Synthesis of indole substituted twistenediones from a 2-quinonyl boronic acid

Article abstract of DOI:10.1021/ol402689b

Indole substituted twistane-like derivatives resulted in a reaction between 3,5-dimethyl-2-quinonyl boronic acid and 2-alkenyl indoles. Their MCPBA oxidation gave 6/6/9 caged systems. Boronic acid acts as a temporal promoter allowing a site-selective conjugate addition of the heteroaromatic system to the methyl substituted C-3 quinone carbon, giving an intermediate diene which is regioselectively trapped by intramolecular [4 + 2] cycloaddition.

Full text of DOI:10.1021/ol402689b

ORGANIC
LETTERS
2
013
Vol. 15, No. 22
686–5689
Synthesis of Indole Substituted
Twistenediones from a 2‑Quinonyl
Boronic Acid
5
Jaime Rojas-Mart ´ı n, Marcos Veguillas, Mar ´ı a Ribagorda,* and M. Carmen Carre ~n o*
Departamento de Quı´mica Org aꢀ nica (M oꢀ dulo 01), Universidad Aut oꢀ noma de Madrid,
C/Francisco Tom aꢀ s y Valiente 7, Cantoblanco, 28049-Madrid, Spain
carmen.carrenno@uam.es; maria.ribagorda@uam.es
Received September 17, 2013
ABSTRACT
Indole substituted twistane-like derivatives resulted in a reaction between 3,5-dimethyl-2-quinonyl boronic acid and 2-alkenyl indoles. Their
MCPBA oxidation gave 6/6/9 caged systems. Boronic acid acts as a temporal promoter allowing a site-selective conjugate addition of the
heteroaromatic system to the methyl substituted C-3 quinone carbon, giving an intermediate diene which is regioselectively trapped by
intramolecular [4 þ 2] cycloaddition.
3
,8
6
type structures. Some reactivity studies evidenced that the
Twistane (tricyclo[4.4.0.0 ]decane), the twist-boat isomer
of adamantane, and its simple functionalized derivatives were
rearrangement of 2-twistanols promoted by acid opens a
1b
direct access to adamantane-cage-shaped structures.
1
first synthesized in 1962. In sharp contrast to adamantane
2
analogues which have received huge attention, these cage-
shaped systems have been the subject of limited studies. To
7
Moreover, 4-ketotwistane has shown antiviral activities.
Despite these features, only a limited number of syntheses
en route to this skeleton are available. These are generally
based on intramolecular enolate alkylations of prefunctio-
3
date, theoretical investigations and applied studies direc-
,4
5
ted toward determining their behavior as liquid crystals
have been reported. The D symmetry makes them ideal
models to evaluate the chiroptical properties of twist-boat
1
nalized bicyclo[2.2.2]octan-2-one or cis-bicicyclo[4.4.0]-
8
decanediones. More direct strategies based on a two-bond
2
disconnection through an intramolecular DielsꢀAlder cy-
3,7
(
1) (a) Whitlock, H. W., Jr. J. Am. Chem. Soc. 1962, 84, 3412–3413.
b) Whitlock, H. W., Jr.; Siefken, M. W. J. Am. Chem. Soc. 1968, 84,
929–4939.
2) For recent reviews, see: (a) Wanka, L.; Khalid, I.; Schreiner, P. R.
cloaddition (IMDA) have proven to favor the formation of
a less strained 5/6/6 isotwistane (tricyclo[4.3.1.0 ]decane)
(
4
9
(
framework (Scheme 1).
Chem. Rev. 2013, 113, 3516–3604. (b) Schwertfeger, H.; Fokin, A. A.;
Schreiner, P. R. Angew. Chem., Int. Ed. 2008, 47, 1022–1036.
(3) For a recent study of molecular surface properties, see: (a)
Keshavarz, M. H.; Zamani, M.; Atabaki, F.; Hosseini Monjezi, K.
Comp. Theor. Chem. 2013, 1006, 105–112. For calculations of gauche
interactions and vibrational energies: (b) Fliszar, S.; Vauthier, E. C.;
Chretien, S. THEOCHEM 2004, 682, 153–158. Electronic distribution:
(6) (a) McCann, D. M.; Stephens, P. J.; Cheeseman, J. R. J. Org.
Chem. 2004, 69, 8709–8717. (b) Barnik, M. I.; Geivandov, R. Ch.;
Gorina, I. I.; Shtykov, N. M. Mol. Cryst. Liq. Cryst. C 1998, 9, 251–
259. (c) Geivandov, R. Ch.; Goncharova, I. V.; Titov, V. V. Mol. Cryst.
Liq. Cryst. 1989, 166, 101–103. (d) Nakazaki, M.; Chikamatsu, H.;
Taniguchi, M. Chem. Lett. 1982, 11, 1761–1764.
(
c) Choi, J. K.; Joncich, M. J.; Lambert, Y.; Deslongchamps, P.; Fliszar,
S. THEOCHEM 1982, 6, 115–122.
4) σ-Radical cations derived from cage-shaped hydrocarbons:
(
(7) Deslongchamps, P. Canadian Patent 800003, 1968.
Novikovskii, A. A.; Gunchenko, P. A.; Prikhodchenko, P. G.;
Serguchev, Y. A.; Schreiner, P. R.; Fokin, A. A. Russ. J. Org. Chem.
(8) (a) Belanger, A.; Poupart, J.; Deslongchamps, P. Tetrahedron
Lett. 1968, 2127–2128. (b) Gauthier, J.; Deslongchamps, P. Can. J.
Chem. 1967, 45, 297–300. 1969, 47, 795–802. (c) Yordy, J. D.; Reusch, W.
J. Org. Chem. 1975, 40, 2086–2088. (d) Bhamare, N. K.; Granger, T.;
John, C. R.; Yates, P. Tetrahedron Lett. 1991, 32, 4439–4442. (e) Lu,
P.-Y.; Chen, K.-P.; Chuang, C.-P. Tetrahedron 2009, 65, 7415–7421.
2011, 47, 1293–1299.
(5) Geivandov, R. Ch.; Lastochkina, S. O.; Goncharova, I. V.;
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A. V.; Titov, V. V. Liq. Cryst. 1987, 2, 235–9.
1
0.1021/ol402689b r 2013 American Chemical Society
Published on Web 10/29/2013

in 1,4-addition reactions, which are accompanied by enoli-
zation leading to the corresponding substituted hydroqui-
nonederivatives. 2,3-Dihydrobenzofurans can be obtained
by Lewis acid catalyzed 1,4-addition of 1,3-dicarbonyl
compounds followed by a sequential enolization and
Scheme 1. Synthetic Approaches to the Twistane Framework
1
5
intramolecular cyclization. Similarly, the reaction of
β-enaminoesters with benzoquinones can give indoles
(
Nenitzescu reaction) or benzofuran-2(3H)-ones (domino
1
6
BlaiseꢀNenitzescu reaction). In spite of these useful
transformations, it is striking that quinones cannot make
use of emblematic domino processes based on Michael
addition/enolate capture.
We initiated our study with 3,5-dimethyl-2-benzoquinonyl
boronic acid 1, easily available by CAN oxidation of
the corresponding dimethyl substituted 2,5-dimethoxy
1
0
arylboronic acid, as previously reported. The required
-alkenyl indoles 2 and N-methyl-2-alkenyl indoles 3
were obtained via Wittig reaction from commercially
Recently, we have synthesized quinonyl boronic acid 1
and achieved highly efficient and regioselective DielsꢀAlder
2
1
0
11
reactions and FriedelꢀCrafts (FC) alkylation reactions.
The 1,4-addition of indoles to 3-methyl-2-quinonyl boronic
acids occurred under very mild conditions, exclusively at the
β-substituted C-3 position, and was followed by a proto-
deboronation. We also demonstrated the formation of an
intermediate boron dienolate such as A (Scheme 1) that
could be trapped in situ in an intermolecular [4 þ 2]
available 1H-indole-2-carbaldehyde or N-methylindole-
1
7ꢀ19
2
-carbaldehyde respectively.
H-2-(phenylvinyl)indole E-2a or 1H-2-(o-bromophenyl-
Reaction of 1 with
1
vinyl)indole E-2b using CH Cl (0.07 M) as solvent at rt
2
2
gave compounds 4a and 4b respectively, resulting from
,4-addition reaction of the indole to the quinone C-3
1
carbon, followed by protodeboronation (Scheme 2).
Although yields were moderate, this result revealed that
1
1
cycloaddition with N-phenylmaleimide. Inspired by these
results, we reasoned that the boron dienolate intermediate
generated from 1,4-addition could be intramolecularly cap-
tured in a reaction with an appropriate dienophile. Herein,
we report a domino process based on a 1,4-addition/
intramolecular DielsꢀAlder/protodeboronation domino
2-alkenyl indoles could act as Michael type nucleophiles
instead of as dienes in the reaction with 1.
2
0
To our delight, when N-methyl substituted (E)-2-[2-(p-
methoxyphenyl)vinyl]indole (E)-3a was reacted with 1, for
2
h at rt, compound 5a was exclusively obtained (63%
process which occurred when 2-benzoquinonyl boronic acid
isolated yield) (Scheme 3). The formation of the twistene-
dienone 5a must result from a domino sequence based
on a 1,4-addition of the indole ring to the C-3 quinonyl
boronic acid, followed by an IMDA/protodeboronation
0
1
reacted with 2-alkenylindoles having a substituent at C-2
in the alkene moiety. This method allows a direct access
to densely functionalized twistenedione-like systems, in
sharp contrast to the reported IMDA process leading to
9
the isotwistane analogues. A key feature of our approach
0
(14) For applications of a domino DielsꢀAlder/pyrolytic sulfoxide
elimination sequence of 2-sulfinylquinones, see: (a) Urbano, A.;
Carre n~ o, M. C. Org. Biomol. Chem. 2013, 11, 699–708. (b) Carre n~ o,
M. C.; Ribagorda, M.; Somoza, A.; Urbano, A. Angew. Chem., Int. Ed.
is the presence of an electron donating group at C-2 in the
alkene dienophile which controlled the regiochemistry of
the IMDA.
Quinones are excellent substrates for domino reactions,
2
002, 41, 2755–2757. (c) Carre n~ o, M. C.; Garcia-Cerrada, S.; Sanz
Cuesta, M. J.; Urbano, A. Chem. Commun. 2001, 1452–1453. (d)
Carre n~ o, M. C.; Hern ꢀa ndez-S ꢀa nchez, R.; Mahugo, J.; Urbano, A.
J. Org. Chem. 1999, 64, 1387–1390.
1
2ꢀ14
especially when cycloaddition reactions are involved.
p-BenzoquinoneshavealsobeenusedasMichael acceptors
(
15) (a) Mothe, S. R.; Susanti, D.; Hong Chan, P. W. Tetrahedron
Lett. 2010, 51, 2136–2140. (b) Mudiganti, N. V. S.; Claessens, S.; De
Kimpe, N. Tetrahedron 2009, 65, 1716–1723.
(
9) For recent examples of synthesis of isotwistanes by intramolecu-
(16) (a) Chun, Y. S.; Ryu, K. Y.; Kim, J. H.; Shin, H.; Lee, S.-G. Org.
Biomol. Chem. 2011, 9, 1317–1319. (b) Suryavanshi, P. A.; Sridharan, V.;
Men ꢀe ndez, J. C. Org. Biomol. Chem. 2010, 8, 3426–3436.
(17) For the synthesis of N-methylvinylindoles, see: (a) Masuda, K.;
Ohmura, T.; Suginome, M. Organometallics 2011, 30, 1322–1325. (b)
For the synthesis of 1H-vinylindoles, see: (c) Gioia, C.; Hauville, A.;
Bernardi, L.; Fini, F.; Ricci, A. Angew. Chem., Int. Ed. 2008, 47, 9236–
9239.
(18) E-Isomer of 3f was exclusively obtained. Compounds E-2a,
E-2b, and E-3a were obtained pure after column chromatography.
Compounds 3bꢀd were used as a mixture of E/Z isomers. For details,
see Supporting Information.
(19) Stereoselective syntheses of E-vinylindoles based on Suzuki
coupling have been reported: (a) Fang, Y.-Q.; Lautens, M. J. Org.
Chem. 2008, 73, 538–549. (b) Rossi, E.; Abbiati, G.; Canevari, V.;
Celentano, G. Synthesis 2006, 299–304.
(20) For examples of 2-alkenyl indoles as dienes, see: (a) Eitel, M.;
Pindur, U. J. Org. Chem. 1990, 55, 5368–5374. (b) Abbiati, G.; Canevari,
V.; Facoetti, D.; Rossi, E. Eur. J. Org. Chem. 2007, 517–525 and
references cited therein. (c) Pirovano, V.; Decataldo, L.; Rossi, E.;
Vicente, R. Chem. Commun. 2013, 49, 3594–3596.
lar [4 þ 2] cycloaddition of a 1,3-cyclohexadiene moiety, see: (a) Zhang,
G.-B.; Wang, F.-X.; Du, J.-Y.; Qu, H.; Ma, X.-Y.; Wei, M.-X.; Wang,
C.-T.; Li, Q.; Fan, C.-A. Org. Lett. 2012, 14, 3696–3699 and references
cited therein. (b) Zhao, C.; Zheng, H.; Jing, P.; Fang, B.; Xie, X.; She, X.
Org. Lett. 2012, 14, 2293–2295. (c) Silva L oꢀ pez, C.; Nieto Faza, O.;
Rodrı
10) (a) Redondo, M. C.; Veguillas, M.; Ribagorda, M.; Carre n~ o,
M. C. Angew. Chem., Int. Ed. 2009, 48, 370–374. (b) Veguillas, M.;
Redondo, M. C.; Garcı
a, I.; Ribagorda, M.; Carre n~ o, M. C. Chem.;
Eur. J. 2010, 16, 3720–3735.
11) Veguillas, M.; Ribagorda, M .; Carre n~ o, M. C. Org. Lett. 2011,
3, 656–659.
12) For cycloaddition/aromatization sequence, see: (a) Podlesny,
´
guez de Lera, A. J. Org. Chem. 2008, 467–453.
(
´
(
1
(
E. E.; Kozlowski, M. C. J. Org. Chem. 2013, 78, 466–476. (b) He, Z.; Liu,
T.; Tao, H.; Wang, C.-J. Org. Lett. 2012, 14, 6230–6233. (c) Kuethe,
J. T.; Comins, D. L. Tetrahedron Lett. 2003, 44, 4179–4182.
(
13) For domino [5 þ 2]/[3 þ 2] cycloadditions, see: (a) Engler, T. A.;
Scheibe, C. M.; Iyengar, R. J. Org. Chem. 1997, 62, 8274–8275. (b)
Jim ꢀe nez-Alonso, S.; Est ꢀe vez-Braun, A.; Ravelo, A. G.; Z ꢀa rate, R.;
L oꢀ pez, M. Tetrahedron 2007, 63, 3066–3074.
Org. Lett., Vol. 15, No. 22, 2013
5687

2
3
yield, could be confirmed by X-ray diffraction (Scheme 4).
No 1,4-addition products were detected under these condi-
tions, and Z-3c and Z-3d isomers remained unreacted.
Scheme 2. Reaction of 1H-2-Alkenylindoles 2 with 1
Scheme 4. Reaction between 1 and N-Methyl-2-alkenylindoles
3
bꢀf, and X-ray Structure of Twistendione 5d
2
1
sequence, where the alkenyl C-2 substituent at the indole
is acting as a dienophile. In this process three new CꢀC
bonds were formed as well as five stereogenic centers, two
of them quaternary at the bridgehead carbons and with
complete diastereoselectivity.
Scheme 3. Reaction of (E)-3a and (Z)-3a with 1
N-Methyl-2-vinylindole 3e did not deliver any appreci-
able reaction product in the presence of 1, probably because
of the instability of the starting 2-vinylindole in the reaction
mixture. The reaction of 1 with the electron-poor methyl
ester substituted alkenyl indole derivative (E)-3f did not
occur, probably due to the diminished reactivity of this
indole system toward the initial conjugate addition.
The formation of these twistane-like structures can be
explained by the mechanism in Scheme 5. Initially, a FC
alkylation of the indole ring occurs at the more electron-
rich C-3 position of the heterocycle. The high electrophi-
licity of the C-3 methyl substituted quinonyl boronic
acid allows this process to occur without external acidic
catalysis. The initial 1,4-addition generates intermediateA,
which can protonate and tautomerize to give B. Subse-
quent boron transfer from carbon to oxygen could afford
the boron dienolate intermediate C. The IMDA reaction
between the dienolate present in C and its dienophilic
moiety would require a parallel disposition of both ap-
proaching partners, only possible if the C1 ꢀC2 double
bond is situated out of the indole ring plane (I or III in
Scheme 5). This out of plane disposition is probably forced
by steric inhibition of resonance in the aromatic indole, due
to the surrounding bulky N-Me group and the quaternary
C-6 of the dienolate moiety. Moreover, the lack of reactiv-
ity of the NH alkenyl indoles 2 toward the IMDA process
The reaction of quinonyl boronic acid 1 with the pure
(
Z) isomer of N-methyl-2-[2-(p-methoxypheny)lvinyl]-
indole (Z)-3a afforded, after 18 h, the 1,4-addition product
Z)-6a after protodeboronation in 72% yield (Scheme 3).
This result indicated that the double bond geometry of
the alkenyl substituent had a great influence on the second
step of the domino sequence. We next examined the scope
of this process by reacting boronic acid 1 with different
-alkenylindoles (Scheme 4). Only the (E)-isomer of an in-
separable 57/43 E/Z mixture of N-methyl-2-(2-phenylvinyl)-
indole 3b reacted with 1affording the twistendione derivative
(
2
0
0
5b in 40% isolated yield, after 4 h. Under these conditions,
no 1,4-addition product was detected, and the (Z)-3b isomer
2
2
was recovered unaltered. 2-[2-(o-Bromophenyl)vinyl]-
indole 3c (E/Z 80:20) also reacted in 2 h at rt with quinonyl
boronic acid 1, to give twistane-like derivative 5c in good
yield (75%). Alkyl susbtituents on the dienophilic group
of the N-methyl alkenyl indole were also able to give
the domino process, as demonstrated in the reaction of
N-methyl-2-propenylindole 3d (90/10 E/Z mixture) with 1.
The structure of twistendione derivative 5d, isolated in 59%
(Scheme 2) corroborates the essential role of the N-Me
group in the second step of the domino sequence.
24
There are two possible regiochemical orientations of
the dienophilic moiety that could lead a 6/6/6 twistane
system (transition state I) or a 5/6/6 isomeric isotwistane
(
(
21) See ref 10a for a similar protodeboronation step.
22) Longer reaction times (18 h) gave a mixture of the twistenedione
r 20 21 1 2
(23) CCDC 952314 (5d): M C H N O . Unit cell parameters:
˚
˚
˚
a 10.4429(3) A; b 11.4676(3) A; c 14.1151(4) A, space group P21/c.
(24) We could not disregard a faster protodeboronation than the
IMDA, after the 1,4-addition step in NH alkenyl indoles reactions.
5
7
b, together with the 1,4-addition compound resulting from (Z)-3b in a
1:29 ratio respectively.
5
688
Org. Lett., Vol. 15, No. 22, 2013

Scheme 5. Mechanistic Proposal: Regio- And Stereochemical
Course of the Domino 1,4-Addition/IMDA/Protodeboronation
Sequence of 1 and 3
Scheme 6. Synthesis of 6/6/9 Cage 7 from 5 and X-ray of 7c
Scheme 6, compounds 5aꢀd evolved, through the oxidative
cleavage of the C-2ꢀC-3 indole bond, to the 9-membered
ring ketolactam derivatives 7aꢀd in good to excellent
yields. The structure of 7c was confirmed by X-ray diffrac-
26
tion. This method opens an easy approach to such
derivatives in only two steps.
In summary, we have reported a direct synthesis of
6/6/6 cage-shaped substituted twistanediones by reaction
between 3,5-dimethyl substituted-2-quinonyl boronic
acid and (E)-2-alkenylindoles. The synthesis is based on a
1,4-addition/IMDA/protodeboronation domino sequence.
0
(transition state I ). The electron donating effect of the
oxygenated substituent at C-2 of the diene increases the
The presence of the boronic acid in the quinone promotes a
regioselective 1,4-addition, giving a reactive dienolate.
Appropiate charge distribution in the diene and dienophile
is essential to direct the regiochemical course of the IMDA
process and leads to the formation of unique twistane-like
structures. Analogue systems lacking this charge distribu-
tion gave the isotwistane framework. A successful synthetic
extension of this method involves oxidative cleavage of the
indole ring to expand 6/6/9 membered ring containing cage
compounds.
ꢀ
electron density (δ ) at the vicinal C-1 carbon. Taking into
account the exclusive formation of the 6/6/6 core after the
protodeboronation step, the regiochemical course must be
governed by the dienophile electron density distribution
shown, leaving a (δ ) at C-1 , which is favored by the
electron-donating effect of the R alkenyl substituent (I in
Scheme 5). The differences observed between the (E)- and
ꢀ
0
(
Z)-alkenyl indoles 3c could originate from a favored endo
approach of the (E)-alkenyl indole and a less favored
IMDA exo approach of the (Z)-alkenyl pendant group,
as shown in transition state III (Scheme 5).
Acknowledgment. This work was supported by Minis-
Our results are complementary to the recent examples
of intramolecular [4 þ 2] cycloaddition between 2-tri-
methylsilyloxy-1,3-cyclohexadienes or simple 1,3-cyclo-
hexadienes with a pendant terminal 6-alkenyl substituent,
where a 5/6/6 isotwistane nucleus is reported to be formed
in the IMDA reaction. The C-2 boronic acid substituent at
1 is essential for the regiocontrol of the initial 1,4-addition
process and to generate a useful dienolate.
ꢀ
teriodeCienciae Innovacion (MICINN, Grant CTQ2011-
4783), Comunidad de Madrid and European Social Fund
Grant SOLGEMAC-S2009/ENE-1617). J.R. and M.V.
2
(
thank MICINN for a FPI fellowship. We thank Prof. Dr.
G. A. Molander (University of Pennsylvania, Philadelphia)
for helpful suggestions.
9
Supporting Information Available. Experimental pro-
1
13
Finally, taking advantage of the indole framework pre-
sent in the twistenedione structures 5, we could achieve
the synthesis of expanded novel 6/6/9 tricyclic systems
cedures, spectroscopic data, copies of H and C NMR
spectra for all new compounds, and cif files of 5d and 7c.
This material is available free of charge via Internet at
http://pubs.acs.org.
2
5
through a Witkop type oxidation promoted by m-CPBA
and catalytic p-TsOH. Under the conditions shown in
r 25 1 4
(26) CCDC 952315 (7c): M C H22BrN O . Unit cell parameters:
a 8.0904(2) A; b 27.0158(7) A; c 9.5814(2) A, space group P21/c.
˚
˚
˚
(
25) (a) Witkop, B.; Patrick, J. B.; Rosenblum, M. J. Am. Chem. Soc.
1
2
951, 73, 2641–2647. (b) Mentel, M.; Breinbauer, R. Curr. Org. Chem.
007, 11, 159–176.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 22, 2013
5689