Rh(I)-Catalyzed Hydroamidation of Olefins via Selective Activation of N-H Bonds in Aliphatic Amines

Article abstract of DOI:10.1021/jacs.5b02218

Hydroamidation of olefins constitutes an ideal, atom-efficient method to prepare carboxylic amides from easily available olefins, CO, and amines. So far, aliphatic amines are not suitable for these transformations. Here, we present a ligand- and additive-free Rh(I) catalyst as solution to this problem. Various amides are obtained in good yields and excellent regioselectivities. Notably, chemoselective amidation of aliphatic amines takes place in the presence of aromatic amines and alcohols. Mechanistic studies reveal the presence of Rh-acyl species as crucial intermediates for the selectivity and rate-limiting step in the proposed Rh(I)-catalytic cycle. (Chemical Formula Presented).

Full text of DOI:10.1021/jacs.5b02218

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Article
Rh(I)-Catalyzed Hydroamidation of Olefins via
Selective Activation of N-H Bonds in Aliphatic Amines
Kaiwu Dong, Xianjie Fang, Ralf Jackstell, Gabor Laurenczy, Yuehui Li, and Matthias Beller
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 12 Apr 2015
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Journal of the American Chemical Society
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Rh(I)-Catalyzed Hydroamidation of Olefins via Selective Activation
of N-H Bonds in Aliphatic Amines
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Kaiwu Dong,† Xianjie Fang,† Ralf Jackstell,† Gabor Laurenczy,‡ Yuehui Li,*,† and Matthias Beller*,†
†LeibnizꢀInstitut für Katalyse e.V. an der Universität Rostock, AlbertꢀEinstein Str. 29a, 18059 Rostock, Germany
‡Institut des Sciences et Ingénierie Chimiques, Ecole Polytechnique Fédérale de Lausanne, 1015 Lausanne, Switzerland
KEYWORDS: Olefins, Aliphatic Amines, Hydroamidation, Rhodium, Ligand-free
Supporting Information Placeholder
ABSTRACT: Hydroamidation of olefins constitutes an ideal, atomꢀefficient method to prepare carboxylic amides from easily
available olefins, CO and amines. So far, aliphatic amines are not suitable for these transformations. Here, we present a ligandꢀ and
additiveꢀfree Rh(I) catalyst as solution to this problem. Various amides are obtained in good yields and excellent regioselectivities.
Notably, chemoselective amidation of aliphatic amines takes place in the presence of aromatic amines and alcohols. Mechanistic
studies reveal the presence of Rhꢀacyl species as crucial intermediates for the selectivity and rateꢀlimiting step in the proposed
Rh(I)ꢀcatalytic cycle.
INTRODUCTION
all these reactions are carried out under severe conditions
(>200 °C; >150 atm CO). Since the 1980s, rutheniumꢀcarbonyl
complexes19 and cobalt on charcoal20 proved to be more
efficient catalysts. Nevertheless, the unavoidable formation of
formamide byꢀproducts and the limited substrate scope
impeded further applications of these processes.
Carbonylation reactions constitute the most important and
largest examples of industrially applied homogeneous catalytic
reactions.1 In addition to hydroformylation,1b,2 the transitionꢀ
metal catalyzed addition of carbon monoxide to alkenes, alꢀ
kynes or aryl/vinyl halides in the presence of a suitable nucleꢀ
ophile, such as water, alcohols, and amines, leads to the forꢀ
mation of saturated or unsaturated carboxylic acid derivatives
which are valuable products for the chemical industry.3 Comꢀ
pared with the wellꢀexplored alkoxycarbonylation of alkenes
and alkynes, related hydroamidations leading to amides are
still in their infancy.
Recently, ColeꢀHamilton21 and Liu22 and coꢀworkers as well as
our group23 independently developed palladiumꢀbased
catalysts for aminocarbonylation of alkenes. Notably, in all
these works aromatic amines were employed. Unfortunately,
when using aliphatic amines as substrates, no desired reaction
occurred due to the stronger basicity of aliphatic amines.
Hence, the generation of catalytically active palladium hyꢀ
drides is retarded. Thus, the development of alternative cataꢀ
lytic systems for the hydroamidation of olefins with aliphatic
amines continues to be a challenging goal.
Amides represent important intermediates, building blocks and
products in organic synthesis, the chemical and life science
industries as well as biological systems.4 Hence, efficient and
selective construction of amide bonds is a longꢀstanding task
for chemists.5 Traditional methods involve condensation of
carboxylic acids and their derivatives with amines in the presꢀ
ence of activation reagents.6 Recently, several interesting
catalytic methods were reported such as oxidative amidation
of amines,7 hydrocarbamoylation of alkenes/alkynes,8 oxidaꢀ
tive coupling of αꢀbromo nitroalkanes with amines,9 transamiꢀ
dation reactions,10 and acylation of amine surrogates.11 Howꢀ
ever, most of these procedures suffer from several drawbacks
such as harsh conditions, generation of (over)stoichiometric
amounts of byꢀproducts or/and limited substrate scope.
Scheme 1. Catalytic hydroamidation of olefins
In general, carbonylation of alkenes, alkynes,12 1,3ꢀdienes,13 or
aryl/vinyl halides1e,14 with amines represents a straightforward
tool for the synthesis of saturated or unsaturated amides. In
hydroamidations of alkenes, cobaltꢀcarbonyl complexes,15
nickel cyanide,16 iron carbonyl complexes,17 and ruthenium
chloride18 were used as catalysts at an early stage. However,
Although rhodium phosphine complexes dominate as catalysts
in alkene hydroformylation reactions,2,24 to the best of our
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knowledge there is no systematic study on related rhodiumꢀ
6
7
Rh(acac)(CO)2/PPh3 (1/2)
3
7
ꢀꢀ
catalyzed aminocarbonylations of alkenes.19 Despite the apꢀ
parent simplicity of the required aminolysis of Rhꢀacyl interꢀ
mediates, no formation of amides was observed in previous
reports on Rhꢀcatalyzed hydroaminomethylations (hydroꢀ
formylation/reductive amination) of olefins.25 Nevertheless,
here we report an efficient, convenient and general hydroamiꢀ
dation of alkenes with a variety of aliphatic amines in the
presence of “phosphineꢀfree” rhodium catalysts.
1
2
3
4
5
6
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8
Rh(acac)(CO)2/Ph2P(2ꢀPy)
(1/2)
95/5
Rh(acac)(CO)2/Xantphos
(1/1)
8
0
ꢀꢀ
9
Rh(acac)(CO)2/dtbpx (1/1)
Rh(acac)(CO)2/Naphos (1/1)
Rh(acac)(CO)2
5
ꢀꢀ
9
10
0
ꢀꢀ
RESULTS AND DISCUSSION
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11b
12c
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94/6
94/6
92/8
96/4
Model Studies. Initial attempts of the hydroamidation of 1ꢀ
octene 1a with hexylamine 2a were carried out at 100 °C with
1 mol% of different metal complexes under 50 bar pressure of
CO. As shown in Table 1, no desired product Nꢀ
hexylnonanamide 3aa was detected when PdCl2, Ru3(CO)12,
CoCl2, or Ni(OTf)2 was used as the catalyst (Table 1, entries
1ꢀ4). To our surprise, the desired 3aa was obtained in moderꢀ
ate yield with excellent regioselectivity in the presence of
Rh(acac)(CO)2 (Table 1, entry 5: 35% yield, n/iso = 93/7).
Encouraged by this result, the addition of different ligands was
investigated (see SI, Table S2). However, no positive effect
was observed and the reactivity was almost fully suppressed in
many cases (Table 1, entries 6ꢀ10). As shown in Table S2
stronger coordinating ligands led to lower activity. For examꢀ
ple, when using electronꢀrich ligands such as L1, L5 and biꢀ
dentate ligands, no product could be obtained. These results
indicated that hexylamine 2a might need effective coordinaꢀ
tion to the vacant site on Rh center for generation of the RhꢀH
intermediates and/or cleavage of the NꢀH bonds.
Rh(acac)(CO)2
Rh4(CO)12
RhCl3•3H2O
a Reaction conditions: 1a (1.0 mmol), 2a (1.0 mmol), metal (1 mol%), CO
(50 bar), toluene (2.0 mL), 100 °C, 20 h. Yield of 3aa was determined by
GC analysis using isooctane as internal standard. The ratio of isomers was
determined by GC analysis. b 1a (2.0 mmol). c 1a (5.0 mmol), toluene (1.0
mL).
diyl)bis(diphenylphosphane).
butylphosphanyl)methyl)benzene.
bis((diphenylphosphanyl)methyl)ꢀ1,1'ꢀbinaphthalene.
Xantphos
=
(9,9ꢀdimethylꢀ9Hꢀxantheneꢀ4,5ꢀ
1,2ꢀbis((diꢀtertꢀ
2,2'ꢀ
dtbpx
=
Naphos
=
Due to the possible activation effect of bases and acids on NꢀH
bonds, several additives were tested in the benchmark reacꢀ
tion, too (see SI, Table S5). Similar activity is obtained in the
presence of the weak base KOAc (Table S5, entry 1). The
addition of Brønsted acids yielded slightly lower amounts of
3aa with the same selectivity (Table S5, entries 2ꢀ4). Notably,
the reaction was inhibited when BmimCl (1ꢀbutylꢀ3ꢀ
methylimidazolium chloride) was added as the additive (Table
S5, entry 6). The activity of the reaction decreased when Lewꢀ
is acids were added into the catalytic system (Table S5, entries
7 and 8).
To our delight, the yield of 3aa was improved significantly to
86% (n/iso: 94/6) when excess amounts of 1ꢀoctene 1a were
used (Table 1, entries 11ꢀ12). Next, we studied the influence
of different rhodium precursors in the aminocarbonylation of
1ꢀoctene 1a. Here, rhodium complexes in different oxidation
states were examined. Among the tested complexes, Rh(I),
Rh(III), and Rh(0) precursors all similarly afforded the desired
product 3aa in high yields with excellent regioselectivities,
which implicates that the same/similar active species are
formed in all the cases (Table 1, entries 12ꢀ14).
Mechanistic Studies. With the above ligandꢀfree and addiꢀ
tiveꢀfree Rhꢀcatalytic system in hand, the mechanism was then
studied by control experiments, mass spectroscopic investigaꢀ
tions and in situ NMR spectroscopy.
Table 1. Catalytic hydroamidation of 1ꢀoctene 1a with
hexylamine 2a: Investigation of different metals and ligꢀ
andsa
First, control experiments were carried out to compare the
reactivity of aliphatic amines with other types of nucleoꢀ
philes.26 In general, with or without phosphine coꢀligands
present the active RhꢀH species is formed efficiently from the
reaction of aliphatic amines and the rhodium precursor comꢀ
plex. In these cases a significant amount of olefin isomerizaꢀ
tion is observed. However, it was found that in the presence of
aromatic amines no desired hydroamidation occurred and only
trace amounts of isomerized olefins were detected. This indiꢀ
cates the difficulty of RhꢀH formation step from aromatic
amines. In agreement with this finding, competition reactions
of 1ꢀhexylamine with aniline or benzyl alcohol showed the
selective carbonylation with aliphatic amines and no reaction
occurred with the aromatic amine or alcohol (Scheme 2). More
specifically, when both hexylamine 2a and aniline were introꢀ
duced into the reaction system (hexylamine/aniline = 1/1),
only hexylamine 2a was transformed into the desired amide
3aa in 89% yield with 95/5 selectivity (Scheme 2, eq 1). Simiꢀ
Entry
Metal/Ligand (1/x)
PdCl2
Yield/%
n/iso
ꢀꢀ
1
2
3
4
5
0
0
Ru3(CO)12
CoCl2
ꢀꢀ
0
ꢀꢀ
Ni(OTf)2
0
ꢀꢀ
Rh(acac)(CO)2
35
93/7
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lar results were obtained for methanol and benzyl alcohol acyl group by CO typically results in a downfield shift of the
1
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(Scheme 2, eq 2). Hence, in contrast to classical carbonylation
reactions, here the catalyst does not only allow for the efficient
formation of the Rh acyl intermediate but is also responsible
for the selective activation of the NꢀH bonds of aliphatic
amines. This dual role of the Rh is a specific feature of this
transformation.
carbon nucleus of the acyl group by ca. 4 ppm.
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Scheme 2. Selective activation of aliphatic NꢀH bonds:
Control experiments using 1ꢀoctene with hexylamine, aniꢀ
line and alcohols.
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Figure 1. 13C NMR of the reaction in eq. 1ꢀ2. Red: at 80 oC;
blue: at 25 oC.
Probably, at 80 °C the various aminorhodiumꢀcarbonyl comꢀ
plexes are in fast equilibrium with each other resulting in a
major peak at around 230 ppm (CO trans to the acyl group).
Meanwhile, peaks around 235 ppm represent the species with
CO trans to the acyl group. At 25 °C, the dynamic exchange
between the different ligands is slower resulting in an inꢀ
creased amount of Rhꢀcarbonyl signals in between 180ꢀ190
ppm. Moreover, substitution of the coordinating amines by CO
might occur due to the increased CO concentration in solution
at lower temperature. Accordingly, the peak at around 235
ppm increased, which is also consistent with the observation
of more Rhꢀcarbonyl signals vide supra.
Previous work on rhodiumꢀcatalyzed hydroamination of alꢀ
kenes, both experimental observations and computational
studies, suggest that the direct oxidative addition of an amine
HꢀN bond to an unsaturated rhodium center is possible.27
However, this route can be excluded under the present (mild)
conditions (80ꢀ100 °C) due to the absence of ureas or formaꢀ
mides which are known to be formed form the corresponding
RhꢀN intermediates. Meanwhile, the formation of formamides
following by fast of rhodiumꢀcatalyzed hydrocarbamoylation
can also be excluded due to the difficulty of the direct activaꢀ
tion of the CꢀH bonds in amides by transition metal.8,28
A preliminary mechanism of the Rhꢀcatalyzed hydroamidation
of olefins with aliphatic amines and CO is proposed in Scheme
3. Firstly, under heating conditions [Rh(I)ꢀH] species a is
formed from the Rh precursor in the presence of amines and
CO.30 Then, insertion of the double bond of olefins into the
RhꢀH bond of a leads to the alkyl Rh species b and b’. Subseꢀ
quent insertion of CO generates the acyl Rh(I) species c and
c’, respectively. Notably, rhodiumꢀacyl intermediates c and c’
are detected by inꢀsitu 13C NMR measurements during the
reaction using 13Cꢀenriched CO. As the rate determining step,
nucleophilic addition of the amine to the rhodiumꢀacyl comꢀ
plexes produces the desired amide products with regeneration
of the Rh(I)ꢀH complex. In contrast, such kind of aminolizaꢀ
tion was shown to be not conceivable in the presence of H2.25
Specifically, in catalytic hydroaminomethylation reactions of
olefins with CO/H2 and amines, it is proposed that Rhꢀacyl
complexes as key intermediates are formed following by the
much more favored hydrogenolysis to generate aldehydes. The
aldehydes proceed via reductive amination to provide the
corresponding products.
Performing MS spectroscopic studies of the reaction solution
showed a variety of signals when the reaction was carried out
in the absence of CO or CO/olefin. In contrast, in the presence
of CO only four major signals (186.2, 229.2, 242.2, 251.2)
were obtained for the MSꢀESI data of the mixture of the reacꢀ
tion shown in eq. 1ꢀ1 including the product peak (241+1).
Next, in situ NMR measurements were carried out to further
investigate the reaction pathway (eq. 1ꢀ2). During the reaction
(12 h at 80 °C), no signals of metal hydrides were observed.
However, after three hours the desired amide product could be
detected by 13C NMR. After 12 h of reaction, in addition to the
product and Rh carbonyl complexes, in situ 13C NMR showed
one major peak at 230.3 ppm and one minor broad peak at
234.9 ppm. These signals are assigned to different Rh(I)ꢀacyl
species (Figure 1, red).29a After the mixture was cooled to 25
°C, the spectrum showed two comparable peaks at 231.3 and
235.9 ppm (Figure 1, blue). Meanwhile, the number of rhodiꢀ
um carbonyl peaks increased at 180ꢀ190 ppm as shown in the
spectra (Figure 1, red vs blue).
This proposal is supported by experimental results shown in
Tables 1 and S2 (ligand effect). Specifically, in the presence of
phosphine ligands, efficient isomerization of olefins via RhꢀH
insertion and βꢀhydride elimination was observed which indiꢀ
cates formation of [RhꢀH] and the related alkylꢀRh species.
Considering the easy formation of Rhꢀacyl intermediates durꢀ
ing hydroformylation reactions in the presence of phosphine
ligands, it is suggested that the amidation step is difficult and
will be retarded by addition of phosphine ligands. Apparently,
in the presence of such additional ligands the crucial amine
coordination/NꢀH bond cleavage on Rh center is blocked.31
In general, the ligand on the Rh center trans to acyl groups has
a significant impact on the chemical shift of the acyl group.29
Substitution of the ligand (e.g. monophosphines) trans to the
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Hence, the most effective catalyst system for hydroamidation
consists of simple rhodium carbonyl complexes.
with our catalytic system and the product 3an was obtained in
76% yield.
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5
6
7
8
9
Scheme 3. Proposed catalytic cycle
Then, the rhodiumꢀcatalyzed hydroamidation of 1ꢀoctene 1a
with different aliphatic amines was investigated. As shown in
Scheme 5, both primary amines (butylamine, hexylamine,
octylamine, cyclohexylamine, and phenethylamine) and secꢀ
ondary amines (Nꢀhexylmethylamine, piperidine and morphoꢀ
line) were smoothly transformed into the desired amides in
high yields with excellent regioselectivities. As expected,
when benzylamines 2gꢀi were used as substrates, similar good
results were obtained in all cases. Interestingly, 3ja represents
a potential drug for the treatment of erectile dysfunction as α2ꢀ
blocker,32 which was prepared efficiently from easily available
tryptamine 2j via our methodology. It is worth mentioning that
functionalized amine with nonꢀprotected hydroxyl group can
be chemoselectively transformed into the desired amide with
excellent regioselectivity. Futhermore, diamines with aliphatic
and aromatic amine moieties could be chemoselectively transꢀ
formed, too.33 Meanwhile, the chiral center in (S)ꢀ1ꢀ
phenylethylamine 2p was not influenced using this catalytic
method, providing the optically pure 3pa in 75% yield and
98/2 regioselectivity. At last, glycine tertꢀbutyl ester was also
proven to be suitable substrate and the corresponding Nꢀ
acylated product 3qa was obtained in 51% yield.
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Meanwhile, the CO gas consumptionꢀtime profile was recordꢀ
ed for the hydroamidation of 1ꢀoctene 1a. As shown in Figure
2, the reaction showed almost no induction period, which
indicated that active RhꢀH species are generated immediately
at 100 °C. Due to the fast isomerization of 1ꢀoctene 1a, the
rate of hydroamidation decreased significantly after 2 h. The
product 3aa was obtained in 87% yield with 95/5 selectivity
after 12 h. To our delight the catalyst loading could be lowered
to 0.1 mol% and 3aa was obtained in 70% yield with 96/4
selectivity after 20 h.
Scheme 4. Rhodiumꢀcatalyzed hydroamidation of alkenes
1aꢀn with hexylamine 2aa
O
RhCl3—3H2O ( 1 mol%)
+
H2N
R
N
R
4
4
CO (50 bar), toluene
100 oC, 20 h
H
1a-n
2a
3aa-an (yield, n/iso)
O
O
O
N
H
N
4
5
4
N
4
H
H
3aa (88%, 96/4)
3ab (84%, ꢀꢀ)b
3ac (83%, 93/7)c
O
O
O
N
H
4
N
4
N
H
4
H
Figure 2. CO gas uptake for rhodiumꢀcatalyzed hydroamiꢀ
dation of 1a with 2a.
3af (55%, 86/14)d
3ad (81%, 97/3)c
3ae (70%, 100/0)c
Substrate Scope. Next, the compatibility and limitations of
alkenes in our rhodiumꢀcatalyzed hydroamidation were tested.
Firstly, we studied the reaction of hexylamine 2a with differꢀ
ent alkenes (Scheme 4). Applying standard aliphatic terminal
olefins such as 1ꢀoctene, ethylene, 1ꢀpentene, and 4ꢀmethylꢀ1ꢀ
pentene, the corresponding products 3aa−ad were obtained in
good yields with high regioselectivities. Bulky group substiꢀ
tuted alkene 1e could also be tolerated and gave the product in
moderate yield with excellent linear selectivity. When using
styrene as an example of an aromatic substrate, the desired
product 3af was achieved too, albeit in lower yield and selecꢀ
tivity. However, when aꢀmethylstyrene was employed, no
desired product was detected even at increased temperature
(130 °C). On the other hand, allylbenzene and alkenes containꢀ
ing functional groups such as additional alkenyl, ether, silyl,
and ester groups reacted smoothly, affording the correspondꢀ
ing products 3agꢀam in moderate to good yields with excellent
regioselectivities. Interestingly, norbornene 1n worked well
O
O
O
Ph
N
4
N
H
N
H
4
4
H
3ag (81%, 94/6)
3ah (87%, 100/0)
3ai (79%, 100/0)
O
O
O
MeO2C
O
4
Et3Si
N
4
N
N
5
4
4
H
H
H
3aj (79%, 91/9)
3ak (74%, 99/1)
3al (40%, 95/5)
O
O
TBSO
N
N
H
4
4
4
H
3am (46%, 94/6)
3an (76%, ꢀꢀ)e
a
Reaction conditions: 1 (5.0 mmol), 2a (1.0 mmol), RhCl3·3H2O (1
mol%), CO (50 bar), toluene (1.0 mL), 100 °C, 20 h. The isolated yields
of 3aaꢀan were based on 2a. The ratios of isomers were determined by
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GC analysis. b 1b (ethylene, 25 mmol), 2a (5.0 mmol), toluene (5.0 mL). c
1cꢀe (15.0 mmol), 2a (3.0 mmol), toluene (3.0 mL). 120 °C. 1n (2.0
mmol).
General procedure for hydroamidation: Under argon atꢀ
mosphere, RhCl3•3H2O (2.6 mg, 1.0 mol%) and a stirring bar
were added into a vial (4 mL). Then, toluene (1.0 mL), 1 (1a
or 1fꢀm, 5.0 mmol) and 2a (0.14 mL, 1.0 mmol) were injected
by syringe. The vial was placed in an alloyed plate, which was
transferred into an autoclave (300 mL) under argon atmosꢀ
phere. At room temperature, the autoclave was flushed with
CO gas three times and pressurized with CO gas to 50 bar.
The reaction was performed at 100 °C for 20 h. After the
reaction was finished, the autoclave was cooled to room temꢀ
perature and the pressure was carefully released. The regioseꢀ
lectivity was measured by GC analysis. Removal of the solꢀ
vent under vacuum and purification of the remaining residue
by flash chromatography on silica gel (eluent: heptane/ethyl
acetate = 5/1–3/1) gave the desired amide 3.
d
e
1
2
3
4
5
6
7
8
CONCLUSION
In conclusion, we have developed a general and efficient
rhodiumꢀcatalyzed hydroamidation of olefins with aliphatic
amines. In the presence of easily available rhodium preꢀ
catalysts, various olefins and aliphatic amines are transformed
into the desired Nꢀalkyl amides in medium to high yields with
excellent regioselectivities. Notably, even in the presence of
aryl amines and alcohols the straightforward hydroamidation
of olefins with aliphatic amines was realized selectively. Preꢀ
liminary mechanistic studies reveal the formation of [Rh(I)ꢀH]
complexes as active species and the aminolysis of the rhodiꢀ
umꢀacyl complexes as the crucial reaction step.
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ASSOCIATED CONTENT
Supporting Information
Scheme 5. Rhodium catalyzed hydroamidation of 1ꢀoctene
1a with amines 2aꢀqa
Additional experimental results and procedures and characterꢀ
ization data. This material is available free of charge via the
Internet at http://pubs.acs.org.
O
R1
RhCl3—3H2O ( 1 mol%)
R1
R2
+
N
R2
HN
AUTHOR INFORMATION
Corresponding Author
5
5
CO (50 bar), toluene
100 oC, 20 h
1a
2b-q
3ba-qa
(yield,
/ )
n iso
Matthias.Beller@catalysis.de
Yuehui.Li@catalysis.de
O
O
O
N
N
H
5
N
5
5
H
H
Notes
3ba (85%, 94/6)
3ca (87%, 95/5)
3da (65%, 95/5)
The authors declare no competing financial interest.
O
ACKNOWLEDGMENT
O
O
N
5
The Federal Ministry of Education and Research (BMBF) and
Evonik Industries are gratefully acknowledged for their general
support. K. Dong thanks Shanghai Institute of Organic Chemistryꢀ
Zhejiang Medicine joint fellowship for financial support. We
thank the analytical department of LeibnizꢀInstitute for Catalysis,
Rostock for their excellent analytical service.
H
N
H
N
5
5
H
3ea
3fa
3ga
(63%, 94/6)
(86%, 95/5)
(94%, 95/5)
O
O
NH
O
N
H
N
5
5
N
H
5
H
Cl
REFERENCES
Br
3ha
3ia
3ja
(90%, 94/6)
(85%, 95/5)
(82%, 95/5)
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O
O
O
N
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5
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O
3ka
3la
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(70%, 94/6)
(68%, 96/4)
(67%, 97/3)
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OH
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NH2
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3na
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(75%, 98/2)
(55%, 94/6)
O
(90%, 95/5)
O
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H
O
3qa
(51%, 98/2)
a
Reaction conditions: 1a (5.0 mmol), 2bꢀq (1.0 mmol), RhCl3·3H2O (1
mol%), CO (50 bar), toluene (1.0 mL), 100 °C, 20 h. The isolated yields
were based on amines 2. The ratios of isomers were determined by GC
analysis.
METHODS
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