Control of the regio- and stereoselectivity in Diels-Alder reactions with quinone boronic acids

Article abstract of DOI:10.1002/anie.200803428

(Chemical Equation Presented) It all adds up: The dienophilic reactivity of 2-methyl-substituted quinones has been substantially increased by the introduction of a boronic acid substituent, which makes them equivalent to a highly reactive quinone. The Diels-Alder reactions of these quinones are followed by spontaneous and stereoselective protodeboronation to give the trans-fused adducts. The boron group is a temporal regiocontroller and leads to the uncommon meta adduct.

Full text of DOI:10.1002/anie.200803428

Communications
DOI: 10.1002/anie.200803428
Domino Reactions
Control of the Regio- and Stereoselectivity in Diels–Alder Reactions
with Quinone Boronic Acids**
Marꢀa C. Redondo, Marcos Veguillas, Marꢀa Ribagorda, and M. Carmen Carreꢁo*
Dedicated to Prof. Dr. Josep Font on the occasion of his 70th birthday
Organoboron compounds are nowadays extensively used in
organic synthesis.[1] Besides the cross-coupling reactions,
alkenyl and dienyl boronic acids participate in Diels–Alder
reactions leading to boron containing adducts, which can
be easily transformed into highly functionalized systems.
Dialkoxyboryl 1,3-butadiene derivatives, with the borate
ester at C2[2] and C1,[3] have been reported to react with
typical dienophiles and heterodienophiles,[4] whereas 3-bor-
onoacrolein derivatives[5] and their imino analogues[6] behave
as heterodienes. Alkenyl boranes[7] and boronates[8] reacted as
dienophiles[9] leading to highly regio- and endo-selective
cycloaddition products. The use of boronates as both inter-
nal[10] and external[11] Lewis acids have been reported to
improve the reactivity and regioselectivity of dienophiles
bearing a boron group.
Our interest in Diels–Alder reactions with quinones[16] led
us to investigate the effect of a boronic acid, situated at C2 of
the quinone framework, on its dienophilic behavior. Herein,
we report our results showing that upon reaction with dienes,
2-quinonyl boronic acids evolve through a domino process
involving a Diels–Alder reaction and a spontaneous proto-
deboronation, which leads, in one step, to quinone adducts.
The trans-fused cycloadducts were formed from acyclic
dienes. Moreover, when unsymmetrical dienes were used
the regiochemical course of the cycloaddition was fully
controlled by the boron substituent to finally yield regioisom-
ers that have never been directly accessed from the quinone
lacking the boron group.
Taking into account the poor reactivity of the methyl-
substituted quinones as dienophiles and the expected
increased reactivity of the boron-substituted systems, we
focused our study on 3-methyl-2-quinonyl boronic acids. The
required 3-methyl-2-benzoquinonyl or naphthoquinonyl bor-
Despite the well recognized utility of quinone Diels–
Alder adducts in the synthesis of complex molecular tar-
gets,[12] to our knowledge, the effect of a boron substituent,
which is directly linked to the quinone
dienophile,[13] upon Diels–Alder reactions
has never been reported. The synthesis and
Suzuki cross-coupling reactions of 2-naph-
thoquinonyl boronic esters and other fused
heterocyclic analogues had been published
by Harrity and co-workers.[14] The method-
ology they developed involved the Dotz
benzannulation of Fischer chromium car-
bene complexes and 2-substituted 1-alkynyl-
boronates to yield hydroxy naphthyl boron
pinacolates, which were further transformed
into naphthoquinone derivatives by ceric
ammonium nitrate (CAN) oxidation.[15]
Scheme 1. Synthesis of 3-methyl-2-quinonylboronic acids 3a–c.
onic acids 3a–c were synthesized from 1,4-dimethoxy aro-
matic precursors 1a–c through a Br/Li exchange protocol and
reaction with B(OiPr)3, followed by acidic hydrolysis of the
boronate ester (Scheme 1). Subsequent oxidative demethyla-
tion of the 1,4-dimethoxy aromatic 2-boronic acids 2a–c with
CAN gave the desired 2-quinonylboronic acids 3a–c, which
were isolated in good to excellent yields as pure and stable
yellow crystalline solids.[17]
[*] Dr. M. C. Redondo, M. Veguillas, Dr. M. Ribagorda,
Prof. Dr. M. C. Carreꢀo
Departamento de Quꢁmica Orgꢂnica (C-I)
Universidad Autꢃnoma de Madrid
Cantoblanco, 28049-Madrid, Spain
Fax: (+34)914-973-966
E-mail: carmen.carrenno@uam.es
Homepage: http://www.uam.es/quinonso
[**] This work was supported by the Ministerio de Educaciꢃn y Ciencia
(MEC, Grant No. CTQ2005-02095/BQU). M.R. thanks the MEC for a
Ramꢃn y Cajal contract and M.C.R. thanks the MEC for a Juan
de la Cierva contract. We are grateful to the referees for helpful
comments.
Diels–Alder reactions of 3a–c were initially conducted
with cyclopentadiene. Addition of the diene to a solution of
3a in CH2Cl2 led to 4a (90% yield), whose structure
corresponded to
the cis-protodeboronated adduct
(Scheme 2). This adduct was formed directly in the reaction
vessel before workup. The reaction was completed in a short
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200803428.
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nation process. The trans-fused quinone cycloadducts are only
accessible from the cis/endo Diels–Alder adducts that are
directly formed from quinones by treatment with strong bases
or acids,[22] and which generally gave different trans/cis
mixtures.[23] Thus, the boronic acid acts as a temporary
controller and therefore opens up straightforward access to
the trans-fused meta-regioisomeric cycloadducts under mild
reaction conditions. Dimethyl-substituted benzoquinonyl bor-
onic acids 3b and 3c behave similarly in the Diels–Alder
reactions with piperylene. Once again, the boronic acid
directed the regiochemical outcome of the reaction[24] and
promoted the formation of 5b and 5c in 60% and 93% yield,
respectively, in short reaction times (Scheme 3). To compare
the reactivity of 3c with that of the analogue lacking the
B(OH)2 group, we tested the reaction of 3,5-dimethyl
benzoquinone with piperylene. Under identical reaction
conditions (CH2Cl2, room temperature), this reaction did
not afford the adduct, even after 3 days. We also undertook
the same experiment in the presence of PhB(OH)2, to rule out
a reaction catalyzed by a boron species,[25] and after 3 days no
adduct was observed.
Scheme 2. Diels–Alder reactions of 3a–c with cyclopentadiene and the
X-ray structure of 4b.
time (10 minutes) and under very mild reaction conditions
(room temperature), and exhibited a significant increase of
the dienophilic reactivity by the presence of the B(OH)2
group.[18] Even more impressive was the increased reactivity
of dimethyl-substituted benzoquinonyl boronic acids 3b and
3c, which afforded 4b (1 hour) and 4c (30 minutes) in 97%
and 81% yields, respectively. The endo structure was con-
firmed by X-ray diffraction analysis of 4b[19] (Scheme 2).
The reaction between boronic acid 3a and piperylene was
completed within 2 h at room temperature to exclusively
afford the protodeboronated adduct 5a in 95% yield
(Scheme 3). Three aspects of this reaction are noteworthy.
The reaction of 3a–c with 1-methoxy-1,3-butadiene in
CH2Cl2 occurred at À208C and led to 6a–c in excellent yields.
In this case the domino sequence, including the Diels–Alder
reaction and protodeboronation, was followed by elimination
of MeOH (Scheme 3). The regiochemical course of the initial
cycloaddition, deduced from the position of the double bond
generated in the elimination, was also directed by the B(OH)2
group.
The cycloaddition of 3a–c with isoprene occurred in a
highly regioselective manner, and lead exclusively to the
meta regioisomer.[26] Once again, the regiochemistry was fully
controlled by the boronic acid. The spontaneous protode-
boronation gave a mixture of trans/cis-fused adducts 7a
(80:20) and 7b (66:34) from 3a and 3b, respectively
(Scheme 4).[27,28] After flash chromatography, 3c gave a
63:32:5 mixture of trans-7c, cis-7c, and 8, as determined by
1H NMR spectroscopy. Although we could not isolate them in
diastereomerically pure form, to our surprise, the crystalliza-
tion of the mixture from AcOEt/n-hexane gave a good quality
single crystal of 8 whose unequivocal structure was estab-
Scheme 3. Diels–Alder reactions of 3a–c with 1-subtituted-1,3-buta-
dienes and the X-ray structure of trans-fused 5a.
First, the mild reaction conditions used and short reaction
time required again revealed the high reactivity of the
dienophile if compared with 2-methylnaphthoquinone.[20]
Second, the exclusive formation of the 1,4a-dimethyl-substi-
tuted derivative 5a indicated that the regiochemistry was fully
controlled by the boron substituent. This result opens easy
access to the meta adducts, which are not favored in cyclo-
addition reactions between 1-substituted dienes and 2-alkyl-
substituted quinones. Third, the trans relative configuration of
the C4a and C9a stereogenic centers in 5a, which was
confirmed by X-ray diffraction analysis,[21] indicated that the
Diels–Alder reaction was followed by a trans-protodeboro-
Scheme 4. Reaction of dimethylquinonyl boronic acids 3a–c with
isoprene and the X-ray structure of dimmer 8.
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lished by X-ray diffraction analysis.[29] The relative amounts of
trans-7c, cis-7c, and 8 remained constant under different
reaction conditions, including longer reaction times. Com-
pound 8 (a dimer of trans-7c) was also formed in the dark,
thus indicating a photochemically allowed [2+2] cycloaddi-
tion (as an explanation for the formation of the cyclobutane
ring) was not the correct mechanistic pathway. Most probably,
the [2+2] cycloaddition of trans-7c to form the cyclobutane
ring[30,31] was catalyzed by the boron species present in the
reaction medium.[32]
Reactions of 3c with 1,3-disusbtitued diene 9 or 1,2,3-
trisubstituted dienes 10 and 11 were also carried out. As
shown in Scheme 5, the cycloaddition reactions were com-
Scheme 6. Regio- and stereochemical course of the Diels–Alder reac-
tions and protodeboronation (the domino process) of 3-methyl-2-
quinonyl boronic acids 3 with cyclic and acyclic dienes.
Scheme 5. Diels–Alder reactions of 3c with 1,3-disubtituted or 1,2,3-
trisubstituted butadienes. TBS=tert-butyldimethylsilyl.
pleted in very short reaction times, and led directly to the
trans-fused meta-regioisomeric cycloadducts 12–14, and thus
is evidence of the regiochemical control exerted by the
B(OH)2 group in the dienophile and the cooperating effect of
the C1 and C3 substituents in the diene partners. These results
show the generality and potential utility of 2-quinonyl boronic
acids as dienophiles.
The high dienophilic reactivity of 2-quinonyl boronic acids
can be a consequence of the conjugation effect of the B(OH)2
group, which must decrease the LUMO (lowest unoccupied
4a–c. The exclusive formation of the trans-fused adducts 5,
12–14 from piperylene and dienes 9–11 can be explained by
the stereoselective axial protonation of the boron enolate C,
which occurs from the less hindered bottom face of the half-
chair conformation shown. This conformation must be the
most stable since the 1-(or 8-)methyl group is situated in the
most favored pseudoequatorial disposition. In the case of the
reaction between quinonyl boronic acids 3a–c and isoprene,
the formation of trans-fused adduct 7 as the major product
can be explained on the basis of the above model, through the
axial protonation of D. The minor product (cis-fused adduct
7) could result from the axial protonation of the half-chair
conformation D’. The relative stability of D (pseudoaxial Me
=
molecular orbitals) energy of the C2 C3 quinonic bond, thus
decreasing the HOMO (highest occupied molecular orbi-
tals)–LUMO energy gap.[33] The high dienophilic reactivity
must also be reinforced by hydrogen bonding between the
boronic acid and the carbonyl group at C1 (TS1 in
Scheme 6).[34] The origin of the efficient regiocontrol exerted
by the boronic acid can also be found in these features. As the
coefficient values of the LUMO orbital for the carbonyl
group at C1 becomes larger and the dienophilic double bond
of 3 is polarized as shown, the regiochemistry is therefore
expected by taking into account the C1,C2 or C1,C3
substitution of the diene partners.
A plausible explanation of the formation of cis or
trans adducts is also summarized in Scheme 6. The evolution
of the initially formed endo adduct A through the boron
enolate intermediate could explain the formation of 4a–c,
which occurs by protonation and loss of the boron group.[35]
When cyclopentadiene was used as the diene, the rigid and
concave shaped boron enolate B could only undergo the
protonation from the external face giving the endo adducts
=
group) and D’ (pseudoaxial C O group) conformers must be
similar, thus explaining the formation of a cis and trans
mixture of adducts 7 after protodeboronation.
In summary, we have shown that 3-methyl-2-quinonyl
boronic acids are excellent dienophiles which behave as
highly reactive synthetic equivalents of the quinone analogues
lacking the boron group. The initially formed adducts evolved
spontaneously into the products resulting from a protode-
boronation process in a highly regio- and stereoselective
manner. This process was dependant on the cyclic or acyclic
nature of the diene partner. The methodology constitutes a
new application of boronic acids as synthetic intermediates,
thus expanding their utility to the straightforward access to
trans-fused quinone adducts (which are not directly available
from the latter) in excellent yields and under very mild
reaction conditions. The overall regiochemical course of the
reaction is the opposite to that which results form quinone
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otherwise elusive meta adducts.
Received: July 15, 2008
Published online: December 8, 2008
Keywords: boron · Diels–Alder reactions · quinones ·
.
regioselectivity · trans-fused adducts
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[31] For [2+2] cycloadditions catalyzed by oxazaborolidine, see: H.
Information) and cyclopentadiene was completed in 1.5 hours
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[34] The activating effect of the hydrogen bonding was demonstrated
by the following experiment: cycloaddition between the pinacol
ester derived from boronic acid 3c (see the Supporting
[35] 11B NMR spectroscopic monitoring of the reaction between 3a
and cyclopentadiene in CD2Cl2 revealed the formation of a
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boronic acid could be responsible of the protonation observed.
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