[3 + 2] coupling of quinone monoacetals by combined acid-hydrogen bond donor

Article abstract of DOI:10.1021/ol201886r

The expeditious and efficient [3 + 2] coupling approach of quinone monoacetals 1 with alkene nucleophiles 2 by the action of an activated Bronsted acid in the presence of a hydrogen bond donor perfluorinated alcohol has been achieved. With the optimized combined acid, the reaction could proceed under mild conditions by only mixing the two reactants to afford the cycloadducts 3 in a short time (within 10 min) with good to quantitative yields.

Full text of DOI:10.1021/ol201886r

ORGANIC
LETTERS
2011
Vol. 13, No. 18
4814–4817
[3 þ 2] Coupling of Quinone Monoacetals
by Combined AcidꢀHydrogen Bond Donor
Toshifumi Dohi, Yinjun Hu, Tohru Kamitanaka, Naohiko Washimi, and Yasuyuki Kita*
College of Pharmaceutical Sciences, Ritsumeikan University, 1-1-1 Nojihigashi,
Kusatsu, Shiga, 525-8577, Japan
kita@ph.ritsumei.ac.jp
Received July 13, 2011
ABSTRACT
The expeditious and efficient [3 þ 2] coupling approach of quinone monoacetals 1 with alkene nucleophiles 2 by the action of an activated
Brønsted acid in the presence of a hydrogen bond donor perfluorinated alcohol has been achieved. With the optimized combined acid, the reaction
could proceed under mild conditions by only mixing the two reactants to afford the cycloadducts 3 in a short time (within 10 min) with good to
quantitative yields.
Quinone monoacetals, which possess not only an un-
saturated carbonyl, but also allyl acetal moieties in one
skeleton, have attracted considerable interest due to their
broad utilities in organic synthesis as intermediates for
natural products and related compounds.1 Due to their
bifunctional structures, varied reactivities during nucleo-
philic attack on quinone monoacetals can be produced, for
instance, conjugated addition to an enone moiety,2 addi-
tion to a carbonyl carbon,3 acetal displacement (such as
hydrolysis), etc. Among them, only a few strategies have
been developed for the construction of substitution reac-
tions to the R-position of the carbonyl group.4
Very recently, we reported a new substitution method
of quinone monoacetals 1 with aromatic nucleophiles
to give oxygenated biaryls catalyzed by montomorillo-
nite clay as a rare example for enabling the substitution
under nonbasic conditions.5,6 Extensive investigation of
this attractive strategy was anticipated, and we have now
found that the use of the bifunctional molecules 1 for
formal [3þ 2] coupling via substitution with the resulting
formation of dihydrobenzofurans 37 would be possible
by further optimizing the activator conditions. Herein,
(1) For preparation and synthetic utility of quinone monoacetals,
see: (a) Magdziak, D.; Meek, S. J.; Pettus, T. R. R. Chem. Rev. 2004, 104,
1383. (b) Liao, C.-C.; Peddinti, R. K. Acc. Chem. Res. 2002, 35, 856.
(2) For selected examples, see: (a) Foster, C. H.; Payne, D. A. J. Am.
Chem. Soc. 1978, 100, 2834. (b) Parker, K. A.; Kang, S.-K. J. Org. Chem.
1980, 45, 1218. (c) Ciufolini, M. A.; Dong, Q.; Yates, M. H.; Schunk, S.
Tetrahedron Lett. 1996, 37, 2881. (d) Stern, A. J.; Rohde, J. J.; Swenton,
J. S. J. Org. Chem. 1989, 54, 4413. (e) Imbos, R.; Brilman, M. H. G.;
Pineschi, M.; Feringa, B. L. Org. Lett. 1999, 1, 623. (f) Grecian, S.;
Wrobleski, A. D.; Aube, J. Org. Lett. 2005, 7, 3167. (g) Giroux, M.-A.;
Guerard, K. C.; Beaulieu, M.-A.; Sabot, C.; Canesi, S. Eur. J. Org.
Chem. 2009, 3871.
(3) Early examples: (a) Evans, D. A.; Cain, P. A.; Wong, R. Y. J. Am.
Chem. Soc. 1977, 99, 7083. (b) Stern, A. J.; Swenton, J. S. J. Org. Chem.
1988, 53, 2465. (c) Imamoto, T.; Takiyama; Nakamura, N.; K.; Hatajima,
T.; Kamiya, Y. J. Am. Chem. Soc. 1989, 111, 4392. (d) Parker, K. A.;
Coburn, C. A. J. Am. Chem. Soc. 1991, 113, 8516.
(4) (a) Coutts, I. G. C.; Hamblin, M. J. Chem. Soc., Chem. Commun.
1976, 58. (b) Sartori, G.; Maggi, R.; Bigi, F.; Giacomelli, S.; Porta, C.;
Arienti, A.; Bocelli, G. J. Chem. Soc., Perkin Trans. 1 1995, 2177. (c)
Henton, D. R.; Anderson, K.; Manning, M. J.; Swenton, J. S. J. Org.
Chem. 1980, 45, 3422. (d) Mal, D.; Pahari, P.; Bidyut, B. K. Tetrahedron
Lett. 2005, 46, 2097.
(5) Dohi, T.; Washimi, N.; Kamitanaka, T.; Fukushima, K.; Kita, Y.
Angew. Chem., Int. Ed. 2011, 50, 6142. A similar transformation using
Pt(IV) catalysts recently appreared during the course of natural product
synthesis. See: Sloman, D. L.; Mitasev, B.; Scully, S. S.; Beutler, J. A.;
Porco, J. A., Jr. Angew. Chem., Int. Ed. 2011, 50, 2511.
€
(6) Related reactions of O,S-acetals: (a) Matsugi, M.; Murata, K.;
Gotanda, K.; Nambu, H.; Anilkumar, G.; Matsumoto, K.; Kita, Y. J.
Org. Chem. 2001, 66, 2434. (b) Matsugi, M.; Murata, K.; Anilkumar, G.;
Nambu, H.; Kita, Y. Chem. Pharm. Bull. 2001, 49, 1658.
r
10.1021/ol201886r
Published on Web 08/15/2011
2011 American Chemical Society

the strategy for the [3 þ 2] coupling of the quinone acetal
1 with a series of alkene nucleophiles 2 utilizing an
activated Brønsted acid in situ formed in equilibrium
by the aid of the hydrogen bond donor solvent, hexa-
fluoroisopropanol (HFIP), is reported (eq 1).
[3 þ 2] coupling concerns the following rational steps
involving charged quinone acetal B generation promoted
by the combined acid species A: Preactivation of the
Brønsted acid first occurs by coordinating the hydrogen
bond donor, HFIP, to the Lewis basic functionality of the
acid (Brønsted acid activation by HFIP).10 The combined
acid would work as an indispensable promoter to generate
the charged species B of the quinone acetal 1a in equili-
brium in the polar solvent, which can then react with the
nucleophile 2a at the less hindered carbon site remote from
the acetal rather than the sterically congested acetal
carbon. This regioselective trend might also be pro-
nounced by the steric factor of the associating acid in
the proposed acetal activation mode. Finally, cyclization
of the carbonyl moiety in the keto-type tautomer C was
accompanied by aromatization as the driving force to
affordthe formal [3 þ 2] coupling product 3aa. To confirm
the hypothesis, we envisioned the use of a Brønsted acid
having a good hydrogen bond-accepting functionality,
and for such acids, a series of carboxylic acids and related
compounds showing varied pH values were evaluated.
As a result, the different product yields were observed
during the optimization of the carboxylic acids in the [3 þ 2]
coupling (Table 1). These results clearly indicated that
Initially, the [3 þ 2] coupling of the quinone acetal 1a
(eq 1, R = H) with allyltrimethylsilane2a8 was testedusing
our reported system along with aluminum pillared mon-
tmorillonite in HFIP.5 This indeed produced the coupling
adduct, dihydrobenzofuran 3aa, in an expectedly (61%),
but the reaction was very slow and required a very long
time (1 day) to consume all the starting material. Further-
more, this method was too case-sensitive for the combina-
tion of the quinone acetal 1a and nucleophile 2a to allow
formation of the extended series of cycloadducts 3. The
montmorillonites unfortunately showed a limited general-
ity and performance in the [3 þ 2] coupling; hence the
Scheme 1. [3 þ 2] Coupling Strategy Based on the Combined
Use of Brønsted Acids and HFIP
Table 1. Effect of the Acid Activator and Solventa
entry
activator
solvent
time
yield of 3aab,c
1
2
acetic acid
HFIP/DCM 7 h
19%
n.d.
4-methyl
//
1 day
benzoic acid
benzoic acid
4-nitro-
3
4
//
//
2 h
2 h
9%
14%
benzoic acid
pentafluoro-
benzoic acid
2,4,6-trichloro-
benzoic acid
phthalic acid
5d
6
//
//
1 h
86%
10 min (90%)e
10 min
59%
7
8
//
10 min
1 h
58%
21%
pentafluoro-
benzoic acid
TFE/DCM
a The screenings were carried out with 2 equiv of acid, 5 equiv of
allyltrimethylsilane 2a at room temperature unless otherwise noted. For
more details of other acids see SI. b Isolated yield after purification.
c Formation of noncyclized allylation product 4aa was observed (see SI).
d Acid (1 equiv) and 2a (2 equiv). e Performed at 0 °C.
screening of several types of Brønsted acid activators was
envisioned instead as just alternatives. As illustrated in
Scheme 1, we hypothesized the [3 þ 2] coupling of the
quinone acetal 1a based on the combined use of a
Brønsted acid and highly polar HFIP having a super
hydrogen bond donor ability, but not showing the prop-
erty as a hydrogen bond acceptor.9 The mechanism of the
only carboxylic acids with a suitable acidic proton
range11 showed good performance in order to develop
(7) For the synthesis and utility of the dihydrobenzofurans, see a
review: Bertolini, F.; Pineschi, M. Org. Prep. Proced. Int. 2009, 41, 385.
(8) For allylsilane in cyclizations, see the examples: (a) Schmidt,
(10) (a) Allard, B.; Casadevall, A.; Casadevall, E.; Largeau, C. Nouv.
J. Chim. 1980, 4, 539. (b) Deaton, M. V.; Ciufolini, M. A. Tetrahedron
Lett. 1993, 34, 2409. Recent works of H2O2 activation by the hydrogen
bonding: (c) Neimann, K.; Neumann, R. Org. Lett. 2000, 2, 2861. (d)
Berkessel, A.; Adrio, J. A. Adv. Synth. Catal. 2004, 346, 275.
€
€
A. W.; Knoelker, H.-J. Synlett 2010, 2207. (b) Knoelker, H.-J. J. Prakt.
Chem. 1997, 339, 304. (c) Berard, D.; Racicot, L.; Sabot, C.; Canesi, S.
ꢀ
Synlett 2008, 1076. (d) Berard, D.; Giroux, M. A.; Racicot, L.; Sabot, C.;
(11) (a) Bordwell, F. G. Acc. Chem. Res. 1988, 21, 456. (b) In
Encyclopedia of Reagents for Organic Synthesis, 2nd ed.; Paquette,
L. A., Crich, D., Fuchs, P. L., Molander, G. A., Eds.; John Wiley & Sons:
Chichester, 2009; Vol. 10, pp 7654ꢀ7656. The pKa order of the tested
> C6H5CO2H >
Canesi, S. Tetrahedron 2008, 64, 7537.
(9) Reviews and accounts: (a) Kita, Y.; Takada, T.; Tohma, H. Pure
Appl. Chem. 1996, 68, 627. (b) Eberson, L.; Hartshorn, M. P.; Persson,
O.; Radner, F. Chem. Commun. 1996, 2105. (c) Begue, J.; Bonnet-delpon,
D.; Crousse, B. Synlett 2004, 18. (d) Dohi, T.; Yamaoka, N.; Kita, Y.
Tetrahedron 2010, 66, 5775.
acids is as follows: AcOH, 4-MeC6H4CO2H
4-NO2C6H4CO2H > C6F5CO2H > 2,4,6-Cl-C6H2CO2H, phthalic
acid > CF3CO2H > MeSO3H > CF3SO3H.
Org. Lett., Vol. 13, No. 18, 2011
4815

the coupling, among which pentafluorobenzoic acid
(pKa: ca. 1.5)11b especially gave the most impressive
result regarding not only the product yield but also the
observed reaction rate (entry 5). Otherwise, incomplete
coversions of the quinone acetal 1a were observed for
the less acidic activators (entries 1ꢀ4), while the stronger
acids, such as trichlorobenzoic and phthalic acids (entries
6 and 7), as well as trifluoroacetic and methanesulfonic
acids, caused considerable decomposition of 1a, afford-
ing the cycloadduct 3aa in poorer yields (see the results in
Supporting Information (SI)). One plausible explanation
for the ineffectiveness of the latter is that the stronger
acids would promote irreversible formation of the phe-
noxenium ion from the quinone acetal 1a by accelerating
the release of MeOH from the acetal group (vide infra).12
HFIP has played an indispensable role in this new
coupling system because the consumption of the quinone
acetal 1a by pentafluorobenzoic acid in other solvents
was very slow, and the product 3aa would not be
smoothly formed, even in the parent but less polar and
weaker hydrogen bond donor, 2,2,2-trifluoroethanol
(TFE, entry 8). Therefore, the combined use of the acid
in HFIP is highly important to achieve an effective
reaction. The mixed solvent system of HFIP and DCM
was employed due to the solubility of the reactants 1a and
2a in the fluoroalcohol.
Table 2. [3 þ 2] Coupling Using Various Alkenes 2bꢀia
With the established reagent and conditions, the
scope of the reactions in the alkene coupling partners
2 was initially investigated using the quinone acetal 1a
as the test substrate (Table 2). To our delight, the use of
the activated alkenes like 2a was not necessary, and the
coupling alkenes 2bꢀi in this strategy would not limit
the reaction scope. The couplings could thus proceed
very fast and provided the expected products 3abꢀai in
good yields at room temperature. It should be noted
that the use of these alkenes as nucleophiles only in this
strategy could afford the corresponding cycloadducts
3abꢀai, which were somewhat troublesome to obtain
by reported methods starting from phenols.13 Utiliza-
tion of the gem-substituted methylstyrene 2f was also
possible for the construction of the cycloadduct 3af
(entry 5). Due to the mildness of the reaction condi-
tions, the vinyl sulfide 2i was also the appropriate
nucleophile, giving the cyclized O,S-acetal 3ai in good
yield (entry 8).
a The reactions were conducted for 10 min at room temprature
according to the optimized reaction condition described in Table 1.
reactions smoothly proceeded in acceptable yields,
some of which were almost quantitative (Table 3).
The reactions occurred quite regioselectively at the
less hindered R-position of the carbonyl in the quinone
acetals. Substitution of the tert-butyl group at the
neighboring position of the acetal in the substrate 1c
somewhat hampered the substrate reactivity due to its
steric demand (entry 2). On the other hand, the halo-
gen functionality and tert-butyl group at the R-posi-
tion of the carbonyl in 1e and 1f permitted the efficient
conversions to the products 3eb and 3fb (entries 4 and 5).
Quantitative formations of the naphthalene dihydro-
furans 3gb and 3hb occurred by using the naphthoqui-
none acetals 1g and 1h (entries 6 and 7). Gratefully, the
valuable indoline skeleton was accessible from the
Regarding the quinone acetals 1, we investigated the
influence of its ring substituent. Employing styrene 2b
as the counterpart, an extensive range of quinone
acetal derivatives 1bꢀh with varied ring moieties did
not alter the activation course of the acid, and the
(12) (a) Davis, B. R.; Gash, D. M.; Woodgate, P. D.; Woodgate, S. D.
J. Chem. Soc., Perkin Trans. 1 1982, 1499. (b) Endo, Y.; Shudo, K.;
Okamoto, T. J. Am. Chem. Soc. 1982, 104, 6393. (c) Kirti, L.; Herczegh,
P.; Visy, J.; Simonyi, M.; Antus, S.; Pelter, A. J. Chem. Soc., Perkin
Trans. 1 1999, 379. These alkenes could also partially cause oligomer-
ization under strongly acidic conditions.
(13) (a) Wang, S.; Gates, B. D.; Swenton, J. S. J. Org. Chem. 1991, 56,
1979. (b) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton,
J. S. J. Org. Chem. 1992, 57, 2135. (c) Berard, D.; Jean, A.; Canesi, S.
Tetrahedron Lett. 2007, 48, 8238. (d) Sabot, C.; Berard, D.; Canesi, S.
Org. Lett. 2008, 10, 4629.
(14) In addition to these, aliphatic alkenes could couple with the
quinone acetals 1, and extended [3 þ 2] coupling for the construction of
spirocycles was possible. See SI.
4816
Org. Lett., Vol. 13, No. 18, 2011

For example, the oxidative annulation of 4-methoxyphenol
with allylsilane 2a involving the generation of the phenox-
enium ion could produce 3aa in only 48% yield at best
Table 3. Scope of the Quinone Acetals 1bꢀi
Scheme 2. Dihydrobenzofuran 3aa from the Phenol
(Scheme 2).8c,d Instead, the synthesis of the target 3aa was
conducted in an overall 89% yield starting from the phenol
by utilizing our new strategy. The one-pot conversion of the
phenol to the cycloadduct 3aa via the formation of the
quinone acetal 1a15 was also developed without purification
of the synthetic intermediate, and the product 3aa could be
obtained in 81% yield.
In summary, we have successfully achieved the [3 þ 2]
coupling of the quinone acetals 1 with various alkenes 2 on
the basis of a new substitution strategy promoted by the
Brønsted acid that is activated by the hydrogen bond
donor, HFIP. The reversible generation of the charged
quinone acetal species developed in situ by the combined
acid, rather than the formation of the unstable phenox-
enium ion, during the stated conditions would suppress the
substrate decomposition to realize a new efficient coupling
strategy under mild conditions at room temperature.
Acknowledgment. This work was partially supported
by Grant-in-Aid for Scientific Research (A) from the
Japan Society for the Promotion of Science (JSPS) and
Ritsumeikan Global Innovation Research Organization
(R-GIRO) project. T.D. is grateful for support from the
Asahi Glass Foundation.
a 2 equiv of the acid activator and 3 equiv of styrene 2b were used.
Ts = p-toluensulfonyl.
iminoquinone acetals as exemplified by the result
using 1i (entry 8).14
Supporting Information Available. The experimental
details and spectroscopic data containing NMR charts of
the all products 3. This material is available free of charge
via the Internet at http://pubs.acs.org.
Finally, we compared the superiority of our coupling
method for synthesizing dihydrobenzofurans 3 starting
from phenols. Previously, the oxidative couplings of phe-
nols with alkenes to produce dihydrobenzofurans have been
rarely reported,8c,d,13 as such methods typically suffered
from the obtained product yield and limited substrate scope.
(15) For preparation of quinone monoacetals 1 using a hypervalent
iodine reagent, see: (a) Tamura, Y.; Yakura, T.; Haruta, J.; Kita, Y. J.
Org. Chem. 1987, 52, 3927. (b) Pelter, A.; Elgendy, S. Tetrahedron Lett.
1988, 29, 677. (c) Moriarty, R. M.; Prakash, O. Org. React. 2001, 5, 327.
Org. Lett., Vol. 13, No. 18, 2011
4817