Chemoselective, Isomerization-Free Synthesis of N-Acylketimines from N–H Imines

Article abstract of DOI:10.1002/adsc.201601406

N-Acylketimines were synthesized through a ruthenium-catalyzed generation of N–H ketimines from secondary azides and subsequent acylation with mixed anhydrides under mild conditions. The synthetic scope was broad to give N-acylimines having various functi

Full text of DOI:10.1002/adsc.201601406

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DOI: 10.1002/adsc.201601406
Chemoselective, Isomerization-Free Synthesis of N-Acylketimines
from N–H Imines
Yearang Kwon,a Young Ho Rhee,a,* and Jaiwook Parka,*
a
Department of Chemistry, POSTECH (Pohang University of Science and Technology), Pohang, 37673, Korea
Fax : (+82)-54-279-0654; e-mail: yhrhee@postech.ac.kr (homepage: http://yhrhee.postech.ac.kr) or pjw@postech.ac.kr
(homepage: http://oml.postech.ac.kr)
Received: December 22, 2016; Revised: February 8, 2017; Published online: && &&, 0000
Supporting information for this article can be found under http://dx.doi.org/10.1002/adsc.201601406.
Abstract: N-Acylketimines were synthesized
through a ruthenium-catalyzed generation of N–H
ketimines from secondary azides and subsequent
acylation with mixed anhydrides under mild condi-
tions. The synthetic scope was broad to give N-acyl-
the a-position are proper precursors of N-acylimines.
Particularly, a-amido sulfones are frequently em-
ployed as the precursors due to their relatively easy
preparation and high stability (Scheme 1d).[10]
Because of the issues associated with the stability
of N-acylimines, most of their synthetic methods are
effective only for N-acyl aldimines possessing no eno-
lizable hydrogens. Other N-acylimines including keti-
mines are hard to be synthesized as a stable entity.
For example, the N-Cbz ketimines synthesized from
lithiated N-Cbz-1-phenylethylamine by oxidation tau-
tomerize even at room temperature when they are
dissolved in chloroform.[8] Thus, a general synthetic
method that gives access to enolizable N-acylimines is
still elusive in synthetic organic chemistry.
ACHTUNGTRENNUNGimines having various functional groups, including
those with aliphatic groups that are prone to tauto-
merization to the corresponding enamides. In addi-
tion, various acyl moieties were accommodated.
The synthetic utility of this chemoselective imine
generation was illustrated by a highly diastereose-
lective nucleophilic addition of a Grignard reagent
to a cyclic N-acylimine.
Keywords: acyl alkyl carbonates; acylimines; carba-
mates; N–H imines; ruthenium
N-Acylimines are pivotal intermediates in organic
synthesis, which have electron-withdrawing acyl sub-
stituents to overcome the low electrophilicity and lim-
ited utility of N-alkylamines and N-arylamines. N-
Acylimines have been employed in numerous C–C
and C–heteroatom bond forming reactions, including
asymmetric arylation,[1] allylation,[2] allenylation,[3]
Mannich,[4] and heteroatom addition reactions.[5,6]
Conventionally, N-Acylimines can be formed by
the direct condensation of their carbonyl and amide
precursors under reversible conditions. Also, they can
be prepared by the reaction of N-silylimines with acyl
chlorides (Scheme 1a),[7] the oxidation of lithiated N-
carbobenzyloxy (Cbz) amines (Scheme 1b),[8] and
a Wittig-like reaction of iminophosphoranes with car-
bonyl compounds (Scheme 1c).[9] However, N-acyl-
ACHTUNGTRENNUNGimines are known to be too unstable to be stored
under ambient conditions. Thus, they are generally
prepared in situ for the reaction with nucleophiles.
Amido derivatives containing a good leaving group at Scheme 1. Conventional synthetic methods for N-acylimines.
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Table 1. Optimization of the reaction conditions.[a]
Based upon our recent reports on the generation of
N–H imines from alkyl azides under ruthenium catal-
ysis,[11] we envisioned that acylation of N–H imines
may offer a solution to this challenging problem. Our
previous attempts to use anhydrides/acid chlorides
failed to generate N-acylimines, due to the fast iso-
merization to the corresponding enamides.[12] We rea-
soned that the use of a mixed anhydride such as A
(Scheme 2) is more suitable for N-acylimine genera-
tion because only CO2 and alcohol are generated as
the by-products during the acylation process. Herein,
we report the one-pot synthesis of various N-acylket-
Entry Solvent[b] 3a (equiv.)[b] Conv. [%][c] Yield [%][c]
1
2
3
4
5
6
7
THF
THF
THF
toluene
CH2Cl2
CH3CN
acetone
EtOAc
THF
1.0
1.5
2.0
2.0
2.0
2.0
2.0
2.0
2.0
>99
>99
>99
>99
>99
63
6
30
71
72
80
96
88
87
59
5
ACHTUNGTRENNUNGimines including enolizable aliphatic ones from the
alkyl azides.
8
26
64
9[d]
[a]
Typical reaction conditions:
a solution of an azide
(0.25 mmol), carbonate (0.50 mmol) and 1 (2.0 mol%) in
a solvent (0.50 mL) was illuminated with 30W fluores-
cent light. The resulting mixture was stirred for 3 h at
room temperature.
[b]
[c]
THF=tetrahydrofuran.
1
Estimated by H NMR using nitromethane as an internal
standard.
1 mol% of 1 was used.
[d]
to a steric effect. Various functional groups such as
halides (4e and 4f), an ether (4g), a thioether (4h),
esters (4i), amides (4j), and nitriles (4k) were compat-
ible with the reaction conditions. Notably, formyl and
acetyl groups (4l and 4m) were compatible with the
reaction conditions. Heteroaromatic (4n and 4o) and
naphthyl derivatives (4p) were also obtained in good
yields. The reaction was successfully expanded to the
synthesis of imines possessing a longer alkyl group
(4q) and a benzyl group (4r). Our procedure was also
effective to prepare benzocyclic derivatives (4s and
4t) as well as aliphatic ones (4u–4w). 1,2-Azido alco-
Scheme 2. Synthesis of N-acylketimines from secondary
azides and acyl alkyl carbonates.
In a preliminary study, the acylation of N–H imine hols were the precursors for the synthesis of a-me-
generated from the azide 2a was examined under var- thoxymethoxy (MOM) N-acylimines (4t, 4x–4z).
ious conditions using acetyl isopropyl carbonate 3a as
Next, we examined variation of the acyl moiety
the mixed anhydride source (Table 1).[13] When an (Table 3). A methacrylamide (5a) and a propiolamide
equimolar mixture of 2a and 3a was used in THF, the (5b) were obtained in high yields in reactions with the
product 4a was obtained in 72% yield (entry 1). The corresponding (isopropyl carbonic) anhydrides. Boc-
yield of 4a was improved substantially by doubling protected keimines (5c–5e) and Cbz-protected ones
the amount of acetyl isopropyl carbonate (entry 2). (5f-5h) were formed in reactions with the correspond-
Reactions conducted in other solvents afforde signifi- ing dicarbonates. Thus, this reaction was successfully
cantly reduced yields (entries 3–7). When the amount expanded to the synthesis of carbamate derivatives of
of the catalyst 1 was halved, the conversion of the re- aliphatic ketimines (5d, 5e, 5g, and 5h), which cannot
action was significantly decreased (entry 8).
be obtained by the previous condensation methods.
Then, the substrate scope was investigated under Notably, 5d could be prepared on a gram-scale and
the optimized conditions (Table 2). Aliphatic azides purified by silica-gel column chromatography.[14]
as well as benzylic azides were successfully trans-
Having established the generality of the chemose-
formed into the corresponding N-acylimines at room lective N-acylimine synthesis, we investigated the po-
temperature by the one-pot procedure. The yield of tential utility of this method in the addition reaction.
the substrate having an ortho-methyl substituent on As described in Scheme 3, addition of the anion gen-
the phenyl ring (4b) was slightly lower than those of erated from malonate proceeded nicely to give the
the meta- and para-derivatives (4b–4d) probably due corresponding tertiary carbinyl amine 6 in 91% isolat-
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Table 2. Synthesis of N-acylimines from secondary azides.
[a]
Typical procedure: a solution of an azide (0.25 mmol), carbonate (0.50 mmol) and 1 (2.0 mol%) in THF (0.50 mL) was il-
luminated with 30W fluorescent light. The resulting mixture was stirred for 3 h at room temperature.
Estimated by H NMR using nitromethane as an internal standard.
[b]
1
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Table 3. Synthesis of acyl ketimines from various carbonates.
Scheme 3. One-pot transformation to a tertiary carbinyl
amine.
ed yield.[15] The high yield of this reaction strongly
suggests that isomerization under basic conditions is
only minimal.
In addition, amides 7a–c were obtained in high
yields with almost perfect diastereoselectivity in the
reactions of N–H imine generated from the azide 2t
with MeMgBr, CH2=CHMgBr, and PhMgBr, respec-
tively (Scheme 4).[16]
Scheme 4. Diastereoselective synthesis of b,b-dibranched
amino alcohols.
In conclusion, we have developed a new method
for the chemoselective synthesis of N-acylketimines
which are labile to tautomerization into enamides.
The substrate scope was broad, and the variation of
the acyl moiety was possible using various electro-
philes for N–H ketimines. The utility of the reaction
was demonstrated in the nucleophilic addition reac-
tions to give amides containing a stereogenic quater-
nary carbon center. Currently, we are investigating
the asymmetric synthesis of these compounds.
[a]
Method A: a solution of an azide (0.25 mmol), electro-
phile (0.50 mmol) and 1 (2.0 mol%) in THF (0.50 mL)
was illuminated with 30W fluorescent light. The resulting
mixture was stirred for 3 h at room temperature. Method
B: a solution of an azide (0.25 mmol) and 1 (2.0 mol%)
in THF (0.50 mL) was illuminated with 30W fluorescent
light. After formation of the imine, the electrophile
(0.50 mmol) was added. The resulting mixture was stirred
for 3 h at room temperature.
Experimental Section
[b]
1
Representative Procedure for the Synthesis of N-
Acylimines
Estimated by H NMR using nitromethane as an internal
standard.
[c]
[d]
[e]
[f]
Reaction was performed in CH3CN.
Reaction was performed in toluene.
The reaction was carried out at 508C.
A gram-scale reaction employing 1.0 g (4.7 mmol) of 2z
and 15 mg (1.0 mol%) of 1 in 10 mL of toluene.
In a Schlenk flask, the azide 2z (0.25 mmol), the ruthenium
catalyst 1 (4.9 mg, 2.0 mol%), and dry THF (0.50 mL) were
charged under an argon atmosphere. The reaction mixture
was stirred at room temperature under 30W fluorescent
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light. The conversion was monitored by TLC. After com-
plete conversion of 2z, di-tert-butyl dicarbonate (0.50 mmol)
was added. The reaction mixture was stirred for 3 h at 508C,
and volatiles were removed under vacuum. The yield of the
N-acylimine 5d was 82% according to 1H NMR analysis
using nitromethane as an internal standard.
When 1.0 g of 2z (4.7 mmol) was employed, the crude
product was purified by flash column chromatography (hex-
ane:ethyl acetate=9:1) using deactivated silica gel with 1%
triethylamine to afford 5d as a yellowish oil; isolated yield:
950 mg (71%).
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6 Chemoselective, Isomerization-Free Synthesis of N-
Acylketimines from N–H Imines
Adv. Synth. Catal. 2017, 359, 1 – 6
Yearang Kwon, Young Ho Rhee,* Jaiwook Park*
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