Synthesis of benzo- And naphthoquinonyl boronic acids: Exploring the diels-alder reactivity

Article abstract of DOI:10.1002/chem.200902796

Substituted 2-quinonyl boronic acids have been synthesised from 1,4-dimethoxy aromatic derivatives in two steps: regiocontrolled boronation and oxidative demethylation. The study of their dienophilic behaviour evidenced that the boron substituent significantly increases the reactivity and triggers an efficient domino process in which the Diels-Alder reaction was followed by a protodeboronation or dehydroboronation, depending on the substitution on both the quinone and diene partners. The boronic acid acts as a temporary controller, opening a direct access to trans-fused meta-regiosomeric adducts when 3-methyl-substi-tuted 2-quinonyl boronic acids react with dienes with a substituent at C-1. A particularly valuable synthetic result was obtained in the reaction between 3,6-dimethyl-2-quinonyl boronic acid and piperylene under an oxygen atmosphere; trans-fused 8a-hydroxy-2,4a,8trimethyl tetrahydronaphthoquinone was formed directly, in excellent yield and in a highly diastereoselective manner.

Full text of DOI:10.1002/chem.200902796

FULL PAPER
DOI: 10.1002/chem.200902796
Synthesis of Benzo- and Naphthoquinonyl Boronic Acids: Exploring the
Diels–Alder Reactivity
Marcos Veguillas,[a] Maria C. Redondo,[a] Isabel Garcꢀa,[b] Marꢀa Ribagorda,*[a] and
M. Carmen CarreÇo*[a]
Abstract: Substituted 2-quinonyl bor-
onic acids have been synthesised from
1,4-dimethoxy aromatic derivatives in
two steps: regiocontrolled boronation
and oxidative demethylation. The study
of their dienophilic behaviour evi-
denced that the boron substituent sig-
nificantly increases the reactivity and
triggers an efficient domino process in
which the Diels–Alder reaction was
followed by a protodeboronation or de-
hydroboronation, depending on the
substitution on both the quinone and
diene partners. The boronic acid acts as
tuted 2-quinonyl boronic acids react
with dienes with a substituent at C-1.
A particularly valuable synthetic result
was obtained in the reaction between
3,6-dimethyl-2-quinonyl boronic acid
and piperylene under an oxygen atmos-
phere; trans-fused 8a-hydroxy-2,4a,8-
a
temporary controller, opening a
direct access to trans-fused meta-regio-
someric adducts when 3-methyl-substi-
trimethyl
tetrahydronaphthoquinone
Keywords: boron · Diels–Alder re-
actions · quinones · regioselectivity ·
fused adducts
was formed directly, in excellent yield
and in
manner.
a
highly diastereoselective
Introduction
The C-2-boron-substituted 1,3-butadienyl derivatives[5] af-
forded alkenyl boron cycloadducts that have been also used
in subsequent palladium cross-coupling reactions.[6] b-Boro-
noacrolein pinacolates[7] and their imino analogues[8] behave
as oxa- and azadienes to afford to dihydropyran or piperi-
dine heterocycles, respectively. Alkenyl boranes[9] and boro-
nates[10] are reactive dienophiles giving highly regio- and
endo-selective cycloadditions.[11] Diels–Alder reactions cata-
lysed by internal and external boron Lewis acids have also
been reported. For instance, a boronate-substituted acrylani-
lide[12] is able to act as an internal Lewis acid, and activates
the dienophile by coordination of the boron with the amide
carbonyl. In situ generated aryloxy boronate esters of ju-
glone[13] were shown to improve both the reactivity and re-
gioselectivity of cycloadditions.
Boranes, boronic acids and their esters are widely used in
organic synthesis, mainly as the precursors of alcohols and
as intermediates in Suzuki–Miyaura couplings.[1] Besides
these applications, dienyl and alkenyl boron derivatives
have been shown to participate in Diels–Alder reactions, in
which they act as dienes and dienophiles, respectively. Thus,
1-dialkoxyboryl-substituted 1,3-butadienes[2] react with typi-
cal dienophiles and azadienophiles to give to allyl boronic
esters,[3] which in turn react with aldehydes to give highly
functionalised cyclohexenes (Vaultier tandem sequence).[2b,4]
[a] M. Veguillas, M. C. Redondo, Dr. M. Ribagorda,
Prof. Dr. M. Carmen CarreÇo
Although quinones are well recognised as highly reactive
and synthetically useful dienophiles in [4+2] cycloadditions,
the effect on Diels–Alder reactions of a boron substituent
placed at the dienophilic double bond had not been investi-
gated.[14] The structure of quinone Diels–Alder adducts is a
recurrent building block for the synthesis of complex molec-
ular targets.[15,16] Controlling the regioselectivity of cycload-
ditions with quinones is an essential task en route to the
synthesis of these targets, including naturally occurring qui-
nones and other complex secondary metabolites.[17] Lewis[18]
and Brønsted[19] acid catalysts are known to improve the re-
gioselectivity of cycloadditions with unsymmetrical quinones
Departamento de Quꢀmica Orgꢁnica (C-I)
Universidad Autꢂnoma de Madrid Cantoblanco
28049 Madrid (Spain)
Fax : (+34)914973966
E-mail: maria.ribagord@uam.es
carmen.carrenno@uam.es
[b] Dr. I. Garcꢀa
Laboratory of Glyconanotechnology, CIC biomaGUNE
Parque Tecnolꢂgico de San Sebastiꢁn, Paseo Miramꢂn 182
20009 San Sebastiꢁn (Spain)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902796.
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by coordination (or protonation) with the least sterically
hindered or the most basic carbonyl group of the quinones.
Some asymmetric catalysts have been reported to promote
highly enantio- and regioselective reactions with qui-
nones.[19,20] The regiochemistry of the Diels–Alder reaction
can also be controlled by remote substituents in benzo-,[21]
naphtho-[22] and 1,4-phenanthrenequinones.[23] In these cyclo-
additions, Lewis acid catalysts are also used to improve the
regioselectivity. The introduction of a substituent such as a
Cl or Br atom (X) at the quinone dienophilic double bond
has been used with the double aim of controlling regioselec-
tivity and recovering the quinone skeleton after the cycload-
dition by HX elimination.[24] Sulfoxides[25] have also been
used to this end. With enantiopure sulfinyl quinones, we
have reached excellent regio- and stereochemical control in
the cycloadditions, en route to synthetically interesting tar-
gets such as helicenequinones[26] and natural angucycli-
nones.[27]
forded the phenyl boronic acids 2b–d[32], isolated pure in
66–74% yield (Scheme 1).
In connection with this project devoted to extend the ap-
plications of quinones in synthesis,[25,26] we decided to inves-
tigate the unknown affect of a boron substitutent on these
dienophiles. In a preliminary investigation, we found that a
boronic acid group placed at C-2 of a 3-methyl-substituted
quinone skeleton produced a dramatic increase of the dieno-
philic reactivity. Full control of the regiochemical and final
stereochemical course of the Diels–Alder reactions is exert-
ed by the metal substituent, which is lost in the course of
the reaction.[28] These interesting findings prompted us to
extend the study of the dienophilic behaviour of 2-quinonyl
boronic acids to other quinones. Herein, we report the prep-
aration of substituted 2-quinonyl boronic acids and the
study of their Diels–Alder reactions. Our previous work is
also discussed in detail, including results not described in
the preliminary communication. Combined, this work has al-
lowed us to establish the advantages and limitations of using
the B(OH)2 substituent as a control element in these cyclo-
additions.
Scheme 1. Synthesis of phenyl boronic acids 2b–d and naphthyl boronic
acids 4a–d.
The naphthyl boronic acid 4a and the diisopropyl amide
derivative 4c were synthesised in 69 and 72% yield, respec-
tively, by ortho-metallation/boronation of 3a and 3c. The
bromo–lithium exchange/boronation process was used to
transform 2-bromonaphthalene derivatives 3b and 3d into
4b and 4d, in 81 and 63% yield, respectively. CAN oxida-
tion of commercially available 2,5-dimethoxyphenyl boronic
acid (2a) led to the formation of the benzoquinone deriva-
tive 5a, which was not stable enough to be isolated and
1
could only be detected by H NMR spectroscopy. The elec-
tron-withdrawing effect of the B(OH)2 substituent must de-
stabilise the quinonic system by decreasing the quinone/hy-
droquinone redox potential. Attempted CAN oxidation of
4-methyl-2,5-dimethoxyphenyl boronic acid (2b) to the
boron-bearing quinone was also unsuccessful. Instead, 4,4’-
dimethyl-1,1’-bicyclohexa-3,6-diene-2,2’,5,5’-tetraone (6)[33]
was formed in an almost quantitative yield and in a regio-
controlled manner, probably due to the initial deboronation
of 2b, followed by coupling of the intermediate radicals and
evolution to the final product by oxidative demethylation.
Fortunately, the oxidative demethylation of 3,6- and 3,5-di-
methyl-2,4-dimethoxyphenyl boronic acids 2c and d was suc-
cessfully achieved by reaction with CAN in CH3CN/H2O at
08C. Under these conditions, pure benzoquinonyl boronic
acids 5c and 5d were obtained as stable yellow-crystalline
solids in excellent yields (99 and 97%, Scheme 2). The oxi-
dative demethylation of the dimethoxynaphthyl boronic
acids 4 also occurred with good to excellent yields, leading
to the naphthoquinones 7a–d. The stability of 7a–d was de-
pendent on the substitution. For instance, 2-naphthoquinon-
yl boronic acids 7a–c could be isolated as orange solids, but
had to be used immediately after preparation because the
initial crystals turned dark on standing. Conversely, 3-
Results and Discussion
Prior to our work, there was only one synthetic approach to
2-boron-substituted quinones, reported by Harrity and co-
workers in 1999.[29] They described the synthesis of 2-naph-
thoquinonyl boronic esters (and other fused heterocyclic an-
alogues) using a Dçtz benzannulation of Fischer chromium
carbene complexes with 2-substituted 1-alkynylboronates,
followed by oxidation of the most electron-rich aromatic
ring. In our case, we decided to use dimethoxy-substituted
phenyl and naphthyl derivatives 1 and 3 as starting materi-
als, which could be easily transformed into the boronic acids
2 and 4 by the conventional ortho-lithiation or Br–Li ex-
change/boronation protocol.[30] Further oxidative demethyla-
tion with ammonium cerium(IV) nitrate (CAN) would yield
the corresponding quinones. Thus, starting from bromodime-
thoxy benzenes 1b–d[31] bromo–lithium exchange, followed
by reaction with B
ACHTUNGTRENNUNG(OiPr)3 and hydrolysis (HCl, 10%) af-
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Naphthoquinoyl Boronic Acids
FULL PAPER
compared with the boron-free quinone analogues.[35] 2-
Naphthoquinonyl boronic acids 7a, 7c and 7d also reacted
with cyclopentadiene, affording the protodeboronated endo
adducts 9a, 9c and 9d in excellent yields. The structure of
9c was secured by X-ray diffraction[36] (Scheme 3). Although
the increase of the quinone dienophilic reactivity is signifi-
cant in all cases, the most impressive increase corresponded
to 3-methyl-2-naphthoquinonyl boron derivative 7d; the re-
action with cyclopentadiene was completed in 10 min at RT
to afford 9d in 90% yield. The analogous cycloaddition
using the boron-free 2-methyl-naphthoquinone only oc-
curred in the presence of Lewis acids.[37] All of these proto-
deboronated adducts were formed directly in the reaction
vessel before any workup, as evidenced from the direct for-
mation of 9a when the reaction between 7a and cyclopenta-
diene was carried out in an NMR tube (CD2Cl2). These re-
sults suggested that the boron substituent at the quinone
triggers an efficient domino process in which the Diels–
Alder reaction is followed by a fast protodeboronation step.
When 5-methoxy-2-naphthoquinonyl boronic acid (7b)
was treated with cyclopentadiene at À208C, the correspond-
ing cis-protodeboronated adduct 9b was formed in 13%
yield, together with 71% of the dehydroboronated product,
characterised as 1,4-dihydro-9,10-anthraquinone (10)
(Scheme 4). Compound 10 could be formed by oxidation of
Scheme 2. Synthesis of 2-benzo and 2-naphthoquinonyl boronic acids 5
and 7.
methyl-naphthoquinonyl boronic acid (7d) was a stable
yellow-crystalline solid.
The study of the Diels–Alder reactions of the quinonyl
boronic acids 5c, 5d and 7a–d was initiated by using cyclo-
pentadiene as a model diene. Addition of the freshly dis-
tilled diene to a solution of 3,6-dimethyl-2-benzoquinonyl
boronic acid (5c) in CH2Cl2 afforded the Diels–Alder
adduct 8c in 97% yield after 1 h at RT. The structure of 8c
corresponded to a protodeboronated endo adduct, as con-
firmed by X-ray diffraction[34] (Scheme 3). 4,6-Dimethyl-2-
benzoquinonyl boronic acid (5d) also reacted with cyclopen-
tadiene under very mild conditions (CH2Cl2, À208C, 30 min)
and the protodeboronated endo adduct 8d was isolated in
81% yield. The short reaction times and mild conditions
used were evidence of a significant increase of the dieno-
philic reactivity in the presence of the B(OH)2 group, if
Scheme 4. Reaction of 7b with cyclopentadiene.
9b, facilitated by the presence of the electron-rich methoxy-
substituted ring. To disregard this mechanism, we carried
out the cycloaddition between 7b and cyclopentadiene
under an argon atmosphere and showed the formation of
the same mixture of 9b and 10. Moreover, compound 9b
was shown to be stable under atmospheric conditions. A
plausible explanation for the formation of 10 could be a pro-
todeboronation process facilitated by the lower acidity of
the boron vicinal hydrogen atom in the initially formed
Diels–Alder adduct I, if compared with the undetected
adduct resulting from naphthoquinone 7a. This must be due
to the electron-donating effect of the OMe group on the
system, which suffers a spontaneous dehydroboronation to
recover the quinone double bond in 10. The evolution ob-
served from 7b, evidenced that the final result of the overall
sequence was dependent on the nature of the substituents
Scheme 3. Reactions of 5c and d and 7a, c and d with cyclopentadiene
and X-ray structures of 8c and 9c.
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M. C. CarreÇo, M. Ribagorda et al.
surrounding the conjugated carbonyl groups, both in the di-
enophile and in the initially formed Diels–Alder adduct.
This influence was also evident in the reactions of naph-
thoquinonyl boronic acids 7 with acyclic dienes. Thus, when
trans-piperylene was submitted to reaction with 7a or 7b,
both with a hydrogen atom at C-3, the products isolated cor-
responded to the 1,4-dihydro-9,10-anthraquinone derivatives
11a and 11b, a result of the [4+2] cycloaddition/dehydro-
boronation process, isolated in 83 and 91% yield, respec-
tively (Scheme 5). The regiochemistry of 11b indicated that
Compound 7c did not react with isoprene, even after long
reaction times.
Benzoquinonyl boronic acids 5c and 5d and the naphtho-
quinonyl derivative 7d, which has a methyl substituent at C-
3 of the dienophilic double bond, also reacted with acyclic
dienes, but the fate of the initially formed adducts was unex-
pected. The reaction between 3-methyl-2-naphthoquinonyl
boronic acid (7d) and piperylene was complete within 2 h at
RT affording, exclusively, the protodeboronated adduct 13d
in 95% yield. The structure of 13d was confirmed by X-ray
diffraction (Scheme 7).[39] Three aspects of this reaction are
Scheme 7. Reaction of 7d with piperylene and X-ray structure of trans-
fused 13d.
Scheme 5. Reactions of 2-naphthoquinonyl boronic acids 7a–c with piper-
ylene.
noteworthy. First, the mild conditions used and short reac-
tion time required revealed again the high reactivity of the
dienophile if compared with boron-free 2-methylnaphtho-
quinone. Reaction of the boron-free analogue with pipery-
lene only occurred under high-pressure conditions at 1508C,
to produce a complex mixture, from which the ortho adduct
was isolated in a poor yield (27%).[40] Second, the exclusive
formation of the 1,4a-dimethyl-substituted derivative 13d in-
dicated that the regiochemistry of the cycloaddition was
fully controlled by the boron substituent, the endo-ortho
adduct formed initially, before protodeboronation, facilitat-
ed the transformation into the product. This result opens an
easy access to the meta adducts, which are not favoured in
cycloadditions between 1-substituted dienes and 2-alkyl-sub-
stituted quinones. Third, the trans relative configuration of
the C-4a and C-9a stereogenic centres in 13d indicated that
the Diels–Alder reaction was followed by a trans-protode-
boronation process occurring in situ. The trans-fused qui-
none cycloadducts are only accessible from the cis-endo
Diels–Alder adducts, directly formed from quinones by
treatment with strong bases or acids,[35b,41] which generally
give different trans/cis mixtures.[42] Thus, the boronic acid is
acting as a temporary controller and opens up a straightfor-
ward access to the trans-fused meta-regiosomeric cycload-
ducts under very mild reaction conditions.
the ortho adduct was formed initially, as expected on the
basis of a regiochemical control exerted by the B(OH)2 sub-
stituent. Surprisingly, the product resulting from the reaction
between
3-N,N-diisopropylcarbamoyl-2-naphthoquinonyl
boronic acid (7c) and piperylene was also identified as 1-
methyl-1,4-dihydro-9,10-anthraquinone (11a) and was isolat-
ed in 83% yield. In this case, a favoured intramolecular as-
sociation between the boron atom and the basic oxygen
atom of the amide group[12,38] could be facilitating the boron
elimination process to recover the quinone double bond.
Similarly, the reaction of naphthoquinonyl boronic acids
7a and 7b with isoprene afforded the dehydroboronated di-
hydroanthraquinones 12a and 12b in 96 and 67% yield, re-
spectively (Scheme 6). The regiochemistry of 12b also sug-
gested that the boronic acid is controlling the regiochemical
course of the initial cycloaddition, to form the expected
para adduct, which yielded 12b after dehydroboronation.
Dimethyl-substituted benzoquinonyl boronic acids 5c and
5d behave similarly in the reactions with trans-piperylene.
Once again, the boronic acid directed the regiochemical out-
come of the reaction and promoted the formation of the
trans-fused meta-adducts 14c and 14d in 60 and 93% yield,
respectively, over short reaction times (Scheme 8). To obtain
such a high yield of 14c, the reaction between piperylene
Scheme 6. Reactions of 2-naphthoquinonyl boronic acids 7a and b with
isoprene.
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group through the intermediate formation of an undetected
ortho adduct.
The cycloadditions of 7d and 5c with isoprene also oc-
curred in a highly regioselective manner, to give the meta
regioisomer exclusively after protodeboronation. Although
the regiochemistry was fully controlled by the boronic acid,
in these cases the spontaneous protodeboronation process
gave a mixture of trans- and cis-fused adducts 17d (80:20)
and 18c (66:34)[47] from 7d and 5c, respectively
(Scheme 10). Diels–Alder reaction of 2,5-dimethylbenzoqui-
none and isoprene had been reported to occur only in tolu-
ene at reflux to give a 50:50 mixture of regioisomeric meta/
para-cis adducts after 36 h.[43]
Scheme 8. Reactions of 5c and 5d with piperylene.
and 5c had to be performed under rigorous inert-atmos-
phere conditions (Argon or N2) otherwise variable amounts
of a hydroxyl-substituted product 30 (see below) were
formed when air was present. A comparison of the reactivity
of 5c and 5d with that reported for 2,5-[43,44] and 2,6-dimeth-
yl benzoquinones,[13,45] evidenced that the boron-free qui-
nones are much less reactive, only giving good yields of the
piperylene adducts when working at high temperatures, in
the presence of Li salts (LiClO4 or LiOTf) or Lewis acids
catalysts. The major regioisomers formed from the boron-
lacking quinones under thermal conditions are the ortho ad-
ducts. The regiochemical course could be inverted to favour
the para adducts in the presence of catalysts. In any case,
the meta adducts are generally obtained as minor compo-
nents. Regarding the stereochemistry, all of these cycloaddi-
tions followed Alderꢄs rule, to give the undetected endo-cis
structures, transformed in situ into the trans systems. Thus,
our methodology opens a direct and straightforward access
to the trans-fused meta-regioisomers. To disregard a cata-
lysed reaction by some boron species,[46] we tested the reac-
tion of 2,6-dimethyl benzoquinone with piperylene in
CH2Cl2 at RT, in the presence of PhB(OH)2. Under these
conditions no cycloadduct was detected, even after three
days.
Reactions of 7d, 5c and 5d were also carried out with 1-
methoxy-1,3-butadiene and led to compounds 15d, 16c and
16d in excellent yields after very short reaction times. In
this case, the domino sequence, including the Diels–Alder
reaction and protodeboronation, was followed by elimina-
tion of MeOH (Scheme 9), which generated directly 1,9a-di-
hydro anthraquinone (15d) or the 4a,5-dihydro-1,4-naphtho-
quinone derivatives 16b and 16c, with an angular methyl
substituent. The regiochemical course of the initial cycload-
dition, deduced from the position of the double bond gener-
ated in the elimination, was also directed by the B(OH)2
Scheme 10. Reactions of 3-methyl-2-quinonyl boronic acids 7d and 5c
with isoprene.
The reaction between 3,5-dimethyl-substituted-2-quinonyl
boronic acid (5d) and isoprene allowed the isolation of a
63:32:5 mixture of trans-19d, cis-19d and 20 as determined
1
by H NMR spectroscopy (Scheme 11). Although we could
not isolate them in a diastereomerically pure form, to our
surprise, the crystallisation of the mixture from EtOAc/n-
hexane gave a good quality single crystal of 20 from which
the unequivocal structure was established by X-ray diffrac-
tion analysis (Scheme 11).[48]
Scheme 11. Reaction of dimethylquinonyl boronic acid 5d with isoprene
and X-ray structure of dimer 20.
To clarify the effect of the substitution pattern of the
diene on the stereochemical outcome of the protodeborona-
tion step (trans/cis ratio) we investigated the reactions of
7d, 5c and 5d with highly substituted dienes 21–23. The re-
sults obtained are summarised in Table 1. Reaction with 1-
phenyl-3-trimethylsilyloxybutadiene (21) or 1,2,3-trisub-
titued dienes 22 and 23 also proceeded under very mild con-
Scheme 9. Reactions of 7d, 5c and 5d with 1-methoxy-1,3- butadiene.
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M. C. CarreÇo, M. Ribagorda et al.
Table 1. Diels–Alder reactions of 7d, 5c and 5d with 1,3-disubtituted
and 1,2,3-trisubstituted-1,3-butadiene derivatives 21–23.
curring after the Diels–Alder reaction. Based on the above
observations of the reaction between 5c and piperylene in
the presence of air, we decided to run this reaction in
CH2Cl2, at room temperature in a flask fitted with a bub-
bling oxygen balloon. Under these conditions, derivative 30
was formed exclusively, and could be isolated in 84% yield
after chromatographic purification. The structure and ste-
reochemistry of 30, an all-trans 8a-hydroxy-2,4a,8-trimethyl-
substituted naphthoquinone-derived meta adduct, was con-
firmed by X-ray diffraction (Scheme 12).[49]
7d
5c
5d
Scheme 12. Reactions of 5c with piperylene or isoprene under an oxygen
atmosphere and X-ray structure of 30.
Considering the synthetic interest of this result, a direct
access to angularly hydroxyl-substituted systems,[50] we de-
cided to investigate the generality of the process. When iso-
prene was used as the diene, the reaction with 5c under an
oxygen atmosphere gave the hydroxy derivative 31, together
with the protodeboronated adduct 18c in a 40:60 ratio.
Compound 31 was isolated pure in 38% as a 94:6 mixture
of trans- and cis-fused angularly hydroxy-substituted ad-
ducts. We also tried to obtain the hydroxy derivatives by re-
action between 5d or 7d and piperylene under an oxygen
atmosphere, unfortunately only the trans adducts 14d and
13d were obtained, respectively.
ditions (CH2Cl2, RT) in very short reaction times. All of the
adducts formed (24–29) corresponded to the protodeboro-
nated trans-fused structures and were obtained with good to
excellent yields (60–95%) (Table 1). These results provided
evidence for the regiochemical control exerted by the
B(OH)2 group in the dienophile and the cooperating effect
of the C-1 and C-3 substituents in the diene partners. More-
over, the exclusive formation of the trans-fused adducts re-
vealed that the stereochemistry of the protodeboronation is
controlled by the C-1 substitution of the diene. These results
show the generality and potential utility of quinonyl boronic
acids as dienophiles.
Taking into consideration the reactivity observed for
these quinonyl boronic acids, and given the power of the or-
ganoboron compounds to incorporate different functionali-
ties into organic substrates, we tried to further functionalise
the resulting quinone adducts. Assuming the initial forma-
tion of an a-boro ketone from the cycloaddition between
the quinonyl boronic acid and the diene, we decided to
carry out a series of experiments to trap the initially formed
boron-containing adduct. With this aim, a solution of cyclo-
pentadiene or piperylene in CH2Cl2 was added to a previ-
ously prepared solution of boronic acid 7a or 5c CH2Cl2
containing different electrophiles (p-nitro- or p-fluoroben-
zaldehyde, N-bromosuccinimide). In all cases, the adducts
9a (Scheme 3) or 14c (Scheme 8) and/or complex reaction
mixtures were detected. All of these attempts to trap the in-
termediate boron derivative failed probably due to the ex-
tremely rapid elimination or protodeboronation process oc-
Regio- and stereochemistry of the reactions: mechanistic as-
pects: The high dienophilic reactivity observed for 2-quinon-
yl boronic acids must be a consequence of the electron-with-
drawing effect of the B(OH)2 group, which must decrease
the LUMO energy of the C-2=C-3 quinonic double bond,
thus decreasing the HOMO–LUMO energy gap.[51] The
electron-withdrawing effect of the boron substituent can be
deduced from the 13C NMR shifts of the methyl-substituted
b-carbon atom of boronic acid 5d or the corresponding pi-
nacolate ester, which are deshielded relative to the b-carbon
atom of the boron-free quinone analogues (Figure 1). This is
also reinforced by the formation of a hydrogen bond be-
tween the boronic acid and the C-1 carbonyl group (TS1 in
Scheme 13), evident in the X-ray of quinone 5d.[52]
The activating effect of the hydrogen bond was also evi-
denced from the results of the cycloaddition between the pi-
nacol ester derived from boronic acid 5d and cyclopenta-
diene. The pinacolate, obtained by treatment of 2d with pi-
3712
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Naphthoquinoyl Boronic Acids
FULL PAPER
the external face, in the axial direction. As such endo ad-
ducts 8 and 9 were observed.
The exclusive formation of the trans-fused adducts 13b,
14c, 14d and 24–29 from piperylene or 1,3- or 1,2,3-substi-
tuted dienes 21–23 can be explained from the stereoselective
axial protonation of the boron enolate C, from the less-hin-
dered bottom face of the half-chair conformation
(Scheme 14). This must be the most stable situation since
the C-1 (or C-8) R3 group is in the pseudo-equatorial posi-
tion. This approach justifies why the trans-protodeborona-
tion only occurred stereoselectively in the adducts resulting
from dienes having a substituent at C-1.
Figure 1. 13C NMR chemical shifts of selected carbon atoms and X-ray
structure of 5d.
Scheme 14. Regio- and stereochemical course of the domino Diels–Alder
reactions and protodeboronation of quinonyl boronic acids with 1-substi-
tuted acyclic dienes.
Scheme 13. Regio- and stereochemical course of the domino Diels–Alder
reactions and protodeboronation of quinonyl boronic acids 5c–d, 7a, 7c
and 7d with cyclopentadiene.
In the case of the reaction between quinonyl boronic
acids 5c, 5d and 7d and isoprene, the major formation of
trans-fused adducts can be explained in a similar way,
through the axial protonation of the boron enolate D
(Scheme 15). The minor cis-fused adducts could result from
the axial protonation of the half-chair conformation D’. The
nacol followed by CAN oxidation, reacted with cyclopenta-
diene after 1.5 h at reflux in CH2Cl2. No reaction occurred
under the conditions in which the free boronic acid 5d
evolved in 30 min (CH2Cl2, À208C), even over extended re-
action time (overnight). The origin of the efficient regiocon-
trol exerted by the boronic acid can also be due to these fea-
tures because the values of the coefficient of the C-1 car-
bonyl group of the LUMO orbital become larger and the di-
enophilic double bond of the quinone is polarised, as shown
in Scheme 13. The regiochemistry is that expected, taking
into account the substitution of the diene partners. A plausi-
ble explanation of the formation of cis- or trans-fused ad-
ducts from the reactions with 3-substituted 2-quinonyl bor-
onic acids is also summarised in Schemes 13–15. The evolu-
tion of the initially formed cyclopentadiene endo adduct A
(resulting from the endo approach shown as TS1, through
the boron enolate intermediate B) could explain the forma-
tion of compounds 8 and 9 after protonation and loss of the
boron group (Scheme 13). 11B NMR spectroscopy was used
to monitor the reaction between 7d and cyclopentadiene in
CD2Cl2 and revealed the formation of a signal appearing at
d=19.1 ppm, which was assigned to boroxine (B3O6H3), the
formation of which could favour the protonation of B.[53]
When cyclopentadiene was the diene, the rigid and concave-
shaped boron enolate B could only suffer protonation from
relative stability of the
D (pseudo-axial Me) and D’
(pseudo-axial C=O) conformers must not be very different,
thus explaining the formation of a mixture of cis- and trans
Scheme 15. Regio- and stereochemical course of the domino Diels–Alder
reactions and protodeboronation of quinonyl boronic acids with pipery-
lene.
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3713

M. C. CarreÇo, M. Ribagorda et al.
adducts from the protodeboronation on the bottom and top
faces of D and D’, respectively.
The stereoselective formation of the pentacyclic com-
pound 20 obtained in the reaction between 3,5-dimethyl-
benzoquinone derivative 5d and isoprene, was not easy to
explain. Its structure corresponded to a dimer of trans-19d,
the formation of which was also observed in the dark, thus
disregarding a photochemically allowed [2+2] cycloaddition
as a mechanistic pathway to explain the formation of the cy-
clobutane ring. To improve the final yields of 20, we effected
the reaction between 5d and isoprene under different condi-
tions, however, the relative amounts of trans-19d, cis-19d
and 20 remained constant, even after extended reaction
times. To explain the formation of 20, we propose a one-pot,
domino sequence including a Diels–Alder cycloaddition be-
tween 5d and isoprene, followed by a trans protodeborona-
tion and a catalysed [2+2] cycloaddition involving the
methyl-substituted cross-conjugated C-2=C-3 double bond
of trans-19d, which leads to the cyclobutane ring.[54,55] Most
likely, some of the boron species present in the reaction
medium could catalyse the stepwise sequence. In the overall
Scheme 17. Mechanistic proposal to justify the formation of hydroxy de-
rivative 30.
column chromatography the isolated product showed a
broad singlet at d=2.10 ppm, which was assigned to the an-
gular OH of 30. The direct oxidation of the initial boron-
containing ortho-endo-adduct B, could be disregarded due
to the trans disposition between the 8a-OH and the 4a-
methyl substituents. We also could disregard the formation
of 30 from the protodeboronated adduct 14c because it re-
mained unchanged in the presence of oxygen in CH2Cl2.
Thus, we assumed that once the initial ortho-endo-adduct B
was formed in the Diels–Alder reaction of 5c and pipery-
lene, the evolution to the boron enolate C (favoured by the
Lewis acidity of the boron atom in B and its proximity to
the carbonyl group) could be followed by reaction with
oxygen. A stereoselective ene-type reaction occurring from
the less-hindered face of the intermediate C could explain
the formation of D, protodeboronation of which would yield
intermediate hydroperoxide E, further reduced to the OH
derivative 30 by the SiO2 used in the chromatographic pu-
rification.
À
process six new C C bonds were formed in a highly stereo-
selective manner.
A detailed analysis of the X-ray structure shown in
Scheme 16 revealed that the pentacyclic compound 20 must
arise exclusively through the reaction between the pair of
Conclusion
We have reported the synthesis of a series of substituted 2-
quinonyl boronic acids by regiocontrolled boronation/oxida-
tion of 1,4-dimethoxybenzene derivatives, in good to excel-
lent yields. The study of their Diels–Alder reactions with
different dienes evidenced the following features:
Scheme 16. Plausible formation and X-ray structure of dimer 20.
enantiomers (4aR*, 8aR*)-trans-19d and (4aS*, 8aS*)-trans-
19d. Both enantiomers must approach each other from the
less-hindered face (opposite to the 8a-axial methyl substitu-
ent) giving a sole meso diastereoisomer 20 with S2 symme-
try.
A mechanistic explanation of the isolation of hydroxyl de-
rivative 30 from the reaction between 5c and piperylene in
the presence of oxygen was not evident. A detailed analysis
of the 1H NMR spectrum of the crude mixture prior to chro-
matographic purification revealed the presence of a broad
singlet at d=8.35 ppm, which was assigned to the hydrogen
atom of hydroperoxide E shown in Scheme 17.[50] After
1) The boron substituent dramatically increased the dieno-
philic reactivity of the quinones, if compared with the
analogous boron-free quinone derivatives. The most im-
pressive increase corresponds to the systems with a
methyl substituent at the dienophilic double bond;
Diels–Alder reactions of quinones 5c, 5d and 7d were
complete in very short reaction times and under very
mild reaction conditions.
2) In all cases, the initially formed adducts spontaneously
lose the boron substituent in a domino process to give
different products, the structures of which are dependent
on the nature of the C-3 substituent of the quinonyl bor-
3714
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Naphthoquinoyl Boronic Acids
FULL PAPER
Compound 4b: Following the general procedure A, the reaction of 2-
bromo-1,4,5-trimethoxynaphthalene (350 mg, 1.18 mmol) with nBuLi
(0.51 mL, 1.29 mmol, 2.5m in hexane) and BACTHNUTRGNEN(UG OiPr)3 (554 mg, 2.94 mmol)
onic acid and the cyclic or acyclic nature of the diene, as
well as the presence or absence of a C-1 substituent in
the diene.
gave 4b, isolated pure after flash column chromatography (hexane/
EtOAc, 6:1) as white solid (250 mg, 81%). M.p. 122–1248C; 1H NMR
(300 MHz, CDCl3): d=7.83 (dd, J=8.5, 0.8 Hz, 1H), 7.60 (t, J=8.1 Hz,
1H), 7.38 (s, 1H), 7.10 (d, J=7.8 Hz, 1H), 4.16 (s, 9H), 4.13 (s, 9H),
4.11 ppm (s, 9H); 13C NMR (75 MHz, CDCl3): d=157.2, 157.1, 157.1,
156.6, 153.0, 152.9, 130.2, 129.9, 126.4, 126.4, 126.2, 120.2, 114.7, 114.4,
109.4, 107.6, 107.4, 63.1, 63.0, 60.0, 56.3, 56.2, 56.1, 20.6, 13.8 ppm; MS
(EI): m/z (%): 315 (48) [M]+, 272 (14), 215 (100); HRMS: m/z calcd for
C19H25NO3: 315.1834 [M]+; found: 315.0392.
3) The boronic acid acts as a temporary regiocontrol ele-
ment, affording regioisomeric adducts not directly avail-
able from the boron-free quinones.
All of these features combined make 2-quinonyl boronic
acids useful dienophiles, providing a direct synthetic access
to otherwise elusive polycyclic quinone adducts. Another
noteworthy observation of this study is the efficient forma-
tion of the trans-fused hydroxy derivative 30 from reaction
between 5c and piperylene, working under an oxygen at-
mosphere. Further studies of this process are currently on-
going.
Compound 3c: 1,4-Dimethoxy-2-naphthoic acid (1.7 g, 7.30 mmol) was
dissolved in thionyl chloride (6.1 mL) and stirred at room temperature
for 15 h. Excess thionyl chloride was then removed in vacuo to afford the
acid chloride as a brown solid in quantitative yield. The crude product
was dissolved in benzene (8.7 mL) and N,N-4-dimethylaminopyridine
(DMAP) (10 mol%) and diisopropylamine (1.5 mL, 10.9 mmol) were
added dropwise at 08C. After stirring at 08C for 1 h, the solvent was re-
moved under pressure and the residue was dissolved in CH2Cl2 (50 mL).
The organic layer was washed with water, dried over MgSO4 and filtered.
The solvent was removed in vacuo and the crude product was purified by
flash column chromatography (hexane/EtOAc, 4:1) to give 3c as a pale
yellow solid (2 g, 85%). M.p. 122–1248C; 1H NMR (300 MHz, CDCl3):
d=8.26–8.23 (m, 1H), 8.11–8.08 (m, 1H), 7.59–7.48 (m, 2H), 6.59 (s,
1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.82 (sept, J=6.8 Hz, 1H), 3.56 (sept, J=
6.8 Hz, 1H), 1.64 (d, J=6.8 Hz, 3H), 1.63 (d, J=6.8 Hz, 3H), 1.21 (d, J=
6.7 Hz, 3H), 1.06 ppm (d, J=6.8 Hz, 3H); 13C NMR (75 MHz, CDCl3):
d=168.6, 152.1, 144.8, 128.5, 127.1, 126.7, 126.3, 125.8, 122.2, 122.1, 101.8,
62.6, 55.7, 51.1, 45.6, 21.0, 20.8, 20.4, 20.2 ppm; MS (EI): m/z (%): 315
(48) [M]+, 272 (14), 215 (100); HRMS: m/z calcd for C19H25NO3:
315.1834 [M]+; found: 315.0392.
Experimental Section
General:[56] 1H, 13C and 11B NMR spectra were recorded on a AV-300
Bruker instrument using CDCl3 or [D6]acetone as solvent at 300, 75 and
96 MHz, respectively. A DRX-500 Bruker instrument was used to record
1H and 13C NMR spectra at 500 MHz. Chemical shifts are reported in
ppm relative to CDCl3 (d=7.27 ppm) and [D6]acetone (d=2.09 ppm). In
the 13C NMR spectra of boron-containing compounds, a typical 13C signal
is missing, which corresponds to the carbon directly linked to the boron
atom. A HP 5985 Hewlett-Packard instrument was used to measure
HRMS at 70 eV. All reactions were monitored by thin-layer chromatog-
raphy, which was performed on precoated sheets of silica gel 60 and flash
column chromatography was performed with silica gel 60 (230–400 mesh)
(Merck). Eluting solvents are indicated in the text. Cyclopentadiene was
freshly distilled before use. The apparatus for inert-atmosphere experi-
ments was flame dried under a stream of dry argon. Trimethylsilyloxybu-
tadienes 21, 22 and 23 were prepared by following standard proce-
dure.[57, 58]
Compound 4c: A solution of sec-BuLi (1.0 mL, 1.43 mmol, 1.4m in
hexane), was added dropwise to
0.95 mmol) in THF (14 mL) under argon at À788C. The mixture was
stirred at room temperature for 2 h and then (OiPr)3 (0.22 mL,
a stirred solution of 3c (300 mg,
BACHTUNGTRENNUNG
1.9 mmol) was added dropwise at À788C. After 10 min the mixture was
allowed to warm to RT and was stirred overnight. The mixture was acidi-
fied with dilute hydrochloric acid and then extracted with EtOAc. The
organic layer was dried over anhydrous MgSO4, filtered and concentrated
in vacuo. The crude product was purified by flash column chromatogra-
phy (hexane/EtOAc, 2:1). The product was obtained as a white solid
(246 mg, 72%). M.p. 132–1348C; 1H NMR (300 MHz, cdcl3): d=8.12–
8.08 (m, 2H), 7.60–7.56 (m, 2H), 6.76 (brs, 2H), 3.98 (s, 3H), 3.95 (s,
3H), 3.48 (m, 2H), 1.62 (d, J=6.8 Hz, 6H), 1.08 ppm (d, J=6.8 Hz, 6H);
13C NMR (75 MHz, CDCl3): d=170.5, 159.1, 147.8, 130.7, 130.1, 128.3,
128.0, 127.0, 122.9, 199.7, 63.8, 62.8, 51.9, 46.2, 20.2 (2C), 20.1 ppm (2C);
11B NMR (96 MHz, CDCl3): d=28.9 ppm; MS (ES): m/z (%): 359 (8)
[M]+, 360 (100) [M+1]+; HRMS: m/z calcd for C19H26NO5: 359.1904
[M]+; found: 359.1898.
General procedure A for the synthesis of the phenylboronic acids: A so-
lution of nBuLi (1.56 mmol, 2.5m in hexane) was added dropwise to a
stirred solution of the corresponding 1,4-dimethoxy aromatic compound
(1.30 mmol) in THF (7.42 mL) under argon at À788C. The mixture was
stirred at this temperature for 5 min and then BACTHNUTRGENUG(N OiPr)3 (3.25 mmol) was
added dropwise at À788C. After 10 min the mixture was allowed to
warm to RT and was stirred overnight. The mixture was acidified with hy-
drochloric acid 10% (~2 mL) and then extracted with Et2O (2ꢅ10 mL).
The organic layer was dried over anhydrous MgSO4, filtered and concen-
trated in vacuo. The crude product was purified by flash chromatography
(eluent indicated in each case).
Compound 6:[59] The reaction of 2b (25 mg, 0.13 mmol) with CAN
(280 mg, 0.51 mmol) in aqueous MeCN gave 7a as an orange solid
(39 mg, 99%). M.p. 179–1828C.
Compound 2b:[59] Following the general procedure A, the reaction of 2-
bromo-5-methyl-1,4-dimethoxybenzene (300 mg, 1.30 mmol) in THF
General procedure B for the synthesis of 2-naphtho and benzoquinonyl
boronic acids: An aqueous solution (5 mL) of CAN (0.55 g, 1.00 mmol)
was added slowly to a solution of the corresponding 1,4-dimethoxy aro-
matic boronic acid (0.4 mmol) in MeCN (5 mL) at 08C. After stirring for
30 min, the organic solvent was evaporated and the mixture was extract-
ed with EtOAc (2ꢅ5 mL). The combined extracts were washed with
water (2ꢅ5 mL) and brine (2ꢅ5 mL), dried over anhydrous MgSO4, fil-
tered and concentrated in vacuo. The crude product was used in next
step without further purification.
(6 mL) with nBuLi (0.57 mL, 1,43 mmol, 2.5m in hexane) and BACTHNUTRGNEUNG(OiPr)3
(0.9 mL, 3.89 mmol) gave 2b, which was isolated after flash column chro-
matography (hexane/EtOAc, 6:1) as white solid (169 mg, 66%). M.p.
108–1108C.
Compound 4a: Following the general procedure A, the reaction of 3a
(100 mg, 0.53 mmol) with nBuLi (0.21 mL, 0.54 mmol, 2.5m in hexane)
and BACHTUNGTRENNUNG(OiPr)3 (0.15 mL, 1.35 mmol) gave 4a, which was isolated after
flash column chromatography (EtOAc/hexane, 1:2) as white solid (78 mg,
63%). M.p. 105–1078C; 1H NMR (300 MHz, CDCl3): d=8.31–8.28 (m,
1H), 8.07–8.04 (m, 1H), 7.60–7.54 (m, 2H), 7.15 (s, 1H), 6.55 (s, 2H),
4.04 (s, 3H), 4.01 ppm (s, 3H); 13C NMR (75MHz, CDCl3): d=157.2,
151.8, 128.8, 127.4, 126.7, 126.5, 122.6, 122.0, 107.1, 63.7, 55.6 ppm;
11B NMR (96 MHz, CDCl3): d=29.5 ppm; MS (EI): m/z (%): 232 (8)
[M]+, 188 (61), 173 (100); HRMS: m/z calcd for C12H13BO4: 232.0907
[M]+; found: 232.1160.
Compound 5c: Following the general procedure B, the reaction of 2c
(220 mg, 1.04 mmol) with CAN (1.38 g, 2.51 mmol) in aqueous CH3CN
gave 5c as a yellow solid (187 mg, 100%). M.p. 118–1208C; 1H NMR
(300 MHz, CDCl3): d=6.65 (q, J=1.5 Hz, 1H), 6.64 (s, 2H), 2.37 (s, 3H),
2.04 ppm (d, J=1.5 Hz, 3H); 13C NMR (75 MHz, CDCl3): d=195.1,
187.7, 157.4, 146.7, 133.8, 15.9, 15.1 ppm; 11B NMR (96 MHz, CDCl3): d=
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M. C. CarreÇo, M. Ribagorda et al.
28.3 ppm; MS (ES): m/z (%): 181.12 (3) [M+1]+; HRMS: m/z calcd for
C8H9BO4: 180.0594 [M+1]+; found: 181.1219.
Compound 10:[61] Following the above procedure, purification by flash
column chromatography gave 10 (76 mg, 71%) as a yellow solid. M.p.
141–1438C.
Compound 7a: Following the general procedure B, the reaction of 4a
(60 mg, 0.26 mmol) with CAN (339 mg, 0.62 mmol) in aqueous MeCN
gave 7a as an orange solid (51 mg, 100%). M.p. 106–1088C; 1H NMR
(300 MHz, [D6]acetone): d=8.14–8.08 (m, 2H), 7.81–7.78 (m, 2H), 7.58
(s, 1H), 6.25 ppm (s, 2H); 13C NMR (75 MHz, [D6]acetone): d=190.9,
184.7, 145.9, 134.2, 134.0, 132.4, 132.3, 126.2, 125.7 ppm; 11B NMR
(96 MHz, [D6]acetone): d=27.8 ppm; MS (ES): m/z (%): 203 (25)
[M+1]+, 189 (29), 61 (100); HRMS: m/z calcd for C10H7BO4: 202.0437
[M]+; found: 202.0550.
Compound 11a: Following the general procedure C, the reaction of 7a
(60 mg, 0.30 mmol) with trans-piperylene (0.12 mL, 1.2 mmol) gave 11a
as a pale yellow solid (55 mg, 83%). Reaction time: 30 min, T: À208C.
M.p. 68–708C; 1H NMR (300 MHz, CDCl3): d=8.11–8.06 (m, 2H), 7.75–
7.70 (m, 2H), 5.85 (m, 2H), 3.64 (m, 1H), 3.35 (ddd, J=24.5, 5.0, 3.6 Hz,
1H), 3.35 (ddd, J=24.5, 6.3, 2.4 Hz, 1H), 1.26 ppm (s, 1H); 13C NMR
(75MHz, CDCl3): d=184.7, 184.2, 146.5, 141.7, 133.5, 133.4, 132.3, 132.0,
130.0, 126.3, 126.1, 121.3, 29.3, 24.6, 22.0 ppm; MS (EI): m/z (%): 224
(51) [M]+, 222 (63), 209 (100); HRMS: m/z calcd for C15H12O2: 224.0837
[M]+; found: 224.0834.
Compound 11b:[61] Following the general procedure C, the reaction of
7b (110 mg, 0.47 mmol) with trans-piperylene (129 mL, 1,90 mmol) gave
11b after flash column chromatography (hexane/EtOAc, 6:1) as a yellow
solid. (110 mg, 91%). Reaction time: 120 min, T: À208C. M.p. 138–
1408C.
Compound 7b: Following the general procedure B, the reaction of 4b
(94 mg, 0.360 mmol) with CAN (473 mg, 0.864 mmol) in aqueous MeCN
gave 7b as an orange solid (53 mg, 63%). M.p. decomposes above
1408C; 1H NMR (300 MHz, CDCl3): d=7.77–7.69 (m, 2H), 7.44 (s, 1H),
7.34 (dd, J=7.9, 1.0 Hz, 1H), 6.25 (brs, 2H), 4.02 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3): d=191.5, 184.3, 159.6, 149.8, 135.2, 134.2, 120.2, 119.4,
118.3, 56.5 ppm; 11B NMR (96 MHz, CDCl3): d=27.5 ppm; MS (ES): m/z
(%): 227 (100), 205 (40); HRMS: m/z calcd for C11H7O3: 187.0395 [M]+;
found: 187.0606.
Compound 12a: Following the general procedure C, the reaction of 7a
(40 mg, 0.19 mmol) with isoprene (75 mL, 0.76 mmol) gave 12a as a
white solid (41 mg, 96%). Reaction time: 2 h, T: 258C. M.p. 124–1268C;
1H NMR (300 MHz, CDCl3): d=8.12–8.08 (m, 2H), 7.73–7.70 (m, 2H),
5.57–5.54 (m, 1H), 3.29–3.22 (m, 2H), 3.17–3.11 (m, 2H), 1.82 ppm (s,
3H); 13C NMR (75 MHz, CDCl3): d=184.6, 184.5, 141.8, 141.6, 133.5,
132.1, 132.1, 132.0, 130.1, 126.4, 126.2, 116.8, 26.1, 26.6, 22.9 ppm; MS
(EI): m/z (%): 224 (2) [M]+, 223 (17), 194 (63), 166 (39), 165 (100);
HRMS: m/z calcd for C15H12O2: 224.0837 [M]+; found: 224.0713.
Compound 7c: Following the general procedure B, the reaction of 4c
(50 mg, 0.14 mmol) with CAN (183 mg, 0.33 mmol) in aqueous MeCN
gave 7c as an orange solid (46 mg, 100%). M.p. 136–1388C; 1H NMR
(300 MHz, CDCl3): d=8.14–8.07 (m, 2H), 7.84–7.78 (m, 2H), 6.96 (brs,
2H), 3.52 (sept, J=6.8 Hz, 2H), 3.52 (sept, J=6.8 Hz, 2H), 3.46 (d, J=
6.8 Hz, 6H), 1.19 ppm (d, J=6.8 Hz, 6H); 13C NMR (75 MHz, CDCl3):
d=191.1, 182.7, 165.7, 152.2, 134.5 (2C), 132.2, 131.3, 126.7, 126.5, 52.0,
46.6, 20.0 (2C), 19.9 ppm (2C); 11B NMR (96 MHz, CDCl3): d=28.2 ppm;
MS (ES): m/z (%): 329 (7) [M]+, 330 (100) [M+1]+; HRMS: m/z calcd
for C10H7BO4: 329.1435 [M]+; found: 329.1558.
Compound 12b: Following the general procedure C, the reaction of 7b
(30 mg, 0.13 mmol) with isoprene (39 mL, 0.39 mmol) gave 12b after
flash column chromatography (hexane/EtOAc, 10:1) as an orange solid
(22 mg, 67%). Reaction time: 2.5 h, T: 258C. M.p. 144–1468C; 1H NMR
(300 MHz, CDCl3): d=7.75 (dd, J=7.6, 0.9 Hz, 1H), 7.64 (t, J=8.0 Hz,
1H), 7.27 (dd, J=8.4, 0.8 Hz, 1H), 5.61–5.44 (m, 1H), 4.01 (s, 3H), 3.19
(m, 2H), 3.10 (m, 2H), 1.80 ppm (s, 3H); 13C NMR (75 MHz, CDCl3):
d=184.7, 183.8, 159.4, 143.3, 139.5, 134.4, 134.3, 130.3, 120.0, 119.0, 117.5,
116.7, 56.4, 29.2, 25.3, 22.9 ppm. MS (EI): m/z (%): 254 (2) [M]+, 252
(98), 165 (100), 152 (41); HRMS: m/z calcd for C16H14O3: 254.0953 [M]+;
found: 254.0959.
General procedure C for Diels–Alder reactions: The appropriate diene
(0.6–0.8 mmol) was added to a solution of the corresponding 2-benzo- or
naphthoquinonylboronic acid (0.2 mmol) in CH2Cl2 (3 mL). The resulting
mixture was stirred at temperature T during the time indicated in each
case. Water (3 mL) was added and the mixture was extracted with
CH2Cl2 (3ꢅ3 mL). The combined organic layers were dried over MgSO4,
filtered and the solvent was removed in vacuo.
Compound 24d: Following the general procedure C, the reaction of 7d
(35 mg, 0.16 mmol) with 2-[(tert-butyldimethylsilyl)oxy]-4-phenyl-1,3-bu-
tadiene (59 mg, 0.23 mmol) gave 24d after flash column chromatography
(hexane/EtOAc, 50:1) as a colourless oil (57 mg, 81%). Reaction time:
30 min, T: À208C. 1H NMR (300 MHz, CDCl3): d=8.01–7.97 (m, 1H),
7.75–7.70 (m, 1H), 7.65–7.53 (m, 2H), 7.34 (brs, 1H) 7.32 (brs, 1H),
7.25–7.16 (m, 2H), 7.14–7.08 (m, 1H), 4.09 (t, J=2.4 Hz, 1H), 3.24 (d,
J=9.8 Hz, 1H), 2.82 (d, J=17.7 Hz, 1H), 2.28 (dd, J=17.7, 1.1 Hz, 1H),
1.25 (s, 3H), 0.87 (s, 9H), 0.09 (s, 3H), 0.08 ppm (s, 3H); 13C NMR
(75 MHz, CDCl3: d=200.7, 197.1, 147.4, 145.2, 136.1, 134.24, 133.9, 132.5,
128.9, 128.2, 127.3, 126.3, 126.2, 106.8, 57.2, 50.1, 39.3, 37.9, 25.6, 20.4,
18.0, À4.1, À4.34 ppm; MS (EI): m/z (%): 433 (100) [M+1]+, 315 (100);
HRMS: m/z calcd for C27H33O3Si: 433.2199 [M]+; found: 433.1990.
Compound 9a:[60] Following the general procedure C, the reaction of 7a
(60 mg, 0.30 mmol) with cyclopentadiene (98 mL, 1.18 mmol) gave 9a as
a pale yellow solid (67 mg, 100%). Reaction time: 20 min, T: À208C.
Compound 9c: Following the general procedure C, the reaction of 7c
(40 mg, 0.12 mmol) with cyclopentadiene (41 mL, 0.48 mmol) gave 9c as
a pale yellow solid (35 mg, 82%). Reaction time: 15 h, T: À208C. M.p.
120–1228C; 1H NMR (300 MHz, CDCl3): d=8.02–7.94 (m, 2H), 7.71–
7.68 (m, 2H), 5.86 (brs, 2H), 3.92 (brs, 1H), 3.51 (sept, J=6.4 Hz, 1H),
3.43 (m, 1H), 3.35 (d, J=3.5 Hz, 1H), 3.27 (sept, J=6.4 Hz, 1H), 1.81 (d,
J=13.7 Hz, 1H), 1.61 (d, J=13.7 Hz, 1H), 1.47 (d, J=7.3 Hz, 3H), 1.38
(d, J=7.3 Hz, 3H), 1.00 (d, J=6.4 Hz, 3H), 0.68 ppm (d, J=6.4 Hz, 3H);
13C NMR (75 MHz, CDCl3): d=197.1, 194.1, 169.3, 137.7, 135.6, 135.1,
134.5, 134.2, 126.9, 126.7, 64.6, 56.5, 56.1, 50.9 (2C), 48.5, 46.5, 29.6, 20.2
(2C), 20.0, 18.7 ppm; MS (EI): m/z (%): 351.2 (8.5) [M]+, 285 (56), 185
(56), 200 (100); HRMS: m/z calcd for C22H25NO3: 351.1834 [M]+; found:
351.1819.
Compound 25d: Following the general procedure C, the reaction of 7d
(26 mg, 0.12 mmol) with 1-(1-cyclohexenyl)-1-[(tert-butyldimethylsilyl)oxy]-
ethene (40 mg, 0.17 mmol) gave 25d after flash column chromatography
(hexane/EtOAc, 55:1) as a colourless oil (37 mg, 75%). Reaction time:
5 min, T: À208C. 1H NMR (300 MHz, CDCl3): d=8.10–8.02 (m, 1H),
7.98–7.91 (m, 1H), 7.75–7.69 (m, 2H), 2.97 (m, 1H), 2.83–2.65 (m, 3H),
2.35–2.23 (m, 2H), 1.84–1.72 (m, 2H), 1.65–1.45 (m, 2H), 1.31–1.18 (m,
1H), 1.16 (s, 3H), 0.98 (s, 9H), 0.87–0.75 (m, 1H), 0.17 ppm (brs, 6H);
13C NMR (75 MHz, CDCl3: d=201.1, 198.1, 137.9, 136.3, 134.1, 133.9,
132.7, 127.3, 126.0, 115.8, 56.6, 48.7, 38.2, 35.3, 34.6, 26.7, 26.1, 25.9, 25.8,
20.2, 18.2, À3.7, À3.8 ppm; MS (FAB+): m/z (%): 410 (100) [M]+, 409
(58), 353 (29); HRMS: m/z calcd for C25H32O4Si: 410.2277 [M]+, found:
410.2286.
Compound 9b: Following the general procedure C, the reaction of 7b
(100 mg, 0.43 mmol) with cyclopentadiene (142 mL, 1.72 mmol) gave a
18:82 mixture of 9b and 10. Reaction time: 50 min, T: À208C. Purifica-
tion by flash column chromatography (hexane/EtOAc, 5:1) gave 9b as a
yellow oil (14 mg, 13%) 1H NMR (300 MHz, CDCl3): d=7.61–7.52 (m,
2H), 7.20 (dd, J=8.0, 1.6 Hz , 1H), 6.05 (dd, J=5.9, 3.0 Hz, 1H), 5.98
(dd, J=5.9, 3.0 Hz, 1H), 3.93 (s, 3H), 3.62–3.55 (m, 2H), 3.47–3.44 (m,
2H), 1.56 (dt, J=8.7, 1.7 Hz
, 1H), 1.48 ppm (d, J=8.7 Hz, 1H);
13C NMR (75 MHz, CDCl3): d=198.5, 197.0, 158.9, 136.3, 135.5, 134.6,
118.8, 117.1, 56.4, 51.4, 50.3, 48.8, 48.4, 48.1 ppm; MS (EI): m/z (%): 254
(9) [M]+, 240 (20), 66 (100); HRMS: m/z calcd for C16H14O3: 254.0943
[M]+; found: 254.0481.
Compound (26d): Following the general procedure C, the reaction of 7d
(28 mg, 0.13 mmol) with 2-[(tert-butyldimethylsilyl)oxy]-3,4-dimethyl-1,3-
butadiene (39 mg, 0.18 mmol) gave 26d after flash column chromatogra-
phy (hexane/EtOAc, 55:1) as a colourless oil (36 mg, 72%). Reaction
3716
www.chemeurj.org
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3707 – 3719

Naphthoquinoyl Boronic Acids
FULL PAPER
time: 5 min, T: À208C. 1H NMR (300 MHz, CDCl3): d=8.10–8.03 (m,
1H), 8.00–7.93 (m, 1H), 7.77–7.70 (m, 2H), 2.78–2.92 (m, 2H), 2.75–2.64
(m, 1H), 2.30 (d, J=17.3 Hz, 1H), 1.66 (t, J=1.16 Hz, 1H), 1.18–1.16 (m,
6H), 0.98 (s, 9H), 0.17 (s, 3H), 0.16 ppm (s, 3H); 13C NMR (75 MHz,
CDCl3): d=201.1, 198.1, 140.0, 136.3, 134.1, 133.9, 132.7, 127.2, 126.0,
113.3, 57.8, 49.1, 38.2, 31.4, 25.8, 20.2, 19.9, 13.5, À3.8 ppm; MS (ES): m/z
(%): 384 (16) [M]+, 369 (100), 351 (18), 327 (15); HRMS: m/z calcd for
C23H32O3Si: 384.2121 [M]+; found: 384.2138.
Acknowledgements
We thank MICINN (grant no. CTQ2008-04691), Comunidad de Madrid
(CM)/UAM (CCG08-UAM/PPQ-3980), Comunidad de Madrid (Grant
SOLGEMAC-S2009/ENE-1617 and CM (grant no. S2009/ENE-1617) for
financial support. M. C. Redondo thanks MEC for a Juan de la Cierva
contract and M.V. for a FPU fellowship.
Compound (27c): Following the general procedure C, the reaction of 5c
(70 mg, 0.40 mmol) with 2-[(tert-butyldimethylsilyl)oxy]-4-phenyl-1,3-bu-
tadiene (203 mg, 0.78 mmol) gave 27c after flash column chromatography
(hexane/EtOAc, 25:1) as a yellow oil (94 mg, 61%). Reaction time:
30 min, T: À208C. 1H NMR (300 MHz, CDCl3): d=7.28–7.07 (m, 5H),
6.37 (q, J=1.4 Hz, 1H), 4.68 (t, J=2.4 Hz, 1H), 3.95 (m, 1H), 3.08 (d,
J=10.0 Hz, 1H), 2.61 (dt, J=17.6, 2.4 Hz, 1H), 2.18 (dd, J=17.6, 1.6 Hz,
1H), 1.87 (d, J=1.4 Hz, 3H), 1.19 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H),
0.04 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=202.8, 199.1, 151.6,
147.5, 144.8, 134.3, 128.9, 128.2, 126.4, 106.8, 57.7, 50.4, 39.0, 37.7, 25.6,
20.6, 17.9, 16.1, À4.2, À4.3 ppm; MS (ES): m/z (%): 398 (100) [M+2]+,
397 (52) [M+1]+.
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Compound (28c): Following the general procedure C, the reaction of 5c
(60 mg, 0.33 mmol) with 1-(1-cyclohexenyl)-1-[(tert-butyldimethylsilyl)oxy]-
ethene (159 mg, 0.67 mmol) gave 28c after flash column chromatography
(hexane/EtOAc, 25:1) as a yellow oil (71 mg, 57%). Reaction time:
5 min, T: À208C. 1H NMR (300 MHz, CDCl3): d=7.28–7.07 (m, 5H),
6.37 (q, J=1.41 Hz, 1H), 4.68 (t, J=2.4 Hz, 1H), 3.95 (m, 1H), 3.08 (d,
J=10.1 Hz, 1H), 2.61 (dt, J=17.6, 2.4 Hz, 1H), 2.18 (dd, J=17.6, 1.6 Hz,
1H), 1.87 (d, J=1.4 Hz, 3H), 1.19 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H),
0.04 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=202.8, 199.1, 151.6,
147.5, 144.8, 134.3, 128.9, 128.2, 126.4, 106.8, 57.7, 50.4, 39.0, 37.7, 25.6,
20.6, 17.9, 16.1, À4.2, À4.3 ppm. MS (FAB+): m/z (%): 374 (100) [M]+,
373 (65), 317 (22); HRMS: m/z calcd for C22H34O3Si: 374.2777 [M]+;
found: 374.2283.
Compound (29c): Following the general procedure C, the reaction of 5c
(40 mg, 0.22 mmol) with 2-[(tert-butyldimethylsilyl)oxy]-3,4-dimethyl-1,3-
butadiene (94 mg, 0.44 mmol) gave 29c after flash column chromatogra-
phy (hexane/EtOAc, 40:1) as a yellow oil (51 mg, 66%). Reaction time:
15 min, T: À208C. 1H NMR (300 MHz, CDCl3): d=6.42 (q, J=1.4 Hz,
1H), 2.70–2.54 (m, 2H), 2.51 (d, J=16.9 Hz, 1H), 2.14 (d, J=16.9 Hz,
1H), 2.02 (d, J=1.4 Hz, 3H), 1.62 (brs, 3H), 1.15–1.04 (m, 6H), 0.96 (s,
9H), 0.13 (s, 3H), 0.12 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=
203.2, 200.2, 151.4, 140.0, 134.3, 113.3, 76.5, 58.2, 49.4, 38.0, 31.0, 25.8,
20.1, 19.6, 18.2, 16.2 ppm. MS (FAB+): m/z (%): 348 (100) [M]+, 291
(63); HRMS: m/z calcd for C20H32O3Si: 348.2121 [M]+; found: 348.2119.
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Compound (30): Following the general procedure C, the reaction of 5c
(70 mg, 0.39 mmol) with piperylene (117 mL, 1.17 mmol) under an O2 at-
mosphere gave 30 as a yellow solid (72 mg, 84%) after flash column
chromatography (hexane/EtOAc, 5:1). Reaction time: 60 min, T: 258C.
M.p. 84–868C; 1H NMR (300 MHz, CDCl3): d=6.44 (q, J=1.5 Hz, 1H),
5.81–5.57 (m, 1H), 5.46–5.30 (m, 1H), 3.06–2.79 (m, 1H), 2.72–2.51 (m,
1H), 2.15 (m, 3H), 2.05 (d, J=1.6 Hz, 3H), 1.14 (d, J=7.1 Hz, 3H),
1.08 ppm (s, 3H); 13C NMR (75 MHz, CDCl3): d=202.1, 199.1, 148.7,
134.5, 128.7, 122.7, 79.7, 52.5, 31.0, 28.8, 20.6, 16.2, 14.3 ppm; MS (EI):
m/z (%): 220 (13) [M]+, 202 (42), 109 (81), 68 (100); HRMS: m/z calcd
for C13H16O3: 220.1099 [M]+; found: 220.1097.
Compound 31: Following the general procedure C, the reaction of 5c
(25 mg, 0.14 mmol) with isoprene (55.6 mL, 0.55 mmol) under an O2 at-
mosphere gave 31 as a yellow solid (12 mg, 38%) after flash column
chromatography (hexane/EtOAc, 6:1). Reaction time: 5 h, T: 258C. M.p.:
1
110–1128C; H NMR (300 MHz CDCl3): d=6.50 (q, J=1.4 Hz, 1H), 5.50
(m, 1H), 2.66 (d, J=16.6 Hz, 2H), 2.21 (m, 2H), 2.05 (d, J=1.4 Hz, 3H),
1.76 (s, 3H), 1.07 ppm (s, 3H);13C NMR (75 MHz, CDCl3): d=202.2,
198.0, 147.5, 135.4, 132.1, 114.8, 76.8, 51.2, 33.9, 30.1, 23.5, 21.8, 16.1 ppm;
MS (EI): m/z (%): 220 (4) [M]+, 202 (64), 187 (60), 159 (100); HRMS:
m/z calcd for C13H16O3: 220.1099; found: 220.1110 [M+].
Copies of the 1H and 13C NMR spectra and X-ray crystallography data
are available in the Supporting Information.
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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data for this paper. These data can be obtained free of charge from
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ac.uk/data_request/cif. Mr C22H25NO3; unit cell parameters: a=
7.7078(8), b=23.610(3), c=10.1924(8) ꢈ; b=90.515(3)8; space
group P21/c.
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[39] CCDC-690060 (13d) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. Mr C16H16O2; unit cell parameters: a=
8.109(3), b=8.130(3) and c=10.793(5) ꢈ; a=99.06(3)8, b=
¯
110.20(3)8 and g=107.72(2)8; space group P1.
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between 2,6 or 2,5-dimethylbenzoquinone with sodium (E)-3,5-hexa-
nodienoate also gave trans-fused cycloadducts: P. A. Grieco, K.
Yoshida, P. Garner, J. Org. Chem. 1983, 48, 3137–3139.
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the Supporting Information of reference [28]; see also a) H. W.
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[48] CCDC-690062 (20) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. Mr C26H32O4; unit cell parameters: a=
10.3410(10), b=7.6410(8), c=26.680(3) ꢈ; space group Pbca.
[49] CCDC-748452 (30) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge from
The Cambridge Crystallographic Data Centre via www.ccdc.cam.
ac.uk/data_request/cif. Mr C13H16O3·H2O; unit cell parameters: a=
12.1146(8), b=11.0495(8), c=8.9789(5) ꢈ; b=93.429(2)8; space
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[31] When not commercially available, the bromo derivatives were ob-
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[52] CCDC-754824 (5d) contains the supplementary crystallographic
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ac.uk/data_request/cif. Mr C8H9BO4; unit cell parameters: a=
8.1967(6), b=17.9782(12), c=5.5969(4) ꢈ; b=95.239(3)8; space
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[32] Compound 2a is commercially available.
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6.4479(6), b=8.1944(7), c=9.9567(10) ꢈ; a=87.441(4)8, b=
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¯
85.376(4)8 and g=86.453(4)8; space group P1.
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ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Eur. J. 2010, 16, 3707 – 3719

Naphthoquinoyl Boronic Acids
FULL PAPER
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Received: October 9, 2009
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Published online: February 19, 2010
Chem. Eur. J. 2010, 16, 3707 – 3719
ꢃ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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