Palladium-catalyzed amidation of N-tosylhydrazones with isocyanides

Article abstract of DOI:10.1002/chem.201102459

Aminocarbonylation of N-tosylhydrazones: The direct formation of ketenimines from carbenes and isocyanides is limited to the reaction of Fischer carbene complexes or some specially stabilized carbenes with isocyanides. A Pd-catalyzed amidation of N-tosylhydrazones with isocyanides via a ketenimine intermediate in the presence of water is described. The method offers a general way to synthesize amides from carbonyl compounds through one-carbon extension (see scheme). Copyright

Full text of DOI:10.1002/chem.201102459

DOI: 10.1002/chem.201102459
Palladium-Catalyzed Amidation of N-Tosylhydrazones with Isocyanides
Fengtao Zhou, Ke Ding,* and Qian Cai*[a]
As two formally divalent organic species, both carbenes[1]
and isocyanides[2] have attracted great attention in the syn-
thetic community owing to their high reactivity. The direct
reaction between carbenes and isocyanides is expected to
produce ketenimines, which are highly useful intermediates
in synthetic chemistry[3–9] and conventionally prepared by
substitution of ketenes,[4] dehydrohalogenation of imidoyl
halides,[5] transformation of nitriles with a Brønsted base,[6]
or copper-catalyzed azide–alkyne cycloaddition reactions.[7]
However, the previously reported methods for the forma-
tion of ketenimines from carbenes and isocyanides are very
limited and mainly focus on the reaction of Fischer carbene
complexes with isocyanides.[8,9] Some other specially stabi-
lized carbenes like N-heterocyclic carbenes or b-lactam car-
benes are also reported to react with isocyanides to form ke-
tenimines or other rearrangement products.[10] Since the
preparation of Fischer carbenes requires several steps and
uses stoichiometric amounts of metal reagents, it is highly
desirable to develop a transition-metal-catalyzed method for
this kind of transformation. To the best of our knowledge,
no Pd-catalyzed approach has been reported for the forma-
tion of ketenimines from carbenes and isocyanides.
N-Tosylhydrazones, which are easily prepared from car-
bonyl compounds, have found extensive applications in or-
ganic synthesis.[11–13] They can be converted into diazo com-
pounds under basic conditions, which can further produce
metal–carbenes in situ by reacting with transition
metals.[12,13] Recently, Wang et al.[13a] reported an efficient
Pd-catalyzed carbonylation of carbenes with carbon monox-
ide. The Pd–carbenes were generated in situ from a-diazo-
carbonyl compounds or N-tosylhydrazones under mild con-
ditions.
Scheme 1. Pd-catalyzed aminocarbonylation of in situ generated carbenes
with isocyanides.
would like to disclose our research results on the Pd-cata-
lyzed aminocarbonylation reaction of in situ generated car-
benes from N-tosylhydrazones with isocyanides.
The investigation was initiated by exploring the Pd-cata-
lyzed reaction of benzaldehyde tosylhydrazone (1a) with
tert-butyl isocyanide (2a, Table 1). When 2 mol% of Pd-
AHCTUNTGRENGUN(N PPh3)4 was used as the catalyst, no desired amide product
was detected with or without DIPEA or DBU at 608C in
CH3CN (Table 1, entries 1–3). However, the amide product
3aa was isolated when using inorganic bases, such as K2CO3,
K3PO4, CsF, or Cs2CO3, and Cs2CO3 seemed to be the best
choice (Table 1, entries 4–7). Further screening of solvents
and Pd sources revealed that the reaction also proceeded
Table 1. Screening conditions for the Pd-catalyzed amidation of benzal-
dehyde tosylhydrazone with tert-butyl isocyanide.[a]
Entry
Catalyst
Base
Solvent
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
N
–
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
dioxane
THF
toluene
DMF
CH3CN
CH3CN
CH3CN
CH3CN
n.d.[c]
n.d.[c]
n.d.[c]
22
40
51
DIPEA
DBU
K2CO3
K3PO4
CsF
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
We conceived that isocyanides, as isoelectronic isomers of
carbon monoxide, might react similarly with Pd–carbenes to
form ketenimines, which can then be transformed into
amides in the presence of water (Scheme 1). Herein, we
[Pd
N
95
[Pd
[Pd
–
[Pd
[Pd
[Pd
[Pd
<5[d]
40[e]
n.d.[c]
87
22
78
58
85
87
94
92
[a] F. Zhou, Prof. Dr. K. Ding, Prof. Dr. Q. Cai
Key Laboratory of Regenerative Biology and
Institute of Chemical Biology
[Pd
G
Guangzhou Institutes of Biomedicine and Health
Chinese Academy of Sciences, No. 190 Kaiyuan Avenue
Guangzhou Science Park, Guangzhou (P. R. China)
Fax : (+86)20-32015266
[Pd
[Pd
[Pd
E-mail: cai_qian@gibh.ac.cn
[a] Reagents and reaction conditions: 1a (0.5 mmol, 1.0 equiv), 2a
(0.55 mmol, 1.1 equiv), Pd catalyst (2 mol%), base, (1.0 mmol, 2.0 equiv),
solvent (1 mL), 10 h. [b] Isolated yield, [c] No desired product was detect-
ed. [d] 0.25 mol% Pd catalyst was used. [e] 358C.
ding_ke@gibh.ac.cn
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201102459.
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Chem. Eur. J. 2011, 17, 12268 – 12271

COMMUNICATION
smoothly in 1,4-dioxane or toluene, and both Pd0 and PdII
catalysts delivered the desired product in high yields, while
no desired product was detected without the addition of a
Pd catalyst (Table 1, entries 9–18). Furthermore, to examine
the influence of water, we tested the reaction in CH3CN
with a water content ranging from 1 to 50%, and all the re-
actions delivered the desired product in more than 85%
yield. In pure water (100%), however, the reaction system
was very complex. Finally, we used CH3CN with a water
content of about 5% as the solvent for our reaction.
With the optimized conditions in hand, we then explored
the substrate scope of the aminocarbonylation. At first, a
series of N-tosylhydrazones derived from aryl aldehydes and
tert-butyl isocyanide (2a) were tested (Table 2). Electron-do-
nating groups, such as a methyl or methoxy group, on the
aryl ring of N-tosylhydrazones were well tolerated and the
corresponding products were obtained in excellent yields
(Table 2, entries 1–6). When electron-withdrawing groups,
such as a trifluoromethyl or methoxycarbonyl group, were
attached to the aryl ring, only moderate yields were ob-
tained (Table 2, entries 8–10). We speculated that the elec-
tron-withdrawing groups destabilize the Pd–carbene inter-
mediate and thus, it easily decomposes, which is unfavorable
for the formation of ketenimine intermediates. For the reac-
tion of N-tosylhydrazones derived from aryl ketones with
tert-butyl isocyanide (2a), a higher reaction temperature was
needed to generate the corresponding products. Excellent
yields were obtained when the reactions were performed in
CH3CN under reflux (Table 2, entries 11–19). Furthermore,
N-tosylhydrazones were tested with other isocyanides and
the desired amide products were obtained in moderate to
good yields (Table 2, entries 20–26), even with the steric
bulky isocyanide 2d. However, when aryl isocyanide 1e was
used, the reaction system became very complex and no de-
sired product was detected (Table 2, entry 27).
To further explore the substrate scope, we tested a series
of N-tosylhydrazones deriving from alkyl aldehydes/ketones
in our reaction system. Only a small amount of the corre-
sponding products was detected in CH3CN under reflux
(data not shown). We speculated that the alkyl groups may
have a weaker stabilization effect on the Pd–carbene species
as compared to the aryl groups. As a result, the Pd–carbene
species is more unstable and decomposes more easily. How-
ever, better results were obtained when the reactions were
heated under reflux in less polar 1,4-dioxane and the corre-
sponding products were generated in moderate yields
(Table 3).
Table 2. Substrate scope of the reaction of N-tosylhydrazones 1 with iso-
cyanides 2 leading to the formation of amides 3.[a]
Table 3. Substrate scope of the reaction of N-tosylhydrazones 4 derived
from alkyl aldehydes/ketones with isocyanide 2a leading to the formation
of amides 5.[a]
Entry
1 (R1, R2)
2
3
Yield [%][b]
1
2
3
4
5
6
7
8
9
10
11
12
14
15
16
17
18
19
20
21
22
23
24
25
26
27
1b (H, p-tolyl)
1c (H, m-tolyl)
1d (o-tolyl, H)
1e (4-methoxyphenyl, H)
1 f (3-methoxyphenyl, H)
1g (4-chlorophenyl, H)
1h (3-thiophenyl, H)
1i (4-trifluoromethylphenyl, H)
1j (4-methoxycarbonylphenyl, H)
1k (3-trifluoromethylphenyl, H)
1l (Ph, Me)
1m (Ph, Et)
1n (Ph, nPr)
1o (Ph, Bn)
1p (Ph, Ph)
1q (4-chlorophenyl, Me)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
2d
2d
2c
2d
2e
3ba
3ca
3da
3ea
3 fa
3ga
3ha
3ia
82
86
90
94
86
91
50
75
Entry
1
Substrate
Product
Yield [%][b]
43
3ja
3ka
3la
57
48
78[c]
85[c]
83[c]
91[c]
80[c]
90[c]
74[c]
61[c] (93)[d]
82
2
3
45
75
3ma
3na
3oa
3pa
3qa
3ra
3sa
3ab
3ac
3ad
3gd
3od
3pc
3qd
3ae
1r (4-methoxyphenyl, Me)
1s (p-tolyl, Me)
4
53
1a
1a
1a
1g
1o
1p
1q
1a
89
78
85
65
5
6
62
71
70
66
[e]
–
[a] Reagents and reaction conditions:
1 (0.5 mmol, 1.0 equiv), 2
(0.55 mmol, 1.1 equiv), [Pd(PPh3)4] catalyst (2 mol%), Cs2CO3,
AHCTUNGTRENNUNG
(1.0 mmol, 2.0 equiv), CH3CN (1 mL), 608C, 10 h. [b] Isolated yield.
[c] CH3CN, under reflux. [d] 1,4-Dioxane, under reflux. [e] No desired
product was detected.
[a] Reagents and reaction conditions: 2a (0.55 mmol, 1.1equiv),
(0.5 mmol, 1.0 equiv), [Pd
2.0 equiv), 1,4-dioxane (1 mL), under relux, 10 h. [b] Isolated yield.
4
(PPh3)4] catalyst (2 mol%), Cs2CO3, (1.0 mmol,
Chem. Eur. J. 2011, 17, 12268 – 12271
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Q. Cai, K. Ding and F. Zhou
The synthesized N-tert-butyl amide products can easily be
transformed into simple amides according to a method re-
ported in the literature.[14] For example, when N-tert-butyl-2-
phenylacetamide (3aa) was heated to reflux in trifluoroace-
tic acid, the desired 2-phenylacetamide product (6aa) was
obtained in more than 80% yield (Scheme 2).
In summary, a novel Pd-catalyzed approach for the ami-
nocarbonylation of N-tosylhydrazones with isocyanides via
ketenimine intermediates has been developed that avoids
the use of stoichiometric organometallic reagents. It repre-
sents a general one-carbon extension transformation of car-
bonyl compounds into amides through the Pd-catalyzed ami-
nocarbonylation of in situ generated Pd–carbenes with iso-
cyanides. Further studies on the applications of this method-
ology are currently underway.
Experimental Section
Scheme 2. Transformation of N-tert-butyl amides into simple amides.
Typical procedure for the Pd-catalyzed amidation of N-tosylhydrazones
with isocyanides: tert-Butyl isocyanide (2a, 0.55 mmol) was added to a
mixture of cesium carbonate (325 mg, 1.0 mmol), PdACTHNUTRGNE(UNG PPh3)4 (12 mg,
To further explore the reaction possibilities of our system,
benzylamine (7a) was used to trap the ketenimine inter-
mediate. However, the reaction system was very complex
and only a trace amount of the desired product 8aa was de-
tected (Scheme 3). The isolated products included amide
3aa and a urea derivative 9aa, which was formed through
the direct reaction of benzylamine with isocyanide 2a.
0.01 mmol,), and benzaldehyde tosylhydrazone (1a, 137 mg, 0.5 mmol) in
CH3CN (5 mL) and the mixture was stirred at 608C for 10 h under argon.
Monitoring by TLC showed that the reaction was complete. Water
(5 mL) was added and the aqueous phase was extracted with ethyl ace-
tate (5 mL ꢁ 3). The combined organic phases were washed with brine,
dried over Na2SO4, and concentrated in vacuum. The residue was puri-
fied by column chromatography (SiO2, petroleum ether/ethyl acetate,
5:1) to afford final product 3aa.
Acknowledgements
The authors are grateful to the 100-talent program of CAS, National Nat-
ural Science Foundation (Grant 21002102), and National Basic Research
Program of China (Grant 2010CB529706), State Key Laboratory of Bio-
organic and Natural Products Chemistry, Shanghai Institute of Organic
Chemistry, Chinese Academy of Sciences for their financial support. We
also thank Prof. F. Qiu for helpful discussions.
Scheme 3. Trapping the ketenimine intermediate with benzyl amine
failed.
Keywords: amidation · isocyanides · ketenimines · synthetic
methods · tosylhydrazones
Based on literature reports[2,13a] and our experimental ob-
servations, a plausible mechanism was proposed (Scheme 4).
The isocyanide-complexed Pd species A is first formed and
acts as an active catalyst in our system. The N-tosylhydra-
zone is detosylated under basic conditions and the newly
formed diazo compound reacts with the Pd catalyst to form
Pd–carbene B, which undergoes migratory insertion to form
the ketenimine intermediate C. The latter then reacts with
water to give the final amide product.
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Scheme 4. A plausible mechanism for the aminocarbonylation of N-tosyl-
hydrazones.
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Palladium-Catalyzed Amidation
COMMUNICATION
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Published online: September 21, 2011
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