Amide bond formation via C(sp3)-H bond functionalization and CO insertion

Article abstract of DOI:10.1039/c3cc47015f

An efficient method for the synthesis of amides via Pd-catalyzed oxidative carbonylation of C(sp³)-H bonds with CO and amines is described. The route efficiently provides substituted phenyl amides from alkanes.

Full text of DOI:10.1039/c3cc47015f

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Amide bond formation via C(sp3)–H bond
functionalization and CO insertion†‡
Cite this: Chem. Commun., 2014,
50, 341
Huizhen Liu, Gabor Laurenczy, Ning Yan and Paul J. Dyson*
Received 13th September 2013,
Accepted 30th October 2013
DOI: 10.1039/c3cc47015f
www.rsc.org/chemcomm
An efficient method for the synthesis of amides via Pd-catalyzed oxidative activation of aromatic C–H bonds.12 Rhodium13 and ruthenium14
carbonylation of C(sp3)–H bonds with CO and amines is described. The complexes that catalyze the formation of amides by activating C(sp2)–
route efficiently provides substituted phenyl amides from alkanes.
H bonds have also been reported.
Palladium–phosphine complexes are widely used to catalyze the
The importance of amides in chemistry and biology is well recognized formation of carbon–carbon, carbon–nitrogen and carbon–oxygen
and, consequently, a variety of methods have been developed for their bonds.15 Bis-phosphine ligands are particularly useful in these
synthesis,1 with notable examples including the Schmidt, Schotten– reactions and the influence of the ligand bite-angle on C–C and
Baumann and Ugi reactions.2 These methods are based on the C–X bond forming cross coupling reactions has been reviewed.16
reactions of activated acid derivatives (acid chlorides and anhydrides) The wide bite-angle bis-phosphine, Xantphos, has found a number
or acid/base induced rearrangement reactions. Recently, attention has of important uses. Notably, Huang and co-workers reported the
been devoted to developing new routes to amides that do not require synthesis of esters from alkanes using a PdCl2–Xantphos catalyst in
acid or base, but to achieve this goal, relatively expensive starting the presence of tBuOOtBu.17 Azidocarbonylation reactions may also
materials such as aldehydes are required. Metal catalyzed routes be catalyzed by a Pd2(dba)3–Xantphos system18 and intermolecular
enable amides to be generated from starting materials other than amidation of aryl halides using Pd(OAc)2–Xantphos has also been
carboxylic acids and these reactions are summarized in two reported.19 Pd-catalyzed direct oxidative carbonylation of allylic C–H
excellent review articles.3,4 Perhaps the most notable achievement bonds with carbon monoxide has also been reported.20 We found that
in this regard has been the direct catalytic conversion of alcohols PdCl2 combined with various bis-phosphines including Xantphos,
and amines into amides.5
Nixantphos, (ꢀ)-Binapo or (R)-Phanephos catalyze the formation of
The synthesis of amides involving transition metal catalyzed C–X amides in the absence of acid or base, by the direct functionalization
(X = H, Br, I etc.) bond functionalization followed by carbonylation of C(sp3)–H bonds with subsequent CO insertion – the outcome of
with CO has received considerable attention as it has a high atom these studies is described herein.
economy.6 Seminal research includes the catalytic aminocarbonyla-
The viability of the reaction was explored with toluene 1 and
tion of alk-1-ynes7 and the application of a homogeneous PdCl2–PPh3 aniline 2 as substrates under CO (50 atm) using various PdCl2-based
catalytic system for direct oxidative aminocarbonylation using CO and catalysts due to their excellent performance in carbonylation reactions
oxygen under basic conditions.8 The catalytic aminocarbonylation of (Scheme 1, Table 1).21 High yields of the desired product (compound
alkenes using a Co/C catalyst has also been reported,9 and palladium 3 in Scheme 1) are obtained with the wide bite-angle bis-phosphines,
catalyzed carbonylation reactions of aryl bromides have been used to Xantphos, Nixantphos, or (R)-Phanephos and also with (ꢀ)-Binapo
prepare benzamides from aryl bromides at atmospheric pressure.10 (Table 1, entries 9–12 and 16–19). The yield of 3 is very low in the
Other notable developments include transition metal-free alkoxy- absence of a ligand co-catalyst (Table 1, entries 1 and 2) or in the
carbonylation of aryl halides,11 and the synthesis of amides by the presence of other bis-phosphines and mono-phosphine ligands
(Table 1, entries 3–8). The influence of the bis-phosphine bite-angle
is apparent (Table 1, entries 3–12), with ligands with bite-angles >901
´
´ ´
Institut des Sciences et Ingenierie Chimiques, Ecole Polytechnique Federale de
Lausanne (EPFL), CH-1015 Lausanne, Switzerland. E-mail: Paul.Dyson@epfl.ch;
Fax: +41-21-6939865
† This article is published in celebration of the 50th anniversary of the opening of
the Chemistry Department at the University of York.
‡ Electronic supplementary information (ESI) available: Full experimental details
including instrumentation, catalytic procedures, mechanistic studies and spec-
troscopic data. See DOI: 10.1039/c3cc47015f
Scheme 1 Reaction of toluene, aniline and CO to afford N,2-diphenylacetamide.
Chem. Commun., 2014, 50, 341--343 | 341
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Table 1 Optimization of reaction conditions for the reaction of toluene
Table 2 Substrate scope of the Pd-catalyzed amide formation with
and aniline with CO
aniline
Entry T (1C) Ligand
Bite angle, b1 Oxidant Yield of 3g (%) Entry
RH
Yielda (%)
1
100
100
100
100
100
100
100
100
100
100
100
100
100
100
80
125
125
125
125
150
125
125
125
125
125
125
125
125
—
—
—
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
—
0.4
0
0.9
2
2a
3
Xantphos
Dppbe
Triphos
PPh3
Dppe
Tapp
1
0
8722 h
4
5
6
7
8
9
8423
2
Branched (46)c Linear (13)d
—
10
8624
0
16
3
3b
4
Branched (53)c Linear (12)d
—
Dppf
9924
10224
102i
Xantphos
Nixantphos
(ꢀ)-Binapo
34
36
31
46
21
30
20
66
54
62
68
48
0
0
0
0.3
7
0
3
0.4
43 (39)
60
10
11
12
13b
14c
15
16
17
18
19
20
21
22
23
24
25
26d
27e
28f
9325
5b
6
(R)-Phanephos 10126
Xantphos
Xantphos
Xantphos
Xantphos
Nixantphos
(ꢀ)-Binapo
10224
10224
10224
10224
102g
66 (62)
68
7b
8
9325
(R)-Phanephos 10126
55 (51), 38b
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
Xantphos
10224
10224
10224
10224
10224
10224
10224
10224
10224
10
12
57 (51), 31b
Trace
Ag2O
AgOAc
H2O2
K2S2O8
DTBP
DTBP
DTBP
Reaction conditions: RH (15 ml), 2 (1 mmol), PdCl2 (5 mol% based on
aniline), Xantphos (0.06 mmol), DTBP (1.2 mmol), CO (50 atm), 125 1C, 24 h.
a Yields were determined by GC analysis relative to aniline with n-decane as
an internal standard (isolated yield in parentheses). b With (R)-Phanephos
Dppbe = 1,2-bis(diphenylphosphino)benzene, Tapp = tris(o-methoxyphenyl)- (0.06 mmol). c N,2-diphenylpropanamide. d N,3-diphenylpropanamide.
phosphine, Dppf = 1,10-bis(diphenylphosphino)ferrocene, Dppe = 1,2-bis-
(diphenylphosphino)ethane, DTBP
= 1
tBuOOtBu. Reaction conditions:
(15 ml), 2 (1 mmol), PdCl2 (5 mol% based on aniline), ligand (0.06 mmol),
oxidant (1.2 mmol), CO (50 atm), 24 h. a Without PdCl2. b CO (30 atm). c CO
(40 atm). d With H2O (15 ml), 1 (15 mmol), and 2 (1 mmol). e Pd2(dba)3
0.05 mmol. f Pd(PPh3)4 0.05 mmol. g Yields were determined by GC analysis
relative to aniline with n-decane as an internal standard. h The bite angle given
corresponds to that in (Dppbe)PdBr2. i The structure of Nixantphos is similar
to Xantphos and it is therefore assumed that their bite-angles are the same.
Xantphos or (R)-Phanephos and DTBP as the oxidant (Table 2).
Products resulting from carbonylation of C(sp2)–H (aromatic) bonds
are not observed (Table 2, entry 1). Cyclohexane reacts in the presence
of DTBP to afford the corresponding amide in reasonable yield
(Table 2, entries 4 and 5), albeit lower than the yield of the product
obtained with toluene (Table 2, entries 6 and 7), presumably due to
generally exhibiting better activity (the exception being dppf). Moreover, the higher bond dissociation energy of the C–H bond in cyclohexane
in the absence of an oxidant or in the presence of a weak oxidant, i.e. compared to toluene.27 With diphenylmethane the main product is
Ag2O, compound 3 is not obtained (Table 1, entries 21 and 22). Aniline 1,3-diphenylurea, presumably due to steric hindrance. Presumably the
reacts more favourably with itself to afford 1,3-diphenylurea when yield of the branched product is higher than the linear product using
H2O2 is employed as the oxidant or H2O as the solvent (Table 1, ethylbenzene as the substrate for the same reason (Table 2, entries 2
entries 24 and 26). The influence of temperature and CO pressure on and 3). Moreover, electron withdrawing –F and –Cl substituents in the
the carbonylation reaction was also investigated under the reaction para-position favor the reaction; however, for the carbonylation of
conditions optimized using the PdCl2–Xantphos system. The highest toluene, ethylbenzene and cyclohexane, the ligand (R)-Phanephos is
yield of 66% is obtained when the reaction is performed under 50 atm superior to Xantphos, whereas for substrates with electron withdrawing
of CO at 125 1C (Table 1, entry 16). Under these conditions a similar –F and –Cl substituents in the para-position, Xanthphos is superior
yield (68%) is obtained with the (R)-Phanephos ligand (Table 1, entry (Table 2, entries 2–11). These combined data confirm that the yield of
19). Pd(0) pre-catalysts were also evaluated, i.e. Pd2(dba)3 and Pd(PPh3)4, the desired product is related, at least in part, to the C(sp3)–H bond
and while they are active the desired product is obtained in low yield, dissociation energies. The PdCl2–Xantphos catalyst tolerates anilines
3% and 0.4%, respectively (Table 1, entries 27 and 28).
with electron withdrawing or donating substituents (Scheme 2 and
Under standard conditions toluene was replaced by toluene-d8 and Table 3), although electron withdrawing groups are more favorable for
after 2 hours the yield of the desired product is 7% (compared to 18% this reaction. The system is, unfortunately, inactive with alkylamines.
for toluene – rH/rD = 2.6) suggesting that the C(sp3)–H bond cleavage
step occurs before the rate-limiting step or might be involved in the
rate-limiting step of this transformation. Hence, the yield of the
desired product should be related to the C(sp3)–H bond dissociation
energies. The substrate scope of the reaction was explored under
optimized conditions (CO 50 atm, 125 1C) using 5 mol% of PdCl2 with Scheme 2 Reaction of toluene and substituted anilines with CO.
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Table 3 Influence of substituents attached to aniline on the carbonylation
reaction
This work was supported by the EPFL and the Swiss National
Science Foundation.
a
Entry
R
Yield of 30 (%)
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4-Cl
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3-OMe
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10
11
12
13
14
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Chem. Commun., 2014, 50, 341--343 | 343