Acid-free regioselective aminocarbonylation of alkenes

Article abstract of DOI:10.1039/c4cc02167c

An efficient method for the synthesis of N-aryl monosubstituted carboxamides via the Pd-catalyzed carbonylation of alkenes with CO and amines is described. Mechanistic insights for this highly selective reaction are provided. This journal is the Partner O

Full text of DOI:10.1039/c4cc02167c

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Acid-free regioselective aminocarbonylation
of alkenes†
Cite this: Chem. Commun., 2014,
50, 7848
Huizhen Liu,* Ning Yan and Paul J. Dyson
Received 24th March 2014,
Accepted 3rd June 2014
DOI: 10.1039/c4cc02167c
www.rsc.org/chemcomm
An efficient method for the synthesis of N-aryl monosubstituted
carboxamides via the Pd-catalyzed carbonylation of alkenes with
CO and amines is described. Mechanistic insights for this highly
selective reaction are provided.
Scheme 1 The conversion of alkenes, amines and CO to amides.
Despite the importance of amides in chemistry and biology
most of the well-established methods for their synthesis are not
very efficient.1,2 While considerable progress has been made in be obtained. Linear carboxamides have been obtaining in yields of
recent years, e.g. the direct catalytic conversion of alcohols and up to 90% with a cobalt catalyst immobilized on charcoal.11
amines,3 new routes to amides are still needed. Two important Aminocarbonylation of olefins with aromatic amines and nitro-
reviews were published in 2011 highlighting developments in arenes using Pd(acac)2 and N-phenylpyrrole-based bis-phosphine
this area.4,5
ligands in the presence of p-TsOH leads to the formation of
The synthesis of amides via the carbonylation of C–X (X = H, linear products in up to 99%.12 Branched carboxamides, on
Br, I, etc.) bonds has received considerable attention.6 Notable the other hand, are useful scaffolds for biologically active
developments include palladium catalyzed carbonylation reac- molecules13 and oxindoles, which are commonly encountered
tions of aryl bromides and alk-1-ynes,7 transition metal-free substructures in natural products and bioactive molecules,
alkoxycarbonylation of aryl halides8 and the synthesis of amides can be synthesized directly from branched carboxamides.14
via the activation of aromatic C–H bonds.9 Recently, we reported Recently, a palladium-catalyzed amidation–hydrolysis reaction was
that PdCl2 combined with various wide bite-angle bis-phosphines shown to afford branched carboxamides from gem-dihaloalkene
including xantphos, nixantphos, (ꢀ)-binapo or (R)-phanephos and aryl amines.15
catalyzes the formation of amides in the absence of acid or base,
Herein, we describe a simple, homogeneous PdX2/tris(2-
by the direct activation of C(sp3)–H bonds with subsequent CO methoxyphenyl)phosphine system (X = Cl or Br) that catalyzes
insertion. However, the selectivity of this reaction is low, e.g. the aminocarbonylation of alkenes with the regioselectivity for
the ratio of branched to linear products in the reaction of branched carboxamides often exceeding 99%.
ethylbenzene and aniline in the presence of CO, is 46: 13 with
The reaction was optimized with respect to the substrate
rations, temperature and pressure and Pd : ligand ratio using
PdCl2/xantphos and 53 : 12 with PdCl2/(R)-phanephos.10
The synthesis of amides from alkenes and amines in the styrene and aniline as the substrates with various combinations
presence of CO represents an ideal, atom economic and environ- of PdCl2–ligand catalysts (see ESI†). The highest yield and selecti-
mentally benign route (Scheme 1), with the potential for asym- vity of the desired amide product, i.e. N,2-diphenylpropanamide,
metric transformations. However, to the best of our knowledge, was obtained in the presence of tris(2-methoxyphenyl)phosphine
reports on this reaction are rare,11,12 and moreover, high regio- under 50 atm of CO at 125 1C (see ESI†). The nature of the ligand
selectivity is important as both linear and branched products can strongly influences the reaction and monophosphine ligands such
as PPh3, tris(2-methoxyphenyl)phosphine, tris(4-methoxyphenyl)-
´
´ ´
Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de
Lausanne (EPFL), CH-1015 Lausanne, Switzerland. E-mail: huizhen.liu@epfl.ch;
Fax: +41-21-6939865
phosphine tris(2,6-dimethoxyphenyl)phosphine and tris(2-methy-
phenyl)phosphine lead to higher selectivities for the branched
product, although the yield with tris(2,6-methoxyphenyl)phosphine
and tri-(2-tolyl)phosphine is lower (Table 1, entries 1–6). Bis-
phosphine ligands afford less selective and less active catalysts
† Electronic supplementary information (ESI) available: Full experimental details
including instrumentation, catalytic procedures, mechanistic studies and spectro-
scopic data. See DOI: 10.1039/c4cc02167c
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Table 1 Optimization of the reaction of styrene with aniline and CO to
afford N,2-diphenylpropanamide
The substrate scope of the reaction was explored under opti-
mized conditions (CO 50 atm, 125 1C) using PdCl2 (5 mol%) and
two equivalents of the tris(2-methoxyphenyl)phosphine co-catalyst
(Table 2). The system is active for anilines with both electron
withdrawing or donating substituents. Under the standard condi-
tions most aromatic anilines react with styrene to afford the
desired product in yields exceeding 90% with the exception of
3- and 4-nitroaniline and N-methylaniline. The system is also
active for aliphatic alkenes, e.g. the reaction of 1-hexene with
Entry
Metal salt
Ligand
Yield (%)
B/L
94 : 6
1
PdCl2
PPh3
94
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19a
20b
21
22c
23d
24e
25 f
26 g
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdBr2
Pd(OAc)2
Pd(acac)2
CoCl2
RhCl3
RuCl3
Ru3(CO)12
Co2(CO)8
Re2(CO)10
Pd2(dba)3
Pd(PPh3)4
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
P(2-OMePh)3
P(4-OMePh)3
P(2,6-OMePh)3
P(2-MePh)3
dmpp
95
92
8
86
8
91
92
0
0
94
Trace
Trace
1
17
3
Trace
Trace
Trace
Trace
17
499 : o1
94 : 6
499 : o1
499 : o1
499 : o1
39 : 61
39 : 61
—
Xantphosa
dppf a
dppea
dppba
—
Table 2 Substrate scope of the palladium catalysed aminocarbonylation
of alkenes (1a) with amines (2a)
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
—
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
P(2-OMePh)3
92 : 8
—
—
499 : o1
499 : o1
499 : o1
—
—
—
—
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
499 : o1
67
26
92
90
94
Reaction conditions: styrene (11 mmol), aniline (1 mmol), PdCl2
(5 mol% based on aniline), ligand (0.12 mmol), THF 10 ml, CO
b
(50 atm), T (125 1C), t (2 h). a Ligand (0.06 mmol). Ligand (0.24 mmol).
c
Reaction was performed in the presence of air (1 atm) and CO
d
e
(50 atm). Toluene (10 ml) used as the solvent. CH3CN (10 ml) used
f
g
as solvent. Styrene (1 mmol) and aniline (1 mmol). CO (10 atm).
P(2-OMePh)3 = tris(2-methoxyphenyl)phosphine, P(4-OMePh)3 = tris(4-
methoxyphenyl)phosphine, P(2,6-OMePh)3 = tris(2,6-dimethoxyphenyl)-
phosphine, P(2-MePh)3
= tris(2-methyphenyl)phosphine, dmpp =
dimethyl phenylphosphonite, xantphos = 4,5-bis(diphenylphosphino)-
9,9-dimethylxanthene, dppf = 1,10-bis(diphenylphosphino)ferrocene,
dppe = 1,2-bis(diphenylphosphino)ethane, dppb = 1,2-bis(diphenylphos-
phino)benzene. Yields were determined by GC analysis relative to aniline
using n-decane as an internal standard.
(Table 1, entries 7–10) – notably with 1,2-bis(diphenylphosphino)-
ethane and 1,2-bis(diphenylphosphino)benzene no product is
obtained. Conducting the reaction in toluene results in a lower
conversion (Table 1, entry 23) and acetonitrile is also a good solvent
for the reaction (Table 1, entry 24). At a styrene : aniline ratio of 1 : 1
the yield of the desired product reaches 90% at longer reaction
times, i.e. 4 hours and at a lower CO pressure, i.e. 10 atm, the yield
is 94% after 4 hours (Table 1, entries 25 and 26, respectively).
PdBr2 can also be used as a catalyst precursor for this
reaction although the selectivity is slightly lower than that
obtained with PdCl2 (Table 1, cf. entries 2 and 11). The other
metal salts evaluated were less efficient than PdCl2 and PdBr2
(Table 1, entries 14–16). Notably, other palladium(II) precursors
(Table 1, entries 12 and 13) and palladium(0) compounds
(Table 1, entries 20 and 21) as well as the transition metal
carbonyl complexes (Table 1, entries 17–19) afford considerably
less active catalysts. The low yield obtained with Pd(acac)2 is
consistent with other studies.12 In the presence of CO and air
diphenylurea is obtained in 24% yield and the yield of
branched product is only 67% (Table 1, entry 22).
Reaction conditions: 1 (11 mmol), 2 (1 mmol), PdCl2 (5 mol% based
on 2). P(2-OMePh)3 (0.12 mmol), THF (10 ml), CO (50 atm), T: 125 1C,
t: 2 h. t: 20 h, yields quoted correspond to isolated yields.
a
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Scheme 2 Transformation of amide to useful compound.
Scheme 3 Proposed catalytic cycle commencing with activation of the
alkene (X = Cl or Br).
aniline in the presence of CO affords the desired product in 80%
yield, and for cyclohexene, the yield of the desired product can be
reached to 96%. With nitrile substituted aliphatic alkene the yield
of the product is 63% and for allylbenzene the yield of corres-
ponding product reaches 72% after 20 hours. However, the
catalytic system is inactive for aliphatic amines.
The aminocarbonylation reaction was used to generate N-(4-
methoxyphenyl)cyclohexanecarboxamide (4) which was subse-
quently converted to pyrimidine derivatives (5) (Scheme 2 see
ESI†).19
product increases to 92%. Importantly, insertion of the hydride
usually takes place at the most sterically crowded carbon atom
of a coordinated alkene, but with this catalytic system the
opposite is observed, hence giving high yields of the branched
product. This is presumably due to the use of bulky monophos-
phine ligands that result in a pseudo-linear geometry (P–Pd–P
angle of ca. 1801) which favors attach at the less crowded
carbon atom.
The data shown in Table S5 (ESI†) implies that the yield of
the product is related to the N–H bond dissociation energy,16
i.e. the lower the bond dissociation energy the higher yield of
the product, and is therefore implicated in the rate determining
step of the catalytic cycle (see below).
The addition of aniline to activated alkenes using palladium/
phosphine catalysts typically requires co-catalytic amounts of
acid17 and, similarly, aminocarbonylation of alkenes using
Pd(acac)2 requires p-TsOH.12 In both cases the co-catalyst is needed
to generate the active palladium hydride species. Carbonylation
reactions involving metal hydride species assisted by the
presence of acid have been reported.18 However, using the
PdX2/tris(2-methoxyphenyl)phosphine (X = Cl or Br) catalysts
the acid is generated in situ (see below).
The hydroamination of alkenes also needs additional acid to
produce metal hydride species and the reaction conditions are
similar to those used for the aminocarbonylation of alkenes.20
However, PdX2/tris(2-methoxyphenyl)phosphine (X = Cl or Br) is
not active for the hydroamination of alkenes in the absence of
acid, and therefore it seems likely that CO not only acts as a
substrate but also helps to regenerate the active Pd(0) catalyst
and generate HCl in situ, also explaining why palladium(II)
halides are the most efficient catalyst precursors. Indeed, an
ESI mass spectrum was recorded of the post-reaction solution
and a peak at m/z 811 is observed that may be tentative assigned
to [L2PdH]+ (L = tris(2-methoxyphenyl)phosphine), and based
on this observation a catalytic cycle may be proposed, see
Scheme 3. In this catalytic cycle water is required to generate
the active catalyst, and in agreement with this hypothesis the
yield of the product is 10% when the reaction is performed in
dry THF, and on addition of water (40 mg) the yield of desired
Two principal pathways appear to be involved, the one men-
tioned above involving initial activation of the alkene, which is
presumably the dominant route, and another involving primary
activation of the amine (Scheme S1, ESI†). In the ESI mass
spectrum a peak at m/z 845.08 may be attributed to [L2PdCl]+
and one at m/z 938.75 to [L2PdClNH2Ph]+ indicative of this latter
pathway (Fig. S1, ESI†). Indeed, Milstein and co-workers reported
the Ir(I)-catalyzed addition of aniline to norbornylene via N–H
activation in absence of a Brønsted acid,21 which supports a
secondary mechanism involving amine activation.
A simple palladium-based catalyst is described for the general
and selective aminocarbonylation of alkenes that affords N-aryl
monosubstituted carboxamides. A wide range of aromatic amines
may be efficiently transformed in good yield and usually with high
regioselectivity. Notably, the catalyst does not require acid, base or
any other promoters and employs a commercially available bulky
monophosphine ligand thus facilitating reaction scale-up. It
seems plausible that a pseudo-linear, cationic P–Pd–P species is
involved in the process that facilitates insertion of the hydride to
the least sterically crowded C-atom of the coordinated alkene.
This work was supported by the EPFL and the Swiss National
Science Foundation.
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