An Efficient Protocol to Synthesize N-Acyl-enamides and -Imines by Pd-Catalyzed Carbonylations

Article abstract of DOI:10.1002/chem.201704704

For the first time, the bidentate phosphinite ligand 1,2-bis(di-tert-butylphosphinoxy)ethane (tBu₂POCH₂CH₂OPtBu₂) was synthesized. In the presence of this ligand, various N-acyl enamides were obtained in good yi

Full text of DOI:10.1002/chem.201704704

A Journal of
Accepted Article
Title: An Efficient Protocol to Synthesize N-Acyl-Enamides and -Imines
via Pd-catalyzed Carbonylations
Authors: Lin Wang, Helfried Neumann, Anke Spannenberg, and
Matthias Beller
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An Efficient Protocol to Synthesize N-Acyl-Enamides and -Imines
via Pd-catalyzed Carbonylations
Lin Wang, [a] Helfried Neumann, [a] Anke Spannenberg [a] and Matthias Beller*[a]
Abstract: For the first time, the bidentate phosphinite ligand 1,2-
bis(di-tert-butylphosphinoxy)ethane (tBu2POCH2CH2OPtBu2) was
synthesized. In the presence of this ligand, various N-acyl enamides
were obtained in good yields and chemoselectivity via Pd-catalyzed
carbonylation reaction of imines containing α-H. Meanwhile, imines
without α-H could be transformed to N-acyl imines, which form highly
hindered amides by straightforward addition of Grignard reagents.
common ligands for Pd-catalyzed coupling reactions[10]
,
phosphinite ligands (R’R’’POR, R, R’ and R’’ = alkyl or aryl
group), which are easier-prepared, might be a suitable choice,
too.[11] Previously, the good properties of especially bidentate
phosphines were demonstrated in aryl halide carbonylations.[12]
Hence, these works inspired us to develop more-economical
diphosphinites.
Scheme 1. The N-acyl enamide moieties (left) and sterically hindered amide
Introduction
The selective generation of amide bonds is one of the most
important methodologies for the synthesis of pharmaceuticals
and bio-active compounds and continues to attract the interest
of synthetic chemists.[1] Traditional protocols which are based on
the condensation of amines and activated carboxylic acids have
been proven to be efficient and are popular; however, it is
undeniable that this approach suffers from limitations, e.g.
necessity of coupling agents and waste formation.[2] Therefore,
alternative protocols have been developed to overcome these
shortcomings.[3] Nevertheless, problems still exist for the
synthesis of special but useful amides such as N-acyl-enamides
and related -imines.[4] N-Acyl enamides and their derivatives are
versatile and powerful building blocks in organic synthesis,
especially for the enantioselective hydrogenation.[5] Moreover, N-
acyl enamide moieties are integral part in various natural
products and pharmaceutical lead compounds (Scheme 1,
left).[6] As for N-acyl imines, they constitute precursors of amides
and can be used to synthesize sterically hindered derivatives –
another useful unit in drug molecules and industrial products
(Scheme 1, right).[7]
moieties (right) in chemical products
Herein, we report for the first time the synthesis of the
bidentate 1,2-bis(di-tert-butylphosphinoxy)ethane (tBu2POCH2-
CH2OPtBu2) ligand and its application in Pd-catalyzed
carbonylations of primary imines. Compared to other common
ligands, the new phosphinite allows the selective formation of
the corresponding N-acyl-enamides and related –imines
(Scheme 2).
The palladium-catalyzed carbonylation of aryl halides allows
to effectively introduce carbonyl groups into (hetero)arenes[8],
which has been applied extensively to produce amides as well.
Generally, it is crucial for Pd-catalyzed carbonylation reactions
of less reactive aryl bromides and chlorides to control and adjust
the reactivity of the active catalyst species.[9] In this respect, the
development of “economical” but highly-efficient ligands is of
significant importance. Although phosphines are the most
[a]
Dr. L. Wang, Dr. H. Neumann, Dr. A. Spannenberg, Prof. Dr. M.
Beller
Leibniz-Institut für Katalyse an der Universität Rostock
Albert-Einstein-Straße 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
Scheme 2. Pd/L1-catalyzed carbonylation of primary imines.
Supporting information for this article is given via a link at the end of
the document.
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Results and Discussion
Table 1. The influence of different ligands on Pd-catalyzed carbonylation of 1-
(2-methylphenyl)-ethan-1-imine (2).[a]
The synthesis of 1,2-bis(di-tert-butylphosphinoxy)ethane
(L1)
Recently, we demonstrated the usefulness of monodentate
di-tert-butylphosphinite ligands for the synthesis of aryl esters.[13]
Based on that work we tried to prepare L1 as a stable dppb-
analogue. However, to the best of our knowledge this ligand has
not been synthesized successfully before. Indeed, Baldwin and
Fink showed that the reaction of di-tert-butylchlorophosphine
(tBu2PCl) with ethylene glycol gave mainly the phosphine oxide
[tBu2PH(O)] rather than L1 (Scheme 3, top).[14] It is believed that
steric hindrance of the tert-butyl groups affects the reaction
negatively.
Entry
Ligand
L1
dppb
dppf
L2
Conv. (%)[b]
Yield of 3a (%)[c]
Yield of 4a (%)[b]
1
2
3
4
5
83
30
70
35
44
83
21
52
28
32
0
9
15
7
L3
9
[a] Reaction conditions: 1.2 mmol (4-trifluoromethyl)bromobenzene (1a), 1.0
mmol 1-(2-methylphenyl)-ethan-1-imine (2), 0.01 mmol Pd(OAc)2, 0.03 mmol
ligand, 1.5 mmol Et3N, 5 bar CO, 17 bar N2, 1.5 mL toluene, 115 oC, 18 h; [b]
determined by GC, hexadecane as standard; [c] isolated yield.
Scheme 3. Synthesis of 1,2-bis(di-tert-butylphosphinoxy)ethane (L1).
In order to improve the reaction with ethylene glycol,
sodium hydride (NaH) was used to form monosodium ethylene
glycolate and then tBu2PCl was added dropwise into this slurry.
As a result, L1 was obtained in 51% yield after overnight stirring
1
(Scheme 3, bottom). In the H NMR spectrum, the signal of the
tert-butyl group appears at 1.13 ppm as a doublet with J3H,P = 12
Hz) while the one of the methylene groups is found at 3.88 ppm.
The singlet in the 31P {1H} spectrum appears at 163.2 ppm,
which indicates the chemical identity of the two phosphorus
atoms.
Pd-catalyzed carbonylation of imines with α-H
Initially,
the
catalytic
carbonylation
of
4-
(trifluoromethyl)bromobenzene (1a) with 1-(2-methylphenyl)-
ethan-1-imine (2) was performed using different ligands (Table
1). In general, mixtures of the corresponding N-acyl enamide 3a
and N-acyl imine 4a are formed. In the presence of the new
ligand
L1,
N-[1-(2-methylphenyl)ethenyl]-4-
trifluoromethylbenzamide (3a) was obtained as the only product
in 83% yield and no traces of 4a were detected (Table 1, entry
1). Other common bidentate phosphine ligands such as dppb
and dppf and two bidentate phosphinite ligands L2 and L3 gave
under similar conditions both lower conversion and mixtures of
products (Table 1, entries 2-5).
Next, we investigated the scope and limitation of this
protocol using three different imines and six aryl bromides. As
shown in Scheme 4 the sterically hindered N-acyl enamide 6a
was produced in good yield (86%). Both electron-rich aryl and
heteraryl bromides gave good yields of the corresponding
products (73% (6b), 78% (6c) and 75% (6d), respectively).
[a] Reaction conditions: 1.2 mmol (hetero)aryl bromide, 1.0 mmol imine, 0.01
mmol Pd(OAc)2, 0.03 mmol L1, 1.5 mmol Et3N, 5 bar CO, 17 bar N2, 1.5 mL
toluene, 115 oC, 18 h; [b] isolated yield; [c] total yield. [(Z)-isomer+(E)-isomer];
[d] ratio of isolated yields of (Z)-isomer to (E)-isomer; [e] determined by 1H
NMR spectrum.
Scheme 4. Pd-catalyzed carbonylation reaction of different (hetero)aryl
bromides with N-H imines with α-H.
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On the other hand, when 1-(2-methylphenyl)-propan-1-
imine 7 was used as substrate in this reaction, a mixture of two
stereoisomers 8a was produced in a total yield of 92% [(Z):(E) =
1:1]. Comparing different aryl bromides in this reaction, we found
that electron-rich derivatives enhanced the selectivity of E-
isomers slightly (8d and 8e). Using an imine substrate with a
sterically demanding substituent at the β-position of the alkyl
group (9), 8g was obtained with the (E)-isomer as the major
product (75% selectivity). Finally, indole can be carbonylated in
a similar manner and N-benzoylindole 11 was produced in 87%
yield.
Pd-catalyzed carbonylation of imines without α-H
The novel catalyst system permits the smooth carbonylation
of imines with as well as without α-H. In case of the latter
substrates, obviously no formation of enamides is possible, and
thus the corresponding N-acyl imines are obtained. After
screening different conditions for the reaction of 4-bromoanisole
(1e) with (2-methylphenyl)(phenyl)methanimine (12a) and CO,
we observed optimal product yields for 13a at lower catalyst
loading in the presence of N,N,N’,N’-tetramethylethylenediamine
(TMEDA) as base (Table 2). Interestingly, the use of stronger
bases decreased the formation of products. Similarly, higher
pressure of CO also lowered the yield of 13a.
Table
2.
Pd-catalyzed
carbonylation
of
2-methyl-α-phenyl-
benzenemethanimine (12) under different conditions. [a]
[a] Reaction conditions: 1.2 mmol aryl bromide, 1.0 mmol imine, 0.005 mmol
Pd(OAc)2, 0.015 mmol L1, 0.75 mmol TMEDA, 5 bar CO, 17 bar N2, 1.5 mL
toluene, 115 oC, 18 h; [b] isolated yield.
Scheme 5. Pd-catalyzed carbonylation of (hetero)aryl bromides with N-H
imines without α-H.
Entry
Variation from standard conditions
Yield of 13a
(%)[b]
1
2
3
4
5
6
1 mol% Pd(OAc)2 and 3 mol% L1 were loaded
1.5 equiv. Et3N instead of 0.75 equiv. TMEDA
1.5 equiv. DBU instead of 0.75 equiv. TMEDA
1.5 equiv. KOtBu instead of 0.75 equiv. TMEDA
10 bar CO instead of 5 bar CO, no N2
91
84
38
15
76
20 bar CO instead of 5 bar CO, no N2
34
[a] Standard reaction conditions: 1.2 mmol 4-bromoanisole (1e), 1.0 mmol 2-
methyl-α-phenyl-benzenemethanimine (12a), 0.005 mmol Pd(OAc)2, 0.015
mmol L1, 0.75 mmol TMEDA, 5 bar CO, 17 bar N2, 1.5 mL toluene, 115 oC, 18
h. [b] Isolated yield.
Scheme 6. Synthesis of sterically hindered amides from N-acyl imines
An important synthetic application of N-acyl imines is the
preparation of highly hindered amides, which is otherwise still
challenging.[15] Due to the electron-withdrawing effect of the acyl
group, the imine is activated, and addition of nucleophilic
Grignard reagents proceeds rapidly. For example, reaction of
13a with two Grignard reagents yielded the corresponding
amines (Scheme 6, 14a and 14b). Notably, the Si-H bond
remained untouched by this method.
As shown in Scheme 5, high yields were observed for the
reactions of various aryl bromides such as 4-bromotoluene, 4-
bromo-N,N-dimethylaniline, 4-bromo-chlorobenzene, etc. In
general, electron-withdrawing substituents (4-CF3- and 4-Cl-) led
to a higher yield (98% (13e) and 95% (13f), respectively)
compared to electron-donating groups (e.g. 4-Me- and 4-N(Me)2-
; 82% (13c) and 70% (13d), respectively). Meanwhile, variation
of the imine (12a-b) influenced the yield of the N-acyl imines (13i
– 13l) only slightly.
Finally, the carbonylation of related aromatic imidates
[ArC(=NH)OR] was investigated. Although N-acylimidates
constitute important precursors for synthesis of triazoles, diacid
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anilides and their derivatives, the methods to prepare these
ponderable compounds are still limited.[16] Hence, imidates 15
and 17 were smoothly converted to corresponding acyl
derivatives via Pd-catalyzed carbonylation, in the presence of
NEt3 as base. The yields of products ranked from 73% to 85%
(Scheme 7, 16a – 16c; 18a – 18c). Moreover, the N-acyl imidate
16a could be converted to diacid anilides (19) readily through
hydrolysis of N-acylimidate (16a) by water (Scheme 8). [17], [18]
carbonylation of 1b under the standard conditions. Consequently,
the reaction resulted in a low conversion and the deuterated N-
acyl imines (6b’-D) rather than N-acyl enamide (6b or 6b-D) was
produced in the yield of 24%. This interesting phenomenon
indicates that: 1) In a small extent, 5b-D could be tautomerized
into 5b’’-D which shows similar property to the imine without α-
H; 2) enamine intermediate 5b’-D cannot react as nucleophile
for generation of corresponding N-acyl enamide (Scheme 9).
[a] Reaction conditions: 1.2 mmol aryl bromide, 1.0 mmol imidate, 0.01 mmol
Pd(OAc)2, 0.03 mmol L1, 0.75 mmol Et3N, 5 bar CO, 17 bar N2, 1.5 mL
toluene, 115 oC, 18 h; [b] Isolated yield.
Scheme 10. Stoichiometric reaction of Pd(allyl)(Cp) (20), L1 and NMM (21);
Carbonylation of 12b and 5 catalyzed by palladium complex 22. Reaction
conditions: (1) 0.816 mmol 20, 0.866 mmol L1 and 0.816 mmol 21 in 4 mL
heptane under ambient temperature overnight, 22 was obtained as pale yellow
crystals in the isolated yield of 56%; (2) 1.2 mmol 1a, 1.0 mmol 12b, 0.005
mmol 22, 0.75 mmol TMEDA, 5 bar CO, 17 bar N2, 1.5 mL toluene, 115 oC,
18 h. 13i was obtained in the isolated yield of 35%; (3) 1.2 mmol 1b, 1.0 mmol
5, 0.01 mmol 22, 1.5 mmol Et3N, 5 bar CO, 17 bar N2, 1.5 mL toluene, 115 oC,
18 h, 6a was obtained in the isolated yield of 27%. NMM = N-methylmaleimide.
Scheme 7. Pd-catalyzed carbonylation of aromatic imidates with CO.
Subsequently, the key intermediate of catalytic cycle was
researched. Pd(L1)(NMM) (22) was obtained in the yield of 56%
by combining Pd(allyl)(Cp) (20) with L1 and N-methylmaleimide
(Scheme 10, Eq. (1)). NMR (1H, 31P and 13C) investigations and
X-ray diffraction analysis unveiled the structure. Although the
crystals of 22 suffered from poor quality, the connectivity of the
molecule in which two phosphorus atoms of L1 coordinate to the
same metal center could be confirmed (see Supporting
Information, Figure S4). In addition, 31P{1H} spectrum shows
only one signal at 186.43 ppm, which provides another powerful
evidence for the coordination mode. In the presence of 22 as
catalyst, the benchmark carbonlyation reactions were performed.
Equation (2) and (3) in scheme 10 demonstrate that the desired
products were obtained in lower yields (35% for 13i and 27% for
6a, respectively), which implies that Pd0L1 may be the active
intermediate in the catalytic cycle while NMM occupies the
vacant site and lowers the reactivity of catalyst.
Scheme 8. Synthesis of diacid anilides 19 by hydrolysis of N-acyl imidate 16a.
Mechanistic investigations
Scheme 9. Isotopic experiment for Pd-catalyzed carbonylation of imine.
Conclusions
Firstly, an isotopic experiment was explored to trace the
proton of imine group (Scheme 9). Deuterated imine 5-D was
prepared and then used into the palladium catalyzed
In summary, we have synthesized the bidentate phosphinite
ligand 1,2-bis(di-tert-butyl-phosphinoxy)ethane (tBu2POCH2CH2-
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OPtBu2) for the first time, which showed excellent reactivity for
Pd-catalyzed carbonylations of imines. On the one hand, imines
containing α-H were converted to N-acyl enamides selectively.
On the other hand, aryl-imines and imidates without α-H were
transformed to the corresponding N-acyl –imines and -imidates
in good yields.
6a. Yield: 86%, 0.24 g. 1H NMR (300MHz, CDCl3, ppm): δ 1.66 (s, 3H,
CH3), 1.89 (s, 3H, CH3), 2.33 (s, 3H, Ar-CH3), 6.98–7.29 (m, 6H, Ar-H),
7.66 (s, 1H, N-H), 7.75–7.79 (m, 2H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3,
ppm): δ 19.70 (CH3), 20.17 (CH3), 20.77 (CH3), 115.26 (C=C), 115.55
(C=C), 125.58 (CAr), 127.42 (CAr), 127.71 (CAr), 129.47 (CAr), 129.57 (CAr),
129.68 (CAr), 130.09 (CAr), 130.20 (CAr), 130.98 (J2 = 3.0 Hz, CAr),
C,F
163.50 (J1C,F = 84.8 Hz, F-CAr), 166.27 (C=O).
HRMS for 6a (ESI) m/z calculated for C18H18FNO (M+H)+: 284.14452,
Experimental Section
found: 284.14448.
8f. E-isomer yield: 41%, 0.103 g. 1H NMR (300MHz, CDCl3 ppm): δ 1.48
(d, J3H,H = 6.0 Hz, 3H, CH3), 2.23 (s, 3H, Ar-CH3), 6,72 (q, J3H,H = 6.0 Hz,
1H, C=CH), 7.16–7.21 (m, 4H, Ar-H), 7.30 (m, 1H, Py-H), 7.76 (m, 1H,
Py-H), 8.15 (m, 1H, Py-H), 8.36 (m, 1H, Py-H), 9.08 (s, 1H, N-H); 13C{1H}
NMR (75 MHz, CDCl3, ppm): δ 13.64 (CH3), 19.27 (CH3), 113.35 (C=C),
122.19 (C=C), 125.95 (CAr), 126.08 (CAr), 128.37 (CAr), 129.91 (CAr),
130.32 (CAr), 133.84 (CAr), 136.11 (CAr), 136.92 (CAr), 137.49 (CAr),
147.82 (CAr), 150.12 (CAr), 162.05 (C=O); Z-isomer yield: 37%, 0.093 g.
1H NMR (300MHz, CDCl3, ppm): δ 1.77 (dd, J3H,H = 6.0 Hz, J H,N(H) = 0.6
Hz, 3H, CH3), 2.21 (s, 3H, Ar-CH3), 5,37 (q, J3H,H = 6.0 Hz, 1H, C=CH),
7.04–7.21 (m, 4H, Ar-H), 7.33 (m, 1H, Py-H), 7.74 (m, 1H, Py-H), 8.12
(m, 1H, Py-H), 8.45 (m, 1H, Py-H), 9.30 (s, 1H, N-H); 13C{1H} NMR (75
MHz, CDCl3, ppm): δ 13.87 (CH3), 20.13 (CH3), 113.35 (C=C), 120.18
(C=C), 122.53 (CAr), 125.67 (CAr), 126.30 (CAr), 127.88 (CAr), 129.62 (CAr),
130.20 (CAr), 134.40 (CAr), 136.24 (CAr), 137.51 (CAr), 138.72 (CAr),
148.02 (CAr), 149.88 (CAr), 161.08 (C=O).
Synthesis of 1,2-bis(di-tert-butylphosphinoxy)ethane (L1)
NaH (17.2 mmol, 0.42 g) and THF (30 mL) were added into a 100 mL
Schlenk equipped with magnetic stirring bar. At -40 oC, ethylene glycol
(7.15 mmol, 0.44 g) was added into the slurry slowly. After finishing
adding, the mixture was allowed to warm to room temperature and be
t
kept stirring for 8 h. Then the mixture was cooled to 0 oC and Bu2PCl
(14.3 mmol, 2.6 g) was added into the mixture dropwise at the same
temperature. The reaction was stirred at room temperature overnight.
Subsequently, THF was removed under reduced pressure followed by
addition of diethyl ether (30 mL) to precipitate salt. After filtration and
removal of solvents, L1 was obtained by reduced pressure distillation
1
(0.04 mbar, 84 – 85 oC). Yield: 51%, 1.3 g. H NMR (300MHz, C6D6,
ppm): δ 1.13 (d, J3H,P = 12 Hz, 36H, C(CH3)3), 3.88 (m, 4H, OCH2CH2O);
31P{1H } NMR (121.5 MHz, C6D6, ppm): δ 163.2 (s); 13C{1H} NMR (75
MHz, C6D6, ppm): δ 27.24 (J2C,P = 15.8 Hz, C(CH3)3), 34.91 (J1C,P = 25.5
Hz, C(CH3)3), 73.64 (q, J2C,P = 21.0 Hz, J3C,P = 8.2 Hz, OCH2CH2O).
General procedure for synthesis of N-acyl enamides
To a vial (12 mL reaction volume) which was charged with Pd(AcO)2 (2.2
mg, 0.01 mmol) and equipped with a septum, a small cannula and a
stirring bar, L1 (10.5 mg, 0.03 mmol), toluene (1.5 mL), Et3N (0.21 mL),
imine (1 mmol) were added. After addition of corresponding aryl bromide
(1.2 mmol), the vials were placed in an alloy plate which was transferred
to a 300 mL autoclave (4560 series from Parr Instruments®) under an
argon atmosphere. The autoclave was flushed three times with CO and
then pressurized to 5 bar CO and 17 bar N2. The reaction was kept
stirring at 115 oC for 18 h. After cooling down to room temperature, CO
was released carefully. Hexadecane (226.0 mg, 1 mmol), the internal
standard, was injected into reaction vials and the mixture was stirred for
10 min. The sample was analyzed by GC to determine the conversion
and yield. Pure product could be obtained by column chromatography on
silica gel (general eluent: hexane/ethylacetate = 6:1).
HRMS for 8f (ESI) m/z calculated for C16H16N2O (M+H)+: 253.13354,
found: 253.13364.
8g. E and Z isomers mixture. Total yield: 72%, 0.22 g. 1H NMR (300MHz,
CDCl3, ppm): δ 0.90 (d, J3H,H = 6.0 Hz, 6H, CH(CH3)2 for E isomer), 1.04
(d, J3H,H = 6.0 Hz, 6H, CH(CH3)2 for Z isomer), 1.98 (m, 1H, CH(CH3)2 for
E isomer), 2.266 (s, 3H, Ar-CH3, for E isomer), 2.271 (s, 3H, Ar-CH3, for
Z isomer), 2.60 (m, 1H, CH(CH3)2 for Z isomer), 3.75 (s, 3H, OCH3, for E
isomer), 3.77 (s, 3H, OCH3, for Z isomer), 5.10 (d, J3H,H = 10.5 Hz, 1H,
C=CH for Z isomer), 6.42 (d, J3H,H = 10.5 Hz, 1H, C=CH for E isomer),
6.77 – 7.72 (m, Ar-H and N-H for E and Z isomers); 13C{1H} NMR (75
MHz, CDCl3, ppm): δ 19.38 (CH3 for E isomer), 20.22 (CH3 for Z isomer),
22.62 (CH3 for E isomer), 23.45 (CH3 for Z isomer), 27.53 (CH for E
isomer), 28.20 (CH for Z isomer), 55.41 (OCH3), 113.82 (C=C for E
isomer), 113.87 (C=C for Z isomer), 125.66 (CAr), 125.86 (CAr), 125.93
(CAr), 126.70 (CAr), 127.46 (CAr), 127.70 (CAr), 128.45 (CAr), 128.61 (CAr),
129.04 (CAr), 130.28 (CAr), 130.40 (CAr), 131.59 (CAr), 133.20 (CAr),
136.67 (CAr), 136.77 (CAr), 162.20 (C=O for Z isomer), 165.03 (C=O for E
isomer).
For 8a – 8g, which exist with two isomers, some of them (8c, 8e and 8f)
were isolated into two pure isomers while some of them were obtained as
a mixture of isomers. For the former, the ratio of isomers is determined
by isolated yield; for the latter, the ratio of isomers is determined by 1H
NMR spectra.
Spectra data for selected N-acyl enamides
HRMS for 8g (ESI) m/z calculated for C20H23NO2 (M+H)+: 310.18016,
3a. Yield: 83%, 0.25 g. 1H NMR (300MHz, CDCl3, ppm): δ 2.32 (s, 3H,
Ar-CH3), 4.30 (d, J H,N(H) = 1.2 Hz, 1H, C=CH), 6.17 (s, 1H, C=CH), 7.11–
7.26 (m, 5H, Ar-H and N-H), 7.61 (d, J3H,H = 6.0 Hz, 2H, Ar-H), 7.78 (d,
J3H,H = 6.0 Hz, 2H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3, ppm): δ 19.69
(CH3), 104.03 (C=C), 123.56 (J1C,F = 270.8 Hz, -CF3), 125.75 (J3C,F = 3.8
found: 310.17998.
11. Yield: 87%, 0.25 g. 1H NMR (300MHz, CDCl3, ppm): δ 6.54 (d, 1H,
J3H,H = 3.0 Hz, Ar-H), 7.08 (d, 1H, J3H,H = 3.0 Hz, Ar-H), 7.22–7.34 (m, 2H,
Ar-H), 7.52 (d, J2H,H = 9.0 Hz, 1H, Ar-H), ), 7.68–7.76 (m, 4H, Ar-H), 8.32
(d, J2H,H = 9.0 Hz, 1H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3, ppm): δ
109.48 (CAr), 116.47 (CAr), 119.92 (J1C,F = 270.8 Hz, -CF3), 121.08 (CAr),
124.39 (CAr), 125.31 (CAr), 125.70 (m, CAr), 126.97 (CAr), 129.38 (CAr),
Hz, CAr), 125.85 (J3 = 3.8 Hz, CAr), 126.19 (CAr), 127.38 (CAr), 128.88
C,F
(CAr), 129.28 (CAr), 130.69 (CAr), 133.47 (J2 = 32.25 Hz, CAr), 135.83
C,F
(CAr), 138.05 (CAr), 138.29 (CAr), 140.27 (CAr), 164.50 (C=O).
HRMS for 3a (ESI) m/z calculated for C17H14F3NO (M+H)+: 306.11003,
found: 306.11008.
130.79 (CAr), 133.48 (J2
= 33.0 Hz, CAr), 135.93 (CAr), 137.97 (CAr),
C,F
167.27 (C=O).
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HRMS for 11 (ESI) m/z calculated for C16H10F3NO (M+H)+: 290.07873,
31.54 (Ar-CH3), 55.45 (OCH3), 65.15 (C-N), 113.88 (CAr), 125.50 (CAr),
125.66 (CAr), 126.83 (CAr), 127.30 (CAr), 127.44 (CAr), 127.71 (CAr),
128.35 (CAr), 128.61 (CAr), 132.76 (CAr), 135.98 (CAr), 143.12 (CAr),),
144.82 (CAr), 162.17 (CAr), 165.06 (C=O).
found: 290.07859.
General procedure for synthesis of N-acyl imines
To a vial (12 mL reaction volume) which was charged with Pd(AcO)2 (1.2
mg, 0.005 mmol) and equipped with a septum, a small cannula and a
stirring bar, L1 (5.2 mg, 0.015 mmol), toluene (1.5 mL), TMEDA (0.11
mL), imine (1 mmol) were added. After addition of corresponding aryl
bromide (1.2 mmol), the vials were placed in an alloy plate which was
transferred to a 300 mL autoclave (4560 series from Parr Instruments®)
under an argon atmosphere. The autoclave was flushed three times with
CO and then pressurized to 5 bar CO and 17 bar N2. The reaction was
HRMS for 14a (ESI) m/z calculated for C24H25NO2 (M+H)+: 360.19581,
found: 360.19558
14b. Yield: 84%, 0.36 g. 1H NMR (300MHz, CDCl3, ppm): δ 0 (t, J3
=
H,H
3.0 Hz, 3H, CH3), 0.64 (m, 2H, CH2), 1.30 (m, 2H, CH2), 1.95 (s, 3H, Ar-
CH3), 2.54 (td, J2H,H = 4.5 Hz, J3H,H = 12.3 Hz, 1H, CH2), 3.26 (td, J2
=
H,H
4.5 Hz, J3H,H = 12.3 Hz, 1H, CH2), 3.82 (m, 1H, Si-H), 3.87 (s, 3H, OCH3),
6.98 (d, J3H,H = 9.0 Hz, 2H, Ar-H), 7.02 (s, 1H, C(O)NH), 7.22 – 7.39 (m,
7H, Ar-H), 7.81 – 7.89 (m, 3H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3,
ppm): δ -4.46 (J1Si,C = 3.8 Hz, Si-CH3), 14.18 (CH2), 19.03 (CH2), 22.04
(CH2), 42.24 (Ar-CH3), 55.41 (OCH3), 64.92 (C-N), 113.86 (CAr), 125.47
(CAr), 125.59 (CAr), 126.81 (CAr), 127.27 (CAr), 127.54 (CAr), 127.70 (CAr),
128.34 (CAr), 128.57 (CAr), 132.76 (CAr), 135.92 (CAr), 143.04 (CAr),),
145.09 (CAr), 162.12 (CAr), 165.06 (C=O).
o
kept stirring at 115 C for 18 h. After cooling down to room temperature,
CO was released carefully. Pure product could be obtained by column
chromatography on silica gel (general eluent: hexane/ethylacetate = 9:1).
Spectra data for selected N-acyl imines
1
13a. Yield: 90%, 0.30 g. H NMR (300MHz, CDCl3, ppm): δ 2.20 (s, 3H,
Ar-CH3), 3.88 (s, 3H, OCH3), 6.92 (d, 2H, J3H,H = 9.0 Hz, Ar-H), 7.08–7.31
(m, 4H, Ar-H), 7.45–7.56 (m, 3H, Ar-H), 7.82 (m, 2H, Ar-H), 7.92 (d, 2H,
J3H,H = 9.0 Hz, Ar-H); 13C{1H} NMR (75 MHz, CDCl3, ppm): δ 20.20 (CH3),
55.45 (OCH3), 113.64 (CAr), 125.43 (CAr), 126.39 (CAr), 127.21 (CAr),
128.68 (CAr), 129.01 (CAr), 129.14 (CAr), 130.23 (CAr), 131.38 (CAr),
131.99 (CAr), 135.34 (CAr), 135.84 (CAr), 136.85 (CAr), 163.38 (CAr),
168.49 (C=N), 179.56 (C=O).
HRMS for 14b (ESI) m/z calculated for C27H33NO2Si (M+H)+: 432.23533,
found: 432.23531.
General procedure for synthesis of N-acyl imidates
To a vial (12 mL reaction volume) which was charged with Pd(AcO)2 (2.2
mg, 0.01 mmol) and equipped with a septum, a small cannula and a
stirring bar, L1 (10.5 mg, 0.03 mmol), toluene (1.5 mL), Et3N (0.21 mL),
imidate (1 mmol) were added. After addition of corresponding aryl
bromide (1.2 mmol), the vials were placed in an alloy plate which was
transferred to a 300 mL autoclave (4560 series from Parr Instruments®)
under an argon atmosphere. The autoclave was flushed three times with
CO and then pressurized to 5 bar CO and 17 bar N2. The reaction was
HRMS for 13a (ESI) m/z calculated for C22H19NO2 (M+H)+: 330.14886,
found: 330.14895.
13i. Yield: 87%, 0.37 g. 1H NMR (300MHz, CDCl3, ppm): δ 7.20 (m, 1H
Ar-H), 7.25 (m, 1H, Ar-H), 7.36 (m, 1H, Ar-H), 7.60 (m, 2H, Ar-H), 7.94 (d,
J2H,H = 9.0 Hz, 1H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3, ppm): δ 123.30
(J1C,F = 226.5 Hz, -CF3), 125.44 (J3C,F = 3.8 Hz, CAr), 126.82 (CAr), 129.12
(CAr), 129.70 (CAr), 129.90 (CAr), 130.40 (CAr), 130.95 (CAr), 131.04 (CAr),
133.98 (CAr), 134.27 (CAr), 134.48 (J2C,F = 32.8 Hz, CAr), 135.81 (CAr),
139.04 (CAr), 165.70 (CAr), 168.49 (C=N), 177.93 (C=O).
o
kept stirring at 115 C for 18 h. After cooling down to room temperature,
CO was released carefully. Pure product could be obtained by column
chromatography on silica gel (general eluent: hexane/ethylacetate = 6:1).
Spectra data for selected N-acyl imidates
1
HRMS for 13i (ESI) m/z calculated for C21H12Cl2F3NO (M+H)+:
422.03208, found: 422.03217.
16a. Yield: 83%, 0.26 g. H NMR (300MHz, CDCl3, ppm): δ 4.05 (s, 3H,
OCH3), 7.21 (ddd, J3H,H = 7.5 Hz, J4H,H = 4.5 Hz, J5H,H = 1.2 Hz, 1H, Ar-H),
7.60 (d, J3H,H = 7.5 Hz, 2H, Ar-H), 7.70 (td, J3H,H = 7.5 Hz, J5H,H = 1.2 Hz,
1H, Ar-H), 7.84 (dt, J3H,H = 7.5 Hz, J5H,H = 1.2 Hz, 1H, Ar-H), 8.00 (d, J2
= 7.5 Hz, 2H, Ar-H), 8.30 (m, 1H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3,
Synthesis of sterically hindered amides from N-acyl imines
To a 100 mL Schlenk tube which was charged with 30 mL THF solution
of N-acyl imine (1 mmol) and equipped with a septum and a stirring bar,
15 mL THF solution of Grignard reagent (0.1 M) was added dropwise at 0
oC. After that, the mixture was allowed to be warmed to room
temperature and kept stirring for 2 h. The reaction process was
monitored by TLC. When N-imine was converted completely, 30 mL
NH4Cl saturated aqueous solution was added into the Schleck tube to
quench the reaction. The product was extracted by ethyl ether (3 × 10
mL). Then this organic solution was dried by Na2SO4. After removal of
organic solvent, pure product could be obtained by column
chromatography on silica gel (general eluent: hexane/ethylacetate = 6:1).
H,H
ppm): δ 55.35 (OCH3), 123.68 (CAr), 123.86 (J1
= 270.8 Hz, -CF3),
C,F
125.18 (m, CAr), 125.85 (CAr), 129.13 (CAr), 133.18 (J2C,F = 32.2 Hz, CAr),
137.22 (CAr), 138.61 (CAr), 145.37 (CAr), 148.71 (CAr), 155.68 (C=N),
176.20 (C=O).
HRMS for 16a (ESI) m/z calculated for C15H11F3N2O2 (M+H)+: 309.08454,
found: 309.08457.
Synthesis of diacid anilides (19) from N-acyl imidate (16a)
To a 100 mL Schlenk tube which was charged with 30 mL THF solution
of 16a (1 mmol) and equipped with a septum and a stirring bar, 15 mL
0.1 M HCl was added dropwise at room temperature. After that, the
mixture was heated to 50 oC and kept stirring at the same temperature
for 2 h. The reaction process was monitored by TLC. When 16a was
converted completely, the product was extracted by ethyl ether (3 × 10
mL). Then this organic solution was dried by Na2SO4. After removal of
organic solvent, pure product 19 was obtained by column
chromatography on silica gel (general eluent: hexane/ethylacetate = 3:1).
Spectra data for sterically hindered amides
1
14a. Yield: 90%, 0.32 g. H NMR (300MHz, CDCl3, ppm): δ 0.72 (t, J3
H,H
= 7.2 Hz, 3H, CH3), 1.81 (s, 3H, Ar-CH3), 2.31 (m, 1H, CH2), 3.18 (m, 1H,
CH2), 3.74 (s, 3H, OCH3), 6.84 (d, J3H,H = 8.7 Hz, 2H, Ar-H), 6.87 (s, 1H,
C(O)NH), 6.95 (d, J3H,H = 7.2 Hz, 1H, Ar-H), 7.08 – 7.13 (m, 3H, Ar-H),
7.16 – 7.26 (m, 4H, Ar-H), 7.69 (d, J3H,H = 9.0 Hz, 2H, Ar-H), 7.75 (m, 1H,
Ar-H); 13C{1H} NMR (75 MHz, CDCl3, ppm): δ 8.66 (CH3), 22.08 (CH2),
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Yield: 78%, 0.23 g. 1H NMR (300MHz, CDCl3, ppm): δ 4.05 (s, 3H,
OCH3), 7.21 (ddd, J3H,H = 7.5 Hz, J4H,H = 4.5 Hz, J5H,H = 1.2 Hz, 1H, Ar-H),
7.60 (d, J3H,H = 7.5 Hz, 2H, Ar-H), 7.70 (td, J3H,H = 7.5 Hz, J5H,H = 1.2 Hz,
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1H, Ar-H), 7.84 (dt, J3H,H = 7.5 Hz, J5H,H = 1.2 Hz, 1H, Ar-H), 8.00 (d, J2
H,H
= 7.5 Hz, 2H, Ar-H), 8.30 (m, 1H, Ar-H); 13C{1H} NMR (75 MHz, CDCl3,
ppm): δ 123.46 (J1 = 270.8 Hz, -CF3), 125.96 (m, CAr), 127.98 (CAr),
C,F
128.33 (CAr), 134.46 (J2
= 33.0 Hz, CAr), 136.69 (CAr), 138.19 (CAr),
C,F
148.14 (CAr), 148.36 (CAr), 161.88 (C=8), 164.00 (C=O).
HRMS for 19 (ESI) m/z calculated for C14H9F3N2O2 (M+H)+: 295.06889,
found: 295.06894.
Synthesis of Pd(L1)(NMM) (22)
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CH=CH), 69.29 (OCH2CH2O), 175.96 (C=O).
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Acknowledgements
We are grateful for the financial support from Sino-German
(CSC-DAAD) Postdoc Scholarship Program (57251553). We
also thank the analytical department in Leibniz-Institute for
Catalysis at University of Rostock (LIKAT) for their excellent
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Keywords: 1,2-Bis(di-tert-butylphosphinoxy)ethane • Pd-
catalyzed carbonylation • carbon monoxide • N-acyl enamides •
N-acyl imines
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Entry for the Table of Contents
FULL PAPER
Lin Wang, Helfried Neumann, Anke
Spannenberg, Matthias Beller*
Page No. – Page No.
An Efficient Protocol to Synthesize N-
Acyl-Enamides and -Imines via Pd-
catalyzed Carbonylations
The new phosphinite ligand 1,2-bis(di-iso-butylphosphinoxy)ethane (tBu2POCH2-CH2OPtBu2) allows for Pd-catalyzed
carbonylation reaction of N-H imines to afford selectively N-acyl-enamides and -imines.
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