Synthesis of azomethines from α-oxocarboxylates, amines and aryl bromides via one-pot three-component decarboxylative coupling

Article abstract of DOI:10.1002/adsc.201000798

A bimetallic palladium/copper catalyst system allows the highly modular synthesis of azomethines via the decarboxylative coupling of aryl halides and α-iminocarboxylates, generated in situ from potassium α- oxocarboxylates and primary amines. The reaction proceeds already at 100a°C, a new record for redox-neutral decarboxylative cross-coupling reactions.

Full text of DOI:10.1002/adsc.201000798

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DOI: 10.1002/adsc.201000798
Synthesis of Azomethines from a-Oxocarboxylates, Amines and
Aryl Bromides via One-Pot Three-Component Decarboxylative
Coupling
Felix Rudolphi,a Bingrui Song,a and Lukas J. Gooßena,*
a
FB Chemie – Organische Chemie, TU Kaiserslautern, Erwin-Schrçdinger-Str. Geb. 54, 67663 Kaiserslautern, Germany
Fax : (+49) 631-205-3921; e-mail: goossen@chemie.uni-kl.de
Received: October 22, 2010; Published online: February 8, 2011
Dedicated to Dr. Dieter Ramin on the occasion of his 85th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000798.
Abstract: A bimetallic palladium/copper catalyst
system allows the highly modular synthesis of azo-
methines via the decarboxylative coupling of aryl
halides and a-iminocarboxylates, generated in situ
from potassium a-oxocarboxylates and primary
amines. The reaction proceeds already at 1008C, a
new record for redox-neutral decarboxylative cross-
coupling reactions.
Keywords: copper; cross-coupling; decarboxylation;
multicomponent reactions; palladium; Schiff bases
Scheme 1. Traditional and modern syntheses of imines.
Imines are valuable intermediates in the synthesis of boronates (V),[10] the palladium-catalyzed addition of
amines[1,2] and nitrogen-containing heterocycles.[3] arenes or boronic acids to nitriles (II or III, respec-
Moreover, imino groups are widely utilized as direct- tively)[11] and the dehydrogenative coupling of alco-
[4]
ing groups in aromatic C H activation reactions and hols and amines.[12] One of the few three-component
À
are key functionalities in ligands for olefin polymeri- imine syntheses consists of the catalytic cross-coupling
zation catalysis.[5] A direct, yet modular access to this of aryl halides with organometallic reagents in the
compound class based on easily available reagents, in presence of toxic and malodorous isonitriles (VI).[13]
which all three substituents can be independently
varied, is thus of high interest.
We herein present a highly modular entry to the
azomethine moiety, involving the decarboxylative
Traditional syntheses of imines include the conden- coupling of aryl halides and a-iminocarboxylates, gen-
sation of the respective carbonyl compound with a erated in situ from potassium a-oxocarboxylates and
primary amine (Scheme 1, I),[6] the addition of organ- primary amines (Scheme 2).
ometallic reagents to nitriles (II),[7] and the arylation
Decarboxylative couplings have recently emerged
of nitriles under Friedel–Crafts conditions (III).[8] as a powerful synthetic strategy to access, for exam-
However, none of these syntheses is fully modular, as
the products result from combinations of only two re-
agents. Moreover, they are often incompatible with
sensitive functional groups due to the harsh reaction
conditions or the use of organometallic reagents. Ex-
amples of modern two-component syntheses are the
catalytic hydroamination of alkynes (IV),[9] the ruthe-
nium-catalyzed oxidative coupling of aldimines and Scheme 2. One-pot, three-component azomethine synthesis.
Adv. Synth. Catal. 2011, 353, 337 – 342
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337

Felix Rudolphi et al.
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Scheme 3. Postulated catalytic cycle for the aryl imine synthesis.
ple, biaryls,[14,15] vinylarenes,[16] aryl ketones,[17] age of the azomethines, the same process would give
esters[18] and allyl compounds.[19] The inherent advant- access also to aryl ketones. The mechanistic blueprint
age of redox-neutral couplings[14] is that simple car- for this synthetic strategy is outlined in Scheme 3.
boxylic acid salts replace preformed organometallic
In the first step, the a-oxocarboxylate 1 would react
reagents as the sources of carbon nucleophiles.[20] with the primary amine 2 via the hemiaminal to the
However, despite all progress achieved,[21] the re- a-iminocarboxylate 5. In the coordination sphere of
quirement for high reaction temperatures remains as the copper, the latter should decarboxylate to give
their principal drawback. For example, the Pd/Cu-cat- the stable imidoyl copper complex c.[25] Under regen-
alyzed decarboxylative coupling of aryl halides with eration of the initial copper halide species a, the imi-
a-oxocarboxylates gives the corresponding aryl ke- doyl residue would then be transferred to the arylpal-
tones only at 1708C.[17a,22] In a search for concepts to ladium halide e, which is formed via oxidative addi-
lower the reaction temperature of the latter reaction, tion of the aryl halide 3 to the palladium(0) species d.
we investigated whether the conversion of a-oxocar- The azomethine product 4 would be liberated by re-
boxylic acids into a-iminocarboxylates would reduce ductive elimination from complex f, closing the cata-
the activation barrier of the decarboxylation lytic cycle for the palladium.
step.[16c,21c,23] This appeared to be a promising strategy,
We started the development of the new decarboxy-
as the higher stability of imidoyl over acyl anions lative cross-coupling process by subjecting the pre-
should make the extrusion of CO2 from a-iminocar- formed a-iminoacetate salt 5a[24b] and 4-bromotoluene
boxylate salts more favorable than the decarboxyla- (3a) to the typical conditions of decarboxylative cou-
tion of the corresponding a-oxocarboxylate salts.[24]
plings [1 mol% PdACTHNGUTERN(UNG F6-acac)2, 2 mol% (o-Tol)3P,
If it were possible to combine the condensation of 15 mol% CuBr, 15 mol% 1,10-phenanthroline, NMP/
an amine with the reactive carbonyl group of an a- quinoline]. At 1708C, azomethine 4w was formed in
oxoACHTUNGTRENNUNGcarboxylate to give the a-iminocarboxylate and its almost quantitative yield as a mixture of stereoiso-
decarboxylative cross-coupling reaction with aryl hal- mers (Scheme 4). The product was detected in notice-
ides into a one-pot process, this might open the door able quantities (5%) even at 1008C, an unprecedent-
to an expedient three-component azomethine synthe- edly low temperature for redox-neutral decarboxyla-
sis. In combination with an optional hydrolytic cleav- tive cross-couplings.
Scheme 4. Synthesis of azomethines from a-iminocarboxylates.
338
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Synthesis of Azomethines from a-Oxocarboxylates, Amines and Aryl Bromides
Table 1. Development of the catalyst system.[a]
Entry
Cu source
Pd source
Ligand
(o-Tol)3P
ACHTUNGTNER(NUNG o-Tol)3P
–
R
ACHTUNGTRENNUNG
U
ACHTUNGTRENNUNG
Solvent
Yield [%]
1
2
3
4
5
6
7
8
CuBr
–
CuBr
CuI
Pd
Pd
–
U
E
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
NMP
quinoline
DMF
DMPU
NMP
NMP
49
0
0
43
5
Pd
Pd
Pd
Pd
N
Cu2O
CuCl2
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
20
14[b]
51
38
42
48
27
82/38
69
81
77
37
43
93
43
5
PdCl2
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
9
Pd
Pd
U
10
11
12
13
14
15
16
17
18
19
20
21
22
23
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
A
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
–
(p-MeOC6H4)3P
binap
dppf
dppb
PCy3
PPh3
dppf
dppf
dppf
dppf
dppf
92[c]
80[c,d]
[a]
Reaction conditions: 15 mol% Cu catalyst, 1 mol% Pd catalyst, 2 mol% ligand (1 mol% for bidentate ligands), 15 mol%
1,10-phenanthroline, 200 mg 3 ꢁ molecular sieves, 2 mL solvent, 1008C, 6 h, yields were determined by GC with n-tetra-
decane as internal standard. dba=dibenzylideneacetone, binap=2,2’-bis(diphenylphosphanyl)-1,1’-binaphthyl, dppf=1,1’-
bis(diphenylphosphanyl)ferrocene, dppb=1,4-bis(diphenylphosphanyl)butane.
Without 1,10-phenanthroline.
16 h.
808C.
[b]
[c]
[d]
Encouraged by the results of these test reactions, imine condensation of the potassium a-oxocarboxy-
we then moved on to identify a suitable protocol for late to proceed without adding any further media-
the desired one-pot, three-component azomethine tor.[26]
synthesis. A first test revealed that the above reaction
The main side reaction was a protodecarboxylation
gave an even higher yield (27%) when the imine com- under formation of the aldimine.[27] In an attempt to
ponent was prepared in situ from the potassium a- optimize the yield, we first varied the copper and pal-
oxoACHTUNGTRENNUNGcarboxylate and the aniline. We then chose the re- ladium catalysts. Control experiments revealed that
action of potassium phenyloxoacetate with the simple both palladium and copper are obligatory (entries 2
aliphatic amine cyclohexylamine (2a) and the moder- and 3). Copper(I) bromide was found to be the most
ately reactive aryl bromide 4-bromotoluene (3a) as a effective copper source, with other copper salts lower
model for further investigations (reaction scheme in yields were obtained (entries 4–6). The presence of
Table 1). The a-iminocarboxylate salt of this aliphatic 1,10-phenanthroline as a ligand for the copper is ben-
amine is very sensitive towards hydrolysis, and could eficial (entry 7). The choice of the palladium precur-
not be isolated in pure form. However, upon mixing sor was found to have only a limited effect on the re-
all reaction components in the presence of molecular action outcome (entries 8–11). The key towards
sieves, the desired azomethine product 4a was directly achieving higher yields was the choice of the phos-
obtained in moderate yields already after 6 h at phine ligand. Moderately electron-rich triarylphos-
1008C (Table 1, entry 1). This indicated that the reac- phines such as tri(p-methoxyphenyl)phosphine, and
tivity of the carbonyl group was sufficient to allow the chelating phosphines with a large bite angle such as
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339

Felix Rudolphi et al.
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Table 2. Substrate scope of the new azomethine synthesis.[a]
Table 2. (Continued)
Product
Yield Product
[%][b]
Yield
[%][b]
45[c]
87
64
94[d]
Product
Yield Product
[%][b]
Yield
[%][b]
60[d]
73[d]
91
92
86
90
85
94
53[d]
16[d,e]
[a]
R1 is shown on the left side of the imino group. Reaction
conditions: 15 mol% CuBr, 1 mol% Pd(F6-acac)2,
1 mol% dppf, 15 mol% 1,10-phenanthroline, 2 mL NMP,
AHCTUNGTRENNUNG
1008C, 16 h.
Isolated yield, mixture of stereoisomers.
After 36 h.
1308C.
GC yield.
[b]
[c]
[d]
[e]
66
93
1,1’-diphenylphosphinoferrocene (dppf, entry 15),
gave best results. Trialkylphoshines and less electron-
rich triarylphosphines were less effective (entries 17
and 18). Among the solvents tested, the polar aprotic
N-methylpyrrolidone (NMP) was found to be optimal.
Using quinoline as the solvent, even higher yields
were detected, but the separation of the azomethine
product from the basic amine proved to be laborious
(entry 19). Similarly, high yields were achieved with
NMP after increasing the reaction time to 16 h
(entry 22). With the optimized catalyst system
57
83
91
34
95
65
85
94
[1 mol% PdACHTNUGTRNEG(UN F6-acac)2, 1 mol% dppf, 15 mol% CuBr,
15 mol% 1,10-phenanthroline, 3 ꢁ molecular sieves,
NMP), azomethine 4a was formed in 92% yield at
1008C as a mixture of stereoisomers. Even at 808C
satisfactory yields were obtained (entry 23).
Having discovered an effective low-temperature
protocol for the desired decarboxylative azomethine
synthesis, we next evaluated its scope by varying all
three reaction components. Representative products
obtained are displayed in Table 2. The reaction is
widely applicable with regard to the aryl bromide, as
demonstrated by compounds 4a–n. A plethora of
electron-rich and electron-deficient aryl and hetero-
66
71
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Adv. Synth. Catal. 2011, 353, 337 – 342

Synthesis of Azomethines from a-Oxocarboxylates, Amines and Aryl Bromides
aryl bromides containing various functional groups, Experimental Section
for example, thioether, halide, nitro or ester moieties,
were coupled in high yields with potassium phenyl- Synthesis of N-[Phenyl-(4-tolyl)-methylene)-
A
cyclohexylamine (4a)
A
mixture of potassium phenyloxoacetate (1a, 4.52 g,
pylbiphenyl instead of dppf allows the coupling also
of aryl chlorides as exemplified by the synthesis of 4a
in 61% yield from 4-chlorotoluene. The oxocarboxy-
late component can also be varied (compounds 4o–s).
Electron-rich and electron-deficient arene- and hetero-
areneoxoacetates gave similarly good results. Ali-
phatic derivatives could also be converted using
slightly longer reaction times. The amine component
is also variable (compounds 4t–z). Both linear and
branched aliphatic amines gave high yields, only the
sterically crowded tert-butylamine failed to react.
Electron-rich aromatic amines are also suitable sub-
strates. The performance limit of this prototype
system is reached in the coupling of electron-deficient
anilines. Even at an increased reaction temperature of
1308C, only moderate yields of compound 4z were
obtained, presumably due to the low reactivity of
such amines in imine condensation reactions.
The new process can also be utilized for the synthe-
sis of aryl ketones, as the azomethine products are
easily hydrolyzed, for example, by adding aqueous
HCl after the reaction is complete. The synthesis of
aryl ketones from a-oxocarboxylates by their in situ
conversion to imines, cross-coupling and subsequent
hydrolysis of the azomethine intermediates is advan-
tageous over the direct coupling of the a-oxocarboxy-
lates because of the dramatically reduced reaction
temperatures (1008C rather than 1708C). For exam-
ple, 4-methylbenzophenone 6a was obtained from the
oxocarboxylate 1a and aryl bromide 3a in the pres-
ence of cyclohexylamine (2a) in 82% overall yield via
the formation and subsequent hydrolysis of azome-
thine 4a (Scheme 3). We are currently investigating
whether this ketone synthesis is also possible using
only catalytic amounts of amine. Moreover, we found
that the azomethines are cleanly reduced to the corre-
sponding amines upon treating them with LiAlH4 in
refluxing THF. Thus, the overall procedure provides a
convenient entry to this important substrate class.
In conclusion, the low-temperature decarboxylative
coupling process disclosed herein allows the assembly
of three easily available building blocks into syntheti-
cally valuable azomethines. The discovery, that a-
24.0 mmol), palladium(II) 1,1,1,3,3,3-hexafluoroacetylaceto-
nate (104 mg, 0.20 mmol), copper(I) bromide (430 mg,
3.00 mmol), and activated ground molecular sieves (3 ꢁ,
200 mg) under nitrogen was treated with a solution of cyclo-
hexylamine (2a, 2.38 g, 2.75 mL, 24.0 mmol), 4-bromoto-
luene (3a, 3.42 g, 2.46 mL, 20.0 mmol), 1,1’-diphenylphos-
AHCTUNGTREGpNNNU hinoferrocene (114 mg, 0.20 mmol), and 1,10-phenanthro-
line (541 mg, 3.00 mmol) in 40 mL NMP and 10 mL cyclo-
hexane, excluding air and moisture. The reaction mixture
was refluxed at 1008C for 16 h. It was then washed twice
with saturated sodium bicarbonate solution, water, and once
with brine, and the aqueous phases were extracted twice
with ethyl acetate. The combined organic phases were dried
over magnesium sulfate and filtered. After removal of the
solvent followed by Kugelrohr destillation (1308C/4ꢂ
10À3 mbar), the product was obtained as yellow oil; yield:
1
4.58 g (83%). H NMR (400 MHz, CDCl3, 2 signal sets for
stereoisomers, approx. ratio 1:1): d=7.47–7.53 and 7.56–7.64
(2m, 2H), 7.28–7.37 and 7.38–7.47 (2m, 3H), 7.14–7.19 and
7.23–7.28 (2m, 2H), 7.04–7.09 and 7.10–7.14 (2m, 2H),
3.17–3.33 (m, 1H), 2.36 and 2.44 (2s, 3H), 1.55–1.82 (m,
7H), 1.10–1.34 (m, 3H); 13C NMR (101 MHz, CDCl3, 2
signal sets for stereoisomers): d=165.4 and 165.7, 140.6,
139.5, 137.6 and 137.7, 134.3, 129.4, 128.9, 128.6, 128.33,
128.26, 128.2, 127.8, 127.6, 61.2 and 61.3, 34.0, 25.7, 24.4,
21.2 and 21.3 ppm; HR-MS: m/z=277.1819, calcd.:
277.1830; MS (70 eV): m/z (%)=278 (100), 277 (38) [M+],
263 (21), 235 (21), 200 (30), 165 (36), 104 (29).
The experiments in Table 2 were carried out on a 1.00-
mmol scale in 20 mL septum-capped vessels. After aqueous
work-up, the products were distilled under vacuum (4ꢂ
10À3 mbar).
Acknowledgements
We thank T. Straub for technical assistance, the DFG and
Saltigo GmbH for financial support, and the Studienstiftung
des deutschen Volkes, the FCI, and the DAAD for fellow-
ships to FR and BS.
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[27] Control experiments revealed that the aldimine does
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way via carbopalladation of this protodecarboxylation
product. An alternative pathway via decarboxylative
cross-coupling of the a-oxocarboxylate followed by
imine condensation can be excluded on the basis that
a-oxocarboxylates did not decarboxylate at 1008C.
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Adv. Synth. Catal. 2011, 353, 337 – 342