Selective α-amination and α-acylation of esters and amides via dual reactivity of O-acylhydroxylamines toward zinc enolates

Article abstract of DOI:10.1039/c3cc49296f

Selective α-amination and α-acylation of esters and amides have been developed, employing O-acylhydroxylamines as a dually reactive aminating and acylating reagent. Treatment of zinc enolates with O-acylhydroxylamines provides solely 1,3-dicarbonyl compounds under mild conditions. Introduction of a copper catalyst into the system shifts the reactivity entirely, yielding α-amination products exclusively.

Full text of DOI:10.1039/c3cc49296f

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COMMUNICATION
Selective a-amination and a-acylation of esters and
amides via dual reactivity of O-acylhydroxylamines
toward zinc enolates†
Cite this: Chem. Commun., 2014,
50, 2535
Received 6th December 2013,
Accepted 8th January 2014
Stacey L. McDonald and Qiu Wang*
DOI: 10.1039/c3cc49296f
www.rsc.org/chemcomm
Selective a-amination and a-acylation of esters and amides have been source, inspired by the pioneering work on electrophilic aminations
developed, employing O-acylhydroxylamines as a dually reactive between organometallic reagents and O-acylhydroxylamines.10,11
aminating and acylating reagent. Treatment of zinc enolates with Simultaneously, we envisioned that O-acylhydroxylamines could also
O-acylhydroxylamines provides solely 1,3-dicarbonyl compounds under act as an electrophilic acylating agent12 toward zinc enolates and
mild conditions. Introduction of a copper catalyst into the system shifts lead to the alternative formation of 1,3-dicarbonyl compounds. Such
the reactivity entirely, yielding a-amination products exclusively.
dual reactivity of O-acylhydroxylamines is valuable and useful,
providing a powerful and divergent strategy for direct and selective
Functionalization of carbonyl enolates represents one of the most access to a-amino carbonyl and 1,3-dicarbonyl compounds, highly
general and efficient approaches to access biologically important desirable motifs in organic synthesis and pharmaceuticals.6,13
a-functionalized carbonyl compounds. Toward this end, zinc
This communication reports our studies on zinc enolates of
enolates have received growing interest as valuable intermediates for esters and amides for the development of selective a-amination
carbonyl a-functionalization.1 In comparison to commonly used and a-acylation reactions using O-acylhydroxylamines as either an
carbonyl a-alkali and alkaline-earth enolates, they offer an ideal aminating or an acylating agent (Scheme 1). The developed amination
combination of good reactivity and tolerance toward many functional conditions bypass the requirement for postreaction amine modifica-
groups.1 So far, zinc enolates have been successfully applied toward tion and overcome the limitation of a narrow amine scope under
carbon–carbon bond formation with aldol additions to carbonyls,2 previous a-amination conditions. It provided the first example of
nucleophilic additions to alkenes,3 as well as a variety of trans- electrophilic amination of zinc enolates for the direct installation of
metalation reactions such as a-arylation1d,4 and a-allylation.5 different amines at the carbonyl a-position in a one-step reaction.
However, the potential of zinc enolates remains underexplored Such a direct and operationally convenient amination procedure
for the synthesis of a-heteroatom substituted carbonyl molecules, represents a valuable advance in the synthesis of a-amino carbonyl
such as a-amino carboxyl derivatives, one of the most biologically compounds. We also identified that acylation effectively occurred
important carbonyl compounds.6
upon the treatment of these zinc enolates with O-acylhydroxylamines
The direct installation of diverse amines at the carbonyl alone at elevated temperatures where O-acylhydroxylamines act as an
a-position has been a long-standing challenge in organic synthesis. acylating agent exclusively. Such an alternative a-acylation reaction
The developed a-amination methods7,8 often rely on the formation of provides an exceptionally simple entry to important 1,3-dicarbonyl
a-hydrazinyl or a-oxy-amino products using highly reactive electro- compounds.13 Collectively, these studies on the dual electrophilic
philic aminating reagents8 followed by reductive cleavage, and are reactivity of O-acylhydroxylamines provide further insight into their
therefore restricted to a narrow scope of substrates that must be potential for developing selective and complementary amination and
compatible with the postreaction modifications and the installation acylation reactions in a broader range of C–H bonds.
of primary or secondary amines. To develop a more direct and general
a-amination strategy,9 we explored zinc enolates for the first time as
a reactive intermediate toward electrophilic a-amination. We were
interested in O-acylhydroxylamines as an electrophilic nitrogen
Department of Chemistry, Duke University, Durham, North Carolina 27708, USA.
E-mail: qiu.wang@duke.edu
Scheme 1 Selective a-amination and a-acylation via the dual reactivity of
O-acylhydroxylamines.
† Electronic supplementary information (ESI) available: Experimental details and
characterization data for new compounds. See DOI: 10.1039/c3cc49296f
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Table 1 Condition optimization for electrophilic amination of ester 1a
and amide 1b with N-(benzoyloxy)morpholine 2a
Table 2 Selective a-amination and a-acylation of carbonyl compound 1
using O-acylhydroxylamine 2a
Entry
1
Catalyst
Ligand Timeb (h) 3c (yield)
4c (yield)
Entry
Carbonyl substrate
1
3b (yield)
3a (98%)
3b (53%)
3c (94%)
3d (90%)
4b (yield)
4a (82%)
4b (61%)
4c (90%)
4d (87%)
1
1a
1a
—
—
—
—
24
3
—
—
4a (58%)
4a (82%)
2d
3
1a CuCl
1a CuCl
1a CuCl
1a CuCN
—
1.5
24
1
24
1
24
24
1
3a (81%)
3a (36%)
3a (99%)
3a (53%)
3a (35%)
3a (55%)
3a (85%)
3a (99%)
3b (6%)
3b (53%)
—
—
—
—
—
—
—
—
—
—
1
2
3
4
1a
1b
1c
1d
4
5
6
7
8
9
10
11
12
Phen
Bipyr
Bipyr
1a CuOTfꢀtol Bipyr
1a Cu(OAc)2
1a Cu(acac)2
1a CuCl2
Bipyr
Bipyr
Bipyr
Bipyr
Bipyr
1b CuCl
1b CuCl2
1
1
a
Reactions conducted on a 0.2–0.3 mmol scale: 1 (2.1 equiv.), Zn(tmp)2
(1.0 equiv.); 2 (1.0 equiv.); Cu catalyst (5 mol%), ligand (10 mol%),
THF. b Time required for the complete consumption of 2. c Determined by
1H NMR spectroscopy with CH2Br2 as a quantitative internal standard. d Step
2 run at 60 1C. Phen = 1,10-phenanthroline. Bipyr = 2,20-bipyridine.
5
6
1e
3e (95%)
4e (71%)
1f
3f (70%)
3g (51%)
4f (75%)
4g (68%)
Our study started from the reaction of ester 1a and O-acylhydroxyl-
amine 2 as model substrates (Table 1). The generation of the
nucleophilic zinc enolate was achieved by the treatment of ester
1a with Zn(tmp)2 solution.14 Excitingly, we found that the acylated
product 4a was formed in 58% yield when 2 was directly treated with
the zinc enolate of ester 1a at room temperature for an extended
period of time (24 h). At 60 1C, this a-acylation reaction proceeded
more rapidly, providing 4a in 82% yield within 3 h. On the other
7
1g
a
Reactions conducted on a 0.2 mmol scale: 1 (2.1 equiv.), Zn(tmp)2 (1.0
equiv.); condition A: 2 (1.0 equiv.), CuCl2 (5 mol%), bipyr (10 mol%),
b
THF, rt. Condition B: 2 (1.0 equiv.), THF, 60 1C. Isolated yields.
hand, when CuCl was applied as a catalyst, the amination reaction desired C-zincates,2b,14b which impedes an effective transmetal-
occurred smoothly at room temperature and provided the aminated ation with the copper catalyst. Meanwhile, we investigated the
product 3a in 81% yield in 1.5 h (entry 3). As a ligand, 1,10-phenan- a-acylation reaction of these carbonyl substrates 1a–g using
throline resulted in a lower yield of 3a in the amination reaction hydroxylamine 2 in the absence of a copper catalyst. In all cases,
while 2,20-bipyridine provided a quantitative formation of 3a (entries the exclusive formation of 1,3-dicarbonyl products was observed.
3 and 4). Thus, we subsequently looked into different copper sources Once again, zinc enolates derived from a-substituted esters and
in the amination reaction of ester 1a with 2,20-bipyridine as the amides were found unreactive toward acylation, suggesting that
ligand (entries 5–9). In comparison to CuCl, CuCN, CuOTfꢀtol and the steric hindrance significantly reduces their nucleophilicity.
Cu(OAc)2 were inferior while Cu(acac)2 and CuCl2 provided compar- Despite current limitations, the a-amination and a-acylation trans-
able efficacy. However, we immediately found that CuCl was not formations nevertheless offer a rapid, efficient and complementary
applicable to the amination of amide substrates such as 1b (entry 11). approach to prepare simple a-functionalized esters and amides,
Encouragingly, the system of CuCl2/bipyr was effective and afforded especially compared to the traditional a-halogenation/nucleophilic
the desired 3b in 53% yield (entry 12).
amination approach.
With conditions identified for a-amination (condition A) and
Next we surveyed the amine scope of the a-amination transforma-
acylation (condition B), we next examined the generality of these tion using model substrate ester 1a with a variety of hydroxylamines
two transformations on a variety of zinc enolate derivatives using derived from simple amines (Table 3). The catalytic system of CuCl2/
hydroxylamine 2 (Table 2). For the amination reactions of bipyr was applicable for introducing different cyclic amines, such as
different ester derivatives, iso-propyl acetate 1c and ethyl acetate piperidines, pyrolidine, and piperazine (5–8). The amination of acyclic
1d both provided the desired a-amino esters 3c–d in excellent hydroxylamines also proceeded efficiently with derivatives containing
yields (entries 3 and 4). Likewise, the amination of different N,N-diethyl, N,N-dibenzyl, and N-benzyl-N-methyl groups (9–12). Note
cyclic and acyclic amides all effectively formed the aminated that the benzyl moiety can be a useful synthetic handle for further
products 3e–g (entries 5–7).8a,15 However, the current conditions manipulations after the selective deprotection. Indeed, the secondary
were ineffective for a-substituted esters and amides (e.g. methyl amine product 13 was also able to form directly from the amination
phenylacetate and N,N-diethylpropionamide) presumably due to reaction. The results with these hydroxylamines also demonstrate that
their preferential formation of O-zinc enolates rather than the the amination conditions are compatible with diverse functionalities
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Table 3 Copper-catalyzed electrophilic a-amination of 1a with various
O-acylhydroxylaminesa
Scheme 2 Reaction pathways for amination and acylation of zinc enolate
with O-acylhydroxylamine 2.
and acylation of ester 1a. When a copper catalyst is present
(condition A), the transmetalation between copper and zinc enolate (I)
occurs and the resulting intermediate (IIIA) subsequently undergoes
oxidative addition of hydroxylamine 2. Finally, the reactive copper
complex (IVA) would readily undergo reductive elimination to afford
the aminated product 3a and regenerate the copper catalyst.17 On the
other hand, in the absence of a copper catalyst (condition B), the
nucleophilic zinc enolate (I) would preferably attack the electrophilic
carbonyl group of 2, possibly via an intermediate (IIB), and selectively
afford the acylated product 4.
a
Results as aminated products in isolated yields. Reactions conducted
on a 0.2 mmol scale: 1a (2.1 equiv.), Zn(tmp)2 (1.0 equiv.), O-acyl-
hydroxylamine (1.0 equiv.), CuCl2 (5 mol%), bipyr (10 mol%).
Table 4 a-Acylation of 1 with O-acylhydroxylamines 2a
Entry
O-Acylated hydroxylamine
Acylated productb (yield)
In summary, this communication describes the development of
selective a-amination and a-acylation of simple carbonyl compounds
on the basis of the dual reactivity of O-acylhydroxylamines.
a-Amination of esters and amides has been achieved by a copper-
catalyzed electrophilic amination of their zinc enolates using
O-acylhydroxylamines. In the absence of a copper catalyst, the direct
treatment of zinc enolates with O-acylhydroxylamines exclusively
formed a-acylated 1,3-dicarbonyl products. These interesting results
also provide insight into the dual electrophilic reactivity of
O-acylhydroxylamines for selective amination and acylation reactions
of other C–H bonds. Currently, studies on a-amination of substi-
tuted carbonyl compounds are underway.
1
2
3
4
a
Reactions conducted on a 0.2 mmol scale: 1a (2.1 equiv.), Zn(tmp)2
(1.0 equiv.), rt, 1 h; O-acylhydroxylamine (1.0 equiv.), THF, 60 1C. b Isolated
yields.
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2538 | Chem. Commun., 2014, 50, 2535--2538
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