Trimethylphosphine-Promoted Alcoholysis of α,β-Unsaturated Imides and α,β-Unsaturated Esters

Article abstract of DOI:10.1055/s-0036-1589162

α,β-Unsaturated imides and α,β-unsaturated esters were found to undergo alcoholysis in the presence of trimethylphosphine. The reaction is initiated by nucleophilic addition of trimethylphosphine to the double bond of the α,β-unsaturated carbonyl compound. Saturated imides also undergo the alcoholysis in the presence of the corresponding α,β-unsaturated imide.

Full text of DOI:10.1055/s-0036-1589162

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SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2018, 50, A–G
paper
A
en
H. Sato, S. Hosokawa
Paper
Synthesis
Trimethylphosphine-Promoted Alcoholysis of α,β-Unsaturated
Imides and α,β-Unsaturated Esters
Ph
Haruka Sato
Ph
Me3P
Seijiro Hosokawa*
N
O
OR
R–OH
r.t.
O
O
O
Department of Applied Chemistry, Faculty of Science and
Engineering, Waseda University, 3-4-1 Ohkubo, Shinjuku-ku,
Tokyo 169-8555, Japan
up to 97% yield
Ph
Me3P
X
seijiro@waseda.jp
O
Me3P
OR
OR'
R'–OH
r.t.
O
O
up to 95% yield
Received: 10.11.2017
Accepted after revision: 06.12.2017
Published online: 16.01.2018
At first, trialkylphosphines and bases were examined to
promote methanolysis of α,β-unsaturated imide 3 (Table
1).7 The reaction using 1.0 equivalent of Me3P was complete
within 5 minutes to give methyl ester 4a and oxazolidone 5
in high yield (entry 1). When a catalytic amount (0.2 equiv)
of Me3P was employed, the reaction was completed within
3 hours to give 4a and 5 in high yield (entry 2). n-Bu3P also
promoted the reaction, but the yield of 4a decreased (entry
3). On the other hand, tricyclohexylphosphine and triphenyl-
phosphine did not promote methanolysis (entries 4 and 5).
The reaction in the presence of triethylamine proceeded
DOI: 10.1055/s-0036-1589162; Art ID: ss-2017-f0726-op
Abstract α,β-Unsaturated imides and α,β-unsaturated esters were
found to undergo alcoholysis in the presence of trimethylphosphine.
The reaction is initiated by nucleophilic addition of trimethylphosphine
to the double bond of the α,β-unsaturated carbonyl compound. Satu-
rated imides also undergo the alcoholysis in the presence of the corre-
sponding α,β-unsaturated imide.
Key words trimethylphosphine, conjugate addition, alcoholysis,
transesterification, unsaturated imides, unsaturated esters
Table 1 Methanolysis of Imide 3a
Trialkylphosphines have been used as nucleophiles in
conjugate addition reactions to alkynyl esters,1 alkenyl
esters,2 and alkenyl ketones.3 The conjugate addition of tri-
alkyl-or triarylphosphine to α,β-unsaturated carbonyl com-
pounds has also been used in [2+3] cycloaddition reactions4
and isomerization.5 During the course of our synthetic
studies on polyacetate compounds, we found that trimeth-
ylphosphine (Me3P) promoted the methanolysis of α,β-un-
saturated imide 1 (Scheme 1).6 The starting material 1 dis-
appeared within five minutes and α,β-unsaturated ester 2
was obtained in moderate yield, while methanolysis using
sodium methoxide took two hours to consume the starting
material. Interested in the accelerated reaction, we investi-
gated the solvolysis reaction using trialkylphosphines.
Ph
O
Ph
O
Ph
additive
Ph
N
OMe
HN
+
MeOH
r.t.
O
O
O
O
3
4a
5
Entry
Additive
Time
Yield (%)
4a
5
1
2
3
4
5
6
7
8
Me3P
Me3Pb
n-Bu3P
Cy3P
5 min
87
88
78
0
98
99
95
0
3 h
5 min
24 h
Ph3P
24 h
0
0
Ph
Ph
Et3N
20 h
89
93
72
98
85
79
Me3P
NaOMe
K2CO3
20 min
10 min
N
O
OMe
MeOH
r.t., 5 min
57%
TBDPSO
O
O
TBDPSO
O
1
2
a Reagents and conditions: 3 (1.0 equiv), MeOH, additive (1.0 equiv), r.t.
b Me3P (0.2 equiv) was employed.
cf. NaOMe in MeOH, r.t., 2 h, 60%
Scheme 1 Alcoholysis of imide 1
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B
H. Sato, S. Hosokawa
Paper
Synthesis
slowly (entry 6), while NaOMe and K2CO3 reacted with 3 in
20 and 10 minutes, respectively (entries 7 and 8). Interest-
ingly, the reaction using Me3P was completed faster than
those with bases.
Next, the solvolysis reaction with other alcohols was ex-
amined (Table 2). Ethanol also converted 3 into α,β-unsatu-
rated ester 4b in excellent yield (entry 2). Isopropyl alcohol
gave the corresponding ester 4c in good yield after an ex-
tended time (entry 3). However, tert-butyl alcohol did not
promote the solvolysis at all (entry 4).
Alcoholysis with other alcohols in CH2Cl2 is shown in
Table 4. Primary alcohols including allyl alcohol, geranyl
alcohol, and benzyl alcohol reacted with 3 to give esters
4e–g in good to excellent yields (entries 1–3), while men-
thol did not react at all (entry 4).
a
Table 4 Alcoholysis with Other Alcohols in CH2Cl2
Ph
Ph
ROH
Me3P
N
O
OR
CH2Cl2
r.t.
Table 2 Alcoholysis of α,β-Unsaturated Imide 3a
O
O
O
3
4
Ph
Ph
Entry
ROH
allyl alcohol
Time
4
Yield (%)
Me3P
N
O
OR
1
2
3
4
2 h
15 h
3 h
4e
4f
97
86
96
0
ROH
r.t.
O
O
O
geranyl alcohol
benzyl alcohol
menthol
3
4
4g
4h
Entry
R
Time
5 min
4
Yield (%)
24 h
a Reagents and conditions: 3 (1.0 equiv), ROH (2.0 equiv), Me3P (1.0 equiv),
CH2Cl2, r.t.
1
2
3
4
Me
Et
4a
4b
4c
4d
87
95
79
0
10 min
3 h
i-Pr
Moreover, saturated ester 6 did not undergo methanoly-
sis in the presence of Me3P (Scheme 2). Addition of a cata-
lytic amount of unsaturated imide 3 to the mixture promot-
ed methanolysis of 6. This reaction proceeded slowly to
complete within ten hours, while the alcoholysis of 3 fin-
ished within five minutes. These results indicate that the
reaction proceeds via the conjugate addition of Me3P to the
unsaturated imide to produce the methoxide anion, and the
resulting α,β-unsaturated ester also generates the methoxide
anion under these conditions.
t-Bu
24 h
a Reagents and conditions: 3 (1.0 equiv), ROH, Me3P (1.0 equiv), r.t.
The solvent effect of the transformation is shown in Ta-
ble 3. In nonpolar solvents including toluene and CH2Cl2
(entries 1 and 2), the reaction proceeded smoothly, while
other solvents required prolonged time (entries 3–6).
Therefore, CH2Cl2 was employed for further alcoholysis re-
actions.
Table 3 Solvent Effect on the Alcoholysisa
Ph
Ph
Me3P
N
O
no reaction
Ph
Ph
MeOH
r.t.
MeOH
Me3P
O
O
6
N
O
OMe
Ph
solvent
r.t.
Ph
O
O
O
3
4a
N
O
(0.1 equiv)
Ph
O
O
O
Entry
Solvent
Time (h)
Yield of 4a (%)
Ph
3
Me3P
N
OMe
1
2
3
4
5
6
toluene
CH2Cl2
Et2O
1.5
1.5
95
99
85
72
64
89
MeOH
r.t., 10 h
93%
O
O
O
6
7
48
Scheme 2 Reaction of saturated imide 6
THF
48
24
24
DMSO
DMF
On the basis of the results of the reactions in Scheme 2,
transesterification of α,β-unsaturated esters with Me3P was
examined (Table 5). Methyl ester 4a was converted into ethyl
ester 4b in ethanol in high yield (entry 1), although the re-
action proceeded slower than the ethanolysis of α,β-unsat-
urated imide 3. When dichloromethane was employed as
a Reagents and conditions: 3 (1.0 equiv), MeOH (2.0 equiv), Me3P (1.0
equiv), solvent, r.t.
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H. Sato, S. Hosokawa
Paper
Synthesis
solvent, the reaction proceeded slower and afforded 4b in
moderate yield (entry 2). The reaction with isopropanol
also gave isopropyl ester 4c in moderate yield (entry 3), but
transesterification with tert-butyl alcohol did not proceed
(entry 4). Isopropyl ester 4c underwent transesterification
with ethanol to give 4b in high yield (entry 5). Therefore,
the transesterification reactions with the primary alcohols
and the secondary alcohol proceeded in the presence of
trimethylphosphine. This is the first report on the trans-
esterification promoted by trialkylphosphine.8
D
OCD3
N
Ph
Ph
O
OCD3
Ph
Ph
D
Me3P
Ph
N
O
Ph
3
CD3OD
r.t.
Me3P
O
O
Me3P
O
O
9
10
OCD3
D
D
OCD3
D
H
Ph
OCD3
Ph
OCD3
Me3P
O
Me3P
O
11
12
Table 5 Transesterification of α,β-Unsaturated Estersa
OCD3
D
D
H
R2OH
Me3P
Ph
OCD3
8
OR1
OR2
Me3P
O
13
r.t.
O
O
4a or 4c
4b–d
Scheme 4 Reaction mechanism of solvolysis in CD3OD
Entry
R1
R2
Time (h)
Product 4
Yield (%)
Additionally, competition reactions of 1:1 mixtures of
α,β-unsaturated imide 3 and saturated imide 6 in the pres-
ence of either MeONa or Me3P were studied by 1H NMR
spectroscopy (Figures 1 and 2). When NaOMe (0.2 equiv) in
MeOH was used (Figure 1), saturated imide 6 was almost
consumed within one minute, while unsaturated imide 3
remained. On the other hand, under the conditions includ-
ing Me3P and MeOH (Figure 2), α,β-unsaturated ester 4a
was generated much faster than saturated ester 7. These re-
sults indicate that the solvolysis of 6 with NaOMe as cata-
lyst is faster than that of 3, while the solvolysis of 3 in the
presence of Me3P is faster than that of 6. Therefore, the sol-
volysis with Me3P is promoted via intermediate 14, in
which the phosphonium ion activates the carbonyl group
(Scheme 5).
1
Me (4a)
Me (4a)
Me (4a)
Me (4a)
i-Pr (4c)
Et
12
48
24
48
17
4b
4b
4c
4d
4b
95
50c
41e
0
2b
3d
4
Et
i-Pr
t-Bu
Et
5
89
a Reagents and conditions: 4a or 4c (1.0 equiv), R2OH, Me3P (1.0 equiv), r.t.
b EtOH (2.0 equiv) in CH2Cl2 was employed.
c Starting material 4a (50%) was recovered.
d Reflux with Bu3P (1.0 equiv).
e Starting material 4a (59%) was recovered.
To investigate the reaction mechanism of the Me3P-
mediated solvolysis, α,β-unsaturated imide 3 was treated
with CD3OD in the presence of Me3P (Scheme 3).9 The reac-
tion proceeded to give 8, of which the α and β positons
were deuterated. This transformation is rationalized as
shown in Scheme 4. The conjugate addition of Me3P to α,β-
unsaturated imide 3 generated zwitterion 9, which ab-
stracted deuterium from CD3OD to afford α-deuterated
10.10 The nucleophilic attack of deuterio-methoxide on the
carbonyl group of imide 10 afforded ester 11. Deuterio-me-
thoxide also extracted the β-proton to give ylide 12, which
removed deuterium from CD3OD to yield β-deuterated 13.
An elimination reaction of 13 gave deuterio-α,β-unsaturat-
ed ester 8 and re-generated Me3P.
Ph
Ph
D
Me3P
N
O
OCD3
CD3OD
r.t., 10 min
O
O
D
O
3
8
Figure 1 1H NMR spectra showing the reactions of a 1:1 mixture of 3
and 6 with NaOMe in MeOH; left column: the methylene protons of the
oxazolidinone groups of 3 and 6; right column: the methoxy signals of
products 4a and 7
Scheme 3 Reaction of α,β-unsaturated imide 3 in CD3OD
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D
H. Sato, S. Hosokawa
Paper
Synthesis
the phosphonium ion of the intermediate activated the car-
bonyl group of imides. Me3P also promoted the transesteri-
fication of α,β–unsaturated esters. Additionally, the reac-
tion was also applied to produce a lactone from (E)-δ-
hydroxy-α,β-unsaturated imide. The Me3P-promoted alco-
holysis is a new type of solvolysis and exhibits features dif-
ferent from those of base-induced alcoholysis.
1H (400 MHz) and 13C (100 MHz) NMR spectra were recorded at with
JEOL ECS-400 instruments. Chemical shifts (δ, ppm) are referenced to
the residual solvent peak (CDCl3: δ = 7.26 for 1H, δ = 77.0 for 13C).
Melting points were determined on a Yanaco MP-S3 instrument. FT-
IR spectra were recorded on a ThermoFisher SCIENTIFIC NICOLET
6700 FT-IR. HRMS and MS were carried out with a ThermoFisher EX-
ACTIVE PLUS and JEOL JMS-GCMATEII, respectively. Optical rotations
were measured with a JASCO P-2200. All reactions were monitored by
TLC (silica gel 60 F254, Merck). THF was distilled from LAH before use.
CH2Cl2 was distilled from P2O5 before use.
Figure 2 1H NMR spectra showing the reactions of a 1:1 mixture of 3
and 6 with Me3P and MeOH; left column: the methylene protons of the
oxazolidinone groups of 3 and 6; right column: the methoxy signals of
products 4a and 7
Methyl Ester 2
Methanolysis of 1 by using sodium methoxide: To a solution of α,β-un-
saturated imide 1 (29.7 mg, 0.0432 mmol) in MeOH (0.7 mL) was
slowly added NaOMe (28% in MeOH, 6.0 μL, 0.0432 mmol, 1.0 equiv)
at r.t. After stirring for 2 h, the reaction mixture was quenched with
sat. aq NH4Cl (0.7 mL). The resulting mixture was concentrated under
reduced pressure to remove MeOH. The mixture was extracted with
CH2Cl2 (3 × 0.3 mL). The combined organic layer was dried over
Na2SO4 and concentrated under reduced pressure. The residue was
purified by column chromatography (silica gel, n-hexane–EtOAc,
10:1) to give ester 2 as a colorless oil.
Ph
Ph
Me3P
Ph
N
O
3
4
R–OH
Me3P
O
O
14
Scheme 5 The reaction mechanism of the solvolysis of imide 3 with
Me3P
Yield: 11.4 mg (0.0260 mmol, 60%); Rf = 0.64 (n-hexane–EtOAc, 8:1);
[α]D25 –10.4 (c 1.04, MeOH).
Finally, this reaction was applied to lactonization
(Scheme 6).11 δ-Hydroxy-α,β-unsaturated imide 15, ob-
tained by de-O-silylation of 1, underwent sequential Mi-
chael addition, lactonization, and elimination to give (S)-
massoilactone (16), the enantiomer of the allomone of for-
micine ants of the genusCamponotus.12,13
IR (ATR): 2930, 2857, 1725, 1658, 1427, 1269, 1167, 1105, 1042, 821,
739, 700 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.69–7.62 (m, 4 H), 7.46–7.33 (m, 6 H),
6.90 (dt, J = 16.0, 8.0 Hz, 1 H), 5.72 (dt, J = 16.0, 1.0 Hz, 1 H), 3.81 (tt,
J = 6.0, 6.0 Hz, 1 H), 3.71 (s, 3 H), 2.38–2.21 (m, 2 H), 1.45–1.37 (m, 2
H), 1.25–1.06 (m, 6 H), 1.05 (s, 9 H), 0.81 (t, J = 7.0 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 166.8, 146.0, 135.9, 135.9, 134.1,
129.6, 127.5, 122.9, 72.1, 51.4, 39.3, 36.4, 31.7, 27.0, 24.5, 22.5, 19.3,
14.0.
Ph
Ph
Me3P
N
O
O
CH2Cl2
r.t., 15 min
78%
HRMS (ESI): m/z [M + Na]+ calcd for C27H38O3Na: 461.2482; found:
461.2482.
RO
O
O
O
16
HF•Py
MeCN
60 °C, 6 h
95%
1 R = TBDPS
15 R = H
Methanolysis of 1 by using trimethylphosphine: To a solution of α,β-
unsaturated imide 1 (30.0 mg, 0.0433 mmol) in MeOH (0.7 mL) was
added 1.0 M Me3P in toluene (43.0 μL, 0.0433mmol, 1.0 equiv) slowly
at r.t. The resulting mixture was concentrated under reduced pressure
to remove MeOH and Me3P. The residue was purified by column chro-
matography (silica gel, n-hexane –EtOAc, 10:1) to give ester 2 as a col-
orless oil.
Scheme 6 Lactonization of an (E)-α,β-unsaturated ester
In conclusion, the Me3P-promoted alcoholysis reactions
of α,β-unsaturated imides and α,β-unsaturated esters were
investigated. α,β-Unsaturated imides underwent solvolysis
smoothly with primary alcohols. The reactions proceeded
via the conjugate addition of Me3P to α,β-unsaturated imid-
es and α,β-unsaturated esters to generate alkoxides. Satu-
rated imide 6 underwent alcoholysis in the presence of α,β-
unsaturated imide 3. The competition experiments with
unsaturated imide 3 and saturated imide 6 confirmed that
Yield: 10.4 mg (0.0246 mmol, 57%).
Cinnamoyloxazolidinone 3
To a solution of 5,5-diphenyl-2-oxazolidinone (3.25 g, 13.6 mmol) in
THF (65.0 mL) was added 2.66 M n-BuLi in n-hexane (5.62 mL, 14.9
mmol, 1.1 equiv) at –78 °C. (The color of the solution changed to yel-
low). After stirring of the mixture for 30 min, cinnamoyl chloride
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2018, 50, A–G