Tandem and One-Pot Hydroformylation/Michael Reactions of Acrylates

Article abstract of DOI:10.1055/s-0036-1588394

The combination of various reactions in one operational step leads to many advantages in synthetic strategies, such as a lower consumption of resources, effort, and time, when intermittent workup and purification steps can be avoided. The hydroformylation reaction of acrylates gives access to 2-formylpropanoates, which thanks to their structural features constitute useful intermediates in the synthesis of more complex compounds. Herein, we report a simple and convenient one-pot strategy to synthesize functionalized carbonyl compounds starting from these readily available substrates, via tandem or one-pot hydroformylation, Michael addition, and aldol reactions.

Full text of DOI:10.1055/s-0036-1588394

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2017, 49, A–H
A
paper
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
Tandem and One-Pot Hydroformylation/Michael Reactions of
Acrylates
Samuel Quintero-Duque
Ivana Fleischer*
base
O
O
O
O
O
CO/H2
cat.
R1
R1
R1
O
EWG
O
H
O
H
Institute of Organic Chemistry, University of Regensburg,
Universitätsstraße 31, 93040 Regensburg, Germany
ivana.fleischer@chemie.uni-regensburg.de
R2
R2
EWG
R2
•
tandem (5 examples) or one-pot reaction (16 examples) • R1 = alkyl
• yields up to 91%
2
R
= H, alkyl
In memory of Professor Marta Sališová, who dedicated her
life to raise and motivate young scientists
Received: 11.11.2016
Accepted after revision: 21.12.2016
Published online: 10.01.2017
2006–2007, Clarke and Roff reported a significant improve-
ment of the branched selectivity by using a monodentate
DOI: 10.1055/s-0036-1588394; Art ID: ss-2016-z0792-op
cage phosphine ligand and a rhodium catalyst precursor
under mild conditions.3
i,m
The catalyst system operated
Abstract The combination of various reactions in one operational step
leads to many advantages in synthetic strategies, such as a lower con-
sumption of resources, effort, and time, when intermittent workup and
purification steps can be avoided. The hydroformylation reaction of ac-
rylates gives access to 2-formylpropanoates, which thanks to their
structural features constitute useful intermediates in the synthesis of
more complex compounds. Herein, we report a simple and convenient
one-pot strategy to synthesize functionalized carbonyl compounds
starting from these readily available substrates, via tandem or one-pot
hydroformylation, Michael addition, and aldol reactions.
with a high turnover frequency (TOF) and notably, the chal-
lenging 1,1-disubstituted unsaturated esters were function-
alized in the α-position.
With the aim to demonstrate the synthetic utility of the
hydroformylation of unsaturated esters, we decided to ex-
plore the possibility of combining this transformation with
a follow up step either in tandem or one-pot fashion by
profiting from the acidity of the 1,3-dicarbonyl product 2
and employing it as a Michael donor in addition reactions
with different types of electron-poor olefins (Scheme 1).
This reaction sequence would provide compounds with
three different functional groups and a quaternary carbon
Key words hydroformylation, acrylates, rhodium, one pot, tandem,
Michael addition
5
Hydroformylation reactions represent a valuable strate-
gy for obtaining industrially relevant linear aldehydes, such
as butanal and other precursors for plasticizers, which are
atom and extend the scope of tandem and one-pot hydro-
formylation reactions.6
Before the investigation of the tandem reaction, we test-
ed several known ligands in the hydroformylation of methyl
1
currently produced in large-scale processes. Nevertheless,
the potential of the branched products has not been exten-
sively exploited in large-scale applications, even though
there are known examples of substrates that are useful for
the development of fine chemicals and pharmaceutical
products which could be obtained at lower costs if hydro-
formylation processes were employed in the synthetic
acrylate under mild reaction conditions (50 °C, CO/H , 1:1,
2
20 bar) in order to assess their general reactivity and selec-
tivity (Table 1).3 The commercially available complex
m
Rh(CO) (acac) was employed as catalyst precursor due to its
2
well-known performance in hydroformylation applica-
7
tions. The tested bidentate ligands L1–L3 led to good to ex-
2
strategy.
cellent conversion of ester 1a, however with different che-
moselectivity (Table 1, entries 1–4). It is noteworthy that
the NMR signals corresponding to methyl 4-oxobutanoate,
the linear hydroformylation product of methyl acrylate,
were not detected, and only considerable amounts of the
hydrogenation product 5 (methyl propionate) were ob-
served when ligands L3–L5, including the self-assembling
One family of substrates amenable to hydroformylation
reactions are the α,β-unsaturated esters, which can give ac-
cess to α- or β-functionalized products that can be used as
building blocks for the synthesis of more complex struc-
tures by selectively reacting each of the functionalities of
3
the core molecule. Usually, the carbonylation occurs on the
8
α-carbon atom providing the branched 1,3-dicarbonyl com-
system L4 (Table 1, entries 4–6) were used as ligands. Re-
pounds, whereas an additional substituent in this position
guides the reaction to the β-carbon atom in most cases. In
markably, by using L1 in THF (Table 1, entry 1) a significant
4
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

B
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
Hydroformylation of acrylates:
O
O
Table 1 Screening of Ligands for the Hydroformylation Reaction of
R2
Methyl Acrylatea
H
O
O
2
3
CO/H2
Rh], ligand
R1
O
O
Rh(acac)(CO)2
ligand
O
O
OH
O
R3
R2
[
O
and/or
O
O
CO/H2 (1:1, 20 bar)
solvent, 50 °C, 18 h
R1
1
O
1a
2a
enol-2a
R3
R2
O
H
O
O
O
R1
+
+
O
O
O
O
O
O
4a
5
Our work:
O
O
Ligands
R2
CO/H2
[Rh], ligand
R2
O
H
O
Ph2P
PPh2
PPh2 PPh2
R1
R1
O
1
2
PPh2
PPh2
L1 (dppb)
L2 (Xantphos)
L3 (dppp)
O
O
R3
R2
base,
EWG
Ph
P
H
R
O
1
PPh3
O
R3
EWG
tandem or one-pot
Ph2P
N
O
O
H
O
L4 (6-DPPon)
L5
L6 (MeCgPPh)
Scheme 1 Hydroformylation of acrylates and its planned utilization in
tandem or one-pot reactions
b
Entry
Ligand (mol%)
Yield (%)
2
a
4a
14
5
amount of the aldehyde signal corresponding to the tandem
Michael addition product 4a was obtained in the absence of
the base. This product was not observed when CH Cl was
1
2
3
4
5
6
7
L1 (0.6)
55
99
99
70
10
9
0
0
L1 (0.6)c
0
0
0
0
1
0
0
2
2
L2 (0.6)
L3 (0.6)
L4 (1.2)
L5 (1.2)
L6 (1.2)
L6 (0.6)d
0
used as the solvent (Table 1, entry 2).
In the reaction with the well-established Xantphos3
d,h
29
24
5
(
L2, Table 1, entry 3) the only product that could be identi-
1
fied in the crude H NMR spectrum was the desired
branched aldehyde 2a and its enol form. Using the
monodentate Clarke’s phosphine L6 as the ligand, a full
conversion was observed, but the hydroformylation was ac-
companied by hydrogenation (Table 1, entry 7). By chang-
ing the solvent to CH Cl , only 0.6 mol% of ligand L6 was
3i
85
99
14
0
3m
8
a
Reaction conditions: methyl acrylate (86 mg, 89 μL, 1.0 mmol),
(acac) (0.5 mg, 0.002 mmol, 0.2 mol%), ligand, THF (1 mL), CO/H
2
Rh(CO)
2
(1:1, 20 bar), 50 °C, 18 h.
2
2
b
c
1
Determined by H NMR.
necessary to achieve full conversion into the desired prod-
uct (Table 1, entry 8).
Reaction performed in CH
2
Cl
Cl
2
(1 mL).
(1 mL) at 40 °C.
d
Reaction performed in CH
2
2
With these results in hand, we could proceed towards
the development of a tandem reaction, where the acrylate
would act as substrate for both reaction steps: the hydro-
formylation and as Michael acceptor (Scheme 2). This reac-
tion was already observed in the evaluation of the hydro-
O
O
O
CO/H2
Rh], L1
[
O
H
O
5
0% conv.
1
a
2a
O
O
formylation of methyl acrylate using ligand L1 in THF (Table
O
O
base
9
1
, entry 1) and also reported in the literature. However, a
O
4
a
systematic study was not conducted. The requirement for
such a reaction sequence is that the first step is slower and
the produced aldehyde can react with the remaining start-
ing material sharing the same time frame of the overall re-
action. Therefore, we chose to employ the moderately ac-
tive catalyst system using L1 to optimize the tandem hydro-
formylation–Michael addition reaction of methyl acrylate.
After screening various bases to optimize this reaction
Scheme 2 The envisioned tandem reaction of methyl acrylate
the standard procedure of hydroformylation described in
Table 1 was performed using acrylate 1a (Table 2, entry 1).
1
H NMR analysis of the crude reaction mixture revealed
the full conversion of the branched aldehyde-enol into the
expected Michael addition product, and only small traces of
methyl acrylate (~1%) were detected. The product was read-
ily purified by column chromatography obtaining 72% of 4a.
(see the Supporting Information), a catalytic amount of
K CO (15 mol%) was introduced to the reaction mixture and
2
3
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

C
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
Table 2 Screening of Acrylates for the Proposed Tandem Reactiona
Table 3 Reaction Scope of the One-Pot Hydroformylation–Michael
Addition Reactiona
O
O
O
Rh(acac)(CO)2
L1, CO/H2 (1:1)
R1
R1
R1
1) Rh(acac)(CO)2
L6, CO/H2 (1:1)
O
O
R2
O
K2CO3, THF
O
O
O
CH Cl , 40 °C, 5 h
O
50 °C, 18 h
R1
2
2
R1
R2
R2
O
O
R3
2)
3, K CO
R2
R
2
3
1
4
R2
40 °C, 4–6 h
1
6–16
R1
R2
Product
Yield (%)
b
Entry
R1
Me
R2
R3
Time (h) Product Yield (%)
b
Entry
1
Me
H
4a
4b
4c
4d
4e
–
72c
78
53
64
40
0
1
H
Ac
Ac
Ac
Ac
CO
CO
CO
Ac
CN
4
6
4
6
6
6
6
6
4
4
4
6
7
70
89
85
85
51
52
30
2
i-Bu
t-Bu
Bn
H
2
t-Bu
H
3d
4d
5d
H
3
Bn
H
8
H
4
(CH
Me
Me
Bn
2
)
2
OPh
H
9
(CH
2
)
2
OPh
H
5c
6c
7c
8c
9
Me
Me
Me
Me
H
Me
Bn
10
11
12
13
14
15
16
2
2
2
6d
Me
Me
a
Reaction conditions: acrylate (1.0 mmol), Rh(CO)
2
(acac) (0.5 mg, 0.002
CO (20
2
(1:1, 20 bar), 50 °C, 18 h.
mmol, 0.2 mol%), dppb (L1, 2.5 mg, 0.006 mmol, 0.6 mol%), K
2
3
Me
mg, 0.15 mmol, 15 mol%), THF (1 mL), CO/H
b
Me
Bn
81
Isolated yield.
c
68% at 10-mmol scale.
91d
d
2
CO/H (1:1, 30 bar).
10
Bn
H
SO
2
Ph
76
57
11
Me
H
CONHBn
The transformation was also performed on a 10-mmol scale
providing 68% yield of 4a. This reaction was reproduced by
using other acrylates. A good yield of product 4b was ob-
tained starting from isobutyl ester (Table 2, entry 2). Some
a
Hydroformylation conditions: acrylate (1 mmol), Rh(CO)
2
(acac) (0.5 mg,
0.002 mmol, 0.2 mol%), MeCgPPh (L6, 1.8 mg, 0.006 mmol, 0.6 mol%),
CH Cl (1 mL), CO/H (1:1, 30 bar), 40 °C, 5 h. Michael addition conditions:
CO (20 mg, 0.15 mmol, 15 mol%), 4–6 h.
Isolated yield.
2
2
2
K
2
3
b
c
Hydroformylation step performed during 3 d.
of the acrylates required a higher pressure of CO/H gas (30
2
d
85% on a 10-mmol scale.
bar) to obtain a full conversion of the corresponding acry-
lates and moderate to good yields (Table 2, entries 3–5).
Nevertheless, in the case of methyl crotonate (1f, Table 2,
entry 6) only 30% of the corresponding aldehyde product
was observed, and no Michael addition product was detect-
ed. On the other hand, employing ethyl cinnamate did not
lead to any reaction and only the starting material was de-
tected. This demonstrates the dependency of the reaction
on the steric bulk of the double bond for both hydroformy-
lation and Michael addition steps.
Encouraged by these results, we decided to perform a
crossed tandem reaction using two different starting mate-
rials, where one of them should be unreactive in the hydro-
formylation reaction while playing the role of the Michael
acceptor. Thus, we chose methyl acrylate and methyl vinyl
ketone as model substrates and followed the protocol for
the tandem reaction. However, a complex product mixture
was obtained and a thorough optimization did not solve the
problem. Among the products, the hydrogenation product
of the ketone was detected. In addition, deactivation of the
hydroformylation catalyst was observed in some cases. This
set of inconveniences led us to the decision to perform the
reaction sequence in a one-pot strategy rather than using
the tandem approach (Table 3).
In our case, this means that the Michael acceptor and the
base are added to the hydroformylation mixture after com-
pletion and gas release. We chose to carry out the hydro-
formylation step in dichloromethane using ligand L6, based
on the initial results for the fast and mild hydroformylation
conditions for methyl acrylate to obtain selectively the
branched aldehyde (Table 1, entry 8). This method proved
to be very effective combined with the Michael addition re-
action between different acrylates and olefins bearing di-
verse functional groups such as sulfones, nitriles, amides,
ketones, and even differently substituted esters. Thus, using
methyl vinyl ketone as the Michael acceptor, different acryl-
ates were converted into the desired products 6–9 in good
yields (Table 3, entries 1–4). With this method, harsher
conditions for the hydroformylation of demanding methyl
and benzyl crotonate could be employed to obtain selec-
tively the branched aldehyde products with high conver-
sions according to 1H NMR (95% and 65%, respectively),
which allowed them to be employed as substrates in the
Michael addition with other esters furnishing products 10–
13 containing two different ester moieties (Table 3, entries
5–8). Finally, various Michael acceptors were successfully
applied in the reaction with methyl or benzyl acrylate (Ta-
ble 3, entries 9–11).
One-pot processes also have the advantages of tandem
reactions, such as the reduction of the number of purifica-
tion steps and performance of the steps in the same vessel.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

D
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
In addition, we have observed follow up aldol reaction
upon longer reaction times when using unsaturated ke-
tones as Michael acceptors, albeit the products were isolat-
ed in lower yields (Table 4, entries 1–3).
tion to the unsaturated ketone. Upon longer reaction time,
an intramolecular aldol reaction of 6 to give 17 occurs, if
K CO is used as the base. Alternatively, the aldol condensa-
2
3
tion product 20 is obtained using TBD as the base.
O
O
O
O
Table 4 Reaction Scope of the One-Pot Hydroformylation–Michael
Addition–Aldol Reaction
CO/H2
[Rh], L6
a
O
H
O
full conv.
base
1a
2a
1
) Rh(acac)(CO)2
L6, CO/H2 (1:1)
CH2Cl2, 40 °C, 5 h
O
O
R2
R1
OH
O
O
O
O
2
)
O
base
K2CO3
40 °C, 6–72 h
HO
R1
R3
O
O
O
R2
O
17–21
O
O
17
6
R3
main product
with K2CO3, 72 h
main product
with K2CO3, 4 h
1
Entry R1
R2
R3
Product
Yield (%)
b
base
hydroformylation
Michael addition
aldol reaction
elimination
OH
O
1
2
Me
Me
H
17
O
30
O
O
O
O
O
O
O
20
main product
with TBD, 6 h
Me
Me
Me
(CH
2
)
3
2
18
19
20
21
O
O
22
15
23
OH
Scheme 3 The simplified mechanism of the one-pot hydroformyla-
tion/Michael addition/aldol reaction
3
(CH
Me
Me
2
)
In conclusion, we have developed a strategy to combine
the hydroformylation of unsaturated esters with Michael
reaction in tandem or one-pot fashion. The reaction fur-
nishes functionalized compounds with a quaternary carbon
atom. First, we investigated a tandem reaction using acryl-
ates as substrates for both the hydroformylation and
Michael addition steps. The methodology was extended to a
one-pot reaction using a different Michael acceptor.
O
OH
O
4c
H
H
O
O
O
O
O
5c
t-Bu
34
a
All commercially available chemicals were used as provided by the
suppliers (TCI, Sigma-Aldrich or abcr) without further purification.
Hydroformylation reactions were carried out in a 4-mL glass vial
which was placed inside a 300-mL high pressure reactor (Parr). Sol-
vents for column chromatography were technical grade and distilled
prior to use. Analytical TLC was performed on Macherey-Nagel silica
gel 60 aluminum plates with F-254 fluorescence marker, visualized
by UV irradiation or by dipping the developed plates in pre-made
Hydroformylation conditions: acrylate (1 mmol), Rh(CO)
2
(acac) (0.5 mg,
0
.002 mmol, 0.2 mol%), MeCgPPh (L6, 1.8 mg, 0.006 mmol, 0.6 mol%),
CH Cl (1 mL), CO/H (1:1, 30 bar), 40 °C, 5 h. Michael addition conditions:
CO (20 mg, 0.15 mmol, 15 mol%), 72 h.
Isolated yield.
2
2
2
K
2
3
b
c
Michael addition conditions: TBD (21 mg, 0.15 mmol, 15 mol%), 6 h.
Starting from methyl acrylate and methyl vinyl ketone
the functionalized cyclic aldol product 17 was formed in
solutions of KMnO (for 4a–e, 6–21). Uncorrected melting points
4
were determined on an Optimelt MPA100 apparatus from Stanford
Research Systems (heating rate 2 °C/min). Gas chromatography was
performed with FID (GC-FID) HP6890 GC-system with injector 7683B
3
0% yield after 3 days reaction time (Table 3, entry 1). Simi-
lar results were obtained by using cyclic ketones as sub-
strates (Table 4, entries 2 and 3). With the purpose of re-
ducing the reaction time for the cyclization products, this
and Agilent 7820A system, carrier gas: N . GC-FID was used for the
2
optimization of the tandem reaction using n-pentadecane as the in-
reaction
was
performed
using
1,5,7-triazabicy-
1
13
ternal reference. H and C NMR spectra were recorded on a Bruker
1
clo[4.4.0]dec-5-ene (TBD) as the base due to its better solu-
bility in CH Cl . This allowed us to obtain the condensation
Avance 300 MHz machine (300 MHz for H experiments; 75 MHz for
1
3
C experiments) in commercially available deuterated solvents with-
2
2
13
10
out Me Si and referenced to trace solvent signals. C NMR experi-
products 20 and 21 (Table 4, entries 4 and 5) after 6 hours.
A simplified mechanism for this transformation using sub-
strates 1a and methyl vinyl ketone is depicted in Scheme 3.
After the hydroformylation of acrylate 1a, the 1,3-dicarbon-
yl compound is deprotonated and undergoes Michael addi-
4
ments were recorded in proton-decoupled mode, and this is not ex-
13
plicitly noted below. Usually, C NMR measurements were accompa-
13
nied by a C-DEPT135 experiment for further structural elucidation,
but these are not noted explicitly in the experimental data. IR spectra
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

E
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
1
were measured on an Excalibur FTS3000 MX FT-IR spectrometer from
BioRad. The samples were applied neat on an ATR setup. HRMS analy-
sis for purified compounds was carried out by the Central Analytical
Department, University of Regensburg on an Agilent Q-TOF 6540
UHD (APCI/ESI-HRMS).
H NMR (300 MHz, CDCl ): δ = 9.70 (s, 1 H), 3.95 (d, J = 6.6 Hz, 2 H),
3
3.85 (d, J = 6.6 Hz, 2 H), 2.45–1.87 (m, 6 H), 1.33 (s, 3 H), 0.94–0.90 (m,
12 H).
13
C NMR (75 MHz, CDCl ): δ = 198.9, 172.7, 171.8, 71.8, 71.0, 57.1,
3
2
9.4, 28.8, 27.80, 27.78, 19.2, 19.1, 17.3.
HRMS (APCI): m/z [M + H]+ calcd for C15H27O : 287.1858; found:
5
Methyl 2-Methyl-3-oxopropanoate (4a) by the Optimization of the
Hydroformylation of Methyl Acrylate; General Procedure for Table 1
287.1857.
A
4-mL reaction vial with a stirring bar was charged with
Di-tert-butyl 2-Formyl-2-methylpentanedioate (4c)
Rh(acac)(CO) (0.5 mg, 2 μmol, 0.2 mol%). Then a defined quantity of
a ligand (x mol%), was added and the catalyst mixture was diluted in
the solvent (1 mL) (see Table 1). Finally, methyl acrylate (86 mg,
2
Pale-yellow oil; yield: 82 mg (53%); R = 0.35 (cyclohexane/EtOAc 8:2).
f
IR (ATR): 2982, 2937, 1718, 1457, 1394, 1368, 1300, 1252, 1148, 1036
–
1
1.0 mmol) was added to the mixture. The reaction vial was fitted
cm .
with a hollow screwcap bearing a pierced butadiene-faced septum
and placed in a Parr stainless steel autoclave. The atmosphere inside
the autoclave was replaced with CO by 3 compression/decompression
cycles, and then pressurized with a defined pressure of CO/H2 (1:1).
The mixture was then stirred at maximum speed at a set temperature
for 18 h; afterwards, the autoclave was cooled to r.t. and decom-
pressed slowly to ambient pressure. Then an aliquot of the crude
1
H NMR (300 MHz, CDCl ): δ = 9.64 (s, 1 H), 2.31–1.96 (m, 4 H), 1.46
3
(
s, 9 H), 1.43 (s, 9 H), 1.25 (s, 3 H).
13
C NMR (75 MHz, CDCl ): δ = 199.5, 172.1, 171.0, 82.7, 80.8, 57.4,
3
3
0.5, 28.9, 28.2, 28.1, 17.0.
+
HRMS (APCI): m/z [M + Na] calcd for C15H O Na: 309.1678; found:
3
26
5
09.1678.
1
product was examined in H NMR to determine the conversion of
methyl acrylate to methyl 2-methyl-3-oxopropanoate (4a).
Dibenzyl 2-Formyl-2-methylpentanedioate (4d)
Pale-yellow oil; yield: 113 mg (64%); R = 0.32 (cyclohexane/EtOAc
f
Tandem Hydroformylation–Michael Addition Reactions; General
Procedure A
8:2).
IR (ATR): 3034, 2944, 1718, 1498, 1453, 1386, 1297, 1259, 1215, 1163,
1110 cm .
–1
A
4-mL reaction vial with
a
stirring bar was charged with
Rh(acac)(CO) (0.5 mg, 2 μmol, 0.2 mol%), dppb (L1, 2.5 mg, 6.0 μmol,
1
2
H NMR (300 MHz, CDCl ): δ = 9.69 (s, 1 H), 7.39–7.30 (m, 10 H), 5.18
3
0
.6 mol%), and K CO (20 mg, 0.15 mmol, 15 mol%). THF (1 mL) was
2 3
(s, 2 H), 5.09 (s, 2 H), 2.43–2.05 (m, 4 H), 1.33 (s, 3 H).
added by syringe, obtaining a clear yellow dispersion, and finally the
acrylate (1.0 mmol) was added to the mixture. The reaction vial was
fitted with a hollow screwcap bearing a pierced butadiene-faced sep-
tum and placed in a Parr stainless steel autoclave. The atmosphere in-
side the autoclave was replaced with CO by 3 compression/decom-
pression cycles, and then pressurized with CO/H2 (1:1, 30 bar). The
mixture was then stirred at maximum speed at 50 °C for 18 h; after-
wards, the autoclave was cooled down to r.t. and decompressed slow-
ly. The obtained dispersion was filtered over a pad of glass fiber, con-
centrated in vacuo and purified by column chromatography (silica
gel, cyclohexane/EtOAc).
1
3
C NMR (75 MHz, CDCl ): δ = 198.7, 172.4, 171.2, 135.6, 135.2, 128.8,
3
1
28.72, 128.69, 128.47, 128.44, 128.3, 67.5, 66.7, 57.0, 29.3, 28.7, 17.4.
HRMS (APCI): m/z [M + H]+ calcd for C21H23O : 355.1545; found:
355.1542.
5
Bis(2-phenoxyethyl) 2-Formyl-2-methylpentanedioate (4e)
Pale-yellow oil; yield: 83 mg (40%); R = 0.39 (cyclohexane/EtOAc 7:3).
f
IR (ATR): 2952, 2877, 1722, 1599, 1495, 1457, 1405, 1293, 1241, 1170,
1
–1
110, 1085 cm .
1
H NMR (300 MHz, CDCl ): δ = 9.68 (s, 1 H), 7.32–7.25 (m, 4 H), 7.0–
3
6
.94 (m, 2 H), 6.92–6.87 (m, 4 H), 4.54–4.51 (m, 2 H), 4.41–4.38 (m, 2
Dimethyl 2-Formyl-2-methylpentanedioate (4a)
H), 4.20–4.12 (m, 4 H), 2.44–2.20 (m, 3 H), 2.13–2.03 (m, 1 H), 1.33 (s,
Pale-yellow oil; yield: 73 mg (72%); R = 0.39 (cyclohexane/EtOAc 8:2).
f
3
H).
13C NMR (75 MHz, CDCl
29.70, 129.66, 121.5, 121.3, 114.71, 114.69, 65.8, 65.5, 63.9, 63.2,
57.0, 29.2, 28.6, 17.5.
IR (ATR): 2997, 2956, 1722, 1438, 1379, 1301, 1259, 1200, 1174, 1118,
–
1
): δ = 198.6, 172.6, 171.7, 158.5, 158.4,
3
9
84 cm .
1
1
H NMR (300 MHz, CDCl ): δ = 9.65 (s, 1 H), 3.74 (s, 3 H), 3.64 (s, 3 H),
3
2.37–2.0 (m, 4 H), 1.30 (s, 3 H).
HRMS (APCI): m/z [M + H]+ calcd for C23H27O : 415.1757; found:
415.1730.
7
13
C NMR (75 MHz, CDCl ): δ = 198.7, 173.0, 172.2, 56.9, 52.7, 51.9,
3
29.2, 28.7.
HRMS (APCI): m/z [M + H]+ calcd for C H O : 203.0919; found:
9
15
5
One-Pot Hydroformylation–Michael Addition–Aldol Condensation
Reaction; General Procedure B
203.0920.
The synthesis of 4a was repeated using 1a (861 mg, 10.0 mmol),
A 4-mL reaction vial with a stirring bar was charged with
Rh(acac)(CO)2 (5.2 mg, 20 μmol), L1 (26.6 mg, 60 μmol), and K CO3
Rh(acac)(CO) (0.5 mg, 2 μmol, 0.2 mol%), and MeCgPPh (L6, 1.8 mg,
2
2
(207 mg, 1.5 mmol) in THF (4 mL) followed by column chromatogra-
6.0 μmol, 0.6 mol%). CH Cl (1 mL) was added by syringe to give a
2
2
phy; yield: 687 mg (68%).
clear yellow solution, and finally the acrylate (1.0 mmol) was added
to the mixture. The reaction vial was fitted with a hollow screwcap
bearing a pierced butadiene-faced septum and placed in a Parr stain-
less steel autoclave. The atmosphere inside the autoclave was re-
placed with CO by 3 compression/decompression cycles, and then
Diisobutyl 2-Formyl-2-methylpentanedioate (4b)
Pale-yellow oil; yield: 112 mg (78%); R = 0.35 (cyclohexane/EtOAc
f
8:2).
pressurized with CO/H (1:1, 30 bar). The mixture was then stirred at
2
IR (ATR): 2963, 1722, 1467, 1379, 1174, 1118, 991 cm–1
.
maximum speed at 40 °C for 5 h; afterwards, the autoclave was
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

F
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
cooled to r.t. and decompressed slowly. Michael acceptor (1 equiv)
was added to the product of the hydroformylation step, and finally a
catalytic amount of base (15 mol%) was added to the mixture. The re-
action vials were closed tightly and stirred at 40 °C for 4–6 h while
following the progress of the reaction by TLC. The obtained dispersion
HRMS (APCI): m/z [M + H]+ calcd for C16H21O : 293.1389; found:
293.1387.
5
Dimethyl 2-Ethyl-2-formylpentanedioate (10)
Pale-yellow oil; yield: 110 mg (51%); R = 0.35 (cyclohexane/EtOAc
f
was washed with water/CH Cl2 and the organic phase was concen-
2
8:2).
trated in vacuo and purified by column chromatography (silica gel,
cyclohexane/EtOAc).
IR (ATR): 2956, 2885, 1718, 1439, 1375, 1237, 1196, 1125, 1025 cm–1
.
1
H NMR (300 MHz, CDCl ): δ = 9.77 (s, 1 H), 3.77 (s, 3 H), 3.66 (s, 3 H),
3
2.38–2.07 (m, 4 H), 1.94–1.79 (m, 2 H), 0.86 (t, J = 7.5 Hz, 3 H).
Methyl 2-Formyl-2-methyl-5-oxohexanoate (6)
13C NMR (75 MHz, CDCl
29.3, 26.34, 26.31, 8.71.
): δ = 200.0, 173.2, 172.2, 60.8, 52.6, 52.0,
3
Pale-yellow oil; yield: 130 mg (70%); R = 0.29 (cyclohexane/EtOAc
f
8:2).
HRMS (APCI): m/z [M + H]+ calcd for C10
217.1066.
H O : 217.1076; found:
17 5
IR (ATR): 2989, 2956, 1715, 1438, 1371, 1297, 1245, 1200, 1170, 1118,
–1
1092 cm
.
1
H NMR (300 MHz, CDCl ): δ = 9.64 (s, 1 H), 3.74 (s, 3 H), 2.51–2.33
3
5-Benzyl 1-Methyl 2-Ethyl-2-formylpentanedioate (11)
(m, 2 H), 2.17–1.94 (m, 2 H), 2.12 (s, 3 H), 1.29 (s, 3 H).
1
3
Pale-yellow oil; yield: 151 mg (52%); R = 0.32 (cyclohexane/EtOAc
f
C NMR (75 MHz, CDCl ): δ = 207.2, 199.0, 172.5, 56.7, 52.7, 38.3,
3
8:2).
3
0.1, 27.4, 17.6.
IR (ATR): 2955, 2885, 1718, 1498, 1453, 1397, 1237, 1163, 1028 cm–1
.
HRMS (APCI): m/z [M + H]+ calcd for C H O : 187.0970; found:
1
9
15
4
1
87.0966.
H NMR (300 MHz, CDCl ): δ = 9.77 (s, 1 H), 7.37–7.34 (m, 5 H), 5.10
3
(s, 2 H), 3.76 (s, 3 H), 2.44–2.05 (m, 4 H), 1.94–1.79 (m, 2 H), 0.87 (t,
J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl
tert-Butyl 2-Formyl-2-methyl-5-oxohexanoate (7)
Pale-yellow oil; yield: 220 mg (89%); R = 0.34 (cyclohexane/EtOAc
3
): δ = 200.0, 172.6, 172.1, 135.9, 128.7, 128.4,
f
8:2).
66.6, 60.8, 52.6, 29.5, 26.4, 26.3, 8.7.
IR (ATR): 2982, 2937, 1714, 1457, 1368, 1256, 1155, 1122, 1028 cm–1
.
HRMS (APCI): m/z [M + H]+ calcd for C16
H O : 293.1389; found:
21 5
1
293.1378.
H NMR (300 MHz, CDCl ): δ = 9.57 (s, 1 H), 2.50–2.28 (m, 2 H), 2.09
3
(
1
s, 3 H), 2.05–1.87 (m, 2 H), 1.41 (s, 9 H), 1.19 (s, 3 H).
1
-Benzyl 5-Methyl 2-Ethyl-2-formylpentanedioate (12)
3
C NMR (75 MHz, CDCl ): δ = 207.2, 199.4, 171.1, 82.6, 57.0, 38.3,
3
Pale-yellow oil; yield: 88 mg (30%); R = 0.29 (cyclohexane/EtOAc 8:2).
3
0.0, 28.0, 27.3, 17.4.
f
+
IR (ATR): 3034, 2952, 2885, 1714, 1499, 1438, 1375, 1200, 1170, 1121,
HRMS (APCI): m/z [M + Na] calcd for C12H20O Na: 251.1259; found:
4
–1
1028 cm .
251.1255.
1
H NMR (300 MHz, CDCl ): δ = 9.79 (s, 1 H), 7.37–7.33 (m, 5 H), 5.21
3
(
s, 2 H), 3.64 (s, 3 H), 2.31–2.09 (m, 4 H), 1.95–1.80 (m, 2 H), 0.84 (t,
Benzyl 2-Formyl-2-methyl-5-oxohexanoate (8)
J = 7.5 Hz, 3 H).
13C NMR (75 MHz, CDCl
Pale-yellow oil; yield: 222 mg (85%); R = 0.29 (cyclohexane/EtOAc
f
8:2).
3
): δ = 199.9, 173.1, 171.5, 135.3, 128.8, 128.7,
1
28.4, 67.3, 60.8, 51.9, 29.2, 26.4, 8.7.
IR (ATR): 2944, 1714, 1498, 1454, 1367, 1293, 1260, 1215, 1170, 1118,
–1
HRMS (APCI): m/z [M + H]+ calcd for C16
1029 cm
.
H O : 293.1389; found:
21 5
1
293.1396.
H NMR (300 MHz, CDCl ): δ = 9.68 (s, 1 H), 7.38–7.33 (m, 5 H), 5.18
3
(
H).
s, 2 H), 2.46–2.26 (m, 2 H), 2.14–1.95 (m, 2 H), 2.06 (s, 3 H), 1.31 (s, 3
Methyl 2-Ethyl-2-formyl-5-oxohexanoate (13)
Pale-yellow oil; yield: 162 mg (81%); R = 0.35 (cyclohexane/EtOAc
:2).
1
3
f
C NMR (75 MHz, CDCl ): δ = 207.1, 199.0, 171.9, 135.3, 128.8, 128.7,
3
8
1
28.4, 67.4, 56.7, 38.2, 30.0, 27.5, 17.6.
IR (ATR): 2974, 2885, 1715, 1438, 1357, 1238, 1170, 1126, 1036 cm–1
.
HRMS (APCI): m/z [M + H]+ calcd for C15H19O : 263.1283; found:
2
4
1
63.1281.
H NMR (300 MHz, CDCl ): δ = 9.73 (s, 1 H), 3.74 (s, 3 H), 2.50–2.25
3
(m, 2 H), 2.10 (s, 3 H), 2.06–1.98 (m, 2 H), 1.90–1.73 (m, 2 H), 0.84 (t,
J = 7.5 Hz, 3 H).
2
-Phenoxyethyl 2-Formyl-2-methyl-5-oxohexanoate (9)
13C NMR (75 MHz, CDCl
30.0, 26.5, 25.0, 8.7.
): δ = 207.3, 200.2, 172.3, 60.6, 52.5, 38.5,
3
Pale-yellow oil; yield: 248 mg (85%); R = 0.26 (cyclohexane/EtOAc
f
8:2).
HRMS (APCI): m/z [M + H]+ calcd for C10
201.1126.
H O : 201.1127; found:
17 4
IR (ATR): 2941, 2877, 1715, 1599, 1495, 1457, 1368, 1241, 1170, 1114,
–1
1085 cm
.
1
H NMR (300 MHz, CDCl ): δ = 9.67 (s, 1 H), 7.32–7.26 (m, 2 H), 7.00–
3
Benzyl 4-Cyano-2-formyl-2-methylbutanoate (14)
6.95 (m, 1 H), 6.90–6.87 (m, 2 H), 4.54–4.51 (m, 2 H), 4.21–4.18 (m, 2
H), 2.54–2.34 (m, 2 H), 2.20–2.10 (m, 1 H), 2.04 (s, 3 H), 2.03–1.95 (m,
Pale-yellow oil; yield: 224 mg (91%); R = 0.40 (cyclohexane/EtOAc
f
1
H), 1.31 (s, 3 H).
8:2).
1
3
C NMR (75 MHz, CDCl ): δ = 207.2, 198.9, 172.0, 158.4, 129.8, 121.5,
IR (ATR): 2945, 2251, 1718, 1488, 1453, 1379, 1259, 1215, 1178, 1118
cm .
3
–1
1
14.7, 65.6, 63.8, 56.8, 38.3, 30.0, 27.5, 17.7.
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

G
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
1
H NMR (300 MHz, CDCl ): δ = 9.68 (s, 1 H), 7.40–7.33 (m, 5 H), 5.22
IR (ATR): 3388, 2952, 1715, 1450, 1312, 1254, 1226, 1177, 1096, 1044
cm .
3
–1
(s, 2 H), 2.38–2.20 (m, 3 H), 2.14–2.04 (m, 1 H), 1.40 (s, 3 H).
13
1
C NMR (75 MHz, CDCl ): δ = 197.6, 170.8, 134.9, 128.98, 128.95,
H NMR (300 MHz, CDCl ): δ = 4.86 (d, J = 3.6 Hz, 1 H), 3.75 (s, 3 H),
3
3
128.6, 118.9, 67.9, 56.7, 29.1, 18.3, 13.0.
2.59–2.37 (m, 3 H), 2.12 (dd, J = 19.1, 3.0 Hz, 1 H), 1.83–1.71 (m, 2 H),
HRMS (APCI): m/z [M + H]+ calcd for C14H16NO : 246.1130; found:
1.59–1.46 (m, 2 H), 1.31 (s, 3 H).
3
13
2
46.1122.
The synthesis of 14 was repeated using benzyl acrylate (1.63 g,
0.0 mmol), Rh(acac)(CO) (5.2 mg, 20 μmol), L6 (18 mg, 60 μmol) in
C NMR (75 MHz, CDCl ): δ = 214.4, 177.6, 71.8, 52.6, 51.3, 49.5, 40.2,
3
37.2, 22.5, 19.6, 18.5.
1
HRMS (APCI): m/z [M + H]+ calcd for C11H17O : 213.1127; found:
2
4
CH Cl (4 mL) in the first step and acrylonitrile (530 mg, 10.0 mmol)
213.1130.
2
2
and K CO (207 mg, 1.5 mmol) in the second step. The reaction times
2
3
were 5 h and 2 h, respectively. Column chromatography gave the
product; yield: 2.08 g (85%).
Methyl 3-Hydroxy-2-methyl-5-oxobicyclo[2.2.1]heptane-2-car-
boxylate (19)
Crystalline white solid; yield: 29 mg (15%); mp 118 °C; R = 0.20 (cy-
clohexane/EtOAc 7:3).
f
Benzyl 2-Formyl-2-methyl-4-(phenylsulfonyl)butanoate (15)
Pale-yellow oil; yield: 273 mg (76%); R = 0.30 (cyclohexane/EtOAc
f
IR (ATR): 3287, 2985, 2956, 2892, 1722, 1446, 1412, 1248, 1163, 1107,
8:2).
–1
1070, 1017 cm
.
IR (ATR): 3004, 2982, 2945, 1718, 1587, 1498, 1446, 1379, 1300, 1263,
1
H NMR (300 MHz, CDCl ): δ = 4.87 (dd, J = 5.1, 1.1 Hz, 1 H), 3.75 (s, 3
3
–1
1144, 1084 cm .
H), 2.94 (m, 1 H), 2.80 (d, J = 5.1 Hz, 1 H), 2.28 (dt, J = 18.4, 2.1 Hz, 1 H),
2.08 (dd, J = 18.4, 4.8 Hz, 1 H), 1.93–1.79 (br, 1 H), 1.69–1.68 (m, 2 H),
1
H NMR (300 MHz, CDCl ): δ = 9.60 (s, 1 H), 7.87–7.83 (m, 2 H), 7.70–
3
7.64 (m, 1 H), 7.59–7.53 (m, 2 H), 7.38–7.34 (m, 3 H), 7.31–7.28 (m, 2
1.22 (s, 3 H).
H), 5.16 (s, 2 H), 3.15–2.92 (m, 2 H), 2.28–2.06 (m, 2 H), 1.33 (s, 3 H).
13
C NMR (75 MHz, CDCl ): δ = 214.3, 177.8, 74.4, 57.9, 52.7, 51.7, 43.1,
3
13
C NMR (75 MHz, CDCl ): δ = 197.6, 170.8, 138.7, 134.9, 134.0, 129.5,
40.0, 34.2, 16.4.
3
1
28.9, 128.5, 128.2, 67.8, 56.3, 51.6, 26.3, 18.2.
HRMS (APCI): m/z [M + H]+ calcd for C10H15O : 199.0970; found:
199.0963.
4
HRMS (APCI): m/z [M + H]+ calcd for C19H21O S: 361.1110; found:
5
361.1103.
Methyl 1-Methyl-4-oxocyclohex-2-enecarboxylate (20)
Methyl 5-(Benzylamino)-4-formyl-4-methyl-5-oxopentanoate
16)
Pale-yellow oil; yield: 160 mg (57%); R = 0.31 (cyclohexane/EtOAc
Colorless oil; yield: 38 mg (23%); R = 0.35 (cyclohexane/EtOAc 7:3).
IR (ATR): 2955, 1729, 1677, 1457, 1371, 1328, 1259, 1174, 1110 cm–1
f
(
.
f
1
H NMR (300 MHz, CDCl ): δ = 6.87 (d, J = 10.2 Hz, 1 H), 5.97 (d, J =
3
8:2).
10.2 Hz, 1 H), 3.73 (s, 3 H), 2.55–2.41 (m, 3 H), 2.02–1.90 (m, 1 H),
IR (ATR): 3347, 3063, 3034, 2952, 1729, 1640, 1528, 1438, 1364, 1259,
1
.43 (s, 3 H).
–1
1
200, 1174, 1121, 1180 cm .
13
C NMR (75 MHz, CDCl ): δ = 198.6, 174.7, 151.8, 128.8, 52.7, 43.9,
3
1
H NMR (300 MHz, CDCl ): δ = 9.61 (s, 1 H), 7.37–7.24 (m, 5 H), 7.00
3
34.6, 32.6, 24.9.
(br s, 1 H), 4.46 (d, J = 5.6 Hz, 2 H), 3.64 (s, 3 H), 2.37–2.15 (m, 4 H),
HRMS (APCI): m/z [M + H]+ calcd for C H O : 169.0865; found:
9
13
3
1.39 (s, 3 H).
169.0862.
13
C NMR (75 MHz, CDCl ): δ = 202.5, 173.1, 170.0, 137.8, 128.8, 127.7,
3
1
27.6, 56.1, 51.9, 43.7, 30.0, 29.4, 19.1.
tert-Butyl 1-Methyl-4-oxocyclohex-2-enecarboxylate (21)
HRMS (APCI): m/z [M + H]+ calcd for C15H20NO : 278.1392; found:
4
Colorless oil; yield: 71 mg (34%); R = 0.35 (cyclohexane/EtOAc 7:3).
f
278.1389.
IR (ATR): 2974, 2937, 1722, 1684, 1457, 1368, 1260, 1218, 1155, 1110
–1
cm
.
Methyl 2-Hydroxy-1-methyl-4-oxocyclohexanecarboxylate (17)
1
H NMR (300 MHz, CDCl ): δ = 6.85 (d, J = 10.2 Hz, 1 H), 5.95 (d, J =
3
Crystalline white solid; yield: 55 mg (30%); mp 63 °C; R = 0.25 (cyclo-
hexane/EtOAc 7:3).
IR (ATR): 3440, 2956, 1699, 1457, 1371, 1330, 1252, 1114 cm–1
f
10.2 Hz, 1 H), 2.55–2.36 (m, 3 H), 1.97–1.88 (m, 1 H), 1.45 (s, 9 H),
1
.39 (s, 3 H).
.
13
C NMR (75 MHz, CDCl ): δ = 199.0, 173.4, 152.7, 128.4, 81.9, 44.5,
3
1
H NMR (300 MHz, CDCl ): δ = 4.35 (dd, J = 8.4, 4.4 Hz, 1 H), 3.77 (s, 3
3
34.8, 32.6, 28.1, 24.9.
H), 2.65 (dd, J = 15.2, 4.4 Hz, 1 H), 2.49–2.35 (m, 3 H), 2.12–1.93 (m, 2
H), 1.87–1.61 (br, 1 H), 1.38 (s, 3 H).
HRMS (APCI): m/z [M + H]+ calcd for C12H19O : 211.1334; found:
3
211.1331.
13
C NMR (75 MHz, CDCl ): δ = 208.7, 177.1, 72.1, 52.6, 46.9, 45.9, 37.4,
3
29.6, 17.6.
HRMS (APCI): m/z [M + H]+ calcd for C H O : 187.0970; found:
9
15
4
Acknowledgment
187.0964.
We thank the Fonds der Chemischen Industrie (Liebig Fellowship I.F.
and S.Q.-D) and the University of Regensburg for the generous finan-
cial support.
Methyl 3-Hydroxy-2-methyl-5-oxobicyclo[2.2.2]octane-2-carbox-
ylate (18)
Crystalline white solid; yield: 46 mg (22%) ; mp 127 °C; R = 0.25 (cy-
f
clohexane/EtOAc 7:3).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–H

H
Synthesis
S. Quintero-Duque, I. Fleischer
Paper
Supporting Information
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H. J. Org. Chem. 1995, 60, 499. (m) Clarke, M. L.; Roff, G. J. Chem.
Eur. J. 2006, 12, 7978.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588394.
S
u
p
p
ortioIgnfrm oaitn
S
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