α-Oxo-Ketenimines from Isocyanides and α-Haloketones: Synthesis and Divergent Reactivity

Article abstract of DOI:10.1002/chem.201703458

The palladium-catalyzed reaction of α-haloketones with isocyanides afforded α-oxo-ketenimines through β-hydride elimination of the β-oxo-imidoyl palladium intermediates. Reaction of these relatively stable α-oxo-ketenimines with nucleophiles such as hydrazines, hydrazoic acid, amines, and Grignard reagent afforded pyrazoles, tetrazole, β-keto amidines, and enaminone, respectively, with high chemoselectivity. Whereas amines attack exclusively on the ketenimine functions, the formal [3+2] cycloaddition between N-monosubstituted hydrazines and α-oxo-ketenimines was initiated by nucleophilic addition to the carbonyl group.

Full text of DOI:10.1002/chem.201703458

A Journal of
Accepted Article
Title: Alpha-Oxo-Ketenimines from Isocyanides and Alpha-
Haloketones: Synthesis and Divergent Reactivity
Authors: Mathias Mamboury, Qian Wang, and Jieping Zhu
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To be cited as: Chem. Eur. J. 10.1002/chem.201703458
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Alpha-Oxo-Ketenimines
from
Isocyanides
and
Alpha-
Haloketones: Synthesis and Divergent Reactivity
Mathias Mamboury, Qian Wang, and Jieping Zhu*
Abstract: The palladium-catalyzed reaction of α-haloketones
with isocyanides afforded a-oxo-ketenimines through b-hydride
elimination of the b-oxo-imidoyl palladium intermediates.
Reaction of these relatively stable a-oxo-ketenimines with
nucleophiles such as hydrazines, hydrazoic acid, amines, and
Grignard reagent afforded pyrazoles, tetrazole, b-keto amidines
and enaminone, respectively, with high chemoselectivity. While
amines attack exclusively on the ketenimine functions, the
formal [3+2] cycloaddition between N-monosubstituted
hydrazines and a-oxo-ketenimines was initiated by nucleophilic
addition to the carbonyl group.
As a continuation of this research program, we became
interested in the reaction of a-haloketones with isocyanides. In
1984, Crociani and co-workers reported that reaction of 2-
chloroacetone (6) with Pd(PPh3)4 afforded carbon s-bonded
palladium complex 7 which, upon addition of tert-butylisocyanide,
was converted to enaminone complex 9 via the imidoylpalladium
intermediate 8.[17] Floriani confirmed the reaction sequence by X-
ray crystal structural analysis of the palladium complexes 7 and
9. [18] Due probably to the need of using stoichiometric amount of
Pd, this interesting transformation remained dormant without
being exploited in synthetic organic chemistry. We reasoned that
by using secondary a-acyl alkylhalides, the hypothetic
intermediate A (R2 ≠H) might undergo reaction different from
that defined for 8. Instead of tautomerization to enamine that
would introduce significant allylic strains, a b-hydride elimination
from A would occur preferentially to afford a-oxo-ketenimines
with concurrent regeneration of Pd species and therefore
making the entire process catalytic. We report the successful
realization of this endeavor as well as the exploration of the
divergent chemical reactivity of this highly functionalized species
1 for the synthesis of 5-aminopyrazoles 12, β-keto amidines 13,
tetrazoles 14 and enaminones 15, important heterocycles and
building blocks in organic synthesis (Scheme 1).
The isoxazolium salt (Woodward’s reagent K) has been used
as an activating reagent of carboxylic acids and phosphoric
acids for peptide synthesis[1] and for phosphorylation,[2]
respectively. The true activating species has been identified to
be the a-oxo-ketenimine generated in situ and indeed a stable
N-tert-butylketoketenimine was isolated from the reaction of N-
tert-butyl-5-phenylisoxazolium perchlorate with trimethylamine.[3]
Since this seminal contribution, two principal methods have
been developed for the synthesis of a-oxo-ketenimines 1: a) the
Wittig reaction of phosphoranes 2 with isocyanates 3;[4] b) the
Aza-Wittig reaction of a-oxo-ketenes 4 with aza-phosphoranes
5.[5] While these two transformations work well in most of the
cases, they do need elaborated and not-so-stable starting
materials and are not atom-economic.[6]
(a) Known synthetic routes to α-oxo-ketenimines
O
PPh3
+
+
O
C
3
O
R1
2
NR3
NR3
NR3
C
R2
R1
O
R2
O
The carbene like reactivity of isocyanide has made it one of
the most versatile reactants in the design of novel
multicomponent reactions.[7] The availability of the lone-pair
electron of the divalent carbon also rendered it an excellent s-
donating ligand. This last property, while well exploited in
organometallic chemistry,[8] has hampered to certain extent its
use in transition metal catalyzed transformations. However, the
last 15 years have witnessed the significant progress in
palladium-catalyzed isocyanide insertion reactions involving
C(sp2)-Pd[9-11] and more recently C(sp3)-Pd species.[12] We have
recently reported a palladium-catalyzed reaction of isocyanides
with allyl carbonates for the synthesis of ketenimines. Migratory
insertion of isocyanide to (h1-allyl)-Pd complex followed by
b-hydride elimination of the resulting allylimidoylpalladium
intermediate[13] was proposed to account for the formation of
ketenimines.[14] Independently, the group of Yang,[15] Wu and
Jiang[16] have developed similar approaches starting from 2-
bromophosphonates and propargylic carbonates, respectively.
1
C
Ph3P
R1
R2
4
5
(b) Crociani and Floriani’s work on the Pd-mediated reaction of 2-chloroacetone
with tBuNC
O
O
O
O
NtBu
Pd(PPh3)2Cl
Pd(PPh3)4
Me
tBuNC
Pd(PPh3)2Cl
Me
Me
Me
Cl
8
6
7
O
NtBu
H
NtBu
Pd(PPh3)2Cl
R1
Pd(PPh3)2Cl
R2
A Unknown
9
(c) This work: Pd-catalyzed reaction of isocyanides with α-haloketones to
α-oxo-ketenimines
NR4
NR4
NHR3
N
O
O
NHR3
N
R1
R1
X
R1
Pd°
O
R2
R2
NR3
R2
13
12
!
R1
10 X = Br, Cl
+
R3NC 11
NHR3
R4
O
N
O
R2
1
N
N
R1
R1
15
R2 R3
14
R2
Scheme 1. Synthesis of a-oxo-ketenimines.
[*]
M. Mamboury, Dr. Q. Wang, Prof. Dr. J. Zhu
Laboratory of Synthesis and Natural Products
Institute of Chemical Sciences and Engineering
Ecole Polytechnique Fédérale de Lausanne
EPFL-SB-ISIC-LSPN, BCH 5304, 1015 Lausanne (Switzerland)
E-mail: jieping.zhu@eplf.ch
Under conditions we previously optimized for the synthesis
of ketenimines,14a the reaction between 2-bromo-1-phenyl
propan-1-one (10a) and tert-butylisonitrile (11a) afforded indeed
the desired a-oxo-ketenimine 1a, albeit in moderate yield (entry
1, Table 1). After systematic screening of the base (entries 1-3),
the solvent (entries 1, 4-5), the palladium source (entries 5-7)
and the temperature (entries 5, 8-9), the optimum conditions
Homepage: http://lspn.epfl.ch
Supporting information for this article is given via a link at the end of
the document. ((Please delete this text if not appropriate))
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10.1002/chem.201703458
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found consisted of performing the reaction in toluene (c 0.2) in
the presence of Pd(OAc)2 (0.05 equiv), K2CO3 (2.0 equiv) at
60 °C. Under these conditions, 1a was formed in 81% isolated
yield (entry 8). Reducing the loading of palladium acetate and
the amount of potassium carbonate afforded product in
diminished yields (entries 10,11). We note that the reaction
outcome was very sensitive to the reaction temperature (entries
5, 9 vs 8) and that the reaction was inhibited under air
atmosphere (entry 12). The a-oxo-ketenimine 1a can be in situ
hydrolyzed (10% aq. HCl) to deliver β-keto amide 16a in 79%
isolated yield. Of note, 2-chloropropiophenone reacted equally
well with 11a to afford, after hydrolysis, 16a in 75% yield.
Remarkably, phenyl vinyl ketone resulting from the b-H
elimination of the C(sp3)-PdBr complex (Vide Supra, Scheme 5,
intermediate B) was not detected in the reaction mixture.
compatible leading to 12o in 90% isolated yield. a-Bromo-b-
ketoester participated in the reaction affording 12p in 80% yield.
Isocyanides other than tBuNC including, most importantly, a
secondary isocyanide, reacted successfully (12q-12r). The
reaction with N-aryl or N-alkyl substituted hydrazines was found
to be highly regioselective leading to the tetrasubstituted 5-
aminopyrazoles (12s-12w) in excellent yields. The structure of
12w was confirmed by X-ray crystallographic analysis.[21]
Reaction of methyl 2-[2-(2-bromoacetyl)phenyl]acetate with tert-
butylisonitrile and hydrazine afforded tricyclic compound 12x in
45% isolated yield. Finally, cleavage of the tert-butyl group of
12a [BF3∙Et2O (10 equiv), dichloroethane, 50 °C] afforded 12y in
78% yield. Such unsubstituted 5-aminopyrazoles are useful
building blocks in the synthesis of more complex heterocyclic
scaffolds.[22]
R4
N
Table 1. Optimization of the formation of α-oxo-ketenimine 1a.
O
N
conditions[a]
Br
R3NC
R4NH2NH2
NHR3
+
+
R1
R1
R2
10
O
O
O
O
R2
H3O+
NtBu
see table
Br
+
C
tBuNC
11
17
12
Ph
Ph
Ph
NHtBu
NH
NH
N
N
NH
N
10a
11a
1a
16a
N
H
N
H
N
H
Ph
Entry
Palladium
Base
Solvent
Temp.
1a [a,b]
Ph
R
R
1
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
PdCl2
K2CO3
Cs2CO3
K3PO4
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
THF
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
50 °C
60 °C
70 °C
60 °C
60 °C
60 °C
34%
13%
34%
53%
71%
51%
49%
12a R = H, 85%
R
12b R = 4-Cl, 75%
12c R = 3-Br, 70%
12d R = 4-MeO, 82%
12e R = 3-Bpin, 80%
2
THF
12f R = CO2Et , 83%
12g R = CH2CN, 80%
12h R = CH2Cl , 70%
12i R = H, 90%
12j R = 4-Cl , 77%
12k R = 2-F, 75%
3
THF
4
1,4-dioxane
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
NH
N
EtO2C
NH
N
NH
N
5
N
H
N
N
Ph
O
H
H
6
EtO2C
Ph
NH
12l 76%
12m 82%
12n 43%
7
NH
N
N
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
84%(81%)
18%
NH
N
NH
N
N
H
N
H
N
H
9
N
H
Ph
Ph
58%[c]
O
OMe
10
11
12
12p 80%
12q 82%
12o 90%
12r 53%
77%[d]
R4
N
Cl
trace[e]
N
N
N
N
H
Ph
NH
N
[a] Standard conditions: 10a (0.4 mmol), tBuNC (0.48 mmol), palladium (0.05
equiv), base (0.8 mmol), solvent (2.0 mL), argon; [b] NMR yield using CH2Br2
as standard, yield in parenthesis corresponds to pure isolated product; [c]
Pd(OAc)2 (0.025 equiv); [d] K2CO3 (0.48 mmol); [e] under air.
Ph
12s R4 = Ph, 77%
12t R4 = Me, 88%
12u R4 = iPr, 78%
12v R4 = Bn, 75%
O
12w 82%
NH
N
NH
N
NH2
Ph
The 5-aminopyrazole is an important class of heterocycles in
pharmaceutical and agrochemical industries.[19] Particularly, N-
aryl-5-aminopyrazoles have been recognized as a privileged
motif in medicinal chemistry.[20] With an efficient synthesis of a-
oxo-ketenimines in hand, a one-pot three-component synthesis
of 5-aminopyrazoles was next sought. Gratefully, stirring a
toluene solution of 10a and 11a under our optimized conditions
[Pd(OAc)2 (0.05 equiv), K2CO3 (2.0 equiv), 60 °C] followed by
addition of a THF solution of hydrazine (17a, 2.0 equiv) at room
temperature afforded 5-aminopyrazole 12a in 85% isolated yield
(Scheme 2). This three-component reaction was applicable to a
wide range of substrates. Both electron-withdrawing (12b-12c)
and electron-donating (12d) groups on the aromatic moiety of 2-
bromopropiophenone were tolerated. Notably, aryl bromide
(12c) and aryl boronate (12e) were compatible to this palladium-
catalyzed transformation. Electrophilic functionalities such as
ester (12f), cyanide (12g) and even alkyl chloride (12h), which
are susceptible to nucleophilic attack by hydrazine, remained
untouched to deliver the desired products in high yields. 3,4-
Diaryl substituted 5-aminopyrazoles could be formed (12i-12k),
as well as 3,4-dialkyl derivatives (12l-12n). A furan unit was also
12y 78%
12x 45%
R4
NH
R4
N
O
NtBu
C
R4NHNH2
N
N
R1
NtBu
NHtBu
12
C
R1
R1
18
R2
R2
R2
1a
Scheme 2. Scope of the one-pot three-component synthesis of 5-
aminopyrazoles from α-bromoketones. [a] Standard conditions: α-
bromoketone (0.4 mmol), isocyanide (0.48 mmol), Pd(OAc)2 (0.05 equiv),
K2CO3 (0.8 mmol), toluene (2.0 mL), argon, 60 °C; then NH2NH2 (0.8 mmol),
room temperature. [b] when hydrochloride salts R4NHNH2•HCl were used,
KOH (1.0 equiv) was added to the reaction mixture.
The exclusive formation of regioisomer 12s-12w could be
accounted for by chemoselective addition of hydrazine to
carbonyl rather than the ketenimine function leading to
intermediate 18 which, upon cyclization, would afford the
observed products 12s-12w. This observed chemoselectivity is
intriguing based on the known reactivity pattern of a-oxo-
ketenimine (see below). We note that there was one single
example in the literature dealing with the reaction of
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phenylhydrazine with a-oxo-ketenimine and a regioisomeric
cyanoketone 20a in 57% yield. Reaction of 1a with HN3 in
toluene delivered tetrazole 14a in 84% yield. Finally, treatment
of 1a with Grignard reagent provided enaminone 15a in 58%
yield resulting from the chemoselective nucleophilic addition to
the ketenimine function. We note that classic synthesis involving
the condensation of tert-butylamine with the corresponding 1,3-
diketone would not afford 15a with such a high regioselectivity.
pyrazole was assigned to the adduct.[5]
Interestingly, the addition occurred chemoselectively on the
ketenimine rather than on the carbonyl function when amine was
used as a nucleophile. Thus, the reaction of the crude α-oxo-
ketenimine 1a with p-anisidine (1.0 equiv) at 90 °C afforded β-
keto amidine 13a in 85% yield (conditions a). In the presence of
a catalytic amount of TFA (0.2 equiv, RT), the reaction
proceeded with the same chemoselectivity to afford 13a in a
similar yield but with shorter reaction time (condition b). The
generality of this protocol is shown in Scheme 3. Various a-
bromo aryl alkyl ketone, aryl aryl ketone, alkyl alkyl ketone, b-
keto ester and malonate participated in this reaction. Both
electron-rich (13a, 13c, 13h), electron-poor (13b, 13d, 13g) and
hindered (13e) anilines were efficient nucleophilic partners, so
was aliphatic amine (13i). It is worth noting that there were very
few methods allowing the direct access to β-keto amidines. A
A plausible reaction pathway accounting for the formation of
a-oxo-ketenimines 1 is described in Scheme 5. Oxidative
addition of α-haloketone 10 to the in situ generated Pd0
species[24] would afford intermediate B which might be in
equilibrium with O-bound tautomer C.[25] Migratory insertion of
RNC from B would generate imidoylpalladium intermediate A
which could tautomerize to
D according to Crociani and
Floriani[17-18]. However, we assumed that the presence of the
CH2R2 group would impose severe steric interaction in the
tetrasubstituted enaminone form D. Therefore, the equilibrium
may not take place or reside mainly on the imine form A. The β-
hydride elimination[13-14] from A would deliver the desired α-oxo-
ketenimine 1 with concurrent regeneration of Pd catalyst.
sulfide contraction reaction is
regard.[23]
a
notable example in this
R3
O
O
HN
conditions[a,b]
Br
+
R3NH2
tBuNC
+
R1
R1
N
R2
R2
O
10
11a
19
13
KX + CO2 + H2O
[Pd0(RNC)2]
X
R1
10
OMe
R
R2
RNC
O
O
N
Cl
K2CO3
HPdII(RNC)2X
O
N
OMe
O
N
Pd0(RNC)2
X
Pd(OAc)2
R1
Ph
NHtBu
Ph
NHtBu
Ph
NHtBu
O
RNC
PdII
CNR
X
EtO2C
R2
Ph
13c 70%[b]
21
R1
13a R = OMe, 85%[a], 84%[b]
13b R = NO2, 52%[b]
13d 83%[b]
R2
B
OPdII(RNC)2X
O
R1
NR
C
C
O
N
R1
O
N
O
NR
O
N
Cl
R2
1
O
R1
PdII(RNC)2X
Ph
NHtBu
NHtBu
R2
NHtBu
CO2Me
H
R2
H
Ph
13f 67%[b]
A
O
NR
13e 70%[b]
13g 68%[b]
OMe
R1
PdII(RNC)2X
R2
D
HN
O
N
Ph
MeO2C
NHtBu
CO2Me
13h 87%[b]
Ph
NHtBu
Scheme 5. Mechanistic hypothesis.
13i 58%[a]
Scheme 3. Scope of the three-component synthesis of β-keto amidines from
α-bromoketones. Standard conditions: α-bromoketone (0.4 mmol), tBuNC
(0.48 mmol), Pd(OAc)2 (0.05 equiv), K2CO3 (0.8 mmol), toluene (2.0 mL),
argon, 60 °C; then [a] amine (0.4 mmol), toluene (2.0 mL), 90 °C; [b] amine
(0.4 mmol), TFA (0.2 equiv), toluene (2.0 mL), room temperature.
The palladium-catalyzed carbonylation of α-haloketones is
known and till now the scope of this synthetically useful
transformation was applied mainly to haloketones lacking the b-
hydrogen[26] since intermediate related to B are known to
undergo rapid b-hydride elimination to enone 21 even under the
carefully optimized conditions.[27] The fact that this supposedly
facile process, a main concern at the outset of our reaction
design, did not take place under our conditions is remarkable.
The migratory insertion might be sufficiently fast from
isocyanide-ligated Pd species B to outcompete the β-hydride
elimination process.
tBuNC (1.2 equiv)
Pd(OAc)2 (5 mol%)
O
BF3.Et2O
(1.0 equiv)
O
O
NtBu
C
CN
Br
Ph
Ph
Ph
K2CO3 (2.0 equiv)
toluene, 60 °C
DCE, 0 °C to RT
10a
1a
20a 57%
BrMg
(1.0 equiv)
OMe
HN3 (1.5 equiv)
toluene, 0 °C to RT
THF, 0 °C to RT
N
In summary, we reported a new protocol for the preparation
of α-oxo-ketenimines from α-haloketones and isocyanides taking
O
N
O
NHtBu
N
Ph
N
Ph
tBu
14a 84%
advantage of
hydride elimination sequence.
a
palladium-catalyzed isocyanide insertion/β-
one-pot three-component
OMe
15a 58%
A
Scheme 4. Further structural diversification of α-oxo-ketenimine 1a.
synthesis of tri- and tetrasubstituted 5-aminopyrazoles was
subsequently developed by trapping in situ the α-oxo-
ketenimines with hydrazines. When amines/anilines, azide and
Grignard reagent were used as nucleophiles, nucleophilic
addition occurred chemoselectively on the ketenimine function to
Further examples of the synthetic transformation of the α-
oxo-ketenimine are depicted in Scheme 4. Treatment of the
crude ketenimine 1a with boron trifluoride etherate afforded a-
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10.1002/chem.201703458
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1429; r) M. Tobisu, S. Imoto, S. Ito, N. Chatani, J. Org. Chem. 2010, 75,
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afford the b-keto amidines, tetrazole and enaminone,
respectively.
Acknowledgements
Financial supports from EPFL (Switzerland) and the Swiss
National
Science
Foundation
(SNSF)
are
gratefully
acknowledged. We thank Dr. R. Scopelliti and Dr. F. T. Fadaei
for X-ray crystallographic analysis of 12w.
Keywords: palladium • isocyanide • ketenimine • heterocycle •
amidine
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Entry for the Table of Contents (Please choose one layout)
Synthetic Method
R4
N
R4NHNH2
N
O
NHR3
Nu
R1
Mathias Mamboury, Qian Wang, and
Jieping Zhu* __________ Page – Page
Alpha-Oxo-ketenimines
Isocyanides and Alpha-Haloketones:
Synthesis and Divergent Reactivity
R2
O
O
?
NR3
Pd0
R3
Nu
NR3
X
Nu
C
+
R1
R1
O
NC
from
R1
Nu = RNH2, RMgX
R2
R2
R2
NR3
PdX
O
N
N
O
PdX
HN3
N
R1
R1
R1
N
H
H
R2 R3
R2
R2
β-H elimination No
yes
b
-Hydride elimination at will. Reaction of α-haloketones with isocyanides in the
presence of a catalytic amount of Pd(OAc)2 afforded a-oxo-ketenimines that can be
further converted to 5-aminopyrazoles, tetrazole, b-keto amidines and enaminone in
good to excellent yields.
This article is protected by copyright. All rights reserved.