Palladium-catalyzed cross coupling reaction of N-alkoxyimidoyl bromides and its application to one-pot synthesis of N-arylamines

Article abstract of DOI:10.1248/cpb.59.1206

The synthetic utility of N-alkoxyimidoyl halides is demonstrated using the palladium-catalyzed cross-coupling reaction. The Sonogashira and Suzuki-Miyaura coupling reactions of N-alkoxyimidoyl bromides produced versatile ketoxime ethers in good to excelle

Full text of DOI:10.1248/cpb.59.1206

1206
Communication to the Editor
Chem. Pharm. Bull. 59(9) 1206—1208 (2011)
Vol. 59, No. 9
Table 1. Sonogashira Coupling of N-Alkoxyimidoyl Bromide 1a)
Palladium-Catalyzed Cross Coupling
Reaction of N-Alkoxyimidoyl Bromides
and Its Application to One-Pot Synthesis
of N-Arylamines
Entry
R1
R2
Product
Yield (%)b)
Masafumi UEDA, Shoichi SUGITA, Naoki AOI, Aoi SATO,
Yuki IKEDA, Yuta ITO, Tetsuya MIYOSHI,
Takeaki NAITO, and Okiko MIYATA*
1
2
3
4
5
6
7
8
9
Ph (1a)
Ph (1a)
Ph (1a)
Ph (1a)
2-Furyl (1b)
4-CF3C6H4 (1c)
2-Furyl (1b)
TMS (2A)
Ph (2B)
n-Bu (2C)
CH2OTBS (2D) 3aD
TMS (2A)
TMS (2A)
CH2OTBS (2D) 3bD
CH2OTBS (2D) 3cD
CH2OTBS (2D) 3dD
3aA
3aB
3aC
79
71
79
73
67
91
66
90
Quant.
Kobe Pharmaceutical University; Motoyamakita, Higashinada,
Kobe 658–8558, Japan.
Received June 8, 2011; accepted June 30, 2011; published online
July 4, 2011
3bA
3cA
4-CF3C6H4 (1c)
4-MeOC6H4 (1d)
The synthetic utility of N-alkoxyimidoyl halides is demon-
strated using the palladium-catalyzed cross-coupling reaction.
The Sonogashira and Suzuki–Miyaura coupling reactions of N-
alkoxyimidoyl bromides produced versatile ketoxime ethers in
good to excellent yields. A one-pot reaction of the imidoyl bro-
mides with arylboronic acid and allylmagnesium bromide to
10 c-Hexyl (1e)
CH2OTBS (2D)
—
Complex mixture
a) Reactions were carried out with acetylene (2.0 eq), PdCl2(PPh3)2 (4 mol%), PPh3
(8 mol%) and CuI (8 mol%) and Et3N in THF. b) Isolated yields.
produce N-arylamines via Suzuki–Miyaura coupling followed by alkynes (Table 1). Treatment of (Z)-N-benzyloxyimidoyl bro-
mide 1a35) with (trimethylsilyl)acetylene (2A), PdCl2(PPh3)2
(4 mol%), PPh3 (8 mol%), CuI (8 mol%) and Et3N in tetrahy-
domino reaction involving sequential addition-eliminative re-
arrangement-addition reactions was developed.
drofuran (THF) at 60 °C led to efficient Sonogashira cou-
pling to give (Z)-alkynyl oxime ether 3aA36) in 79% yield
(entry 1). The reaction not only occurs with (trimethyl-
Key words imidoyl bromide; Suzuki–Miyaura coupling; Sonogashira
coupling; one-pot reaction; N-arylamine
Imidoyl halides are often used as a versatile scaffold in or- silyl)acetylene (2A) but also with phenylacetylene (2B)
ganic synthesis.1,2) In particular, N-alkyl or N-arylimidoyl (entry 2) as well as with alkynes substituted by aliphatic
halides are utilized in transition metal-catalyzed cross-cou- groups 2C and 2D (entries 3 and 4), producing the corre-
pling reactions.3—8) In contrast, although the substitution re- sponding (Z)-alkynyl oxime ethers 3aB—3aD in good
actions of N-alkoxyimidoyl halides with nucleophiles such yields. Variation of the substituent for R1 was then examined.
as carbanion,9) alkoxide,10,11) amine,12,13) azide14) and halo- We were pleased to observe that electron-rich and electron-
gen15,16) have been developed, the catalytic cross-coupling re- poor aryl groups were readily accommodated (entries 5—9),
action is less studied, despite the fact that the oxime ethers while imidoyl bromide 1e, which contains the cyclohexyl
produced are useful intermediates for the syntheses of group as R1, did not undergo detectable coupling reaction
amines and heterocycles.17—20) Kim and Chang’s group re- and thus led to an unidentified complex mixture probably due
ported that N-alkoxyimidoyl halides are efficient coupling to decomposition of 1e (entry 10). It is noteworthy that ex-
partners in the Stille reaction.21) Weinreb and co-workers also cellent chemical yield was observed in the reaction of sub-
reported the palladium-catalyzed coupling reaction of N- strate 1d bearing a p-methoxylphenyl group (entry 9). The
methoxyimidoyl bromide bearing imidazole with vinylstan- alkynyl oxime ethers produced can be used for both synthesis
nane proceeded with relatively lower yield, however no de- of isoxazoles and radical reactions.18,37,38)
sired coupling product was obtained in the reaction with
We next focused our attention on the Suzuki–Miyaura re-
boronic acid or organozinc halide due to the undesirable for- action of imidoyl bromide. After simple screening of cata-
mation of nitrile by elimination.22) Although a few examples lysts, ligands, bases, solvents and reaction temperature, the
exist where Suzuki–Miyaura coupling has been employed for optimal reaction conditions were found to be boronic acid
the synthesis of biologically active compounds by pharma- (2.0 eq), Pd(OAc)2 (10 mol%), PPh3 (20 mol%) and Cs2CO3
ceutical companies,23—25) systematic research focused on the (5.0 eq) in refluxing toluene (Table 2). The coupling reaction
reactivity of N-alkoxyimidoyl halides has not been reported. of (Z)-N-benzyloxyimidoyl bromide 1a with phenylboronic
Moreover, one-pot transformation of the coupling product, acid (4A) proceeded smoothly to afford the desired oxime
which would demonstrate the potential utility of this reac- ether 5aA in 74% yield with retention in the double-bond
tion, has never been reported. Furthermore, the Sonogashira geometry (entry 1).36) Interestingly, replacement of the ben-
coupling reactions of N-alkoxyimidoyl halides have not yet zyl group with a methyl group improved the chemical yield,
been described in the literature.26,27) Herein, we report Sono- thus O-methyl oxime 5fA was obtained in 82% yield (entry
gashira28,29) and Suzuki–Miyaura30,31) coupling reactions of 2). The electronic and steric effects were then evaluated by
N-alkoxyimidoyl bromide and their application to one-pot re- using various arylboronic acids. Phenylboronic acids carry-
actions of the resulting oxime ether with allylmagnesium ing electronic donating (methoxy, methyl) and withdrawing
bromide in connection with our recent efforts to synthesize groups (trifluoromethyl, chloro) at the para or meta positions
N-alkyl arylamines by domino reaction with organometallic gave good to excellent yields of coupling products 5fB—5fD
reagents.32—34)
We initially studied palladium-catalyzed reactions with not clear why employing electron poor boronic acid bearing
and 5fG—5fI, respectively (entries 3—5 and 8—10). It is
© 2011 Pharmaceutical Society of Japan
∗ To whom correspondence should be addressed. e-mail: miyata@kobepharma-u.ac.jp

September 2011
1207
Table 2. Suzuki–Miyaura Coupling of N-Alkoxyimidoyl Bromide 1a)
Table 3. One-Pot Synthesis of N-Arylamines from N-Methoxyimidoyl
Bromide 1f a)
Entry Substrate R3
Ar
Ph (4A)
Product Yield (%)b)
1
1a
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
1f
Bn
5aA
5fA
5fB
5fC
5fD
5fE
5fF
5fG
5fH
5fI
74
82
91
85
77
14
4
77
87
96
21
82
2
3
4
5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Ph (4A)
4-MeOC6H4 (4B)
4-MeC6H4 (4C)
4-CF3C6H4 (4D)
4-CNC6H4 (4E)
4-CO2MeC6H4 (4F)
4-ClC6H4 (4G)
3-MeOC6H4 (4H)
3-CF3C6H4 (4I)
2-MeC6H4 (4J)
2-Naphthyl (4K)
6c)
7d)
8
Entry
Ar
Ph (4A)
4-MeOC6H4 (4B)
4-CF3C6H4 (4D)
4-ClC6H4 (4G)
Product
Yield (%)b)
1
2
3
4
6A
7B
6D
6G
85
68
31
59
9
10
11d)
12
5fJ
5fK
a) Reactions were carried out with boronic acid (2.0 eq), Pd(OAc)2 (10 mol%), PPh3
(20 mol%), CsCO3 (5.0 eq) and then allylMgBr (4.0 eq). b) Isolated yields.
a) Reactions were carried out with boronic acid (2.0 eq), Pd(OAc)2 (10 mol%), PPh3
(20 mol%) and Cs2CO3 (5.0 eq). b) Isolated yields. c) Reaction time was 6 h. d)
Reaction time was 3 h.
p-cyanophenyl (4E) or p-methoxycarbonylphenyl groups References and Notes
1) For radical reactions, see: de Lijser H. J. P., Burke C. R., Rosenberg J.,
(4F) resulted in a marked drop in yields (entries 6 and 7).
The sterically demanding 2-methylphenylboronic acid (4J)
proved to be a difficult substrate (entry 11). 2-Naphthyl-
boronic acid was also employed in this reaction (entry 12),
affording oxime ether 5fK in 82% yield.
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To demonstrate the synthetic utility of N-alkoxyimidoyl
bromides as highly versatile building blocks, we investigated
their one-pot transformation via Suzuki–Miyaura coupling
reaction and domino reaction involving sequential addition-
eliminative rearrangement-addition into N-alkyl arylamines
containing a quaternary carbon (Table 3). After completion
of Suzuki–Miyaura coupling of 1f with phenylboronic acid
4A as described in Table 2, allylmagnesium bromide (4 eq)
was added to the reaction vessel and the reaction mixture was
stirred in refluxing toluene. The simple procedure provided
(diallyl)methyl amine 6A in 85% yield (entry 1). The one-pot
reaction with 4-methoxyphenylboronic acid (4B) produced
7B in good yield via rearrangement of the 4-methoxyphenyl
group onto the nitrogen atom (entry 2). In contrast, when 4-
trifluoromethylphenylboronic acid (4D), an electron-deficient
coupling partner, was employed, selective migration of the
phenyl group was observed to afford 6D, albeit in lower yield
(entry 3). The chloro group did not affect the course of the
reaction, thus chemoselective migrative allylation gave 6G in
59% yield.
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In summary, we have shown the synthetic utility of N-
alkoxyimidoyl halides using the palladium-catalyzed cross
coupling reaction. The Sonogashira and Suzuki–Miyaura
coupling of N-alkoxyimidoyl bromides produced ketoxime
ethers, which are versatile synthetically. The Suzuki–Miyaura
coupling reaction was successfully applied to the one-pot
synthesis of N-alkyl arylamines containing a quaternary car-
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Acknowledgments This work was supported in part by Grants-in-Aid
from the Ministry of Education, Culture, Sports, Science and Technology of
Japan. M.U. is grateful to the Research Foundation for Pharmaceutical Sci-
ence.
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Vol. 59, No. 9
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1
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