Reactions of p-Quinols with Aldehydes and Imines: Stereoselective Access to Polyheterobicyclic and Tricyclic Systems

Article abstract of DOI:10.1002/ejoc.201403114

Dihydrobenzo[1,3]dioxolanones, tetrahydrobenzo[d]oxazolones and heterotricyclic derivatives have been stereoselectively synthesized from p-quinols upon reaction with aldehydes or benzaldimines under basic catalysis. Reactions occurred in an experimentally

Full text of DOI:10.1002/ejoc.201403114

Job/Unit: O43114
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Date: 02-10-14 12:33:39
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FULL PAPER
DOI: 10.1002/ejoc.201403114
Reactions of p-Quinols with Aldehydes and Imines: Stereoselective Access to
Polyheterobicyclic and Tricyclic Systems
Carolina García-García,[a] María C. Redondo,[a] María Ribagorda,*[a] and
M. Carmen Carreño*[a]
Keywords: Fused-ring systems / Nitrogen heterocycles / Quinones / Aldehydes / Domino reactions / Michael addition /
Diastereoselectivity
Dihydrobenzo[1,3]dioxolanones, tetrahydrobenzo[d]oxazo- cyclo[2.2.2]octane (DABCO) as catalyst and MeOH, tetra-
lones and heterotricyclic derivatives have been stereoselec-
tively synthesized from p-quinols upon reaction with alde-
hydes or benzaldimines under basic catalysis. Reactions oc-
curred in an experimentally simple one-pot procedure
through a domino sequence of two or three reactions. The
choice of 4-(dimethylamino)pyridine (DMAP) or 1,4-diazabi-
hydrofuran (THF), or dichloromethane as solvent was essen-
tial to achieve the synthesis of bicyclic dioxolanes from alde-
hydes or bicyclic or tricyclic N,O-aminals from imines. The
stereochemical course of these processes is highly dependent
on the nature of the electrophiles.
?>tions. In fact, the desymmetrization of the cyclohexadien-
one moiety has become an active area of research.[12] All
these structural features make p-quinols a unique scaffold
with which to develop domino or multicomponent reac-
tions[13] for the construction of complex molecules.
Introduction
The p-quinol moiety (4-alkyl-4-hydroxy-2,5-cyclohexadi-
enone) is present in a great number of natural products with
simple[1] or complex structures.[2] Some of the compounds
show a wide range of interesting biological properties such
as antitumoral[3] and trypanocide[4] action. Their antitu-
moral activity is thought to be due to the double Michael
acceptor system, which facilitates interaction with proteins
by formation of covalent bonds. As precursors of aryloxen-
ium ions,[5] p-quinols have been the subject of mechanistic
studies because such intermediates are involved in oxidation
reactions of phenols, which are of interest both from syn-
thetic and industrial points of view.[6] Differently substi-
tuted p-quinols and their derivatives are valuable building
blocks that have been used by a number of research groups
as starting materials en route to a wide range of natural
products.[7,8] From the synthetic point of view, the double
Michael acceptor system present in the p-quinol structure
could lead to highly functionalized systems.[9,10] The nucle-
ophilic hydroxy group at C-4 increases the synthetic useful-
ness of p-quinols, which can behave as ambident systems.[11]
The presence of a prochiral center at C-4 in symmetrical p-
quinols challenges the development of stereoselective reac-
Among the methods described for the synthesis of p-
quinols,[9] the oxidation of p-alkyl phenols is the most fre-
quently used. Hypervalent iodine(III) reagents[14] such as
[(diacetoxy)iodo]benzene (PIDA) and [bis(trifluoroacetoxy)-
iodo]benzene (PIFA) enable direct access to p-quinols.
Other oxidants, such as singlet oxygen (1O2), generated
both by irradiation of gaseous oxygen with ultraviolet light
in the presence of sensitizers[15] or by decomposition of
Oxone[16] or H2O2,[17] gave p-peroxy quinols, which are eas-
ily reduced to p-quinols. These methods are useful for ac-
cessing simple p-quinols. The synthesis of more function-
alized systems generally requires unpractical multistep pro-
cesses for the phenol precursors. We recently described a
direct functionalization of p-quinols through Morita–
Baylis–Hillman (MBH) type reactions that allow the intro-
duction of C-2 substituents on simple p-quinols in a con-
trolled manner. The MBH reaction[18] is a carbon–carbon
bond-formation process that occurs between electron-de-
ficient alkenes and aldehydes in the presence of nucleophilic
cae investigated the reaction between 4-methyl-4-hydroxy-
2,5-cyclohexadienone derivatives[19] and aromatic aldehydes
under MBH conditions. Our results provided evidence for
the essential role of the OH substituent at C-4 as well as
the reaction conditions, which influenced the final evolution
of the system. We reported an unprecedented autocatalytic
reaction in the MBH process, in which the C-4 hydroxy
group of the p-quinol has the ability to act as an internal
oxygenated catalyst that is essential to trigger the MBH re-
[a] Departamento de Química Orgánica (Módulo-01), Universidad
Autónoma de Madrid,
c/ Francisco Tomás y Valiente no. 7, Cantoblanco,
28049 Madrid, Spain
E-mail: maria.ribagorda@uam.es
carmen.carrenno@uam.es
http://www.uam.es/quinonso
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201403114.
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C. García-García, M. C. Redondo, M. Ribagorda, M. C. Carreño
FULL PAPER
action. A reversible intramolecular oxa-Michael addition were prepared by following different procedures, depending
was followed by the aldol-type reaction, enabling controlled on the relative amount required. For a 1 g scale (8 mmol),
access to mono- or bis-MBH adducts. We observed that a one-pot/two-step process based on the oxidative dearoma-
changing the solvent modified the p-quinol evolution tization of p-methyl phenols with Oxone/NaHCO3, as a
towards an acetalization/oxa-Michael domino process, to source of singlet oxygen, and reduction of the p-peroxy-
give cis-dihydrobenzo[1,3]dioxol-5(7aH)-ones in a single quinol intermediates in situ with Na2S2O3, gave p-quinols 3
step (Figure 1).
and 4 in 81 and 72% isolated yield, respectively (Scheme 1,
Method A).[16] Application of this method to the synthesis
of larger amounts required large volumes of NaHCO3 solu-
tion, which made isolation difficult, thus decreasing the
yields significantly. We scaled up the synthesis of 3 (up to
5 g, 40 mmol) by using a different strategy based on the
addition of MeLi to p-benzoquinone dimethyl monoket-
al,[23,11a] followed by hydrolysis of the intermediate acetal
with oxalic acid (62% overall yield).
Our initial results on the study of MBH reactions with
4-methyl-4-hydroxy-2,5-cyclohexadienone[19] provided evi-
denced for a particular behavior of this ambident system
that was highly dependent on the conditions of the Morita–
Baylis–Hillman reaction. We decided to optimize the reac-
tions of p-quinol 3 by using p-nitrobenzaldehyde (6a) as a
model reactive electrophile, in the presence of different nu-
cleophilic catalysts, to establish better conditions for the
Figure 1. MBH reaction of p-quinol 1.
Jefford and co-workers have reported the synthesis of bi- generation of products that differed from those previously
cyclic 1,3-dioxolanes and 1,2,4-trioxanes through an acid- observed. Thus, when the reaction of 3 and 6a was carried
catalyzed domino reaction of p-quinol or p-peroxyquinol out in the presence of a catalytic amount of 4-(N,N-dimeth-
derivatives and aliphatic aldehydes.[20] Recently, Rovis de- ylamino)pyridine (DMAP) at room temperature in CH2Cl2,
veloped an asymmetric version for the synthesis of dioxol- no MBH adducts were formed. The products resulting un-
anes and 1,2,4-trioxane derivatives by reaction of p-quin- der these conditions were a 90:10 mixture of the p-
ols[21a] or p-peroxyquinols[21b] and aldehydes catalyzed by nitrophenyl-substituted dihydrobenzo[d][1,3]dioxol-5(7aH)-
chiral Brønsted acids. In spite of the huge synthetic poten- one derivative 7a and its C-2 epimer epi-7a. Both dia-
tial of the p-quinol derivatives, to our knowledge, no base- stereomers were separated by flash column chromatography
catalyzed acetalization/oxa-Michael domino process has (7a: 67%; epi-7a: 3%) (Scheme 2).
been explored.[22] Following our previous studies on the
When the reaction was effected in tetrahydrofuran (THF)
synthesis and applications of p-quinols,[16,10] we now report or MeCN, the [1,3]dioxolane was formed, albeit with lower
a detailed investigation of the reactions of p-quinols with conversion and diastereoselectivity (Scheme 2). The un-
aromatic and aliphatic aldehydes. To broaden the scope of equivocal structure of the major diastereoisomer 7a was
the p-quinol reaction, we examined the behavior of these confirmed by X-ray diffraction analysis,[24] which con-
cyclohexadienones upon reaction with aromatic aldimines firmed the cis-relative relationship between the methyl
under base-catalyzed conditions; as a result, we uncovered group at C-7a and the p-nitrophenyl substituent situated
a novel domino transformation for the synthesis of polyhet- at C-2 (Scheme 2). The dihydrobenzo[d][1,3]dioxol-5(7aH)-
erotricyclic systems.
ones formed under base-catalyzed conditions must proceed
from the 1,2-addition reaction of a p-quinol alkoxide,
formed in the presence of the base, to the electrophilic carb-
onyl aldehyde, to generate an intermediate hemiacetal
anion, the evolution of which through an intramolecular
Results and Discussion
The starting materials, 4-hydroxy-4-methyl-2,5-cyclo- oxa-Michael addition explained the formation of the final
hexadienone (3) and the 3-methyl-substituted analogue 4, bicyclic system.
Scheme 1. Synthesis of p-quinols 3 and 4.
2
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Reactions of p-Quinols with Aldehydes and Imines
Scheme 2. Dihydrobenzo[d][1,3]dioxol-5(7aH)-one formation from p-quinol 3 and p-nitrobenzaldehyde 6a.
With these results in hand, we evaluated the scope of the be separated by flash column chromatography and isolated
DMAP-catalyzed protocol in the reactions of 3 with other in diastereomerically pure form. Their relative configura-
aldehydes. Thus, as shown in Table 1, p-trifluoromethyl tions were established by comparison of the spectroscopic
(6b), p-cyano (6c) and p-fluorobenzaldehyde (6d) reacted parameters with the isomers previously obtained in the re-
with p-quinol 3 in CH2Cl2 solution in the presence of actions with p-nitrobenzaldehyde (6a). A complex reaction
DMAP at room temp., affording a mixture of the corre- mixture resulted when o-nitrobenzaldehyde (6e) was sub-
sponding bicyclic dioxolanes 7b–d and their C-2 epimers in mitted to the same reaction conditions (entry 4), whereas
58–60% yields (Table 1, entries 1–3). All the products could no evolution was observed with o-(trifluoromethyl)benzal-
dehyde (6f) or with benzaldehyde (6g), even after extended
reaction times.
Table 1. DMAP-catalyzed reactions of p-quinol 3 with aromatic
aldehydes 6 in CH2Cl2.
We also investigated the behavior of different heteroaro-
matic aldehydes. Thus, when a mixture of pyridine-2-carbal-
dehyde 8 and p-quinol 3 was treated with DMAP (15 mol-
%) in CH2Cl2 solution, a 73:27 mixture of dioxolanes 9 and
its C-2 epimer epi-9 was formed in a 48% yield (Scheme 3).
TMSOTf had been reported to act as a Lewis acid catalyst,
increasing the electrophilic character of pyridine-2-carbal-
dehyde as acceptor in Baylis–Hillman reactions,[25] leading
to the formation of indolizidines. Intrigued by these results,
we investigated the reaction of 8 with 3 in the presence of
TMSOTf by using CH3CN/H2O as solvent and observed
the formation of the [1,3]dioxolanes in 33% yield as a mix-
ture of 9 and epi-9 (17:83).[26] Although the formation of
bicyclic 1,3-dioxolanes 9 and epi-9 with TMSOTf (3 equiv.)
in CH3CN/H2O was not useful from the preparative point
Entry
6
R (Ar = R-C6H4)
7/epi-7 7 [%][a] epi-7 [%][a]
1
2
3
4
5
6
6b 4-CF3
6c 4-CN
6d 4-F
6e 2-NO2
6f 2-CF3
6g Ph
80:20
80:20
85:15
44
42
53
–
14
18
10
–
[b]
–
–
–
–
–
–
–
[a] Yield of pure diastereomer. [b] Complex mixture.
Scheme 3. Reactions of p-quinol 3 with pyridine-2-carbaldehyde 8.
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Scheme 4. Reactions of p-quinol 3 with 6-bromopyridine-2-carbaldehyde (10).
of view, it is worth mentioning the inversion of the dia- (pTsOH, THF, room temp., Table 2, entry 1), for the reac-
stereoselectivity observed in comparison with the DMAP- tion between 3 and 13a. Under these conditions, a 60:40
catalyzed process.
mixture of epimeric hydrobenzodioxolanones 15a and epi-
Reactions with other heteroaromatic aldehydes were 15a was formed from which both were isolated pure in 57
highly dependent on the particular structure. Thus, 6- and 20% yield, respectively. The reported asymmetric reac-
bromopyridine-2-carbaldehyde (10) reacted under base-ca- tion of p-quinols[21a] or p-peroxyquinols[21b] with aliphatic
talysis conditions, to give a 70:30 mixture of 11 and epi-11 aldehydes catalyzed by enantiopure phosphoric acid deriva-
in a moderate 41% yield (Scheme 4). Reaction with π-rich tives prompted us to extend the use of these Brønsted acids
heteroaromatic aldehydes such as pyrrole-2-carbaldehyde, in the reactions of p-quinol 3. Up to 20:1 dr and 45%ee
indole-2-carbaldehyde or quinoline-2-carbaldehyde did not had been reported by Rovis for a SPINOL-derived phos-
react with p-quinol 3 in the presence of DMAP, thus dem- phoric acid catalyzed reaction between p-quinol 3 and iso-
onstrating that the base-catalyzed formation of acetals only butyraldehyde.[21a] After checking several enantiopure
occurred when the heteroaromatic substituent is an elec- phosphoric acids derived from binaphthol for the reaction
tron-withdrawing group, which increases the electrophilic between 3 and 3-methylbutanal (13a), which was chosen as
character of the aldehyde.
a model reaction (see the Supporting Information for de-
We then evaluated the reaction of 3-methyl-substituted tails), we could not improve on the results reported by
p-quinol 4 with p-nitrobenzaldehyde (6a) under the optimal Rovis. Nevertheless, when racemic BINOL derived phos-
conditions, en route to the bicyclic acetal. Thus, treatment phoric acid 14 was used as catalyst, the formation of two
of a CH2Cl2 solution of 4 and 6a in the presence of DMAP, diastereomers in moderate to good yields allowed the isola-
afforded 1,3-dioxolane 12 in good yield and diastereoselec-
tivity (90:10, 12/epi-12). Both diastereomers could be iso-
Table 2. Reactions of p-quinol 3 with aliphatic aldehydes 13a–g in
lated pure in 67 and 7% yield, respectively. In this case, CH2Cl2 catalyzed by BINOL phosphoric acid derivative 14.
the intramolecular oxa-Michael addition of the hemiacetal-
derived alkoxide took place through the more electrophilic
unsubstituted double bond of the cyclohexadienone moiety,
giving the all-cis-substituted bicyclic structure 12 as major
isomer (Scheme 5).
Scheme 5. Reaction of 3-methyl p-quinol 4 with p-nitrobenzalde-
hyde (6a) in the presence of DMAP in CH2Cl2.
Entry 13
R1, R2
15/epi-15 15 [%][b] epi-15 [%][b]
1
2
3
4
5
6
7
8
13a[a]
H, iPr
H, iPr
Me, Me
–(CH2)5–
H, Ph
H, H
H, Me
H, Pr
60:40
76:24
89:11
83:17
87:13
67:33
76:24
76:24
57
65
83
20
23
4
More challenging aliphatic aldehydes were next screened.
Under basic conditions (DMAP, CH2Cl2), 3-methylbutanal
(13a) did not react with p-quinol 3. This result was not sur-
prising because the base-catalyzed formation of acetals only
occurred with highly reactive benzaldehydes with electron-
withdrawing substituents. The use of different protic acids
had been reported to catalyze the reaction of p-quinols with
aldehydes to give cis-bicyclic dioxolanes as mixtures of C-2
13a
13b
13c
13d
13e
13f
13g
81
16
8
86
41[c]
50
10[c]
15
21
75
[a] pTsOH (1 mol-%) was used instead of 14. [b] Yield of pure dia-
stereomer. [c] Calculated from the H NMR spectrum of the mix-
1
diastereomers.[20,21a] We also tested acidic conditions ture.
4
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Reactions of p-Quinols with Aldehydes and Imines
tion and complete characterization of both epimers. Thus,
as shown in Table 2, reaction between p-quinol 3 and 3-
methylbutanal (13a) was catalyzed by 14 to give a 76:23
mixture of diastereomeric hydrobenzo[1,3]dioxol-5(7aH)-
ones 15a and epi-15a (Table 2, entry 2). Better diastereo-
selectivities (ranging from 87:13 to 89:11) were obtained in
the analogous reactions of isobutyraldehyde, cyclohexane-
carbaldehyde and 2-phenylacetaldehyde 13b–d (Table 2, en-
tries 3–5). In all cases, the major diastereomers 15 had the
cis relative configuration of the methyl group at C-7a and
the alkyl substituent arising from the aliphatic aldehyde in
the dioxolane ring. All diastereomers, could be isolated
pure in the yields indicated in Table 2.[27] α,β-Unsaturated
aldehydes such as methacrolein, cinnamaldehyde, or 2,4-
hexadienal did not react under these conditions.[28]
Figure 2. Structure and significant NMR parameters of 7a, epi-7a,
epi-15a, and epi-11.
The structure and relative stereochemistry of all the hy-
drobenzodioxol-5(7aH)-ones 7, 9, 11, 12, and 15 and their
C-2 epimers, were established based on their spectroscopic
parameters, mainly 1H NMR spectroscopic data and
NOESY experiments. Moreover, the stereochemical assign-
ment of the major diastereomers and the C-2 epimers was
ence of 15 mol-% DMAP at room temp., afforded bicyclic
N,O-acetal 17a as the only diastereomer detected in the
crude reaction mixture; the product could be isolated pure
in 50% yield (Scheme 6).[29] This tetrahydrobenzo[d]oxaz-
olone derivative must have been formed in an initial nucleo-
philic 1,2-addition of the hydroxy group of the p-quinol to
the imine, facilitated by DMAP, followed by an intramole-
cular aza-1,4-conjugated addition of the resulting hemi-
aminal intermediate to the cyclohexadienone. The structure
of 17a was confirmed by X-ray diffraction analysis[30]
(Scheme 6). As can be seen, the phenyl group at C-2 is situ-
ated in a trans-disposition with respect to both the C-7a
methyl group and H-3a, which, in turn, are cis to each
other. It is interesting to note that the relative trans disposi-
tion of the aromatic C-2 substituent in the hydrobenzoxaz-
olone derivative 17a is the opposite to the major dia-
stereomers obtained in the synthesis of the analogous
hydrobenzodioxolanones 7 formed in the reaction of 3 with
aromatic aldehydes (see Figure 2 for X-ray crystal structure
analysis of 7a). Therefore, the stereochemical outcome of
the initial 1,2-addition of the hydroxy group of the p-quinol
to the imines or aldehydes must have a substantial differen-
tiation.
1
based on comparison of their H NMR parameters with
those of 7a, the structure of which had been unequivocally
established by X-ray crystallographic analysis.
One of the most significant features in the NMR param-
eters, indicated in Figure 2, are the appearance of a long-
range coupling constant between the olefinic proton H-7
4
and H-3a of JH,H ≈ 2 Hz in both diastereomers. This W-
type coupling is only possible if H-3a is situated in a
pseudoequatorial disposition. Another significant feature is
1
the chemical shift of H-2 in both diastereomers. The H
NMR spectra revealed a small but noticeable difference in
the chemical shift of H-2 in both diastereomers. In the
major diastereomer (7, 9, 11, 12, and 15), having the aryl
or alkyl substituent in the equatorial disposition, the axial
H-2 appeared at higher field (δH2 ca. 5.9 ppm in 7a, Fig-
ure 2). In the minor epimers, H-2, situated in the equatorial
disposition, appeared at lower field (δH2 ca. 6.1 in epi-7a,
Figure 2). The stereochemistry of the minor epimers was
also corroborated as epi-15a by the presence of an NOE
effect between H-2 and H-3a (Figure 2) and as epi-11 by an
NOE between H-2 and the methyl group.
Having established the reaction conditions (DMAP,
CH2Cl2) that allowed the synthesis of the cis-dihydro-
benzo[1,3]dioxol-5(7aH)-one derivatives from p-quinol and
aromatic aldehydes, we extended this study to include aryl
imines. The synthesis of amino-functionalized p-quinol de-
rivatives is of huge interest because the resulting multifunc-
tional systems open the way to a variety of structures that
are not easily accessible in a direct manner. In spite of the
potential interest of p-quinols, the reactivity between this
ambident system and imine derivatives had never been in-
vestigated. We started our study by screening the reaction
conditions found to be optimal in the synthesis of cis-di-
hydrobenzo[1,3]dioxolanones from 3 and aldehydes. N-(p-
Tolylsulfonyl)benzaldimine (16a) was chosen as a model
electrophilic substrate, due to its stability and reactivity. The
Scheme 6. DMAP-catalyzed reaction of p-quinol 3 and benzaldim-
reaction between p-quinol 3 and 16a in CH2Cl2, in the pres- ine 16a.
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The reaction of 3 and 16a using 1,4-diazabicyclo[2.2.2]- Table 3. Base-catalyzed reactions of 3 and 16a.
octane (DABCO) as base and LiClO4 as additive in CH2Cl2
solution gave a 90:10 mixture of the bicyclic tetrahydro-
benzoxazolones 17a and C-2 epi-17a in moderate conver-
sion. When MeOH was used as solvent, a 70:30 mixture of
epimers was obtained (Scheme 7). In both cases, 17a was
obtained as the major diastereomer.
Entry Conditions
18a/epi-18a
Yield 18a
dr
[%]
1
2
3
DABCO (15 mol-%), LiClO4,
THF, room temp.
DABCO (15 mol-%), LiClO4,
THF, 66 °C
DABCO (15 mol-%), LiClO4,
THF, MW
Ͼ98
50
53
53
95:5
95:5
4
5
Cs2CO3, THF, room temp.
Cs2CO3, MeOH, room temp.
63:37
60:40
31
40
Scheme 7. DABCO/LiClO4-catalyzed reactions of p-quinol 3 and
benzaldimine 16a.
Upon heating the reaction of 3 and 16a in THF to 65 °C
or irradiating in a microwave oven (MW), a 95:5 mixture of
inseparable 18a and its epimer C-9 epi-18a resulted (Table 3,
entry 3). The non-nucleophilic base Cs2CO3 could also pro-
moted the formation of the tricyclic derivatives 18a and epi-
18a in lower diastereoselectivity by using THF (63:37, 31%)
To our surprise, a change of the solvent in the DMAP-
catalyzed reaction from CH2Cl2 to MeOH triggered an
interesting domino process. Thus, when p-quinol 3 reacted
with 16a in MeOH, in the presence of DMAP (15 mol-%)
at room temp., heterotricyclic compound 18a was the only
product that could be isolated from the reaction mixture,
albeit in moderate 19% yield (Scheme 8). The use of LiClO4
as an additive allowed the isolation of 18a in 50% yield.
The structure of 18a was confirmed by X-ray diffraction
analysis.[31]
or MeOH (60:40, 40%) as solvent. Therefore, conditions
[32]
involving DABCO/LiClO4
in THF at room temp. were
established as optimal to obtain 18.
We next evaluated the influence of substitution at the
aromatic ring of the benzaldimine, as well as at the N-aryl-
sulfonyl group, in the reaction with p-quinol 3 under the
DMAP base-catalyzed conditions (Table 4). Surprisingly,
when the aromatic ring of the N-arylsulfonyl moiety of the
imine had an EWG substituent (16b; R1 = NO2, R2 = H),
the reaction proceeded with a low conversion (21%) after
five days, to give a 86:14 mixture of N,O-aminals 17b and
epi-17b (entry 2). Higher conversion was obtained with elec-
tron-donating N-(4-methoxy) 16c (R1 = OMe). The dia-
stereomeric ratio was 86:14 (entry 3), whereas only dia-
stereomer 17a was detected for the N-tosyl derivative (en-
try 1, 50% yield). Characterization of epi-17 was not an
easy task because purification by column chromatography
gave only epi-17 contaminated with the major isomer 17;
the structure of epi-17e could nevertheless be characterized
unequivocally based on the 1H NMR spectrum of the 76:24
mixture. Working with the N-p-tolylsulfonylimines (R1
=
Scheme 8. Synthesis and X-ray diffraction structure analysis of het-
erotricycle 18, hydrogen atoms are omitted for clarity.
Me), we could evaluate the behavior of imines having dif-
ferent substituents at the aromatic ring arising from the al-
dehyde. Imine 16d, with an electron-donating substituent
The tricyclic structure of 18a is of remarkable interest (R2 = OMe) decreased significantly the conversion and
due to the presence of pyperidine and hydroxazole rings, stereoselectivity (entry 4). Imine 16e (R2 = CF3) led to the
which are common cores of natural products and biolo- formation of a 76:24 mixture of 17e and epi-17e in an al-
gically significant compounds. The influence of the solvent most complete process (conversion Ͼ98; entry 5).
was significant in the DABCO/LiClO4 catalyzed reactions.
Imines 16f (R2 = F), 16g (R2 = CN), and 16h (R2
=
Thus, 18a was formed as the exclusive diastereomer (50% NO2) also evolved through an efficient process in a highly
yield) when 3 and the N-tosyl-imine 16a were treated with diastereoselective manner to give the N,O-aminals (Table 4,
DABCO (15 mol-%) and LiClO4 (70 mol-%) in THF entries 6–8), thus demonstrating that the presence of an
(Table 3, entry 1).
EWG at the imine moiety favors the formation of dia-
6
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Reactions of p-Quinols with Aldehydes and Imines
Table 4. Influence of the substitution at the arylsulfonyl group (R1)
Table 5. Influence of the substitution at the arylsulfonyl group (R1)
and at the arylaldimine (R2) group on the synthesis of 17.
and at the arylaldimine (R2) group on the synthesis of 18.
Entry
16
R1
R2
18/epi-18
Yield 18
[%]
dr
1
2
3
4
5
6
16a
16b
16c
16d
16e
16f
Me
H
H
H
OMe
CF3
F
Ͼ98
75:25
Ͼ98
92:8
85:15
90:10
50
48[a]
80
41
47
NO2
OMe
Me
Me
Me
40
[a] From the 75:25 mixture.
Entry 16 R1
R2
Conversion 17/epi-17[a] Yield 17
[%]
dr
[%]
anal and cyclohexanecarbaldehyde were also used as elec-
trophiles in the DABCO/LiClO4 catalyzed reaction with p-
quinol 3 in THF; however, their poor reactivity did not al-
low significant conclusions to be reached.
We finally investigated the reaction of 3-methyl-4-
hydroxy-4-methylquinol (4) with N-tosylbenzaldimine
(16a), under the conditions previously established for both
the heterobicyclic and tricyclic systems. The bicyclic N,O-
aminal derivative 19 was isolated as a unique diastereomer
in both cases. Thus, DABCO/LiClO4, THF, room temp.
conditions gave 19 in 86% isolated yield, whereas the
DMAP-catalyzed process in CH2Cl2 gave the same com-
pound in 20% yield (Scheme 9).
1
2
3
4
5
6
7
8
16a Me
16b NO2
16c OMe
16d Me
16e Me
16f Me
16g Me
16h Me
H
H
H
OMe
CF3
F
CN
NO2
Ͼ98
21
70
20
Ͼ98
78
Ͼ98
86:14
86:14
63:37
76:24[b]
94:6
50
–
[a]
75
[a]
–
50
50
77
68
88
70
Ͼ98
Ͼ98
[a] Compound could not be isolated pure and could not be fully
characterized. [b] Characterized from the 76:24 mixture.
stereomers 17f, 17g, and 17h. This was expected because
the electrophilic character of the iminic carbon is higher
when an EWG is present.
A parallel substrate scope study was conducted for the
one-pot stereoselective formation of heterotricyclic skeleton
18. Reaction of 3 and N-(p-nitrophenylsulfonyl)benzald-
imine (16b) with DABCO/LiClO4 in THF at room temp.
gave a diastereomeric mixture of 18b and epi-18b in a 75:25
ratio and 48% yield (Table 5, entry 2). When the N-(p-meth-
oxyphenyl)benzaldimine 16c was the electrophile, the only
diastereomer detected was 18c, which was isolated in 80%
yield (entry 3). The influence of the substituent on the aro-
matic aldimine on the results was studied by using N-tosyl-
aldimines (R1 = Me) derived from p-methoxy-, p-trifluoro-
methyl-, p-fluoro-, p-nitro-, and p-cyano-substituted benz-
Scheme 9. Reaction of 3-methyl-p-quinol (4) with 16a.
Mechanisms and Stereochemistry
The p-quinol structure encompasses a number of organic
aldimines 16d–h. The methoxy phenyl-substituted N-tosyl- functionalities precisely blended for domino reactions.[33]
aldimine 16d (R2 = OMe) afforded a 92:8 mixture of 18d The 2,5-cyclohexadienone moiety can behave as a double
and epi-18d in the crude reaction mixture (entry 4). The electrophilic 1,4-acceptor and/or suffer 1,2-carbonyl ad-
minor diastereomer could not be isolated pure nor could it ditions, whereas the oxygen present at the C-4 position is a
be fully characterized. The p-CF3 and p-fluoro-substituted nucleophile. Due to the presence of a prochiral center at C-
benzaldimines 16e and 16f, respectively, afforded mixtures 4 in symmetrical p-quinols (Figure 3), conjugate additions
of diastereomeric tricyclic compounds from which only the generate two stereocenters at C-3 and C-4. Therefore, up to
major diastereomers 18e and 18f could be isolated pure (47 four possible stereoisomers could be formed in such pro-
and 40%, respectively; entries 5 and 6).
cesses. When dealing with such cyclohexadienone deriva-
Unfortunately, the p-nitro- and p-cyano-substituted tives, two stereochemical aspects should be considered: the
benzaldimines 16g and 16h afforded complex reaction mix- double bond selectivity (pro-S and pro-R β-carbons) and
tures. Aliphatic tosyl aldimines derived from 3-methylbut- the face selectivity, because the nucleophile could attack
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FULL PAPER
from the re face or si face of each one of the β-carbon termediate Ia, Scheme 10) affords the major diastereoiso-
atoms (see in Scheme 10 top or bottom nucleophile attack) mer 7 (2S*,3aR*,7aS*) with the methyl group and the aryl
to give two possible diastereoisomers, in racemic series.
groups in a cis disposition in the 1,3-dioxolane ring. Attack
on the pro-R β-carbon (intermediate Ib) gives the minor
epimer (2R*,3aR*,7aS*)-epi-7.[35] Intermediate Ib has a de-
stabilizing 1,3-parallel interaction between the aryl group
and the C–C bond (bolded bond), which is not present in
Ia. This could explain the preferred formation of dia-
stereomer 7. A similar approach to the re-face of the alde-
hyde would give the same mixture of diastereomers with the
opposite configurations. Thus, initial OH attack on the re-
face of the aldehyde generates the intermediate hemiacetal
alkoxide II. In this case, the intramolecular oxa-Michael ad-
dition to the pro-R β-carbon (intermediate IIb) gives access
to the major dioxolane 7 (enantiomer not shown). Attack
on the pro-S β-carbon (intermediate IIa) is less favored due
to the destabilizing 1,3-parallel interaction between the aryl
group and the C–C bond (bolded bonds).
Figure 3. Stereochemical map of conjugate addition reactions of a
symmetrical p-quinol.
The TMSOTf-catalyzed reaction of 3 with pyridine-2-
carbaldehydes 8 and 10 gave the major diastereomer epi-9,
having the heteroaromatic substituent trans with respect to
the methyl group at C-7a. The diastereoselectivity observed
in this case can be explained by taking into account that
the reactive species formed by association of TMSOTf, act-
ing as a Lewis acid, on the aldehyde must situate the TMS
anti with respect to the heterocycle, to avoid steric interac-
tions (Scheme 11). The approach of the nucleophilic p-
quinol OH to the si-face of this activated aldehyde can
occur through orientations III and V, represented in
Scheme 11.[35] When the p-quinol OH approaches the si-
face, a destabilizing interaction between the bulky TMS
group and the C=C pro-S double bond of the cyclohexadi-
enone moiety appears (intermediate III). Once the interme-
diate OTMS acetal IV is formed, the 1,4-attack of the oxy-
gen to the β-carbon of the pro-S double bond, promoted
by TfO– would afford the minor diastereomers
(2S*,3aR*,7aS*)-9. If we consider the attack of the nucleo-
philic p-quinol OH to the re-face of the TMSOTf activated
heteroaromatic aldehyde, represented as V, the bulky TMS
is situated far from the cyclohexadienone moiety. Although
Scheme 10. Stereochemical proposal for the domino reactions of p-
quinol with aldehydes under base catalysis.
The reaction of p-quinols with aldehydes involves a 1,2- the transition species VI, leading to epimer epi-9, shows a
addition of the C-4 hydroxy group of the p-quinol 3, acting 1,3-parallel interaction between the heteroaromatic group
as a nucleophile, to the aldehyde, followed by an intramo- and the C–C bond of the p-quinol (bolded bonds), this is
lecular oxa-Michael addition of the intermediate alkoxide the preferred evolution. Thus, the observed diastereoselec-
to the cyclohexadienone moiety to give an approximate tivity suggests that the 1,3-parallel interaction appearing in
80:20 mixture of diastereoisomeric dihydrobenzo[1,3]di- the initial attack to the aldehyde III between the TMSO
oxol-5(7aH)-one 7 and epi-7. In this domino process there group and the C=C pro-S double bond is highly destabiliz-
is an additional stereochemical aspect that should be con- ing and explains the preferred evolution through species V,
sidered: the initial 1,2-addition step generates a new stereo- lacking such interaction, to give the major diastereomers
center as a consequence of the attack of the p-quinol OH (2R*,3aR*,7aS*)-epi-9.
to the si- or re-face of the aldehyde (Scheme 10). The initial
A similar approach could explain the stereochemistry ob-
1,2-addition of the nucleophilic p-quinol oxygen to the si- served in the case of the reaction of p-quinol with N-tosyl-
face of the aldehyde generates the intermediate hemiacetal arylimines under DABCO/LiClO4 catalysis and using
alkoxide I. The oxa-Michael addition step could occur on CH2Cl2 as solvent. The reactive N-tosylarylimine must situ-
either of the two prochiral β-carbon atoms of the cyclo- ate the tosyl group anti with respect to the aromatic group
hexadienone, from the face of the p-quinol containing the to avoid steric interactions. The initial deprotonation of p-
initial OH group, which is favored on steric grounds.[34] The quinol 3 by DABCO gives a p-quinol alkoxide, the ap-
1,4-intramolecular addition to the pro-S β-carbon (see in- proach of which to the aldimine 16a can take place from
8
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Reactions of p-Quinols with Aldehydes and Imines
Scheme 11. Proposed mechanism and stereochemical outcome of formation of hydrobenzo[1,3]dioxol-5(7aH)-ones 9.
the si-face or the re-face. The re-face attack oriented to the the negative nitrogen to the pro-S β-carbon, represented as
pro-S double bond,[35] represented as VII, places the bulky VIII, explains the formation of the major diastereomer
SO2Tol group far from the cyclohexadienone moiety. Al- (2R*,3aR*,7aS*)-17a. The X-ray structure of 17a showed a
though a 1,3-parallel interaction between the Ph and the pyramidalization of the nitrogen, which demonstrated the
C3–C4 bond of the 2,5-cyclohexadienone moiety appears in preference of both vicinal aryl groups to be trans in the five-
VII (bolded bond), this 1,4-approach must be favored be- membered ring. The attack of the p-quinol alkoxide to the
cause the bulkiest tosyl group is far from any other group. si-face of the anti N-(p-tolylsulfonyl)benzaldimine 16a, ori-
Once the O–C–N bond is formed, an aza-Michael attack of ented to the pro-S double bond of the cyclohexadienone,
Scheme 12. Proposed mechanism and stereochemical outcome of formation of 17a.
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C. García-García, M. C. Redondo, M. Ribagorda, M. C. Carreño
FULL PAPER
gives species IX, with the bulky SO2Tol group developing a
highly destabilizing 1,3-parallel interaction with the C=C
double bond of the cyclohexadienone moiety. The evolution
through the aza-Michael addition to the pro-S β-carbon,
represented as species X, could explain the formation of the
minor diastereomer (2S*,3aR*,7aS*)-epi-17a. The results
suggest that interactions due to the 1,3-parallel disposition
of the Ph and the C3–C4 bond (see VII) are less energeti-
cally demanding than those arising when the SO2Tol group
and the C2=C3 double bond are 1,3-parallel (Scheme 12,
approach IX).
Conclusions
We have studied the reactions of p-quinols with aromatic
and aliphatic aldehydes and arylsulfonyl-substituted aryl-
aldimines under DMAP and DABCO/LiClO4 catalysis. Our
work demonstrates that highly functionalized polyhetero-
cyclic derivatives are directly available in a one-pot reaction
from p-quinols by taking advantage of their ambident na-
ture as well as their double enone moiety. We have synthe-
sized dihydrobenzo[d][1,3]dioxolones 7, 9, 11, and 12, and
tetrahydrobenzo[d]oxazolones 17 from p-quinol and alde-
hydes or aldimines in a process that embraces an acetaliza-
tion/oxa-Michael or hemiaminalization/aza-Michael dom-
ino process, respectively. Tricyclic derivatives 18 were also
prepared by a one-pot, three-step sequence with excellent
diastereoselectivities. Five new stereocenters and four new
bonds are formed in this process, in which a domino se-
quence including 1,2-addition (hemiaminalization), an aza-
Michael, and a hetero-Diels–Alder process occurred. The
stereoselectivity of the initial approach between the nucleo-
philic p-quinol OH and the aldehyde or imine defines the
overall stereochemical course of the reaction.
When the reaction between p-quinol 3 and N-(p-tolylsulf-
onyl)benzaldimine (16a) was effected with DABCO/LiClO4
using THF as solvent, tricyclic compound 18a was formed
as the sole diastereomer. Taking into account that the rela-
tive configuration of the stereogenic centers of the hydro-
benzoxazolone moiety of 18a is the same as in compound
17a (phenyl and methyl substituents trans), we can assume
that the first steps of the domino sequence are common.
Thus, 18a must result from a sequential process starting
from deprotonation of the p-quinol 3 and addition to the
re-face of the imine (Scheme 13, species VIII) followed by
aza-Michael addition to the pro-S β-carbon of the cyclo-
hexadienone moiety. The final tricyclic compound 18a
could be formed from the dienolate intermediate XI by a
Experimental Section
regio and diastereoselective aza-Diels–Alder reaction[36] General Remarks: H (300 MHz) and 13C NMR (75 MHz) spectra
1
were recorded with a Bruker AV-300 spectrometer using CDCl3 as
solvent. A Bruker DRX-500 was used in specific cases for 13C
NMR (125 MHz) and double resonance experiments. Chemical
shifts are reported in ppm relative to CDCl3 (δ = 7.26 ppm).
HRMS were measured at 70 eV (EI). All reactions were monitored
by thin-layer chromatography, which was performed on precoated
sheets of silica gel 60, and flash column chromatography was per-
formed with silica gel 60 (230–400 mesh) from Merck. Eluting sol-
vents are indicated in the text. Melting points were obtained in
open capillary tubes and are uncorrected. Synthesis of p-quinols 3
and 4 and fused acetals 7 have been described previously.[11,16,19]
with a second equivalent of imine 16a. The diastereoselec-
tivity observed could be explained through the transition
state represented as XII in Scheme 13,[37] in which the anti-
sulfonyl imine approaches the less hindered bottom face of
the dienolate. Minimized steric interactions are responsible
for the favored attack of the imine, acting as heterodienoph-
ile, by the si-face. This approach leads to intermediate XIII
with the S-configuration at the new stereogenic phenyl-sub-
stituted carbon. Final enolate protonation affords the ob-
served diastereomer 18a.
Base-Catalyzed Synthesis of Dihydrobenzo[d][1,3]dioxol-5(4H)-one
(11); Typical Procedure: To a mixture of p-quinol 3 (190 mg,
1.53 mmol, 1 equiv.) and 6-bromo-2-pyridinecarbaldehyde 10
(285 mg, 1.53 mmol, 1 equiv.) in CH2Cl2 (3 mL, 0.5 m), was added
DMAP (28 mg, 0.23 mmol, 15 mol-%) at room temp. After 3 d,
the mixture was concentrated in vacuo to give a 70:30 mixture of
diastereoisomers 11/epi-11. The crude mixture was purified by flash
column chromatography (hexane/EtOAc, 2:1) to give the minor
diastereoisomer epi-11 (less polar fraction; 52 mg, 11% yield) and
major diastereoisomer 11 (most polar fraction; 143 mg, 30% yield).
Acid-Catalyzed Synthesis of Dihydrobenzo[d][1,3]dioxol-5(4H)-ones
(15a/epi-15a); Typical Procedure: To a mixture of 3 (70 mg,
0.56 mmol) and 3-methylbutanal 13a (66.5 μL, 0.62 mmol) in
CH2Cl2 (5.6 mL, 0.1 m), was added phosphoric acid 14a (19 mg,
0.056 mmol, 10 mol-%). After 2 d, the mixture was concentrated in
vacuo and the residue was purified by flash column chromatog-
raphy (hexane/EtOAc, 7:1) gave a 76:24 mixture of diastereoiso-
mers 15a/epi-15a. Major diastereoisomer 15a (less polar fraction;
77.5 mg, 65% yield) and minor diastereoisomer epi-15a (most polar
fraction; 27 mg, 23% yield).
Base-Catalyzed Synthesis of Tetrahydrobenzo[d]oxazolones (17a);
Typical Procedure: To a mixture of p-quinol 3 (57 mg, 0.46 mmol)
and imine 16a (115 mg, 0.46 mmol) in CH2Cl2 (0.92 mL, 0.5 m),
Scheme 13. Proposed mechanism and stereochemical outcome for
the synthesis of 18a.
10
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Reactions of p-Quinols with Aldehydes and Imines
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After 3 d, the crude mixture was concentrated in vacuo to give
compound 17a as the unique diastereoisomer. Purification by flash
column chromatography (hexane/EtOAc, 2:1) gave 17a (88 mg,
50% yield).
Base-Catalyzed Synthesis of Tricyclic Derivative (18a); Typical Pro-
cedure: To a mixture of p-quinol 3 (30 mg, 0.24 mmol) and imine
16a (120.5 mg, 0.48 mmol), DABCO (4 mg, 0.036 mmol), LiClO4
(18 mg, 0.17 mmol) and THF (0.5 m, 0.96 mL) were added. The
mixture was stirred at room temp. for 4 d, then the crude material
was concentrated in vacuo and purified by flash column
chromatography (hexane/EtOAc, 3:1) gave 18a (77 mg, 50% yield),
as the unique diastereoisomer.
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Supporting Information (see footnote on the first page of this arti-
cle): Experimental details and copies of the 1H and 13C NMR spec-
tra.
Acknowledgments
This work was supported by the Ministerio de Ciencia e Innovación
(MICINN) (grant number CTQ2011-24783), the Comunidad de
Madrid and European Social Fund (grant number SOLGEMAC-
S2009/ENE-1617). C. G. G. thanks UAM for a FPI-UAM fellow-
ship.
[11]
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[13]
[14]
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Jurewiz, R. K. Johnson, Tetrahedron 1997, 53, 5047; for elisa-
bethol, see: c) A. Ata, R. G. Kerr, C. E. Moya, R. S. Jacobs,
Tetrahedron 2003, 59, 4215; for coproverdine, see: d) S. Urban,
J. W. Blunt, M. H. G. Munro, J. Nat. Prod. 2002, 65, 1371.
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rias, N. Girola, D. C. Arruda, J. A. B. Scutti, P. Romoff, O. A.
Favero, M. J. P. Ferreira, J. H. G. Lago, L. R. Travassos, PLoS
One 2012, 7, 1–11; b) E.-H. Chew, J. Lu, T. D. Bradshaw, A.
Holgren, FASEB J. 2008, 22, 2072; c) A. McCarroll, T. D.
Bradshaw, A. D. Westwell, C. S. Matthews, M. F. G. Stevens, J.
Med. Chem. 2007, 50, 1707; d) J. M. Berry, T. D. Bradshaw, I.
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Eur. J. Org. Chem. 0000, 0–0
© 0000 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Job/Unit: O43114
/KAP1
Date: 02-10-14 12:33:39
Pages: 13
C. García-García, M. C. Redondo, M. Ribagorda, M. C. Carreño
FULL PAPER
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[24] CCDC-755300 (for 7a) contains the supplementary crystallo-
graphic 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 C14H13NO5; unit cell
1011199 (for 17a) 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.
[31] Mr C35H34NO6S2; Unit cell parameters: a = 13.5646(2) Å, b =
15.0472(2) Å, c = 16.6283(3); space group P21/n. CCDC-
1011200 (for 18a) 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.
parameters:
a = 7.58380(10) Å, b = 17.6558(6) Å, c =
9.6242(3) Å, β = 98.371(2)°; space group P21/c.
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[26] Minor amounts of TMSOTf (0.5 to 2 equiv.) or other solvents
(MeOH or CH2Cl2) gave poorer yields and/or diastereoselec-
tivities. The reaction was inhibited in THF.
[27] Flash chromatographic separation proved to be difficult due to
the similar Rf values of the diastereomers, thus decreasing, in
some cases, the amount of pure products isolated, when com-
pared with their relative ratio in the crude mixture.
[28] Unfortunately, all the attempts to develop an efficient desym-
metrization of the p-quinol system with several enantiopure
phosphoric acids derived from binaphthol gave very low or null
ee values, see the Supporting Information for details.
[29] For an enantioselective synthesis of acyclic N,O-aminals cata-
lyzed by chiral phosphoric acids, see: L. Guilong, F. R. Fron-
czek, J. C. Antilla, J. Am. Chem. Soc. 2008, 130, 12216.
[30] Mr C21H21NO4S; Unit cell parameters: a = 9.1130(2) Å, b =
13.7775(4) Å, c = 31.2336(9) Å; space group P21/c. CCDC-
[35] Only the intermediates resulting from the pro-S double bond
addition are shown. A similar approach to the pro-R double
bond of the p-quinol would give the same mixture of dia-
stereomers with the opposite configurations. These enantio-
meric molecules are omitted to simplify the scheme.
[36] a) G. R. Heintzelman, I. R. Meigh, Y. R. Mahajan, S. M.
Weinreb, Diels–Alder Reactions of Imino Dienophiles, in: Or-
ganic Reactions, John Wiley & Sons, 2005, vol. 65, pp 141–599.
[37] A stepwise sequence of 1,2-enolate addition of XI to the imine
16a, followed by a new aza-Michael addition to the cyclohex-
enone fragment could not be disregarded.
Received: August 19, 2014
Published Online: ᭿
12
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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O43114
/KAP1
Date: 02-10-14 12:33:39
Pages: 13
Reactions of p-Quinols with Aldehydes and Imines
Quinones
Base-promoted reactions of p-quinols with
aldehydes or sulfonyl imines enable direct
access to dihydrobenzo[d][1,3]dioxolone or
tetrahydrobenzo[d]oxazolone skeletons. A
stereoselective synthesis of tricyclic systems
was achieved by using sulfonyl imine and
DABCO/LiClO4 in THF through a dom-
ino sequence of 1,2-addition, intramolecu-
lar aza-Michael and aza-Diels–Alder reac-
tions.
C. García-García, M. C. Redondo,
M. Ribagorda,* M. C. Carreño* ..... 1–13
Reactions of p-Quinols with Aldehydes and
Imines: Stereoselective Access to Polyhet-
erobicyclic and Tricyclic Systems
Keywords: Fused-ring systems / Nitrogen
heterocycles
/ Quinones / Aldehydes /
Domino reactions / Michael addition /
Diastereoselectivity
Eur. J. Org. Chem. 0000, 0–0
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