Synthesis of hindered functionalized ethers via high-pressure addition of alcohols to acrylic compounds

Article abstract of DOI:10.1016/S0040-4039(01)00872-3

The phosphine-catalyzed 1,4-addition of alcohols to activated alkenes is studied from a synthetic point of view. α- or β-Substituted acrylic compounds react sluggishly or not at all. In this case, high-pressure activation can remove steric inhibition leading to good yields of the corresponding ethers. Reactions involving crotonic compounds (hindered β reaction center) show higher pressure dependence than the corresponding additions of alcohols to methacrylic analogs (free β reaction center). This is in agreement with the concept that sterically demanding reactions show enhanced sensitivity to pressure. The result, obviously, is of high synthetic value as pressure may be capable of removing steric inhibition.

Full text of DOI:10.1016/S0040-4039(01)00872-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 4807–4810
Synthesis of hindered functionalized ethers via high-pressure
addition of alcohols to acrylic compounds
Ge´rard Jenner*
Laboratoire de Pie´zochimie Organique (UMR 7509), Faculte´ de Chimie, Universite´ Louis Pasteur, 67008 Strasbourg, France
Received 21 May 2001
Abstract—The phosphine-catalyzed 1,4-addition of alcohols to activated alkenes is studied from a synthetic point of view. a- or
b-Substituted acrylic compounds react sluggishly or not at all. In this case, high-pressure activation can remove steric inhibition
leading to good yields of the corresponding ethers. Reactions involving crotonic compounds (hindered b reaction center) show
higher pressure dependence than the corresponding additions of alcohols to methacrylic analogs (free b reaction center). This is
in agreement with the concept that sterically demanding reactions show enhanced sensitivity to pressure. The result, obviously, is
of high synthetic value as pressure may be capable of removing steric inhibition. © 2001 Elsevier Science Ltd. All rights reserved.
As part of an ongoing program directed toward evalu-
ating the effects of steric hindrance on high-pressure
reactions,1 we became interested in specific nucleophilic
reactions. The addition of alcohols to activated alkenes
is a well-known reaction.2 Hetero-Michael reactions
involving alcohols occur under mild conditions either
inter-3 or intramolecularly.4 Much emphasis is usually
placed on the 1,4-addition of acrylonitrile with alco-
hols. The process is called cyanoethylation.5 The reac-
tion is an easy and convenient method for the
preparation of a large number of quite interesting multi-
functional compounds. Unfortunately, the reaction
does not tolerate sterically encumbered substrates.
Unlike acrylonitrile, unsaturated nitriles substituted by
alkyl groups on the a or b carbon usually react with
extreme difficulty requiring harsh conditions (strong
base, elevated temperatures, prolonged reaction times)
to give acceptable yields.2 In fact, it fails utterly in most
cases. The paucity of data in this field led us to develop
an interest in these reactions.
ion in the initial stage followed by nucleophilic attack
on the electrophilic b position of the acrylic compound.
This step is rate determining. A rapid proton transfer
yields the final product.
The pressure effect has been considered in related
schemes.6,7 Since the rate-determining step is bimolecu-
lar, SN2 reactions should undergo rate acceleration on
application of pressure, simply via reduction of the
reaction volume. However, it was shown that the effect
of pressure in the process was actually complex. The
transition state is highly dipolar so that solvation
effects must be taken into account. Even the counterion
seemingly plays a specific role. The situation is further
complexed by the possibility of reverse reactions, par-
ticularly in the rate-determining step.8
The synthetic issue of the pressure reaction depends
therefore, on the magnitude of the overall activation
volume. It was shown to amount ca. −20 cm3 mol−1 in
the base-catalyzed Michael addition of nitromethane to
methyl vinyl ketone.8 Based on this value, the pressure
induced speeding up of the rate of these molecular
transformations should contribute to afford fair to
The considered reaction is a Michael-like addition only
occurring in the presence of a base. It is a multistep
process. It involves the formation of the alkoxy carban-
R1
C
base
X
X
R1
R2
RCH2O
CH
RCH2OH +
R3
R3
R2
Keywords: Michael reactions; acrylic compounds; alcohols; phosphines; steric effects; high pressure.
* Tel./fax: (33)03.90.24.16.79; e-mail: jenner@chimie.u-strasbg.fr
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00872-3

4808
G. Jenner / Tetrahedron Letters 42 (2001) 4807–4810
good yields of functionalized ethers. As an illustrative
example, sterically hindered nitroalcohols could be syn-
thesized mainly at high pressures according to Henry
processes which exhibit similar activation volumes.8
throughout. This was done by examining the addition of
linear primary C1–C5 alcohols to cinnamonitrile (R1=H,
R2=Ph, R3=H, X=CN). This acrylic nitrile showed
strong reluctance to enter addition due to the congested
b reaction center (phenyl group) (Table 2).
We, therefore, examined the pressure effect on the
nucleophilic addition of unbranched primary alcohols
to acrylic compounds (nitriles, amides, ketones, methyl
esters). All reactions were carried out neat in the given
primary alcohol in the presence of tri-n-butylphosphine
(the selection of the base will be justified in a forthcom-
ing paper). The results are listed in Table 1 reporting
the yields obtained when ROH is ethanol. Following
comments are in order:
According to Table 2, it is clear that the steric behavior
of the alcohol conditions the yield of cyanoether. The size
of the alkyl rest R is overriding. Only methanol reacts
under ambient pressure. Pressure in excess of 300 MPa
induces an obvious accelerating effect. At 800 MPa
excellent yields are obtained with lower primary alcohols
and fair reactivity is observed with higher alcohols. The
results indicate that the cyanoalkylation with hindered
unsaturated nitriles is a highly pressure dependent reac-
tion.
ꢀ
At ambient pressure steric-free reactions centers are
extremely reactive (entries 1, 6 and 8). However,
acrylamide does not add under conditions due to the
poorly activated amido group (entry 4). Methacrylo-
nitrile (entry 2) and crotononitrile (entry 3) also react
though at a lower rate than acrylonitrile does, despite
the substitution at a and b positions.
In a last step, we tried to support the correlation between
the accelerating effect of pressure and steric congestion
by investigating the respective addition of 1-propanol
and 1-butanol to methacrylonitrile (a substituted reac-
tion center) and crotononitrile (having a b substituted
methyl group). Figs. 1 and 2 diagrammatically represent
the yields. It can be observed that the crotononitrile
reactions (A and C) are more affected by pressure than
the respective methacrylonitrile reactions (B and D).
These results verify our earlier statement that sterically
demanding reactions are subjected to enhanced sensitiv-
ity to pressure.11 The results presented here open the way
to synthetic possibilities which otherwise are not avail-
able by classical routes.
ꢀ
Pressure is unquestionably exerting a positive directive
effect on yields. This is demonstrated in entries 2 and
3. A 300 MPa pressure brings the reactions to comple-
tion or almost. Even acrylamide adds though poorly
(entry 4). The reaction involving mesityl oxide is
precluded at ambient pressure as a result of the
prohibitive bulk of the two gem-b-methyl groups.
However, increasing the pressure to 800 MPa affords
a 35% yield of the corresponding adduct (entry 7).10
Under the same pressure methacrylamide also reacts
leading to a modest 10% yield (entry 5).
Table 2. Addition of linear primary alcohols to cinnamo-
nitrile (conditions as in Table 1; time: 24 h)
Considering these results, an interesting observation can
be made. Reactions involving acrylic compounds with
reduced accessibility at the b reaction center (entries 3,
7, and 10) are clearly more pressure dependent than their
unhindered analogs (entry 4) or even those substituted
at the a-position (entries 2, 5, and 9).
ROH
Yields (%) at various pressures
0.1 MPa
300 MPa
800 MPa
CH3OH
13
0
0
0
0
73
31
10
4
No run
No run
96
C2H5OH
C3H7OH
C4H9OH
C5H11OH
Taking into account this observation, we were moved to
consider in a second stage the influence of the alkyl part
of the alcohol keeping a given acrylic compound
80
0
48
Table 1. Addition of ethanol to acrylic compoundsa
Entry
X
R1
R2
R3
Time (h)
Yields (%) at various pressures
0.1 (MPa)
300 (MPa)
800 (MPa)
1
2
3
4
5
6
7
8
9
CN
CN
CN
CONH2
CONH2
COCH3
COCH3
COOCH3
COOCH3
COOCH3
H
H
H
H
H
H
CH3
H
H
H
H
CH3
H
H
H
CH3
H
H
CH3
H
CH3
H
H
CH3
H
H
H
CH3
H
2
3
3
24
24
99
33
32
0
nr
78
99
5
0
nr
0
nr
19
30
nr
nr
nr
9
10
nr
35
nr
nr
nr
0
b
100
0
24
3
3
53c
5
10
H
3
3
a Acrylic compound (1.8 mmol), tributylphosphine (0.3 mmol), ethanol (0.8 mL), 50°C; nr, no run.
b Instantaneous reaction.
c The dimer of methyl acrylate was also formed resulting from a Morita–Baylis–Hillman reaction.9

G. Jenner / Tetrahedron Letters 42 (2001) 4807–4810
4809
Figure 1. Effect of pressure in the addition of ethanol to crotononitrile (A) and methacrylonitrile (B) (conditions as in Table 1;
reaction time: 4 h).
Figure 2. Effect of pressure in the addition of butanol to crotononitrile (C) and methacrylonitrile (D) (conditions as in Table 1;
reaction time: 4 h).
reactions,1,11,12 pressure is a powerful way to overcome
the lethargy of reaction centers frozen by steric require-
ments. This interesting facet of piezochemistry will be
developed in a forthcoming full paper.
Conclusions
In the tri-n-butylphosphine-catalyzed addition of pri-
mary alcohols to hindered unsaturated acrylic com-
pounds, the salient features are:
ꢀ
the beneficial though variable effect of pressure in
the synthesis of sterically hindered functionalized
ethers
References
1. Jenner, G. Tetrahedron Lett. 2001, 42, 243–245.
2. Burson, H. A. Org. React. 1949, 5, 89–123.
ꢀ
the remarkable capacity of the pressure parameter to
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T.; Simpson, G. W. J. Chem. Soc., Perkin Trans. 1 1996,
remove steric inhibition
In conclusion, in harmony with our earlier studies
related to the pressure effect in sterically congested

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G. Jenner / Tetrahedron Letters 42 (2001) 4807–4810
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