Exploring Morita-Baylis-Hillman reactions of p-quinols

Article abstract of DOI:10.1021/ol902763g

[Chemical equation presented] The Morita Baylis Hillman reaction of p-methylquinols with activated aromatic aldehydes has been studied. Depending on the reaction conditions (solvent and additives), three different products were formed. A mono or double Mo

Full text of DOI:10.1021/ol902763g

ORGANIC
LETTERS
2010
Vol. 12, No. 3
568-571
Exploring Morita-Baylis-Hillman
Reactions of p-Quinols
Mar´ıa C. Redondo, Mar´ıa Ribagorda,* and M. Carmen Carren˜o*
Departamento de Qu´ımica Orga´nica (Mo´dulo 01), UniVersidad Auto´noma de Madrid,
C/ Francisco Toma´s y Valiente 7, Cantoblanco, 28049-Madrid, Spain
carmen.carrenno@uam.es; maria.ribagorda@uam.es
Received November 30, 2009
ABSTRACT
The Morita-Baylis-Hillman reaction of p-methylquinols with activated aromatic aldehydes has been studied. Depending on the reaction
conditions (solvent and additives), three different products were formed. A mono or double Morita-Baylis-Hillman adduct and a fused
1,3-dioxolane could be obtained in good chemical yields. The use of non-nucleophilic bases to promote the reaction suggested an autocatalytic
mechanism.
The Morita-Baylis-Hillman reaction1 (MBH) is a base-
catalyzed carbon-carbon bond formation process which
involves electron-deficient alkenes and aldehydes. Nucleo-
philic bases such as amines and phosphines2,3 are necessary
since the commonly accepted mechanism4 involves an initial
conjugate addition of the catalyst to the activated alkene
leading to a zwitterionic enolate, whose reaction with the
aldehyde is followed by a reversible elimination of the base
to generate the product. Different types of activated alkenes
such as cyclic and acyclic R,ꢀ-unsaturated ketones, alde-
hydes, esters, amides, nitriles, and alkenes substituted by nitro
groups, sulfoxides, sulfones, sulfonic acids, or phosphonate
derivatives have been used in the MBH reaction. In spite of
the advances reached, reactions of 4-hydroxy-4-substituted
cyclohexadienones (p-quinols) have not been reported to date.
Such cyclohexadienone derivatives are of huge synthetic
interest since these moieties are valuable starting materials
(3) For recent asymmetric MBH reactions, see: (a) Tang, H.; Zhao, G.;
Zhou, Z.; Gao, P.; He, L.; Tang, C. Eur. J. Org. Chem. 2008, 126–135. (b)
Gruttadauria, M.; Giacalone, F.; Lo Meo, P.; Masculescu, A. M.; Riela, S.;
Noto, R. Eur. J. Org. Chem. 2008, 1589–1596. (c) Shi, M.; Liu, X.-G.
Org. Lett. 2008, 10, 1043–1046. (d) Masson, G.; Housseman, C.; Zhu, J.
Angew. Chem., Int. Ed. 2007, 46, 4614–4628. (e) Berkessel, A.; Roland,
K.; Neudorfl, M. J. Org. Lett. 2006, 8, 4195–4198. (f) Nakano, A.;
Takahashi, K.; Hatakeyama, S. Org. Lett. 2006, 8, 5357–5360. (g) Matsui,
K.; Takizawa, S.; Sasai, H. J. Am. Chem. Soc. 2005, 127, 3680–3681, For
reviews, see. (h) Krishna, P. R.; Sharma, G. V. M. Mini-ReV. Org. Chem.
2006, 3, 137–153.
(1) (a) Baylis, A. B.; Hillman, M. E. D. Ger. Offen. 1972, 2,155,113;
Chem. Abstr. 1972, 77, 34174q. Hillman, M. E. D., Baylis, A. B. U.S. Patent
1973, 3,743,669. (b) Morita, K.; Suzuki, Z.; Hirose, H. Bull. Chem. Soc.
Jpn. 1968, 41, 2815–2819. (c) Rauhunt, M.; Currier, H. Chem. Abstr. 1963,
58, 11224a; American Cyanamid Co. U.S. Patent 1963, 3074999.
(2) For reviews, see: (a) Ma, G.-N.; Jiang, J.-J.; Wei., Chem. Commun.
2009, 5496–5514. (b) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511–
4574. (c) Y. Shi, Y.-L.; Shi, M. Eur. J. Org. Chem. 2007, 2905–2916. (d)
Basavaiah, D.; Rao, K. V.; Reddy., R. J. Chem. Soc. ReV. 2007, 64, 1581–
1588. (e) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV. 2003,
103, 811–891. (f) Langer, P. Angew. Chem., Int. Ed. 2000, 39, 3049–3052.
(g) Ciganek, E. In Organic Reactions; The catalyzed R-hydroxyalkylation
and R-aminoalkylation of actiVated olefins (The Morita-Baylis-Hillman
reaction); Paquette, L. A., Ed.; Wiley: NewYork, 1997; Vol. 51, p 201. (h)
(4) For recent mechanistic studies, see: (a) Roy, D.; Patel, C.; Sunoj,
R. B. J. Org. Chem. 2009, 74, 6936–6943. (b) Aggarwal, V. K.; Fulford,
S. Y.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706–1708.
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Ciganek, E. Org. React. 1997, 51, 201–350
.
10.1021/ol902763g  2010 American Chemical Society
Published on Web 01/07/2010

en route to a wide range of natural products,5 and they are
present in a group of novel therapeutic agents.6 Further
expansion of their reactivity will provide new tools for the
rapid construction of more complex structures.
of the p-quinol occurs from the si-face of the aldehyde, the
subsequent intramolecular oxa-Michael addition can take
place on either of the two prochiral ꢀ-carbons of the
cyclohexadienone moiety. The attack at the pro-R ꢀ-carbon
is favored due to the proposed transition structure I, with
the aryl group at the equatorial position. Approach at the
pro-S ꢀ-carbon (see II) shows a destabilizing 1,3-syn diaxial
interaction, which would make such an attack less favor-
able.14
Following previous studies on the synthesis and applica-
tions of p-quinols,7,8 we now report a study of the behavior
of these cyclohexadienones under Morita-Baylis-Hillman
conditions upon reaction with aromatic aldehydes. Our results
suggest an essential role of the OH group of the p-quinol
systems to initiate the MBH process.
The starting material, 4-hydroxy-4-methyl-2,5-cyclohexa-
dienone 1, was easily prepared in a one-pot/two step process
from p-methylphenol. Thus, oxidative dearomatization of
p-cresol with Oxone and NaHCO3, as source of singlet
oxygen,9 led to the p-peroxyquinol intermediate that was
reduced in situ with Na2S2O3 to the p-quinol 1 in 76%
isolated yield.7a Initial MBH experiments were carried out
with different para-substituted benzaldehydes 2a-d in the
presence of a catalytic amount of DMAP at room temperature
in CH2Cl2 as solvent. Under these conditions, p-quinol 1 did
not lead to the desired MBH products. Instead, ketal
derivatives 3a-d were exclusively obtained in good yields
(60-70%) (Scheme 1). Compounds 3 resulted as a mixture
of epimers at the stereogenic benzylic carbon (dr 80:20 to
90:10). The unequivocal structure of the major diastereoi-
somer was confirmed by X-ray diffraction of 3a.10 Similar
results were obtained using DABCO as base catalyst, though
the reaction was not always completed. The formation of
the cyclic ketal presumably involved a base-promoted 1,2-
addition of the hydroxy group of the p-quinol to the carbonyl
function of the aldehyde, followed by an intramolecular oxa-
Michael syn-addition of the intermediate alkoxide to the
cyclohexadienone moeity (Scheme 1).11,12 The stereoselec-
tive oxa-Michael syn-addition from the face containing the
OH group was expected on steric grounds.13 When reaction
Scheme 1. Synthesis of p-Quinol 1 and Fused Ketal Derivatives 3
Similar results were obtained using THF or MeCN as
solvents and the above-mentioned catalysts. In view of these
results, we decided to carry out the reactions using protic
solvents (e.g., MeOH or H2O) that are known to enhance
the rate of MBH processes.15 Fortunately, the reaction of
p-quinol 1 with different aromatic aldehydes 2 in the presence
of a catalytic amount of DMAP in MeOH at room temper-
ature led to the MBH products 4 in good yields (60-72%).
In all cases, two benzyl diastereomers were formed in a 60:
40 ratio that could be easily separated by column chroma-
(5) (a) Thebtaranonth, Ch.; Thebtaranonth, Y. Acc. Chem. Res. 1986,
19, 84–90. (b) Balci, M.; Sutbeyaz, Y.; Secen, H. Tetrahedron 1990, 46,
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2363.
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Burger, A. M.; Seaton, A.; Wang, B.; Westwell, A. D.; Stevens, M. F. G.
J. Med. Chem. 2003, 46, 532–541.
(11) For the synthesis of similar dioxolanes via acid-catalyzed reactions of
p-benzo- and p-naphthoquinols with aliphatic aldehydes, see: Jefford, C. W.;
Rossier, J.-C.; Kohomoto S.; Boukouvalas, J. Synthesis 1985, 29-31.
(12) For similar processes on acyclic systems see: (a) Evans, D. A.;
Gauchet-Prunet, J. A. J. Org. Chem. 1993, 58, 2446–2453. (b) Watanabe,
H.; Machida, K.; Nagatsuka, H.; Kitahara, T. Chirality 2001, 13, 379–385.
(c) Aouzal, R.; Prunet, J. Org. Biomol. Chem. 2009, 7, 3594–3598.
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J. Org. Chem. 1998, 63, 3687–3693.
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Int. Ed. 2006, 45, 2737–2741. (b) Barradas, S.; Carren˜o, M. C.; Gonza´lez-
Lo´pez, M.; Urbano, A. Org. Lett. 2007, 46, 5019–5022. (c) Barradas, S.;
Urbano, A.; Carren˜o, M. C. Chem.sEur. J. 2009, 15, 9286–9289
.
(8) For recent synthetic applications of p-[(p-tolylsulfinyl)methyl]-p-
quinols, see: Carren˜o, M. C.; Somoza, A.; Ribagorda, M.; Urbano, A.
Chem.sEur. J. 2007, 13, 879–890. (b) Carren˜o, M. C.; Merino, E.;
Ribagorda, M.; Somoza, A.; Urbano, A. Chem.sEur. J. 2007, 13, 1064–
1077. (c) For a recent overview of our work, see: Carren˜o, M. C.;
Herna´ndez-Torres, G.; Ribagorda, M.; Urbano, A. Chem. Commun. 2009,
(14) Similar approaches to the re-face of the aldehyde would give the
same mixture of diastereomers with the opposite configurations.
(15) (a) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc.
2007, 129, 15513–15525. (b) Park, K.-S.; Kim, J.; Choo, H.; Chong, Y.
Synlett 2007, 3, 395–398. (c) Cai, J.; Zhou, Z.; Tang, C. Org. Lett. 2002,
4, 4723–4725. (d) Aggarwal, V. K.; Fean, D. K.; Mereu, A.; Williams, R.
J. Org. Chem. 2002, 67, 510–514. (e) Luo, S.; Zhang, B.; He, J.; Janczuk,
A.; Wang, P. G.; Cheng, J.-P. Tetrahedron Lett. 2002, 43, 7369–7371. (f)
Yu, C.; Liu, B.; Hu, L. J. Org. Chem. 2001, 6, 5413–5418. (g) Yamada,
Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41, 2165–2169. (h) Auge,
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Ameer, F.; Drewes, S. E.; Freese, S.; Kaye, P. T. Synth. Commun. 1998,
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6129–6144
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105, 3371–3387. (b) Evans, D. F.; Upton, M. W. J. Chem. Soc., Dalton
Trans. 1985, 1151–1153. (c) Ball, D. L.; Edwards, J. O. J. Am. Chem. Soc.
1956, 78, 1125–1129.
(10) CDCC 755300 (3a): Mr C14H13NO5, unit cell parameters a )
7.58380(10) Å, b ) 17.6558(6) Å, c ) 9.6242(3) Å, ꢀ ) 98.371(2)°, space
group P21/c. For details, see the Supporting Information.
Org. Lett., Vol. 12, No. 3, 2010
569

tography (Scheme 2). The formation of a mixture of
diastereomers is a consequence of the prochiral character of
cyclohexadienone moiety. The configuration of the most
polar minor one was established by X-ray diffraction of the
p-nitro derivative 4a.16
Table 1. MBH Reactions of p-Quinol 1 with 2a-d in the
Presence of LiClO4
Scheme 2. MBH Reactions of p-Quinol 1 with Aromatic
Aldehydes and X-ray Diffraction of 4a (Minor Diastereoisomer)
entry
R
time (d)
product (ratio)a
yield (%)
1
2
3
4
NO2
CF3
CN
F
3
2
4
4
5a/6a/7a (50:10:40)
5b/6b/7b (50:10:40)b
5c/6c/7c (46:12:42)
5d/6d/7d (53:13:34)
65
60
60
73
a The ratio was obtained from the 1H NMR spectrum of the crude
reaction mixture. b The ratio was obtained from HPLC Chiral Chromatog-
raphy (Diacel Chiralpack OD chiral column, 95/5 hexane/2-propanol, 0.9
mL/min, 210 nm).
Other nitrogen bases such as DABCO gave similar results
in the presence of the protic solvent. The use of metal salts,
which are known to accelerate the MBH reaction17 due to
stabilization of the intermediate alkoxide, turned out to a be
very useful. In particular, when we performed the reaction
with DABCO (15 mol %) and LiClO4 (70 mol %) as a
cocatalyst18 in THF, both R,ꢀ-unsaturated moieties of the
cyclohexadienone participated in the MBH reaction giving
rise, in a one-pot process, to the double MBH adducts (5-7)
in 60-75% yield. The double MBH adducts were character-
ized as a mixture of three diastereoisomers that could be
separated by column chromatography (Table 1).19 The
structure and stereochemistry of 5 (most unpolar spot-TLC)
and 7 (most polar spot-TLC) could be unequivocally assigned
by X-ray diffraction of the p-ciano derivatives (5c and 7c)20
(Figure 1). The relative configuration of the intermediate TLC
spot isomer 6 was assigned to the meso-diastereoisomer
shown in Figure 1.
Figure 1
5c and 7c.
. Structures of compounds 5-7 and X-ray structures of
hydroxyl group of the p-quinol in the MBH process that
could be inhibited due to the oxophilic nature of the
phophorus. To test this hypothesis, p-quinol methyl ether
(4-methoxy-4-methyl-2,5-cyclohexadienone), lacking the free
OH, was used as substrate. Its reaction with p-nitrobenzal-
dehyde 2a, using DABCO or DMPA as catalysts failed, and
the starting materials were recovered unchanged. Moreover,
the reaction of 1 with aldehyde 2a using a non-nucleophilic
base, such as K2CO3 or Cs2CO3 in a methanolic solution,
was faster (18 h instead of 3 d) and gave a 70:30 mixture of
4a and double MBH adducts (5a-7a) (Scheme 3).22
When different phosphines, known catalysts for the
Baylis-Hillman reaction, were used as base catalysts (PPh3,
PBu3, PCy3),21 the starting p-quinol was recovered unaltered.
This result induced us to consider the participation of the
(16) CDCC 755301 (4a minor): Mr C14H13NO5, unit cell parameters a
) 6.9945(3) Å, b ) 8.7663(6) Å, c ) 10.6230(6) Å, R ) 101.662(3)°, ꢀ
) 98.586(3)°, γ ) 91.319(3)°, space group P-1. For details, see the
Supporting Information.
Scheme 3
.
Reaction of p-Quinol 1 with 2a using Cs2CO3 as
(17) (a) Imagawa, T.; Uemura, K.; Nagai, Z.; Kawanishi, M. Synth.
Commun. 1984, 14, 1267–1273. (b) Aggarwal, V. K.; Mereu, A.; Tarver,
G. J.; McCague, R. J. Org. Chem. 1998, 63, 7183–7189. (c) Kataoka, T.;
Iwama, T.; Tsujiyama, S. Chem. Commun. 1998, 197–198.
(18) Kawamura, M.; Kobayashi, S. Tetrahedron Lett. 1999, 40, 1539–
1542.
Base
(19) Using MeOH as solvent reaction was sluggish, and double MBH
adducts were obatined in low yields.
(20) (a) CCDC 753513 (5c): Mr C23H18NO4, unit cell parameters a )
9.71730(10) Å, b ) 10.03110(10) Å, c ) 10.20860(10) Å, R )
87.6830(10)°, ꢀ ) 80.2460(10)°, γ ) 86.4870(10)°, space group P-1. (b)
CCDC 755302 (7c): Mr C23H18NO4, a ) 8.3330(6) Å, b ) 22.7385(15) Å,
c ) 10.3520(7) Å, ꢀ ) 105.193(4)°, space group P21/n. For details, see
the Supporting Information.
The formation of MBH compounds from p-quinol 1 in
the absence of a nucleophilic tertiary amine, and the lack of
570
Org. Lett., Vol. 12, No. 3, 2010

reaction of the p-quinol methyl ether suggest a domino
intramolecular oxa-Michael/aldol condensation/elimination
mechanistic pathway, instead of the commonly accepted
MBH mechanism. As shown in Scheme 4, the cycle could
start by an acid-base equilibrium reaction of 1 followed by
an entropically favored oxa-Michael intramolecular addition,
leading the enolate-epoxide intermediate A. Subsequent
aldol reaction with 2 (B) and abstraction of the acidic
R-proton, favored by the protic solvent, could explain the
formation of a new enolate-epoxide C, which evolve to the
Baylis-Hillman adduct 4 by epoxide ring-opening. The
double-MBH adducts (5-7) could be formed through an
analogous sequence from 4a. Among the variety of bases
explored as catalysts for MBH reactions in the literature,
nucleophilic oxygenated bases have been scarcely used.23,24
To our knowledge, an autocatalytic Morita-Baylis-Hillman
process similar to the one proposed in the p-quinol system
has never been reported.
tuted double bond of the cyclohexadienone moiety to give
the cis-fused bicyclic structure 9. When DMAP and MeOH
were used, the starting p-quinol 8 was recovered unchanged.
On the other hand, the use of DABCO/LiClO4 in THF gave
the desired adduct 10 as a 77:23 mixture of diastereoisomers,
easily separable by column chromatography in 48% and 13%
isolated yields, respectively. Compound 10 could also be
obtained in a similar diastereomeric ratio and 60% yield using
Cs2CO3 as base in MeOH. In this case, no double MBH
products were detected, probably due to the diminished
electrophilic character of the ꢀ-methyl-substituted double
bond of p-quinol 8.
Scheme 5. Reaction of Methyl p-Quinol 8 with
p-Nitrobenzaldehyde 2a with DMAP in CH2Cl2
Scheme 4
.
Proposed Mechanism for the Synthesis of MBH
Adducts from p-Quinol 1
In summary, the reactions of p-quinols with aromatic
aldehydes under Morita-Baylis-Hillman conditions have
been explored for the first time. Fused dioxolanes 3 and 9
or mono and double MBH adducts can be synthesized by
choosing the reaction conditions. Highly functionalized
p-quinol derivatives are directly available in a one-pot
reaction. Our work evidenced an unprecedented autocatalysis
in the MBH process of p-quinol systems. The C-4 hydroxy
group of the p-quinol has the ability to act as an internal
oxygenated nucleophilic catalyst essential to trigger the MBH
reaction through an intramolecular oxa-Michael addition
followed by the aldol-type reaction.
Finally, we examined the behavior of 3-methyl-4-hydroxy-
4-methylquinol 87a reacting with p-nitrobenzaldehyde 2a
under the reaction conditions previously used for 1 (Scheme
5). Thus, reaction of p-quinol 8 with p-nitrobenzaldehyde
in the presence of DMAP in CH2Cl2 afforded the ketal 9 in
good yield (74%) and diastereoselectivity (90:10). In this
case, the formation of the ketal took place by the oxa-Michael
intramolecular addition to the more electrophilic unsubsti-
Acknowledgment.WethankMICINN(GrantNo.CTQ2008-
04691) and Comunidad Auto´noma de Madrid-UAM (CCG08-
UAM/PPQ-3980) for financial support. M.C.R. thanks MEC
for a Juan de la Cierva contract.
(21) Methot, J. L.; Roush, W. R. AdV. Synth. Catal. 2004, 346, 1035–
1050
.
(22) The use of the protic solvent methanol was shown to be essential
since when CH2Cl2 was used, the heterogeneous mixture of p-quinol 1 and
Cs2CO3, yielded the fused bicyclic ketal derivative 3a.
Supporting Information Available: Experimental pro-
cedures, spectroscopic data, and copies of 1H NMR and 13
C
(23) For examples of MBH reaction intermolecularly catalyzed by
oxygen nucleophiles, see: (a) Ciganek, E. J. Org. Chem. 1995, 60, 4635–
4637. (b) Luo, S.; Mi, X.; Wang, P. G.; Cheng, J.-P. J. Org. Chem. 2004,
69, 8413–8422. See also ref 2b.
NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(24) For an example of oxa-Michael/aldol-type condensation process,
see: Lesch, B.; Bra¨se, S. Angew. Chem., Int. Ed. 2004, 43, 115–118
.
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