSO]
IBX
OH
O

N
DCE, rt
R2
R2
Ar
ref. 3
stable
unstable
R2
R2
ArO2S
H
H
O
R1
O
R3
BF3 Et2O
R3
O
R1
Ar
CN
(c)
(b)
previous
work
previous
work
DCE, 40 o
C
Cs2CO3
CN
R2
1,4-dioxane, rt
R2
ref. 4
ref. 5
O
R1
R3
R3
•
R3
•
O
O
R1
R1
R1
R2
R
R3
NBS
R 3
(d)
this work
IBX or
DMP
R2
OH
O
O
O
=
Ar
Selectfluo
R1
R2
unstable
stable R2
r
R2
O
Scheme 1 The allenynone framework as a platform for the synthesis of fused
carbocycles: Prior art and our method.
O
R3
•
R1
R
R3
DMP
H
R3
Starting substrates, allenynols 2a–k, were prepared from alkynyl-
benzaldehydes 1 and 3-substituted prop-2-ynyl bromides using an
indium-mediated allenylation under Barbier conditions in aqueous
media (Scheme 2). Further oxidation with IBX or Dess–Martin
R1
R
R1
R
CH2Cl2, 0º C
Br
O
OH
or
IBX
In, THF/NH4Cl
R
R2
R2
R
R2
(aq. sat.) (1:5), rt
R
MeCN, 80º C
R = H, R1 = H, R2 = Ph
R = H, R1 = H, R2 = Ph
R
3 = Me (69%)
3 = Ph (60%)
3 = Ph (65%)
3 = Ph (53%)
3 = Ph (67%)a
3 = Ph (49%)
(69% or 35%)
(82% or 65%)
(85% or 65%)
(88% or 51%)
(77% or 69%)
(80% or 58%)
(82% or 45%)
(80% or 47%)
(70% or 52%)
(56% or 39%)
(81% or 57%)
1a
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
3a
3b
3c
3d
3e
3f
R
R = H, R1 = H, R2 = TMS
R = H, R1 = H, R2 = 4-MeOC6H4
R = H, R1 = H, R2 = 4-MeC6H4
R = H, R1 = H, R2 = 4-BrC6H4
R = H, R1 = H, R2 = 2-MeC6H4
R = H, R1 = F, R2 = Ph
R
R
a. Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Química
Orgánica, Unidad Asociada al CSIC, Facultad de Química, Universidad
Complutense de Madrid, 28040-Madrid, Spain
R
R
2g
2h
2i
3g
3h
3i
R
3 = Ph (41%)a
3 = Ph (35%)a
3 = Ph (68%)
3 = Me (77%)
b. Departamento de Química Orgánica I and Centro de Innovación en Química
Avanzada (ORFEO-CINQA), Facultad de CC. Químicas, Universidad Complutense
de Madrid, 28040-Madrid, Spain
1g
1h
1i
R
R = H, R1 = MeO, R2 = Ph
R = MeO, R1 = H, R2 = Ph
R = MeO, R1 = H, R2 = Ph
R
R
2j
3j
c. Instituto de Química Orgánica General, IQOG-CSIC, Juan de la Cierva 3, 28006-
Madrid, Spain; E-mail: palmendros@iqog.csic.es
1i
2k
3k
R
3 = Ph (49%)
†In memory of Prof. Odón Arjona
Scheme 2 Synthesis of tricyclic cyclobutenes 3a–k. a The reaction was carried
J. Name., 2013, 00, 1-3 | 1
‡Electronic Supplementary Information (ESI) available: Experimental procedures,
compound characterization data, and copies of NMR spectra for all new
compounds. See DOI: 10.1039/x0xx00000x
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out in THF/H2O (1:1).
naphthoquinones 4 is delineated in Scheme 4. The reaction is
presumed to possess a radical nature, which was based on the
View Article Online
DOI: 10.1039/C9CC08628E
To explore the reactivity of cyclobutene-fused naphthalen-1-ones
3, at the beginning of the study we selected N-bromosuccinimide
(NBS) as a convenient electrophilic source of bromine and tricyclic
cyclobutene 3a as a model substrate. In the event, the use of THF as
solvent led to reaction failure. Fortunately, the replacement of THF
suspension of the transformation after the addition of TEMPO to the
reaction medium. Initially, the formation of allylic radical species INT-
1 should occur by bromine radical attack. The formation of this
radical should be followed by oxidation to the carbocationic species
INT-2 by single electron transfer (SET) to the succinimide. Next, water
attack takes place with formation of bromohydrin INT-3 which is
followed by HBr release. Hydration of the resulting intermediate
cyclobutenol INT-4 leads to diol INT-5, which evolves into
zwitterionic intermediate INT-6. According to Density Functional
Theory calculations (see ESI), this step proceeds with a low activation
barrier of only 10.6 kcal/mol (for 3a). A subsequent proton transfer
leads to dihydroquinone 4H in a highly exergonic transformation
(∆GR = –40.3 kcal/mol, for 3a), which is finally oxidized to its quinone
form 4.
by
acetonitrile
provided
2-methyl-3-(2-oxo-2-
phenylethyl)naphthalene-1,4-dione 4a,7 but only in a modest 29%
yield. Because of the structure of 4a, it may be apparent that
adventitious water in the reaction medium was necessary. To prove
this assumption, we carried out the reaction with the addition of 5.0
equiv of water. Indeed, in this way a significant improvement of the
yield of 4a up to 72% was achieved (Scheme 3). With the optimal
conditions in hand, we evaluated the influence of substituents at the
different positions of tricycles 3. A variety of aromatic moieties were
well tolerated both at R2 and R3, while an aliphatic substituent was
accommodated at R3 (Scheme 3). Even precursor 3j bearing two
electron-donating substituents (R = MeO) on the aromatic ring,
conveniently afforded naphthalene-1,4-dione 4j after NBS
treatment. By contrast, the reaction of TMS- cyclobutene 2c was not
satisfactory. Interestingly, the presence of a fluorine atom at the
benzene ring such as in tricyclic cyclobutene 3h resulted in an extra-
bromination on the final adduct 4h-Br (Scheme 3). The same
phenomenon was observed starting from tricycle 3a under otherwise
identical reaction conditions but through mild heating, which
resulted in the formation of 4a-Br (Scheme 3). Pleasingly, it has been
reported that several 2-methyl-3-alkyl-naphthalene-1,4-diones
related to bicycles 4 possess interesting biological activities.8
O
O
O
O
O
R1
R3
R1
R3
R1
R3
R1
R3
R1
R3
Br
SET
H2
O
–BrH
–H
HO
Br
HO
Br
Br
R2
R2
R2
R2
R2
H2
INT-1
INT-2
INT-3
INT-4
3
O
O
O
OH
O
R1
R3
R1
R3
R1
R3
O
R1
R3
H
O
O
air
R2
R2
R2
H
O
H
OH
O
OH
O
R2
H
4
4H
INT-6
INT-5
Scheme 4 Mechanistic explanation for the NBS-promoted synthesis of 2-oxo-
naphthalene-1,4-diones 4.
Aiming to explore the effect of different reagents in the selective
oxidative reorganization of cyclobutene-fused naphthalen-1-ones,
we decided to expose tricycles 3 to the action of Selectfluor. The
reaction of adduct 3a with Selectfluor was problematic and a
complex mixture was obtained. By contrast, an encouraging result
was obtained when adduct 3b having a phenyl group was used,
because we unexpectedly isolated in a 19% yield tetracycle 5b that
should arise from an angular benzannulation process. The presence
of sodium bicarbonate in the reaction between Selectfluor and 3b
caused an appreciable rise in the yield of 5b (Scheme 5). On this
point, we next tested the scope of this rearrangement reaction using
diverse fused-cyclobutenes 3 which contain a phenyl moiety at the
cyclohexenone ring. A variety of differently substituted precursors 3,
including fluoro- and methoxy-derivatives 3h and 3i were suitably
rearranged. By contrast, the reaction of dimethoxy-substituted
precursor 3k with Selectfluor was troublesome and the desired
tetracycle 5k was not isolated in reasonable purity. Synthetically
useful yields of tetracycles 5b and 5d–i were attained (Scheme 5). For
all examples included in Scheme 5 no products of type 4 were
observed. Noteworthy, tetracycles5beartheABCD-ringoflandomycins.
Landomycins such as tetrangulol are a class of natural quinones
characterized by an angular conjugated tetracyclic core, which confers
them with interesting bioactivities.9 The major difficulty associated with
the synthesis of landomycins is the formation of the B-ring due to
hindranceissues. Thiselusiveaspect iseasilyaddressedinourpreparation
of the landomycin core.
O
O
R1
R
R3
R1
R
R3
H2O (5 equiv)
MeCN, rt
O
+ NBS (2 equiv)
R2
R
R2
R
O
R = H, R1 = H, R2 = Ph, R3 = Me
R = H, R1 = H, R2 = Ph, R3 = Ph
R = H, R1 = H, R2 = TMS, R3 = Ph
R = H, R1 = H, R2 = 4-MeOC6H4, R3 = Ph
R = H, R1 = H, R2 = 4-MeC6H4, R3 = Ph
R = H, R1 = H, R2 = 4-BrC6H4, R3 = Ph
R = H, R1 = MeO, R2 = Ph, R3 = Ph
R = MeO, R1 = H, R2 = Ph, R3 = Me
(72%)
(61%)
(0%)
3a
3b
3c
3d
3e
3f
4a
4b
4c
4d
4e
4f
(58%)
(55%)
(60%)
(53%)
(57%)
3i
4i
3j
4j
O
O
R1
R3
R1
R3
H2O (5 equiv)
MeCN, T
O
+ NBS (2 equiv)
R2
R2
1 = H, R2 = Ph, R3 = Me
1 = F, R2 = Ph, R3 = Ph
O
Br
3a
3h
4a-Br
4h-Br
R
(65%,T = 50º C)
(62%,T = rt)
R
O
O
O
O
CF3
N
N
O
N
( )
OH
N
5
O
O
plasmodione
antimalarial
inhibitor of glutathione
reductase
CN
antimalarial
Scheme 3 Synthesis of 2-substituted-3-(2-oxo-2-arylethyl)naphthalene-1,4-
diones 4 and 4-Br.
A plausible mechanism for the NBS-promoted genesis of 1,4-
2 | J. Name., 2012, 00, 1-3
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O
rapidly evolves into INT-13 via a 1,3-hydrogen migration. According
to DFT calculations on 3b (see ESI), this step proceeds with an
View Article Online
DOI: 10.1039/C9CC08628E
R1
R
O
O
R1
R
NaHCO3 (2 equiv)
MeCN, rt
Selectfluor
(2 equiv)
+
activation barrier of 21.9 kcal/mol in
a highly exergonic
R2
R
transformation (∆GR = –28.2 kcal/mol) driven by the gain in
aromaticity in the system. Finally, INT-13 is oxidized into the
observed tetracycles 5. Our calculations indicate that the concerted
H2 release from either INT-13 or even from INT-12 thus directly
forming 5 is unfeasible (∆G≠ = 89.9 and 77.4 kcal/mol, respectively).
This points to a different mechanism for this final aromatization
step,12 which is not evident to us at the moment.
R2
R
R = H, R1 = H, R2 = Ph
R = H, R1 = H, R2 = 4-MeOC6H4
R = H, R1 = H, R2 = 4-MeC6H4
R = H, R1 = H, R2 = 4-BrC6H4
R = H, R1 = H, R2 = 2-MeC6H4
R = H, R1 = F, R2 = Ph
R = H, R1 = MeO, R2 = Ph
R = MeO, R1 = H, R2 = Ph
(49%)
3b
3d
3e
3f
5b
5d
5e
5f
(55%)
(59%)
(52%)
(54%)
(60%)
(48%)
3g
3h
3i
5g
5h
5i
HO
O
A
C
O
B
3k
D
5k
(messy reaction)
Cl
Cl
Cl
N
N
N
N
N
I
III
=
II
=
=
N
OH
F
2BF4
tetrangulol
Selectfluor
O
O
O
O
O
R1
R1
R1
R1
R1
Ar
Ar
Ar
I
Ar
II
II
Ar
H
Scheme 5 Synthesis of 5-aryltetraphene-7,12-diones 5b and 5d–i.
III
–H
+H
H2
O
F
R2
SET
–H
O
H
In order to gain some mechanistic insights, control experiments
were planned (Scheme 6). First, when tricycle 3b was treated with
Selectfluor under the optimized conditions but using anhydrous
acetonitrile, the yield of 5b decreased to 8% (Scheme 6). This result
unveiled the origin of the oxygen at the C-ring, that should come
F
F
O
F
R2
R2
R2
R2
BH
INT-10
INT-8
3
INT-9
INT-7
–FH
R3
R3
R3
R3
O
O
O
R1
R1
R1
O
R1
aromatization
1,3-H
shift
6-electrocyclic
H
R2
R2
R2
ring closure
R2
O
H
O
INT-12
O
from ambient water. Succeeding in performing
a divergent
O
5
INT-13
INT-11
preparation of 2-substituted-3-(2-oxo-2-arylethyl)naphthalene-1,4-
diones 4 and 5-aryltetraphene-7,12-diones 5, we speculated about
the possible intermediacy of 1,4-naphthoquinones 4 in the formation
of angular tetracycles 5 in the presence of Selectfluor. When 1,4-
naphthoquinone 4b was treated with Selectfluor and sodium
bicarbonate under the optimized reaction conditions for the
formation of pentacycles 5, the reaction failed and starting material
4b was fully recovered (Scheme 6). From the above experiment, it
may be inferred that naphthalene-1,4-diones of type 4 should be
discarded as intermediates for this reaction. The radical scavenger
TEMPO effectively suppressed the formation of the required
product, pointing to a radical reaction mechanism.
Scheme 7 Mechanistic explanation for the Selectfluor-promoted synthesis of
tetraphene-7,12-diones 5.
In conclusion, we have developed
transformation of the previously
a
divergent outcome
non-isolable
cyclobuta[a]naphthalen-4(2H)-one system to afford either 1,4-
naphthoquinones or tetraphene-7,12-diones, which has been
accomplished through the reorganization of the above fused tricyclic
cyclobutenes in the presence of NBS or Selectfluor.
This work was supported in part by AEI (MICIU) and FEDER
(Project PGC2018-095025-B-I00 to P.A. and CTQ2016-78205-P
and CTQ2016-81797-REDC to I. F.). F. H. thanks UCM for a
predoctoral contract. We are grateful to M. Tiemblo in our
group for the preparation of compounds 2j,k and 3j and Prof. B.
Alcaide for continued support.
O
O
Ph
R1
NaHCO3 (2 equiv)
Selectfluor
+
(2 equiv)
anhydrous MeCN, rt
R2
O
Ph
3b
5b
5b
(8%)
Conflicts of interest
There are no conflicts of interest to declare.
O
Ph
O
X
NaHCO3 (2 equiv)
MeCN, rt
Selectfluor
(2 equiv)
+
Ph
O
Notes and references
4b
X
optimal conditions
TEMPO
1
(a) S. Liu, T. Shen, Z. Luo and Z.-Q. Liu, Chem. Commun., 2019, 55, 4027
and references therein. For representative reviews, see: (b) Y. Wang,
S. Zhu and L.-H. Zou, Eur. J. Org. Chem., 2019, 2179; (c) Y. Ando and K.
Suzuki, Chem. Eur. J., 2018, 24, 15955; (d) E. J. Son, J. H. Kim, K. Kim
and C. B. Park, J. Mater. Chem. A, 2016, 4, 11179; (e) S. N. Sunassee
and M. T. Davies-Coleman, Nat. Prod. Rep., 2012, 29, 513; (f) C. Asche,
Mini-Rev. Med. Chem. 2005, 5, 449; (g) R. H. Thomson, Naturally
Occurring Quinones IV, Blackie Academic & Professional, London,
1997; (h) P. J. O’Brien, Chem.-Biol. Interact. 1991, 80, 1; (i) The
Chemistry of the Quinonoid Compounds, eds. S. Patai and Z.
Rappoport, Wiley: New York, 1988.
3b
5b
Scheme 6 Control experiments.
Based on the above experiments, we assume a mechanism as
presented in Scheme for the reaction of aryl-substituted
7
cyclobutene-fused naphthalen-1-ones 3 with Selectfluor. Similar to
the above-described reaction involving NBS, tricycles 3 can be
converted into cationic intermediates INT-8 after Selectfluor
treatment with concomitant formation of III. Next, this intermediate
should suffer water attack to produce halohydrin INT-9, which
evolves through cyclobutane ring opening followed by base-assisted
HF release10 into the quinone INT-11. The so-formed polyene is able
to undergo a 6π-electrocyclic ring closure to produce INT-12,11 which
2
For recent references, see: (a) Q. Qin, X. Luo, J. Wei, Y. Zhu, X. Wen,
S. Song and N. Jiao, Angew. Chem. Int. Ed., 2019, 58, 4376; (b) G.-Q.
Xu, J.-T. Xu, Z.-T. Feng, H. Liang, Z.-Y. Wang, Y. Qin and P.-F. Xu,
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and M. Sawamura, Adv. Synth. Catal., 2018, 360, 670; (d) M. E. de
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 3
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6
7
For a review on [2+2] cycloaddition chemistry with allenes, see: B.
Alcaide, P. Almendros and C. Aragoncillo, Chem. Soc. Rev., 2010, 39,
783.
Naphthoquinones have attracted considerable interest because of
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4 | J. Name., 2012, 00, 1-3
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DOI: 10.1039/C9CC08628E
Graphical Abstract
R3
•
R3
•
O
O
O
R1
R1
R1
R1
R3
R3
O
IBX or
DMP
R2
NBS
OH
O
R2
R2
R2
stable
unstable
9 examples
up to 72% yield
R3 = Ar
Selectfluor
R
O
A
O
R1
C
B
D
R2
7 examples
up to 60% yield
O
O
ABCD-ring of landomycins
The divergent preparation of 1,4-naphthoquinones and tetraphene-7,12-diones, which bear the
ABCD-ring of landomycins, has been accomplished directly through reorganization of previously
non-isolable cyclobuta[a]naphthalen-4(2H)-ones by NBS or Selectfluor treatment.