Organocatalytic head-to-tail dimerization of methacrolein via conjugate addition of methanol: An alcohol activation mechanism proved by electrospray ionization mass spectrometry

Article abstract of DOI:10.1016/j.tetlet.2011.10.070

The head-to-tail dimerization of methacrolein via the conjugate addition of methanol is catalyzed by various organic bases, such as an amine, phosphine, and N-heterocyclic carbene, to give 2,4-dimethyl-2-methoxymethylpentane-1,5-dial in moderate yields. Based on the interpretation of the key intermediates by electrospray ionization mass spectrometry, we propose a reaction mechanism involving the initial conjugate addition of the organic bases to methacrolein to generate a zwitterionic base followed by the activation of methanol.

Full text of DOI:10.1016/j.tetlet.2011.10.070

Tetrahedron Letters 52 (2011) 6835–6838
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Tetrahedron Letters
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Organocatalytic head-to-tail dimerization of methacrolein via conjugate
addition of methanol: an alcohol activation mechanism proved
by electrospray ionization mass spectrometry
⇑
Shin-ichi Matsuoka , Shintaro Shimakawa, Koji Takagi, Masato Suzuki
Department of Materials Science and Engineering, Graduate School of Engineering, Nagoya Institute of Technology, Gokiso-cho, Showa-ku, Nagoya 466-8555, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
The head-to-tail dimerization of methacrolein via the conjugate addition of methanol is catalyzed by var-
ious organic bases, such as an amine, phosphine, and N-heterocyclic carbene, to give 2,4-dimethyl-2-
methoxymethylpentane-1,5-dial in moderate yields. Based on the interpretation of the key intermediates
by electrospray ionization mass spectrometry, we propose a reaction mechanism involving the initial
conjugate addition of the organic bases to methacrolein to generate a zwitterionic base followed by
the activation of methanol.
Received 15 September 2011
Revised 11 October 2011
Accepted 13 October 2011
Available online 18 October 2011
Keywords:
Dimerization
Ó 2011 Elsevier Ltd. All rights reserved.
Methacrolein
Organocatalysis
N-Heterocyclic carbene
Conjugate addition
Introduction
trast to the amine and phosphine-catalyzed reactions, they pro-
posed a mechanism involving direct deprotonation of alcohol by
Head-to-tail dimers of functionalized olefins can be promising
monomers for stepwise and chain polymerizations. Organic bases
are effective catalysts for the dimerization of activated olefins such
as methyl acrylate and acrylonitrile (Scheme 1).1 However, the
selective dimerization of other reactive substrates has been only
slightly reported because of their potential polymerizability.
Almost half a century ago, patents reported that the conjugate
addition of methanol to methacrolein (MACR) in the presence of
several bases, such as alkali metal hydroxides and ammonium
hydroxides, produced the head-to-tail dimer, 2,4-dimethyl-2-
methoxymethylpentane-1,5-dial (1).2 To our surprise, no attention
has yet been paid to this dimerization, though aliphatic dialdehy-
des, such as glutaraldehyde, are useful reagents.
NHC. Since these organic catalysts act as either a Lewis or a
Brønsted base, the mechanistic aspect has not been systematically
understood and continues to be an important issue that has to be
addressed.
We now report the head-to-tail dimerization of MACR via the
conjugate addition of methanol with the aid of amine, phosphine,
and NHC catalysts (Scheme 3). A reaction mechanism is proposed
on the basis of the interpretation of the reaction intermediates
using electrospray ionization mass spectrometry (ESI-MS).
The hydroalkoxylation of an olefin is an important O–C bond
forming reaction. Toste and co-workers reported the trialkylphos-
phine-catalyzed reactions of enones,3 and Connon and co-workers
reported the amine-catalyzed reactions of acrylates.4 They pro-
posed that the conjugate addition of the organic bases to olefins
generates a zwitterionic intermediate that subsequently undergoes
the deprotonation of an alcohol (Scheme 2). Recently, Scheidt and
co-workers reported that N-heterocyclic carbene (NHC) also serves
as an efficient catalyst for the hydroalkoxylation of enones.5 In con-
Scheme 1. Head-to-tail dimerization of activated olefins (Rauhut–Currier reaction).
⇑
Corresponding author. Tel./fax: +81 52 735 7254.
E-mail address: matsuoka.shinichi@nitech.ac.jp (S. Matsuoka).
Scheme 2. Alcohol activation mechanism for the phosphine and amine-catalyzed
hydroalkoxylation.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.070

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S. Matsuoka et al. / Tetrahedron Letters 52 (2011) 6835–6838
Table 1
Organocatalytic head-to-tail dimerization of MACRa
Entry
Cat. (0.70 mol %)
[Alcohol] /[MACR]
Alcohol
Yield (%)
1
2
3
4
5
6
7
8
2
3
10
10
10
10
10
10
10
1
1
1
1
1
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CD3OD
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
23
28
18
<1
11
40
24
40
32
<1
20
<1
<1
<1
30
PEt3
DABCO
DMAP
DBU
TBD
2
Scheme 3. Head-to-tail dimerization of MACR via conjugate addition of methanol
catalyzed by organic bases (this work).
9
2
3
10
11
12
13
14
15
Results and discussion
PEt3
DABCO
DMAP
DBU
TBD
1
1
1
The dimerization of MACR was examined using a variety of
organic catalysts, 1,3-bis(2,6-diisopropylphenyl)imidazol-2-yli-
dene (2), 1,3,4-triphenyl-4,5-dihydro-1H-1,2,4-triazol-5-ylidene
(3), PEt3, 1,4-diazabicyclo[2.2.2]octane (DABCO), 4-(dimethylamino)
pyridine (DMAP), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), and
1,5,7-triazabicyclo[4.4.0]dec-5-ene (TBD). Two different concen-
trations of methanol were employed; [Alcohol]/[MACR] = 10 and
1. Methanol acted as both the solvent and reactant in the former
case (entries 1–7), and THF was used as the solvent in the latter
case (entries 8–15). The dimer 1 was obtained as a diastereomeric
mixture (Figs. S1, S2, and S8, Supplementary data). Even with a low
catalyst loading (0.70 mol %), moderate yields were observed in
several entries. All the organic bases used, except for DABCO, could
catalyze the dimerization, and the best yield was obtained using
DBU and 2 (entries 6 and 8). When using 3, DMAP, and DBU, an ex-
cess amount of methanol was required to promote the reaction.
Even with the low concentration of methanol, the dimerization
could be catalyzed by 2, Et3P, and TBD with comparable or higher
yields (entries 8, 9, 11 and 15). The reaction with methanol-d4 (en-
try 9) gave 1 with >99% and 78% deuterium incorporations at the
methoxy group and tertiary C4 position, respectively. Given that
the NHCs catalyze a variety of umpolung reactions of aldehydes,6
it is interesting to note that the aldehyde group of MACR remained
unchanged during the present reaction.
a
[MACR] = 2.0 mol/L, for 6 h, in THF (entries 8–15).
Table 2
Hydromethoxylation of activated olefins catalyzed by 2a
Entry
1
Olefin
Product
Yield (%)
41
2
3
—
—
<1
<1
4
5
42
<1
—
The distilled dimer 1 was stable for at least 3 days at 5 °C under
nitrogen. However, the stirring of 1 in air for a few hours caused
the viscosity to increase, and the resulting mixture gave broad 1H
NMR signals. The SEC profile showed that oligomerization oc-
curred. The conversions of the aldehyde evaluated by 1H NMR were
49% for 3 h and 81% for 27 h. Moisture in the air probably initiated
the oligomerization by the nucleophilic reaction to the aldehyde
carbon followed by intramolecular cyclization (Scheme 4). Inter-
estingly, 1 could be recovered from the oligomer by distillation;
heating it at 100 °C for 30 min under reduced pressure (2 mmHg)
afforded 1 in an 88% yield, indicating an equilibrium between 1
and the oligomer. These characteristics are similar to those of
glutaraldehyde.
6
>99
a
For 16 h at rt, [2]/[olefin]/[MeOH] = 1:140:1400, [olefin] = 2.0 mol/L.
dimethyl itaconate, and N-phenyl maleimide. The ring-opened iso-
mers were quantitatively produced from N-phenyl maleimide. The
reactions of methacrylonitrile, methyl acrylate, and crotonalde-
hyde provide neither the hydromethoxylated product nor the di-
mers. Thus, MACR exhibits a unique reactivity for the selective
dimerization.
Recently, high-resolution ESI(+)-MS and tandem MS (MS/MS)
analyses have been used as powerful tools for investigating reac-
tion mechanisms by the analysis of intermediates. For the reac-
tions catalyzed by 1, 2, PEt3, and DBU, the proton adducts of the
key intermediates [Nu+2 MACR+MeOH] (Nu = 1, 2, PEt3, and
DBU) were detected by ESI(+)-MS (Fig. 1a and c, Figs. S3 and S6).
The MS/MS experiment of these ions clearly gives fragment ions
of [Nu+2 MACR+H]+ via the loss of methanol (Fig. 1b and d, Figs.
S4 and S7). As shown in Figure 2, there are two possible structures
for the intermediates, 4 and 5. Their formation is dependent on the
first step of the reaction cycle. 4 can be generated via the activation
of methanol by an organic base, while 5 via the conjugate addition
of the organic base to MACR. Considering fragmentation of the
Encouraged by the selective formation of 1, we examined the
various substrates listed in Table 2. The reactions were carried
out for 16 h under the same conditions as entry 1 in Table 1. The
corresponding dimers were not formed in all the entries, while
hydromethoxylated products were obtained from methyl acrylate,
Scheme 4. Equilibrium between 1 and oligomer.

S. Matsuoka et al. / Tetrahedron Letters 52 (2011) 6835–6838
6837
Figure 3. Proposed mechanism of the head-to-tail dimerization of MACR via the
conjugate addition of methanol.
possess the C–C bond formed between the carbene carbon and
the b-carbon of MACR.
Based on the analysis of the intermediates using ESI-MS, we
propose the mechanism of the dimerizations catalyzed by 2, 3,
Et3P, and DBU in Figure 3. First, the consecutive conjugate addition
of the organic base to two molecules of MACR generates the eno-
late 6, which will be equilibrated with the hemiacetal alkoxide.
The reaction of 6 with methanol gives 5, and the conjugate addi-
tion of methoxide of 5 to two molecules of MACR results in the for-
mation of 7. Due to the equilibrium between 7 and the hemiacetal
alkoxide, 7 was reluctant to undergo a further conjugate addition
to MACR. The reaction of 7 with methanol produces the dimer, 1,
and regenerates 5. This mechanism is similar to the previously
reported phosphine and anime-catalyzed hydroalkoxylations.3,4 It
is known that NHCs serves as a Brønsted8 and Lewis base.7,8a,b,9
We propose that the direct activation of methanol by NHCs is
unlikely in the present reaction. Additionally, NHC can promote
the umpolung of methacrylates via the conjugate addition and
the subsequent proton transfer,7,9d but this is not the case for
MACR.
Figure 1. ESI(+)-MS spectra of the reaction solutions of entry 2 (a) and 3 (c) in Table
1. ESI(+)-MS/MS spectra of the ions of m/z 470.24 (b), and m/z 291.21 (d).
Figure 2. Two possible structures (4, 5) of the intermediate.
Conclusions
We have shown that the head-to-tail dimerization of MACR via
the conjugate addition of methanol is catalyzed by organic bases,
such as DBU, PEt3, NHCs, producing an aliphatic dialdehyde. In
addition, the NHC-catalyzed hydroalkylations of methyl acrylate,
dimethyl itaconate, and N-phenyl maleimide are also reported.
We succeeded in interpreting the key intermediates by ESI-MS,
and thereby propose a catalytic cycle initiated by the conjugate
addition of the organic bases to MACR to generate the zwitterionic
intermediates, followed by the activation of methanol. We expect
that such zwitterions generated in situ are versatile Brønsted bases
for developing new organocatalysis.
Scheme 5. Fragmentation of the adduct of 3 and MMA (3+MMA).
proton adducts of 4 and 5 in the MS/MS spectra, [4+H]+ would
probably produce a fragment ion of [Nu+H]+, while [5+H]+ would
readily lose methanol to give [Nu+2 MACR+H]+. Therefore, it is rea-
sonable to assume that 5 is the key intermediate. This conclusion is
further supported by the fragment peak due to [3+CH]+ in Figure
1b. This fragment is also observed in the MS/MS spectrum of the
adduct of 3 and methyl methacrylate (3+MMA) (Scheme 5).7
Therefore, the key intermediate of the present reaction should
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.10.070.

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S. Matsuoka et al. / Tetrahedron Letters 52 (2011) 6835–6838
8. (a) Enders, D.; Breuer, K.; Raabe, G.; Runsink, J.; Teles, J. H.; Melder, J.-P.; Ebel, K.;
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