Copper-catalyzed α-amination of phosphonates and phosphine oxides: A direct approach to α-amino phosphonic acids and derivatives

Article abstract of DOI:10.1002/anie.201308890

A direct approach to important α-amino phosphonic acids and its derivatives has been developed by using copper-catalyzed electrophilic amination of α-phosphonate zincates with O-acyl hydroxylamines. This amination provides the first example of C=N bond formation which directly introduces acyclic and cyclic amines to the α-position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope. A direct approach to important α-amino phosphonic acids and derivatives, by using copper-catalyzed electrophilic amination of α-phosphonate zincates using O-acylhydroxylamines, is described. This amination is the first example of C=N bond formation which directly introduces acyclic and cyclic amines to the α-position of phosphonates in one step. The reaction proceeds at room temperature with as little as 0.5 mol % of the catalyst. Copyright

Full text of DOI:10.1002/anie.201308890

Angewandte
Chemie
DOI: 10.1002/anie.201308890
Synthetic Methods
Copper-Catalyzed a-Amination of Phosphonates and Phosphine
Oxides: A Direct Approach to a-Amino Phosphonic Acids and
Derivatives**
Stacey L. McDonald and Qiu Wang*
Abstract: A direct approach to important a-amino phosphonic
acids and its derivatives has been developed by using copper-
catalyzed electrophilic amination of a-phosphonate zincates
with O-acyl hydroxylamines. This amination provides the first
À
example of C N bond formation which directly introduces
acyclic and cyclic amines to the a-position of phosphonates in
one step. The reaction is readily promoted at room temperature
with as little as 0.5 mol% of catalyst, and demonstrates high
efficiency on a broad substrate scope.
a-Amino phosphonic acids and their derivatives serve as
functional surrogates for a-amino carboxylic acids and exhibit
a wide range of intriguing biological properties.[1] Their well-
recognized importance in agrochemicals and medicine,[2] such
as herbicides,[3] plant virucides,[4] antibiotics,[5] anticancer
agents,[6] and inhibitors of HIV proteases,[7] has driven
continuous synthetic efforts to prepare this class of com-
pounds.[8–13] Among them, the electrophilic a-amination of
phosphonates represents an attractive strategy for a rapid and
direct access (Scheme 1).[9,10] Furthermore, the amination
approach is alternative and complementary to other
À
Scheme 1. Synthesis of a-amino phosphonic acids by C N bond
formation.
secondary or tertiary amines to the a-position of phospho-
nates, thus limiting the synthesis and discovery of novel a-
amino phosphonic acids of biological importance.[8] There-
fore, it is of great value to develop a general amination
method under mild reaction conditions and thus significantly
extend the scope of the synthesis of a-aminophosphonates.
We propose that a novel amination approach to a-amino
phosphonic acids can be achieved by a copper-catalyzed
amination of phosphonate a-zincates using electrophilic
hydroxylamines (Scheme 1b). This strategy was inspired by
pioneering studies on the electrophilic amination of arylzinc
reagents with hydroxylamines.[14–17] In our studies, we
explored the formation of a-zincates of phosphonates and
phosphine oxides, a novel class of organozinc reagents, and
[11]
[12]
[13]
À
À
À
approaches (e.g., by C P, C C, or C H bond forma-
tion) which typically start from aldehydes or imines in the
preparation of a-amino phosphonic acids, thus diversifying
the range of the starting substrates.
Toward this end, previous studies explored a-aminations
of phosphonates using reactive azodicarboxylate esters or
arylsulfonyl azides, which subsequently formed a-amino
À
phosphates upon reductive cleavage of the resulting N N
bond (Scheme 1a).[9] Despite the success, these methods were
restricted to the formation of primary amines (the installation
of an NH2 group), the use of highly electrophilic nitrogen
atoms, and a narrow scope of phosphonates because they
needed to be compatible with the reductive cleavage con-
ditions. Even with the significant advances in the arsenal of
À
their reactivity toward C N bond formation. Different from
those organozinc reagents typically prepared from their
orgonolithium or Grignard precursors,[14] the phosphonate
a-zincates are proposed to form by H–Zn exchange.[18] Thus,
this strategy is direct and potentially more efficient, and it
would also allow a broader substrate scope and better
functional group compatibility. Herein, we demonstrate the
efficacy of phosphonate a-zincates as nucleophiles in copper-
catalyzed amination with O-benzoylhydroxylamines, and the
À
modern synthetic chemistry, the potential of C N bond
formation as a powerful approach to a-amino phosphonic
À
acids remains underexplored. So far no examples of C N
bond formation have been reported for directly introducing
[*] S. L. McDonald, Prof. Dr. Q. Wang
Department of Chemistry, Duke University
Durham, NC 27708–0346 (USA)
E-mail: qiu.wang@duke.edu
À
development of a new C N bond-formation approach to
rapidly access a-amino phosphonic acids. This a-amination
strategy provides the first example enabling the direct
introduction of a variety of acyclic and cyclic amines to the
a-position of phosphonates and phosphine oxides. The
amination reaction proceeds in good to excellent yields at
room temperature with as little as a 0.5 mol% catalyst
[**] We gratefully acknowledge Duke University for financial support on
the research and the Burroughs Wellcome Endowment for the
fellowship to S.L.M.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308890.
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Table 2: a-Amination of different phosphonates and phosphine oxides.[a]
loading. The good functional-group compatibility and broad
substrate scope observed in this reaction also contribute to its
promising utility for the preparation of a-amino phosphonic
acids and derivatives.
Our studies began with the amination reaction between
the model substrate phosphonate 1a and the hydroxylamine
2a (Table 1). As the a-zincation of substituted phosphonates
Table 1: Optimization studies for copper-catalyzed amination of the
phosphonate 1a with the hydroxylamine 2a.
Entry 1a Zn(tmp)2 2a Copper
Ligand
t
3a
[equiv]
(10mol%) (20mol%) [h][a] Yield [%][b]
1
2
3
4
5
6
7
8
9
10
2.1 1.0
1.0 CuOTf·tol
1.0 CuCl
1.0 CuCN
1.0 CuCl2
1.0 Cu(OAc)2
1.0 Cu(OTf)2
1.0 CuCN
1.0 CuCN
1.0 CuCl2
–
–
–
–
–
–
2
16
77
96
78
78
31
48[c]
99
96
99
2.1 1.0
2.1 1.0
2.1 1.0
2.1 1.0
2.1 1.0
2.1 1.0
2.1 1.0
2.1 1.0
2.1 1.0
20
20
20
20
20
20
20
1
phen
bipyr
phen
bipyr
1.0 CuCl2
4
[a] Time required for complete consumption of 2a. [b] Yields determined
by 1H NMR spectroscopy using CH2Br2 as a quantitative internal
standard. [c] 2a recovered in 24% yield. bipy=2,2’-bipyridine,
phen=1,10-phenanthroline, Tf=trifluoromethanesulfonyl.
[a] Isolated yields. Standard reaction conditions: 1 (2.1 equiv), 2
(1.0 equiv), Zn(tmp)2 (1.0 equiv), Cu(OAc)2 (10 mol%), bipyr
(20 mol%), RT. Reactions typically run on 0.2 mmol scale. THF=
tetrahydrofuran.
has not been reported previously, we first confirmed that the
corresponding a-zincate of 1a was effectively formed upon
the treatment with Zn(tmp)2, a strong and non-nucleophilic
base.[19] Next we looked into the formation of the aminated
product 3a by using different copper salts as catalysts
(entries 1–6). Encouragingly, all the reactions led to the
desired product 3a, which was produced in the highest yield
with CuCN (entry 3). In contrast, no aminated product was
detected in the absence of a copper catalyst, thus suggesting
the essential role of copper in the amination. We then
examined several ligands including 1,10-phenathroline and
2,2’-bipyridine for accelerating the reaction. Although the use
of a ligand did not imporove the CuCN-catalyzed reactions
(entry 3 versus 7 and 8), it significantly improved the
efficiency of those reactions catalyzed by CuCl2 (entry 4
versus 9 and 10). With this information, we chose CuCl2/bipyr
as the standard catalyst system for the amination step.
With effective a-amination conditions identified, we
examined the scope of phosphonates and derivatives using
2a (Table 2). Similar to the model substrate 1a, dibutyl
butylphosphonate and ethyldiphenyl phosphine oxide both
readily afforded the desired aminated products 3b,c. The
simple analogous substrates, such as dimethyl and diethyl
methylphosphonates as well as methyldiphenylphosphine
oxide, also proceeded smoothly to give 3d–f in excellent
yields. Besides a methyl group, other substituents at the a-
position are also compatible with the amination reaction,
including allyl, phenyl, and aryl groups (3g–k). Regardless of
an electron-donating or electron-withdrawing group present
on the aryl ring, the reactions all occurred efficiently.
Especially useful is the tolerance of the chloro and bromo
groups in the aminated products 3j,k, thus allowing additional
functionalization by transition-metal-catalyzed couplings. For
disubstituted phosphonates, direct a-zincation was ineffective
with Zn(tmp)2, possibly because of the increased steric
hinderance.[20]
A defining attribute of this new a-amination protocol is its
potential to provide direct access to a broad array of amines at
the a-position of a phosphonate. As shown in Table 3,
different cyclic amines were successfully installed in the
amination reactions of 1h, to give products such as the N-Boc
piperazine 4a, piperidines (4b–c), the diazepane 4d, and the
bicyclic amine 4e. The reactions for introducing acyclic a-
amines into the phosphonate products (4 f–i) also occurred
smoothly with amines containing N,N-diethyl, N,N-diallyl,
N,N-dibenzyl, and N-benzyl-N-methyl substituents. Note that
the resultant allyl and benzyl moieties can be useful synthetic
handles for further manipulations after the selective depro-
tection. However, the sterically encumbered N,N-diisopropyl-
substituted amine 4j was not formed. For the synthesis of
a secondary amine, the reaction with 1h was effective, thus
providing 4k in 40% yield. To further probe the feasibility
and efficacy of hydroxylamines (2j–k) in the amination
reaction, we tested them in the reaction with 1e, a simple
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Table 3: The scope of the amines.[a]
Scheme 2. Control experiments to probe the presence of radical
intermediates.
absence of an aminyl radical species or a copper-coordinated
radical complex in the amination pathway.
À
Although the detailed mechanism for C N bond forma-
tion remains obscure, a possible mechanism is proposed for
the amination step based on these experimental results and
observations (Scheme 3). The bisphosphonate zincate A
[a] Isolated yields. Standard reaction conditions (see Table 1). [b] Yields
1
determined by H NMR spectroscopy using CH2Br2 as a quantitative
internal standard, and confirmed by GC/MS. Boc=tert-butoxycarbonyl.
phosphonate lacking an a-substituent. Interestingly, the
desired aminated product 5j, containing a sterically hindered
N,N-diisopropyl group, was formed in 90% yield and the
secondary amine 5k (R = H) was formed in a greater yield
(76%) compared to that of 4k (R = Ph). This outcome
suggests that both the electronic and steric nature of
phosphonates and hydroxylamines can influence the effi-
ciency of the amination step.
Scheme 3. Proposed mechanism for the a-amination reaction.
To investigate if the copper-catalyzed amination step may
involve any radical intermediates, we performed the following
two control experiments: 1) the reaction of 1l, which contains
the cyclopropyl substituent at the a-position, with the model
hydroxylamine substrate 2a, and 2) the amination using N-4-
pentenylhydroxylamine on the model phosphonate 1h
(Scheme 2). Both reactions produced the aminated products
exclusively in excellent yields. In the reaction of 1l, no ring-
opened product derived from the cyclopropyl substituent was
observed.[15f] The exposure of N-4-pentenylhydroxylamine to
the copper catalyst did not give any detectable cyclization
product, such as the pyrrolidine-containing structure from the
copper-catalyzed 5-exo radical cyclization reported previous-
ly.[15a] The results from both control experiments indicate the
could initially undergo transmetallation with copper(I) to
generate a reactive copper complex (C), which subsequently
[21]
À
reacts with hydroxylamines to form the desired C N bond.
We believe that the zincate intermediate B did not undergo
transmetallation to form the copper complex C as a stoichio-
metric amount of the zincate (A) was needed for the complete
conversion of the hydroxylamines.
Finally, we evaluated the efficacy of this transformation
on a larger scale with a lower catalyst loading of only
0.5 mol% of CuCl2 and 1 mol% of bipyridine ligand
(Scheme 4). Although a longer reaction time (36 h) was
required in this case, the aminated product 8 was formed in
96% yield, thus demonstrating high efficiency and practical
utility of this amination reaction.
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Scheme 4. An efficient scale-up amination reaction with 0.5 mol%
catalyst loading.
In summary, we have developed a highly efficient copper-
catalyzed a-amination of phosphonates and phosphine oxides
using O-benzoyl hydroxylamines. The amination reaction
proceeds in excellent yields at room temperature and exhibits
broad substrate scope and good functional group compati-
bility, thus demonstrating great potential in preparing a vari-
ety of a-amino phosphonic acids and derivatives. Currently,
development of an asymmetric a-amination reaction using
a chiral catalyst system is underway. With the application of
3
2
À
Zn(tmp)2 in direct zincation of other sp and sp C H bonds,
such as ketones, amides, and heteroarenes, this work also
À
provides insights into developing C H zincation/copper-
À
catalyzed aminination as a general C H amination strategy.
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Experimental Section
General procedure for the synthesis of 3 and 4: A mixture of
Zn(tmp)2 (0.5m solution in toluene, 0.4 mL, 0.2 mmol, 1.0 equiv) and
substrate 1 (0.42 mmol, 2.1 equiv) was stirred at room temperature
for 1 h. Then a mixture of the O-benzoyl hydroxylamine 2 (0.2 mmol,
1.0 equiv), CuCl2 (2.7 mg, 0.02 mmol, 0.1 equiv), and 2,2’-bipyridyl
(6.2 mg, 0.04 mmol, 0.2 equiv) in THF (1 mL) was added. The
reaction mixture was stirred at room temperature. Upon complete
consumption of O-benzoylhydroxylamine (monitored by TLC: 50%
ethyl acetate/hexanes, typically 2–6 h), the reaction mixture was
filtered through silica and washed with isopropyl alcohol. The filtered
solution was concentrated under reduced pressure. The crude residue
was purified by column chromatography.
Received: October 11, 2013
À
Keywords: amination · amines · C H functionalization ·
.
copper · zinc
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[19] See the Supporting Information for details.
[20] No deuterium incorporation was detected for phosphonate
starting materials by GC/MS upon quenching the reaction of
disubstituted phosphonates and Zn(tmp)2 with D2O.
[21] However, we cannot exclude an alternative that includes
1) oxidative addition of the hydroxylamine to a low-valent
copper species, 2) transmetalation with a a-phosphonate zinc
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À
carbanion, and 3) reductive elimination to form desired C N
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