Conventional and tandem hydroformylation

Article abstract of DOI:10.1055/s-0030-1258169

Transition-metal-catalyzed hydroformylation has become an essential tool for the synthesis of aldehydes. In this paper, we highlight several examples of synthetically useful applications of homogeneous and heterogeneous rhodium-catalyzed hydroformylation, as well as several examples of tandem processes involving hydroformylation as a reaction step developed in our laboratory.

Full text of DOI:10.1055/s-0030-1258169

SPECIAL TOPIC
2893
Conventional and Tandem Hydroformylation
C
onventiona
l
and
T
and
a
em
H
ydrof
k
ormylation sym Vasylyev, Howard Alper*
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie Curie, Ottawa, ON, K1N 6N5,
Canada
Fax +1(613)5625871; E-mail: Howard.Alper@uottawa.ca
Received 1 April 2010
+
–
+
–
Abstract: Transition-metal-catalyzed hydroformylation has be-
come an essential tool for the synthesis of aldehydes. In this paper,
we highlight several examples of synthetically useful applications
of homogeneous and heterogeneous rhodium-catalyzed hydro-
formylation, as well as several examples of tandem processes in-
volving hydroformylation as a reaction step developed in our
laboratory.
N
N
CO
CO
N
N
CO
CO
Cl
Cl
Cl
Cl
Rh
Rh
Rh
Rh
1
2
Figure 1 Ionic (TMDA) rhodium(I) complexes
Key words: hydroformylation, rhodium, catalysis, tandem reac-
tions
As shown in Table 1, reaction of aryl alkenes bearing
electron-donating or -withdrawing functional groups with
complex 2 afforded branched aldehydes in excellent se-
lectivity. Oct-1-ene gave a mixture of branched (b) and
linear (l) aldehyde products in equal amounts.5
The reaction of an olefin with carbon monoxide and hy-
drogen effected by a transition metal catalyst to give a ho-
mologous aldehyde defines the hydroformylation
reaction. Since its discovery by O. Roelen in 1938,1 the
hydroformylation reaction has become a useful tool for
the synthesis of aldehydes as a laboratory-scale method,
as well as an industrial process, representing one of the
most important chemical manufacturing processes today
with capacity amounting to more than 9 million tons of
hydroformylated products worldwide per year.2 The
method has been evolving over the years as the complexes
of transition metals other than cobalt, notably rhodium,
platinum, and ruthenium, were found to catalyze the reac-
tion.1b,c,3 Advances in hydroformylation reactions result-
ing from catalyst design and better mechanistic
understanding have been utilized broadly, including ap-
plications to several types of asymmetric hydroformyla-
tion.1b,c,3,4
Table 1 Hydroformylation of Alkenes with Ionic Rhodium(I) Com-
plex 2
2 (0.2 mol%)
CO/H2 (1000 psi)
PhMe, 25 °C, 22 h
CHO
+
CHO
R
R
R
R
Conv. (%)
Ratio b/l
4-ClC6H4
4-i-BuC6H4
C6H13
99
99
99
21
26
1
The regio- and stereoselective hydroformylation of the 4-
vinyl-b-lactams catalyzed by a zwitterionic rhodium(I)
complex 3 (Figure 2) in the presence of (S,S)-2,4-
bis(diphenylphosphino)pentane [(S,S)-BDPP] provides
easy access to the corresponding branched aldehydes,
which are the key synthetic precursors for the synthesis of
4-methylcarbapenem antibiotic framework 4 (Figure 2).6
In this paper, we survey the homogeneous and heteroge-
neous hydroformylation of alkenes, as well as hydro-
formylative tandem transformations with a focus on
recent work from our own laboratory using rhodium com-
plexes to effect these transformations.
–
Although rhodium-catalyzed homogeneous hydroformy-
lation of alkenes most typically involves the use of mono-
or bidentate phosphine ligands and a rhodium source, or a
preformed complex of rhodium with these ligands, we
found that the ionic rhodium(I) diamine complexes 1 and
2 (Figure 1) effectively catalyze hydroformylation reac-
tion of terminal alkenes at ambient temperature providing
aldehyde products with excellent regioselectivity.5
R1
O
BPh3
SR2
COOH
+
Rh
N
4
3
Figure 2 Zwitterionic rhodium(I) complex 3 and a general structure
of 4-methylcarbapenem antibiotics 4
As illustrated in Table 2, 4-vinyl-b-lactams 5a–c were
converted into the corresponding branched aldehydes 6a–
c in moderate to high regioselectivity, and with excellent
stereoselectivity. The results using 5c as the reactant are
SYNTHESIS 2010, No. 17, pp 2893–2900
Advanced online publication: 12.07.2010
DOI: 10.1055/s-0030-1258169; Art ID: C03310SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
0

2894
M. Vasylyev, H. Alper
SPECIAL TOPIC
Table 2 Regio- and Stereoselective Hydroformylation of 4-Vinyl-b-lactams 5a–c
OR1
OR1
H
OR1
3 (5 mol%)
CO/H2 (1:1; 1200 psi)
L (10 mol%)
(R)
CHO
H
N
CHO
+
70 °C, PhH, 24 h
N
N
O
Boc
O
Boc
O
Boc
5a–c
6a–c
7a–c
5
R1
L
Conv.
(%)
Ratio
6/7
Ratio
R/S
a
b
c
c
Boc
OAc
Me
(S,S)-BDPP
(S,S)-BDPP
(S,S)-BDPP
(R)-BINAP
98
>99
70
76:24
82:18
>99:1
60:40
99:1
92:8
>99:1
>99:1
Me
30
Table 3 Hydroformylation of Styrene and Vinyl Benzoate Effected
by G1 and G2 Rhodium Dendrimer-Grafted Resin Complexes
particularly impressive. In contrast to the hydroformyla-
tion effected in the presence of (S,S)-BDPP ligand, the use
of (R)-BINAP ligand in a similar reaction provides the de-
sired aldehyde 6c in significantly lower yield and poor re-
gioselectivity.6
Gn (1 mol% of Rh)
CO/H2 (1:1; 1000 psi)
O
R
+
R
R
CH2Cl2, 25 °C, 22 h
O
Gn
R
Cycle
Conv.
(%)
Ratio
b/l
One of the directions of the research towards the develop-
ment of environmentally more benign and economically
sustainable processes is the heterogenization of homoge-
neous catalytic systems. The reason why this direction of
research has and is receiving much attention lies in many
obvious advantages of heterogeneous over homogeneous
catalysts including facile separation, easy recycle, and the
fact that they have potential applications in continuous
processes.7
G1
G1
G1
G1
G1
G1
G2
G2
G2
G2
G2
G2
Ph
1
2
8
1
2
6
1
2
8
1
2
8
>99
>99
95
36:1
36:1
34:1
32:1
31:1
32:1
39:1
38:1
36:1
33:1
33:1
32:1
Ph
Ph
PhC(O)O
PhC(O)O
PhC(O)O
Ph
>99
>99
93
One of the strategies used for the heterogenization of ho-
mogeneous catalysts is the use of dendrimers as a support
for transition metal complexes.8 In this context, we recent-
ly demonstrated that rhodium complexes supported on
resin having dendritic extensions terminated with phos-
phine functional groups (Figure 3) are efficient catalysts
for the hydroformylation of olefins, affording the
branched aldehydes with excellent yields, and in excep-
tionally high regioselectivity. Table 3 illustrates some ex-
amples for the hydroformylation of styrenes and vinyl
esters catalyzed by generation 1 (G1) and generation 2
(G2) rhodium dendrimer-grafted resin complexes.9
>99
>99
>99
>99
>99
>99
Ph
Ph
PhC(O)O
PhC(O)O
PhC(O)O
The reactions shown in Table 3 occur at ambient temper-
ature and the dendritic catalysts can be recycled by simple
filtration and reused without loss of activity and selectiv-
ity.9
Cl Ph
Ph
(OC)2
Ph
Ph
Rh
P
P
Ph
(CO)2
P
N
Rh
Cl
Ph
Ph
N
P
O
H
Ph
Despite many advantages, resins, as most organic poly-
mers, have potential problems associated with the lack of
mechanical stability and tendency to swell in organic sol-
vents. In order to avoid these drawbacks we used a meth-
od in which polyamidoamine (PAMAM) dendrimers
were grown divergently on the aminopropyl silica gel sup-
port. Terminal amino groups of the dendrons were then
functionalized with diphenylphosphinomethyl groups
serving as ligands to rhodium(I) (Figure 4).10
H
N
N
N
O
O
O
H
Ph
Ph
Ph
Ph
N
P
(CO)2
N
Rh
Cl
Ph
Ph
(OC)2
Rh
Ph
P
Cl Ph
Figure 3 Generation G1 rhodium dendrimer-grafted resin complex
Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conventional and Tandem Hydroformylation
2895
SiO2
(OC)2
Cl
(CO)2
Ph
Cl
Ph
O
O
Ph
Ph
Rh
Rh
P
P
Si
Ph
O
P
P
Ph
Ph
Ph
N
N
N
n
n
N
O
N
N
H
O
H
O
O
H
N
Ph
H
N
N
N
O
O
H
Ph
P
H
Ph
Cl
P
n
N
N
Ph
Cl
n
N
N
H
Rh
n
N
N
n
n
n
O
P
N
O
Rh
(CO)2
Ph Ph
H
P
(OC)2
Ph
Ph
H
H
N
O
N
O
n
n
N
N
O
O
O
O
N
N
Ph
P
N
N
H
H
n
H
Ph
P
H
Ph
(CO)2
n
N
Ph
Ph
Ph
n
n
N
Ph
Rh
N
P
Rh
P
Ph
N
(OC)2
P
P
Cl
Ph
Ph
Rh
Cl
(CO)2
Ph
P
Ph
Rh
Cl
Ph
(OC)2
Cl
P
Ph
Ph
Ph
Figure 4 Rhodium(I) phosphine PAMAM-on-SiO2 catalysts, generation G3
Results, presented in Table 4, demonstrate that rhodi- Although the reactions shown in Table 5 were carried out
um(I) phosphine PAMAM-on-SiO2 catalyst of zero and at slightly elevated temperature than those effected by
first generations, G0 and G1, are highly active and regio- rhodium dendrimer-grafted resin complexes (Table 3),
selective catalysts for the hydroformylation of aryl olefins they afforded the hydroformylation product in higher se-
and vinyl esters. In contrast, higher generation catalysts lectivity for the branched aldehyde. However, the catalyt-
displayed significantly lower catalytic activity. One of the ic activity of the rhodium-dendronized nanoparticles
reasons for the observed decrease in catalytic activity as complex G0 shows a decrease in activity with an increas-
the generation increases is an incomplete phosphination ing number of runs.11
of the dendrimer arising from steric crowding. To relieve
The high reactivity of the carbonyl group introduced by
the steric strain and allow for increased catalyst loading at
the hydroformylation reaction allows the development of
higher generations the chain length was extended by the
the reaction sequences (tandem processes) in which the
use of 1,4-diaminobutane, 1,6-diaminohexane, and 1,12-
carbonyl compound formed becomes subject to nucleo-
diaminododecane instead of the ethylenediamine linker
philic attack or, as in the form of the corresponding eno-
(Figure 4, n = 3, 5, 11).10
late, to electrophilic attack.12 Moreover, tandem reactions
As the spacer length increases, the reactivity and recycla- involving a hydroformylation process can also include re-
bility of the rhodium(I) phosphine PAMAM-on-SiO2 cat- actions of intermediates of the hydroformylation reaction,
alysts increases; however, the selectivity for the branched such as metal alkyl and metal acyl species, which can un-
chain aldehyde decreases somewhat at elevated reaction dergo coupling, isomerization, or elimination processes
temperatures (Table 4).10
(metal alkyls), or can be attacked by a nucleophile (metal
acyls) (Scheme 1).12
A valuable alternative to the rhodium dendrimer-grafted
resin complexes and rhodium(I) phosphine PAMAM-on- In the most typical cases the hydroformylation tandem re-
SiO2 catalysts are the rhodium-phosphine heterogeneous actions involve hydroformylation as the first step of the
complexes prepared by complexation of rhodium(I) with reaction sequence. An interesting exception to this is syn-
phosphine ligands attached to the PAMAM dendrons of thesis of 4-carbaldehydepyrrolin-2-ones 10 from a-imino
various generations divergently grown on silica-coated alkynes 8 catalyzed by rhodium(I) zwitterionic complex 9
magnetic nanoparticles. The reactivity, selectivity, and re- in the presence of a triphenyl phosphite ligand under car-
cyclability of the catalysts are illustrated by the examples bon monoxide and hydrogen gas atmosphere as illustrated
shown in Table 5.11
in Scheme 2. In this reaction a hydrocyclocarbonylation
step giving rise to a pyrrolinone, precedes the formylation
process.13
Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York

2896
M. Vasylyev, H. Alper
SPECIAL TOPIC
Table 4 Hydroformylation of Alkenes with Rhodium(I) Phosphine
PAMAM-on-SiO2 Catalyst of Different Generations and Spacer
Lengths
Table 5 Hydroformylation of Styrene with Rhodium-Dendronized
Magnetic Nanoparticle Complexes of Generations G0 and G1
dendr. nanop. Gn
(1 mol% of Rh)
CO/H2 (1:1; 1000 psi)
Gn (1 mol% of Rh)
CO/H2 (1:1; 1000 psi)
O
R
+
Ph
O
Ph
Ph
O
+
R
CH2Cl2, 40 °C, 20 h
CH2Cl2, 25 °C, 22 h
R
O
R
Cycle
Gn
Conv.
(%)
Ratio
b/l
Dendronized magnetic Cycle
nanoparticles
Conv.
(%)
Ratio
b/l
Ph
G0
G1
G2
G3
G2
G3
98
98
99
5
25:1
27:1
30:1
n.d.
19:1
18:1
9:1
G0
1
2
5
1
2
5
>99
>99
69
45:1
41:1
43:1
48:1
48:1
42:1
Ph
Ph
Ph
G1
>99
>99
98
PhC(O)Oa
PhC(O)Oa
Phb
99
99
99
90
6
1
2
4
1
2
4
1
2
4
G3, n = 3
G3, n = 3
G3, n = 3
G3, n = 5
G3, n = 5
G3, n = 5
G3, n = 11
G3, n = 11
G3, n = 11
Phb
7:1
9 (2 mol%)
R
Et
O
O
P(OPh)3 (8 mol%)
N
CO (17.5 atm), H2 (3.5 atm)
Phb
n.d.
10:1
12:1
11:1
8:1
CH2Cl2, 90–100 °C, 18–24 h
N
Phb
99
92
80
99
99
76
Et
R
Phb
8a R = n-Bu
8b R = i-Pr
10a 82%
10b 79%
–
BPh3
Phb
+
Rh
Phb
Phb
11:1
10:1
9
Phb
Scheme 2 Rhodium-catalyzed hydrocyclocarbonylation/formyla-
tion of a-imino alkynes
a At 75 °C.
b At 65 °C.
The scope of the reaction covers a-imino alkynes with
both alkyl and aryl substituents at imine carbon, and a va-
riety of alkyl substituents at imine nitrogen and the alkyne
terminus making it an excellent preparative method.13
A new type of tandem reaction, hydroaminovinylation,
occurring under hydroformylation conditions, was ob-
served when vinyl sulfones and vinyl phosphonates were
subjected to hydroformylation conditions using rhodium
electrophile
MLn
H
H
O
CO/H2
R
H
R
H
R
R
R
R
MO
HMLn(CO)n
nucleophile
can undergo:
H
β-hydrogen elimination,
isomerization, insertion,
coupling, etc.
H
R
R
R
R
O
MLn(CO)n
MLn(CO)n
nucleophile
Scheme 1 Hydroformylation reaction as part of a tandem process: sites amenable for further reactions
Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conventional and Tandem Hydroformylation
2897
complex 9 as the catalyst and ( )-BINAP as the ligand. Table 8 Synthesis of Tetrahydroquinolines by Rhodium-Catalyzed
Hydroaminomethylation
The reaction is generally selective for the corresponding
enamines (e.g., 12a–c), affording products in good isolat-
1 (5 mol%)
ed yields. Some examples of vinyl sulfones hydroamino-
CO/H2 (7:3; 1000 psi)
R1
vinylation are shown in Table 6.14
R1
PhMe, 120 °C, 48 h
N
NHR2
Table 6 Rhodium-Catalyzed Hydroaminovinylation of Vinyl Sul-
R2
15a–e
fones
14a–e
9 (1 mol%)
14/15
R1
R2
H
Yield (%) of 15
R2NH2 (1.2 equiv)
R2
( )-BINAP (3–8 mol%)
CO/H2 (1:1; 200–600 psi)
a
b
c
H
89
98
85
80
80
N
R1
R1
H
THF, 80–100 °C, 1–5 h
H
Bn
H
11a,b
12a–c
8-Me
8-MeO
6-Me
11
12
R1
R2
Yield (%)
d
e
H
11a
11a
11b
12a
12b
12c
MeSO2
MeSO2
PhSO2
t-Bu
Ph
89
73
68
H
i-Pr
ty of intramolecular hydroaminomethylation even further,
allowing for the reaction to occur in one pot via a five-step
cascade.17
Hydroformylation of styrene catalyzed by the zwitterionic
complex 9 in the presence of amine resulted in hydro-
formylation–reductive amination tandem sequence (over-
all hydroaminomethylation) producing predominantly
branched secondary amines as exemplified in Table 7.15
The scope of the one-pot reaction was found to be quite
general and the synthetic protocol tolerates 2-(prop-1-en-
2-yl)benzaldehyde 18 and anilines of diverse nature af-
fording 2,3,4,5-tetrahydro-1H-2-benzazepines 17 in ex-
cellent yields.
Table 7 Hydroaminomethylation of Styrene Catalyzed by Zwitter-
ionic Complex 9
We found that cyclic N,O-acetals can be prepared diaste-
reoselectively by a hydroformylation-SiO2-induced de-
formylation reaction sequence starting from the easily
accessible chiral N-(allyl)oxazolidines 19.18 The method
made it possible to synthesize the five-membered 5-un-
substituted oxazabicycloalkane ring systems, which were
not previously accessible by hydroformylation-acetaliza-
tion of 2-(alkenylamino)ethanols and prepared previously
only by a stoichiometric oxidative cyclization of 2-pyrro-
lidino-1-ethanol derivatives.19 An example of the devel-
oped hydroformylation-SiO2-induced deformylation
reaction is shown in Table 10, where hydroformylation of
(4R)-3-allyl-4-phenyloxazolidine (19a), followed by a sil-
ica-induced diastereoselective deformylative cyclization
9 (0.5 mol%)
H
N
RNH2 (1.2 equiv)
CO/H2 (1:1)
H
N
Ph
+
Ph
Ph
R
R
THF, 80 °C, 24 h
13
13′
13
R
Isolated yield Ratio
Pressure
CO/H2 (psi)
(%) of 13
13/13¢
11.5
15
a
b
c
i-Pr
n-Bu
Bn
85
68
78
200
600
14
1000
affords
(3R,7aS)-3-phenylhexahydropyrrolo[2,1-b]ox-
azole (20a) in 87% yield.18
The scope of the hydroaminomethylation tandem reaction
is not restricted only to intermolecular processes, as it can
also occur intramolecularly. This strategy was successful-
ly used in the development of a practical method for the
construction of tetrahydroquinolines from 2-(prop-1-en-
2-yl)anilines 14, using ionic rhodium(I) diamine com-
plexes 1 as the catalyst (Table 8).16
We examined the scope of the cyclization reaction of N-
(allyl)oxazolidines 19a–d. As one may see from the
results presented in Table 10, the hydroformylation–
deformylation reaction sequence gave hexahydropyrro-
lo[2,1-b]oxazoles 20a–d in good yields with a variety of
substituents located at the 3-position of the hexahydropyr-
rolo[2,1-b]oxazole.18
The intramolecular hydroaminomethylation strategy was
further extended to the synthesis of seven-membered ring
heterocycles, tetrahydro-1H-2-benzazepines 17, from 2-
(prop-1-en-2-yl)benzylamines under similar reaction con-
ditions (Table 9).16
In conclusion, we have presented results demonstrating
the application of homogeneous and supported rhodium
catalysts for regio- and in some cases the stereoselective
hydroformylation of alkenes. Additionally, we have dem-
onstrated an application of rhodium-catalyzed tandem hy-
droformylation reactions for the synthesis of five-, six-
and seven-membered heterocycles.
An efficient synthesis of 2,3,4,5-tetrahydro-1H-2-benz-
azepines 17 from prop-2-enylbenzaldehyde (18) and
anilines illustrated in Table 9, method B extends the utili-
Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York

2898
M. Vasylyev, H. Alper
SPECIAL TOPIC
Table 9 Synthesis of Tetrahydro-1H-2-benzazepines by Hydroaminomethylation from Presynthesized Benzylamine (Method A) and a Five-
Steps-In-One-Pot Cascade (Method B)
1 (7.5 mol%)
CO/H2 (7:3; 800 psi)
4-RC6H4NH2
1 (7.5 mol%)
CO/H2 (7:3; 800 psi)
PhMe, 120 °C, 48 h
Method A
PhMe, 120 °C, 48 h
Method B
HN
CHO
N
18
R
16a–c
17a–c
R
17
R
H
Method A
yield (%)
Method B
yield (%)
a
b
c
91
94
98
90
89
96
MeO
Ph
(3S,4R)-tert-Butyl 3-[(R)-1-methoxyethyl]-2-oxo-4-[(R)-1-oxo-
propan-2-yl]azetidine-1-carboxylate (6c)6
Table 10 Synthesis of Hexahydropyrrolo[2,1-b]oxazoles by Hy-
droformylation–SiO2-Induced Deformylation Reaction Sequence
IR (CH2Cl2): 1830 cm–1 (C=O, carbamate), 1737 (C=O, lactam),
1694 (C=O, aldehyde).
1. Rh(CO)2(acac) (5 mol%)
Xanthphos (20 mol%)
CO (25 atm), H2 (10 atm)
THF, 70 °C, 24 h
1H NMR (300 MHz, CDCl3): d = 1.12–1.20 (m, 6 H), 1.45 (s, 9 H),
2.5–2.6 (m, 1 H), 3.5–3.6 (m, 1 H), 4.0–4.2 (m, 1 H), 4.5–4.6 (m, 1
H), 9.625–9.630 (d, J = 1.0 Hz, 1 H).
R
R
N
N
O
7a
2. SiO2, r.t.
O
H
13C NMR (100 MHz, CDCl3): d = 9.32, 20.27, 28.16, 51.91, 54.04,
19a–d
20a–d
65.33, 70.43, 80.13, 148.51, 165.91, 201.10.
20
R
Config.
at C-7a
dr
Isolated
yield (%)
HRMS: m/z calcd for C14H23NO5: 285.1576; found: 285.1570.
a
b
c
(R)-Ph
S
S
S
R
25:1
87
63
85
73
Cyclohydrocarbonylative/CO Insertion of Acetylenic Imines
8;13 General Procedure
(R)-i-Bu
(R)-Bn
(S)-i-Pr
6:1
9:1
In a 45 mL autoclave containing a glass liner and stirring bar was
placed zwitterionic rhodium complex 9 (0.03 mmol), P(OPh)3 (0.12
mmol), acetylenic imine 8a,b (1.5 mmol), and CH2Cl2 (10 mL). The
autoclave was flushed three times with CO, pressurized from 17.5
to 38.5 atm followed by the introduction of H2 to a total pressure of
21–42 atm. The autoclave was placed in an oil bath at 75–100 °C for
18–36 h and then allowed to cool to r.t. The autoclave was depres-
surized, the reaction mixture filtered through Celite, and the solvent
removed by rotary evaporation. The resulting residue was purified
by silica gel chromatography using an EtOAc–hexanes gradient
ranging from 33:67 to 50:50 as the eluent.
d
10:1
Solution 1H NMR and 13C NMR were recorded in CDCl3, contain-
ing TMS as internal standard, on a Bruker Avance spectrometer at
300 MHz (or 400 MHz). Chemical shifts (d) are reported in ppm
with the solvent signals as reference (1H NMR at 7.26 ppm and 13
C
NMR at 77.1 ppm), and coupling constants (J) are given in hertz
(Hz). Flash column chromatography was undertaken with silica gel
(60 Å, 200–430 mesh) supplied by VWR. IR spectra were obtained
with a Shimadzu FTIR8400S spectrometer. Mass spectra were de-
termined using a VG 7070E spectrometer.
1-Butyl-4-carbaldehyde-3-ethyl-5-methyl-3-pyrrolin-2-one
(10a)13
Purification by flash chromatography provided the title compound
in 82% yield.
IR (neat): 1727 (C=O), 1644 cm–1 (C=O).
Hydroformylation of 5a–c;6 General Procedure
The hydroformylation reaction was carried out in a 45 mL Parr au-
toclave fitted with a glass liner and a stirring bar. The 4-vinyl-b-lac-
tam (0.5 mmol), Rh complex 3 (5 mmol%), and phosphorus ligand
(10 mmol%) were placed in the glass liner, which was then protect-
ed with a septum. CO was bubbled through a needle for several min
prior to the addition of benzene (5 mL). The glass liner was trans-
ferred into the autoclave, and the system was purged three times
with CO and subsequently pressurized with CO and H2. The auto-
clave was heated in an oil bath; at the end of the reaction time, it was
cooled to r.t., the gas was vented, and the reaction mixture was fil-
tered through Flurosil to remove the catalyst. The conversion of the
starting material was determined by GC. After evaporation of the
solvent, the branched/linear ratio of the isomeric aldehydes and the
stereoselectivity were determined by 1H NMR by integration of the
resonances corresponding to the aldehyde protons.
1H NMR (500 MHz, CDCl3): d = 9.71 (s, 1 H), 3.55 (t, J = 7.7 Hz,
1 H), 3.45 (t, J = 7.7 Hz, 1 H), 3.30 (m, 1 H), 2.38 (br, 3 H), 2.01
(m, 2 H), 1.52 (q, J = 7.7 Hz, 2 H), 1.32 (sext, J = 7.7 Hz, 2 H), 0.92
(t, J = 7.4 Hz, 3 H), 0.71 (t, J = 7.5 Hz, 3 H).
13C NMR (200 MHz, CDCl3): d = 182.9, 180.1, 159.9, 118.8, 46.0,
40.5, 31.9, 22.5, 20.7, 14.3, 11.4, 9.6.
MS (EI): m/z = 209 [M+].
HRMS: m/z calcd for C12H19NO2 [M+]: 209.14158; found:
209.14173.
Hydroaminomethylation of 14a–e;16 General Procedure
A glass liner, equipped with a magnetic stirring bar, containing the
olefin 14a–e (1.00 mmol), catalyst 1 (5.0 mol%, 25.6 mg), and tol-
Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York

SPECIAL TOPIC
Conventional and Tandem Hydroformylation
2899
uene (2 mL) was placed in a 45 mL autoclave. The autoclave was
flushed three times with CO and pressurized to 700 psi of CO and
then 300 psi of H2. The autoclave was then placed in an oil bath pre-
set to 120 °C on a stirring hot plate. The total pressure increased to
1200 psi. After 48 h, the autoclave was removed from the oil bath
and cooled to r.t. prior to the release of excess CO. The solvent was
concentrated and the residue was purified by silica gel chromatog-
raphy with a mixture of hexane and EtOAc (9:1) as the eluent to af-
ford the desired products.
The reaction mixture was concentrated and the residue was subject-
ed to flash chromatography using the indicated eluent.
(3R,7aS)-3-Phenylhexahydropyrrolo[2,1-b]oxazole (20a)18
Purification by flash chromatography with 20% of EtOAc in hex-
anes used as eluent provided the title compound in 87% yield;
[a]D22 –95.3 (c = 1.29, CHCl3).
1H NMR (400 MHz, C6D6): d = 1.5 (m, 1 H), 1.7 (m, 2 H), 1.9 (m,
1 H), 2.5 (dt, J = 9.8, 6.9 Hz, 1 H), 2.9 (dt, J = 9.7, 6.3 Hz, 1 H), 3.5
(dd, J = 7.6, 8.1 Hz, 1 H), 3.8 (t, J = 7.2 Hz, 1 H), 4.1 (dd, J = 7.9,
6.8 Hz, 1 H), 5.0 (dd, J = 5.1, 1.9 Hz, 1 H), 7.1 (tt, J = 7.3, 2.0 Hz,
1 H), 7.2 (m, 2 H), 7.3 (m, 2 H).
4-Methyl-1,2,3,4-tetrahydroquinoline (15a)16
Purification by flash chromatography provided the title compound
in 89% yield.
1H NMR (300 MHz, CDCl3): d = 1.28 (d, J = 6.9 Hz, 3 H), 1.62–
1.72 (m, 1 H), 1.92–2.02 (m, 1 H), 2.85–2.96 (m, 1 H), 3.21–3.35
(m, 2 H), 3.82 (br s, 1 H), 6.45–6.65 (m, 2 H), 6.93–7.06 (m, 2 H).
13C NMR (101 MHz, C6D6): d = 24.2, 31.9, 55.4, 70.1, 73.7, 98.9,
126.9, 127.1, 128.6, 143.2.
HRMS: m/z calcd for C12H15NO: 189.1154; found: 189.1132.
13C NMR (75.4 MHz, CDCl3): d = 22.7, 29.9, 30.3, 39.0, 114.2,
117.0, 126.6, 126.8, 128.5, 144.3.
Acknowledgment
Hydroaminomethylation of 16a–c;17 Method A; General Proce-
dure
The work carried out by the authors of this manuscript benefited
from generous support by the Natural Sciences and Engineering Re-
search Council of Canada and by Sasol Technology.
A glass liner, equipped with a magnetic stirring bar, containing the
benzylamine 16a–c (0.50 mmol), catalyst 1 (7.5 mol%), and toluene
(2.5 mL) was placed in a 45 mL autoclave. The autoclave was
flushed three times with CO and pressurized to 700 psi of CO and
then 100 psi of H2. The autoclave was then placed in an oil bath pre-
set to 120 °C on a stirring hot plate. The total pressure increased to
1200 psi. After 48 h, the autoclave was removed from the oil bath
and cooled to r.t. prior to the release of excess CO. The solvent was
concentrated and the residue was purified by silica gel chromatog-
raphy with a mixture of hexane and EtOAc (9:1) as the eluent to af-
ford the desired products.
References
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Hydroaminomethylation of 18; Method B; One-Pot Procedure
A glass liner, equipped with a magnetic stirring bar, containing the
olefin 18 (0.50 mmol), suitable aniline (0.50 mmol), catalyst 1 (7.5
mol%, 19 mg), and toluene (2.5 mL) was placed in a 45 mL auto-
clave. The procedure continues as described for olefins 16a–c.
5-Methyl-2-phenyl-2,3,4,5-tetrahydro-1H-benzo[c]azepine
(17a)17
Purification by flash chromatography provided the title compound
in 91% yield (Method A) (in 90% using the one-pot procedure,
Method B).
1H NMR (400 MHz, CDCl3): d = 1.35 (d, J = 7.1 Hz, 3 H), 1.50–
1.59 (m, 1 H), 2.10–2.18 (m, 1 H), 3.09–3.18 (m, 1 H), 3.57–3.68
(m, 2 H), 4.54 (q, J = 14.9 Hz, 2 H), 6.63 (t, J = 7.2 Hz, 1 H), 6.78
(d, J = 8.0 Hz, 2 H), 7.10–7.23 (m, 5 H), 7.28 (d, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): d = 19.7, 33.5, 36.6, 47.0, 54.8,
112.3, 116.0, 125.8, 126.7, 127.6, 129.2, 129.4, 137.3, 144.7, 148.0.
HRMS: m/z calcd for C17H19N: 237.1517; found: 237.1509.
Catalytic Hydroformylation–Decarbonylation Reaction of
19a–d;18 General Procedure
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solved in anhyd THF (10 mL) under an atmosphere of argon in a
glass liner equipped with a magnetic stirring bar. The solution was
stirred for 2 min until the evolution of CO had ceased. To this solu-
tion was added N-(allyl)oxazolidine 19a–d (1 mmol) and the liner
was inserted into a 45 mL autoclave, which was then sealed. CO, 25
atm, was introduced to the autoclave by the two consecutive pump–
release cycles. Finally, H2 gas was introduced into the autoclave
bringing the overall pressure to 35 atm. The autoclave was placed
in a thermostated oil bath at 100 °C and the reaction was carried out
for 24 h. The autoclave was then cooled, and pressure was released.
Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York

2900
M. Vasylyev, H. Alper
SPECIAL TOPIC
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Synthesis 2010, No. 17, 2893–2900 © Thieme Stuttgart · New York