Acceleration of the Morita-Baylis-Hillman reaction by a simple mixed catalyst system

Article abstract of DOI:10.1021/jo900603w

(Chemical Equation Presented) By using a catalytic amount of 4-dimethylaminopyridine (DMAP) as a nucleophile in the presence of an equal amount of tetramethylethylenediamine (TMEDA) and MgI₂, Morita-Baylis-Hillman adducts can be obtained in good to excellent yields from various aromatic and aliphatic aldehydes and cyclic enones/enoates at room temperature after convenient reaction times.

Full text of DOI:10.1021/jo900603w

nucleophile catalyst. This activation allows for the use of weaker
nucleophiles or less electron-deficient alkenes in the MBH
reaction.5
Acceleration of the Morita-Baylis-Hillman
Reaction by a Simple Mixed Catalyst System
For example, in 1998, Aggarwal et al. reported the use of
La(OTf)3 (5 mol %) and triethanolamine (50 mol %) to
accelerate the reaction rates for the MBH reaction between
aldehydes and vinyl esters in the presence of DABCO (100 mol
%). While successful MBH adducts were obtained with these
conditions, excess DABCO was required to maximize the
reaction rates due to the association of DABCO with the metal
at equimolar ratios.6
Alejandro Bugarin and Brian T. Connell*
Department of Chemistry, Texas A&M UniVersity,
P.O. Box 30012, College Station, Texas 77842-3012
connell@mail.chem.tamu.edu
ReceiVed March 23, 2009
In 1999, Kobayashi et al. reported the use of LiClO4 as the
Lewis acid in the presence of DABCO to catalyze the MBH
reaction between aldehydes and vinyl esters in good yields.
However, extended reaction times were required, and for some
activated alkenes the use of excess Lewis acid was required.7
In addition, other strategies to mediate the MBH reaction have
been examined, including the use of amino- or phosphino-type
catalysts as nucleophiles,8 ionic liquids as both a nucleophile
and solvent system,9 as well as biocatalysis.10 Generally, each
of these approaches faces certain limitations, although there is
notable effort in this area,11 there has yet to be developed a
general, enantioselective version of the MBH reaction.
We were interested in developing a catalytic system for the
MBH reaction, which would be amenable to asymmetric
catalysis in a straightforward manner. Here we report the use
of a mild catalytic system that combines equimolar amounts of
the Lewis acid MgI2, the electron-donating ligand TMEDA, and
the nucleophile DMAP to promote the MBH reaction in a
reasonable reaction time.
By using a catalytic amount of 4-dimethylaminopyridine
(DMAP) as a nucleophile in the presence of an equal amount
of tetramethylethylenediamine (TMEDA) and MgI2, Morita-
Baylis-Hillman adducts can be obtained in good to excellent
yields from various aromatic and aliphatic aldehydes and
cyclic enones/enoates at room temperature after convenient
reaction times.
(3) (a) Hill, J. S.; Isaacs, N. S. Tetrahedron Lett. 1986, 27, 5007–5010. (b)
Bode, M. L.; Kaye, P. T. Tetrahedron Lett. 1991, 32, 5611–5614. (c) Price,
K. E.; Broadwater, S. J.; Jung, H. M.; McQuade, D. T. Org. Lett. 2005, 7, 147–
150. (d) Robiette, R.; Aggarwal, V. K.; Harvey, J. N. J. Am. Chem. Soc. 2007,
129, 15513–15525. (e) Santos, L. S.; Henrique, C.; Fernando, A.; Eberlin, M. N.
Angew. Chem., Int. Ed. 2004, 43, 4330–4333. (f) Aggarwal, V. K.; Fulford,
S. Y.; Lloyd-Jones, G. C. Angew. Chem., Int. Ed. 2005, 44, 1706–1708.
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(b) Kumar, A.; Pawar, S. S. Tetrahedron 2003, 59, 5019–5026. (c) Cai, J.; Zhou,
Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723–4725. (d) Aggarwal, V. K.;
Dean, 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, 66,
5413–5418. (g) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett. 2000, 41,
2165–2169. (h) Auge´, J.; Lubin, N.; Lubineau, A. Tetrahedron Lett. 1994, 35,
7947–7948. (i) Ameer, F.; Drewes, S. E.; Freese, S.; Kaye, P. T. Synth. Commun.
1988, 18, 495–500.
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2002, 43, 8219–8222. (c) Yamada, Y. M. A.; Ikegami, S. Tetrahedron Lett.
2000, 41, 2165–2169. (d) McDougal, N. T.; Schaus, S. E. J. Am. Chem. Soc.
2003, 125, 12094–12095.
(6) Aggarwal, V. H.; Mereu, A.; McCague, R. J. Org. Chem. 1998, 63, 7183–
7189.
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(8) (a) Barrett, A. G. M.; Cook, A. S.; Kamimura, A. Chem. Commun. 1998,
2533–2534. (b) Iwabuchi, Y.; Nakatani, M.; Yokoyama, N.; Hatakeyama, S.
J. Am. Chem. Soc. 1999, 121, 10219–10220. (c) Shi, M.; Jiang, J. K. Tetrahedron:
Asymmetry 2002, 13, 1941–1947. (d) Mocquet, C. M.; Warriner, S. L. Synlett
2003, 357–360. (e) Hayase, T.; Shibata, T.; Soai, K.; Wakatsuiki, Y. Chem.
Commun. 1998, 1271–1272.
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45, 6425–6428.
(10) Reetz, M. T.; Mondiere, R.; Carballeira, J. D. Tetrahedron Lett. 2007,
48, 1679–1681.
The Morita-Baylis-Hillman (MBH) reaction is an important
carbon-carbon bond-forming reaction between electron-
deficient alkenes, such as R,ꢀ-unsaturated ketones, and alde-
hydes or activated ketones. The products of MBH reactions are
highly functionalized and hence can be used as components of
further reactions such as aldol, Michael, Diels-Alder, or 1,2-
additions, for instance, which in turn can lead to the synthesis
of biologically important materials or natural products, such as
furaquinocins.1 The reaction is catalyzed by nucleophilic amines
or phosphines, most commonly DABCO (1,4-diazabicyclo-
[2.2.2]octane) or tertiary phosphines.2
The mechanism of the MBH reaction is believed to proceed
through a conjugate addition followed by an aldol addition, and
then ꢀ-elimination.3 Various efforts have been made to acceler-
ate this reaction sequence by using Lewis acid cocatalysts.4 The
Lewis acid catalyst is generally believed to activate electron-
deficient alkenes to facilitate the conjugate addition of the
(1) (a) Trost, B. M.; Thiel, O. R.; Tsui, H. C. J. Am. Chem. Soc. 2002, 124,
11616–11617. (b) Trost, B. M.; Thiel, O. R.; Tsui, H. C. J. Am. Chem. Soc.
2003, 125, 13155–13164.
(2) For recent reviews, see: (a) Basavaiah, D.; Rao, P. D.; Hyma, R. S.
Tetrahedron 1996, 52, 8001–8062. (b) Langer, P. Angew. Chem., Int. Ed. 2000,
39, 3049–3052. (c) Basavaiah, D.; Rao, A. J.; Satyanarayana, T. Chem. ReV.
2003, 103, 811–891. (d) Singh, V.; Batra, S. Tetrahedron 2008, 64, 4511–4574.
(e) France, S.; Guerin, D. J.; Miller, S. J.; Lectka, T. Chem. ReV. 2003, 103,
2985–3012. (f) Basavaiah, D.; Rao, K. V.; Reddy, R. J. Chem. Soc. ReV. 2007,
36, 1581–1588. (g) Maher, D. J.; Connon, S. J. Tetrahedron Lett. 2004, 45,
1301–1305.
(11) Masson, G.; Housseman, C.; Zhu, J. Angew. Chem., Int. Ed. 2007, 46,
4614–4628.
4638 J. Org. Chem. 2009, 74, 4638–4641
10.1021/jo900603w CCC: $40.75 2009 American Chemical Society
Published on Web 05/18/2009

TABLE 1. MBH Reaction between Cyclopenten-2-one and
Benzaldehyde in the Presence of MgI2, TMEDA, and DMAP
TABLE 2. MBH Reaction of Cyclopenten-2-one
entry
R
time, h
product
% yielda
entry
% MgI2
% TMEDA
% DMAP
10
% yielda
1
2
3
4
5
6
7
8
9
(CH3)2CH-
Ph(CH2)2-
Ph(CH)2-
p-NO2(C6H4)-
(C6H5)-
15
15
15
5
15
15
48
15
48
1
2
3
4
5
6
6
7
7
62
89
93
94
91
67
83
66
91
1
2
3
4
5
6
NR
NR
NR
91
54
36
10
10
10
20
10
10
10
10
10
p-MeO(C6H4)-
p-MeO(C6H4)-
(C6H11)-
20
a Isolated yield after purification by silica gel chromatography.
(C6H11)-
a Isolated yield after purification by silica gel chromatography.
Our initial studies identified several Lewis acidic metal salts
which were capable of catalyzing the reaction of benzaldehyde
with cyclopentenone in the presence of TMEDA and a catalytic
Lewis base (DMAP). The metal salts NiCl2, PdCl2, SnCl4, LiCl,
LiClO4, Cu(OTf)2, and SmI2 catalyzed MBH reactivity under
these conditions, but the yields were low. No reactions were
observed when Zn(II) halides were employed, but unfortunately
Zn(OTf)2 catalyzed the quantitative dimethylacetalization of
benzaldehyde. However, Mg(II) salts proved to be quite reactive,
with MgI2 showing higher reactivity than its congeners MgBr2
and MgCl2.
Potential nucleophiles, including DABCO, DBU, triethyl-
amine, Hu¨nig’s base, and pyridine, were screened for compat-
ibility with the combination of Lewis acidic MgI2 and TMEDA.
The strong base DBU deactivates the catalyst, whereas weak
nucleophiles like triethylamine and pyridine show very low
reaction rates and Hu¨nig’s base shows no reaction at all. It was
found that the MBH reaction was accelerated dramatically by
using MgI2 and DMAP as catalytic partners.
No reaction was observed between benzaldehyde and cyclo-
pentenone in the absence of MgI2 (10 mol % of DMAP or 10
mol % of TMEDA) in MeOH (eq 1). However, the addition of
10 mol % of MgI2 to the reaction mixture afforded the adduct
in low yield when combined with either 20 mol % of DMAP
(36% yield) or 20 mol % of TMEDA (54% yield). Increasing
the amount of DMAP present provided no improvement in
reaction yields. On the other hand, the use of equimolar amounts
of Lewis acid, ligand, and Lewis base in the system afforded
the adduct in 91% yield (Table 1, entry 4).
After optimizing the Lewis acid and nucleophile used as
catalysts, various solvent systems were investigated. It was
observed that the reaction was faster in MeOH than in THF,
EtOAc, CH2Cl2, or dioxane. Although beneficial in other
systems, a mixed solvent system of MeOH-H2O also afforded
lower yields in this system.12
aldehydes cyclohexane carboxaldehyde and isobutyraldehyde
were obtained in 66% and 62% yields, respectively (Table 2,
entries 8 and 1). The system was also efficient for R,ꢀ-
unsaturated aldehydes; the MBH adduct for trans-cinammal-
dehyde was obtained in 93% yield (Table 2, entry 3). It is worth
mentioning that the lower yields obtained for several of the
MBH adducts were the result of incomplete reaction. The
presence of starting materials was observed after 15 h for all
entries with yields lower that 90%. This reaction time of 15 h
was used as benzaldehyde, a moderately reactive aldehyde with
neither electron-rich nor electron-poor characteristics, was
completely consumed after this time period. By performing all
reactions in this 15 h time window, we could compare the effects
of electron-donating or electron-withdrawing functionalities on
the rate of reaction.
To further examine the scope and utility of these catalytic
reaction conditions, a variety of R,ꢀ-unsaturated ketones, esters,
and thioesters were treated with benzaldehyde under the same
reaction system conditions (Table 3). Again, most reactions were
quenched after 15 h for comparison purposes, although starting
material was still remaining. In all cases, the reaction proceeds
smoothly in the presence of catalytic amounts of equimolar
Lewis acid, ligand, and the nucleophile to afford the corre-
sponding adducts in good to high yields at room temperature.
Notable examples from Table 3 include reactions with
γ-disubstituted enones such as 4,4-dimethylcyclopenten-2-one
(Table 3 entry 1) and 4,4-dimethylcyclohexen-2-one (Table 3,
entry 3), which gave 86% and 75% yield, respectively, after
15 h.
The reactivity of transformations was also shown for cyclic
enones, which contain five- (Table 2, entry 5), six- (Table 3,
entry 2), and seven-membered rings (Table 3, entry 4) in
moderate to high yields of 91%, 84%, and 56%, respectively.
The synthesis of xanthenes starting from 2-hydroxybenzal-
dehydes and 2-cyclohexenone with DABCO as catalyst has
previously been reported by Brase et al.13 He employed DABCO
(50 mol %) as a catalyst in water under sonication conditions
to obtain 2,3,4,4a-tetrahydro-1H-xanthen-1-one (15) in 83%
yield after 48 h by a presumed sequence of MBH, conjugate
addition, and elimination reactions. When we investigated this
sequence under our reaction conditions, we obtained the product
We investigated the scope of the MgI2/TMEDA/DMAP-
catalyzed MBH reaction by examining a variety of electrophiles
(Table 2). For electron-deficient aldehydes, the system is very
efficient; the MBH adduct of p-nitrobenzaldehyde and cyclo-
pentenone was obtained after only 5 h in 94% yield (Table 2,
entry 4). Additionally, this system afforded reasonable yields
for electron-rich aldehydes. The MBH adduct for the aromatic
aldehyde p-methoxybenzaldehyde was obtained in 67% yield
(Table 2, entry 6), and the MBH adducts for the aliphatic
(12) Cai, J.; Zhou, Z.; Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723–4725.
(13) Brase, S. Angew. Chem., Int. Ed. 2004, 43, 115–118.
J. Org. Chem. Vol. 74, No. 12, 2009 4639

TABLE 3. MBH Reaction of Benzaldehyde
is likely to be the active Lewis acid catalyst. Formation of a
1
complex of TMEDA:MgI2 is clearly visible in the H and
13C NMR spectra of a 1:1 mixture of the two (see the
Supporting Information), as expected by the wealth of data
on chelating amine/Mg(II) complexes in the literature.15
Further studies will be necessary to adequately support or
refute this hypothesis.
In summary, this new reaction system employing a 1:1:1 ratio
of catalytic amounts (10 mol %) of MgI2, TMEDA, and DMAP
proved to be highly effective at promoting the reaction of a
variety of electrophiles, including both electron-poor and
electron-rich aldehydes, with various cyclic enones as the
nucleophilic substrate in the MBH reaction. Both R,ꢀ-unsatur-
ated esters and thioesters were also shown to undergo the MBH
sequence even more readily. Furthermore, these studies provide
a valuable platform for the development of chiral ligands to
promote enantioselective MBH reactions, as chiral TMEDA-
equivalent ligands are well-known.16
Experimental Section
Typical Reaction Procedure for known compounds 1-12
and 15. To a stirred mixture of aldehyde (0.5 mmol) and activated
alkene (0.55 mmol) in MeOH (1.2 mL) at room temperature under
argon was added a solution of magnesium iodide (13.9 mg, 0.05
mmol) and TMEDA (8.3 mg, 0.05 mmol) in MeOH (0.2 mL),
followed by dropwise addition of a solution of 4-dimethylami-
nopyridine (6.1 mg, 0.05 mmol) in MeOH (0.1 mL). Afterward
the mixture was stirred for 15 h at rt under argon. The reaction
was quenched by addition of saturated aqueous NH4Cl solution (1.0
mL). The solution mixture was extracted twice with dichlo-
romethane (5.0 mL) and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified
by flash silica gel column chromatography (20% EtOH/hexanes or
dichloromethane).
3-(Hydroxy(phenyl)methyl)furan-2(5H)-one (13). To a stirred
mixture of benzaldehyde (53 mg, 0.5 mmol) and furan-2(5H)-one
(46.2 mg, 0.55 mmol) in EtOH (1.2 mL) at room temperature under
argon was added a solution of magnesium iodide (13.9 mg, 0.05
mmol) and TMEDA (8.3 mg, 0.05 mmol) in EtOH (0.2 mL)
followed by dropwise addition of a solution of 4-dimethylami-
nopyridine (6.1 mg, 0.05 mmol) in EtOH (0.1 mL). Afterward the
mixture was stirred for 2 h at rt under argon. The reaction was
then quenched by addition of saturated aqueous NH4Cl solution
(1.0 mL). The solution mixture was extracted twice with dichlo-
romethane (5.0 mL) and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified
by flash silica gel column chromatography (dichloromethane) to
give compound 13 (50.4 mg, 53%) as a colorless oil: IR (thin film)
a Isolated yield after purification by flash silica gel chromatography.
b EtOH solvent. c Reaction performed at -15 °C.
SCHEME 1. Reaction of Cyclohexen-2-one and
Salicylaldehyde
1
3424, 2869, 1745, 1201 cm-1; H NMR (CDCl3, 300 MHz) δ
7.43-7.31 (m, 5 H), 7.19 (q, J ) 1.55 Hz, 1 H), 5.56 (s, 1 H),
4.78 (t, J ) 2.0 Hz, 2 H), 3.45 (d, J ) 4.0 Hz, 1 OH); 13C NMR
(75 MHz, CDCl3) δ 172.9, 146.0, 140.0, 136.3, 128.5, 128.2, 126.3,
70.5, 69.0; MS (ESI) calcd for C11H10O3 + Li requires m/z
197.0790, found 197.0795.
3-(Hydroxy(phenyl)methyl)thiophen-2(5H)-one (14). To a
stirred mixture of benzaldehyde (53 mg, 0.5 mmol) and thiophen-
2(5H)-one (55 mg, 0.55 mmol) in EtOH (1.2 mL) at -15 °C under
(Scheme 1) in 77% yield in significantly less time (15 h) and
under milder reaction conditions.
Additions to acyclic enones and enoates under catalytic
conditions is a longstanding problem. Scheidt and co-workers
have recently begun to overcome this limitation by utilizing
the addition of silyloxyallenes to aldehydes, specifically
normally unreactive ꢀ-substituted substrates.14 We envisioned
that our catalytic system might also address this limitation.
Unfortunately, our current system is not capable of accelerat-
ing the MBH reaction of acyclic enones or acrylates with
aldehydes.
(14) (a) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008, 10,
5227–5230. (b) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008,
10, 2449–2452. (c) Reynolds, T. E.; Scheidt, K. A. Angew. Chem., Int. Ed. 2007,
46, 7806–7809. (d) Reynolds, T. E.; Bharadwaj, A. R.; Scheidt, K. A. J. Am.
Chem. Soc. 2006, 128, 15382–15383.
(15) Gaderbauer, W.; Zirngast, M.; Baumgartner, J.; Marschner, C. Orga-
nometallics 2006, 25, 2599-2606 and references cited therein.
(16) Coldham, I.; O’Brian, P.; Whittaker, P. T. E. Tetrahedron: Asymmetry
2007, 18, 2113–2119.
Elucidation of the mechanistic details of this system are
currently in progress. We surmise that a TMEDA-bound MgI2
4640 J. Org. Chem. Vol. 74, No. 12, 2009

argon was added a solution of magnesium iodide (13.9 mg, 0.05
mmol) and TMEDA (8.3 mg, 0.05 mmol) in EtOH (0.2 mL)
followed by dropwise addition of a solution of 4-dimethylami-
nopyridine (6.1 mg, 0.05 mmol) in EtOH (0.1 mL). Afterward the
mixture was stirred for 1 h at -15 °C under argon. The reaction
was quenched by addition of saturated aqueous NH4Cl solution (1.0
mL). The solution mixture was extracted twice with dichlo-
romethane (5.0 mL) and dried over anhydrous Na2SO4. The solvent
was removed under reduced pressure, and the residue was purified
by flash silica gel column chromatography (dichloromethane) to
give compound 14 (94.8 mg, 92%) as a pale yellow oil: IR (thin
35.5; MS (ESI) calcd for C11H10O2S + Li requires m/z 213.0562,
found 213.0573.
Acknowledgment. We are grateful to Texas A&M University
and the Robert Welch Foundation (A-1623) for financial support
and Dr. Shane Tichy for MS analyses.
Supporting Information Available: Experimental proce-
1
dures for the preparation of MBH adducts and copies of H
and 13C NMR spectra of all new and known compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
1
film) 3419, 2918, 1659, 1170 cm-1; H NMR (CDCl3, 300 MHz)
δ 7.42-7.32 (m, 5 H), 7.16 (m, 1 H), 5.63 (s, 1 H), 3.98 (t, J )
1.08 Hz, 2 H), 3.20 (d, J ) 3.63 Hz, 1 OH); 13C NMR (75 MHz,
CDCl3) δ 199.9, 148.9, 147.7, 140.6, 128.6, 128.1, 126.4, 70.1,
JO900603W
J. Org. Chem. Vol. 74, No. 12, 2009 4641