Phosphorylation of Glycine Derivatives via Copper(I)-Catalyzed Csp3?H Bond Functionalization

Article abstract of DOI:10.1002/adsc.201600539

A simple and efficient one-pot approach has been developed for a copper-catalyzed phosphorylation of glycine derivatives under air and at room temperature. The present cross-dehydrogenative coupling allows various methoxyphenyl-protected glycine derivativ

Full text of DOI:10.1002/adsc.201600539

UPDATES
DOI: 10.1002/adsc.201600539
Phosphorylation of Glycine Derivatives via Copper(I)-Catalyzed
3
À
Csp H Bond Functionalization
Huizhen Zhi,a,b Sosthene Pierre-Marie Ung,a Yun Liu,a,c Liang Zhao,a
and Chao-Jun Lia,*
a
Department of Chemistry, McGill University, 801 Sherbrooke Street West, Montreal, Quꢀbec H3A 0B8, Canada
Fax : (+1)-514-398-3797; e-mail: cj.li@mcgill.ca
School of Chemistry and Materials Science, Nanjing Normal University, Nanjing 210046, Peopleꢁs Republic of China
Jiangsu Key Laboratory of Green Synthetic Chemistry for Functional Materials, Institute of Chemistry and Chemical
b
c
Engineering, Jiangsu Normal University, Xuzhou, Jiangsu, Peopleꢁs Republic of China
Received: May 20, 2016; Revised: July 5, 2016; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201600539.
Abstract: A simple and efficient one-pot approach
has been developed for a copper-catalyzed phos-
phorylation of glycine derivatives under air and at
room temperature. The present cross-dehydrogena-
tive coupling allows various methoxyphenyl-pro-
tected glycine derivatives to be phosphorylated
alyzed phosphinylation of a-amino carbonyl com-
pounds to afford imidoylphosphonates in nitrome-
thane [Scheme 1, Eq. (a)]. On the other hand, the Li
group[14] also reported the C H/P H oxidative cou-
pling between N-phenyltetrahydroisoquinoline com-
pounds and dialkyl phosphites [Scheme 1, Eq. (b)].
Recently, development of the cross-dehydrogena-
À
À
using diverse alkyl and aryl phosphites through an
3
oxidative coupling between Csp H and P H bonds
catalyzed by copper iodide. This method provides
a new synthetic tool to obtain biologically active a-
aminophosphonates.
tive coupling (CDC) reaction[15] has allowed the C H
À
À
À
functionalization of amino acids and short-chain pep-
tides at the N-terminus effectively (Scheme 2).[16]
À
Direct phosphorylation of glycine derivatives via C
H/P H cross-dehydrogenative coupling with phos-
À
phine will potentially provide a convenient method to
generate diverse organophosphorus compounds for
biomedical applications. However, to the best of our
knowledge, no example of phosphorylation of glycine
derivatives has ever been reported. Herein, we report
a novel phosphorylation of glycine derivatives via cop-
Keywords: aminophosphonates; copper; glycine de-
rivatives; organophosphorus compounds; phosphor-
ylation
3
À
per(I)-catalyzed Csp
H
bond functionalization
Organophosphorus compounds have received much (Scheme 2).
interest because of their broad applications in the
To optimize the experimental conditions, we chose
fields of pharmaceuticals[1] and agrochemicals.[2] They a model coupling reaction between N-PMP (p-me-
effectively show antibacterial,[3] antifungal,[4] enzyme
inhibitory[5] and catalytic antibody activities.[6] They
are also widely used for organic synthesis,[7] most no-
tably in Horner–Wadsworth–Emmons and Wittig-type
reactions,[8] and also exhibit high triplet energy char-
acteristics making them suitable host materials for
phosphorescent organic light-emitting diodes.[9] Be-
cause of the importance of organophosphorus com-
pounds, there is a continuing demand for the develop-
[10]
2
À
À
ment of new synthetic tools forming Csp P, Csp
3
[12]
P[11] and Csp
P
bonds. Among these, the selective
phosphorylation of the relatively unreactive Csp
À
3
À
H
bond is an attractive pathway to explore in order to
introduce a phosphorus moiety in saturated organic
3
À
Scheme 1. Methods for phosphorylation of the Csp
H
compounds. Yang[13] previously reported a copper-cat- bond.
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Table 1. Copper-catalyzed phosphorylation of N-PMP (p-
methoxyphenyl) glycine amide derivative.[a]
Solvent Yield [%][b]
Scheme 2. Functionalization of glycine derivatives.
Entry Catalyst Oxidant
1
2
3
4
5
6
7
8
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr2
CuBr2
CuCl
CuCl2
TBHP in water
TBHP in decane
tert-butyl peroxide DCM
DCM
DCM
12[c,e]
48[c,e]
15[c,e]
6[c,e]
thoxyphenyl)glycine amide derivatives 1a (as amine
substrates) and dimethyl phosphonate 2a (as pro-nu-
cleophile). Interestingly, most of the oxidants
(Table 1, entries 1–7) and copper salts (Table 1, en-
tries 8–16) investigated were not effective for this re-
action. The combination of CuI as catalyst and TBHP
as oxidant provided the desired product in high
(92%) yield (Table 1, entries 17–19). Water could also
be used as solvent for the reaction, albeit resulting in
a 34% yield (Table 1, entry 20). Examination of sol-
vent effects showed that DCE was the best solvent
and gave a 98% yield of the corresponding product
(Table 1, entry 21). Notably, the reaction could also
proceed at room temperature under air atmosphere
with CuI as catalyst and TBHP as oxidant (Table 1,
entries 22–28).
dicumyl peroxide DCM
MCPBA
benzoyl peroxide
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
H2O
0[c,e]
0[c,e]
46[c,e]
48[d,e]
44[c,e]
50[d,e]
6[d,e]
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
0[d,e]
Cu(Ac)2 TBHP
3[d,e]
CuO
Cu2O
CuF2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
7[d,e]
5[d,e]
1[d,e]
74[c,f]
76[d,f]
92[d,e]
34[d,e]
98[d,e]
Under the optimized conditions, the new method to
3
À
DCE
generate Csp P bonds was found to be effective for
MeOH 0[d,e]
CH3CN 45[d,e]
a number of different phosphonates. Excellent yields
were achieved using diethyl phosphite (2b) (Table 2,
entry 2), diisopropyl phosphite (2c) (Table 2, entry 3)
and dibenzyl phosphite (2e) (Table 2, entry 5) respec-
tively. However, only a moderate 51% yield was ob-
tained when diphenyl phosphite (2d) (Table 2,
entry 4) was applied (Table 2, entries 8, 10, 18, and
20), which we attributed to steric effects.
Then, various glycine derivatives were coupled with
dialkyl phosphites under the optimized conditions
(Table 2). Secondary amides all afforded the corre-
sponding products effectively. For example, methyl-
substituted (1a, 1b, Table 2, entries 1–6), phenyl-n-
propyl-substituted (1c, Table 2, entrie 7–9) n-butyl-
substituted (1d, Table 2, entries 10–14), phenyl-n-
butyl-substituted (1e, Table 2, entries 15–19) and n-
octyl-substituted (1f, Table 2, entries 20–22) all react-
THF
23[d,e]
EtOAc 20[d,e]
dioxane 45[d,e]
hexane 4[d,e]
toluene 23[d,e]
[a]
Reaction conditions: glycine derivative (0.30 mmol), dia-
lkyl phosphite (0.90 mmol), TBHP (54 mL, 5–6M in
nonane otherwise mentioned), catalyst (0.03 mmol), sol-
vent (0.5 mL).
[b]
[c]
[d]
[e]
[f]
NMR yields using an internal standard.
Under N2.
Under air.
For 19 h.
For 12 h.
ed well to give the corresponding phosphorylated the success of the reaction. We hypothesize that R1
products. When a tertiary amide 1h or an ethyl ester plays a dual role in the reaction, possibly both by de-
1i (Table 2, entries 23 and 24) was used, the reaction creasing the oxidation potential of the substrate and
did not proceed at all under the current conditions. by stabilizing the generated reaction intermediate.
The reaction of 1j (Table 2, entry 25) gave a mixture
The aryl protecting group on the amine of the gly-
of unidentified compounds. These results show that cine derivatives also plays an important role in both
the substituents on the amine play a significant role in the phosphorylation reaction as well as in the poten-
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Table 2. Scope of glycine amide derivatives.[a]
[a]
Reaction conditions: glycine derivative (0.30 mmol), dialkyl phosphite (0.90 mmol), TBHP (54 mL, 5–6M in nonane), cata-
lyst (0.03 mmol), solvent (0.5 mL), under air for 19 h.
Isolated yields are based on amines, and NMR yields using an internal standard are given in parentheses.
[b]
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tial further structural modifications performed for
biological applications. An easily removable aryl
group will offer a ready access to the free amine.
There is a wide variety of aryl-based amine protecting
groups, such as the alkylphenyl, the halophenyl, and
the phenyl groups. Therefore in order to investigate
the influence of the amine protecting group on the re-
action, various protected glycine amide derivatives
Figure 1. Chelation and deactivation of the glycine amide
derivative 1b with copper.
were synthesized and examined under the optimized fortunately, no desired product was observed under
reaction conditions with dimethyl phosphonate or di- these conditions for the present reaction (Table 3, en-
phenyl phosphite (Table 3, entries 8–10). However, no tries 1–5). The results illustrated that diphenyl phos-
desired coupling product was found with those sub- phite endows better nucleophilic ability than dialkyl
strates, illustrating the decisive effect of the N-PMP phosphites, thus allowing a more effective coupling
group on the phosphorylation reaction.
reaction. Finally, (m-methoxyphenyl) glycine amide
Nevertheless, the desired product was also obtained and other glycine derivatives 1l–1o could not react
in good yield (92%) when (o-methoxyphenyl) glycine with 2a–2e at all (Table 3, entries 6 and 7).
amide derivative 1b was employed in place of (p-me-
A tentative mechanism for this phosphorylation re-
thoxyphenyl) glycine amide derivative to react with action is proposed with the generation of an iminol
2d (Table 2, entry 6) under the same conditions. Sur- intermediate (Scheme 3). First of all, the imino amide
prisingly, the conditions were not applicable to phos- intermediate A was produced via the reaction of start-
phonites 2a, 2b, 2c and 2e. We postulated that 1b ing material 1 with TBHP catalyzed by CuI. Then,
could easily form a stable five-membered ring via the isomerization and chelation generated intermediate
coordination with the Cu catalyst, thus slowing down B. The more nucleophilic phosphite form, in equilibri-
the reaction rate (Figure 1). To overcome this issue, um with the phosphonate reagent, will finally attack
we decided to perform the reaction with a preformed intermediate B to provide the product 3 and regener-
chelated Cu-complex. Di(2-pyridyl) ketone was our ate the active copper catalyst.
À
first choice of ligand as it was previously shown to be
In summary, an efficient formal C H phosphoryla-
efficient for a number of oxidative couplings;[17] un- tion of glycine derivatives via a copper-catalyzed
CDC with various phosphonates has been developed.
This new method provides a simple approach to syn-
Table 3. Examination of various protecting groups.[a]
thesize biologically important a-aminophosphonates
from readily available glycine derivatives. The scope,
mechanism and application of this phosphorylation
are currently under investigation.
Entry 1/R3
2
Di(2-pyridyl) ketone 3/Yield [%][b]
1
2
3
4
5
6
7
8
9
10
1b/o-OCH3 2d
–
3f/84 (92)
NR
NR
NR
NR
NR
NR
NR
NR
1b/o-OCH3 2a 0.2 mmol
1b/o-OCH3 2b 0.2 mmol
1b/o-OCH3 2c 0.2 mmol
1b/o-OCH3 2e 0.2 mmol
1l/m-OCH3 2d
1l/m-OCH3 2a
1m/p-CH3 2a
–
–
–
–
–
1n/p-Br
1o/H
2a
2a
NR
[a]
Reaction conditions: glycine derivative (0.30 mmol), dia-
lkyl phosphite (0.90 mmol), TBHP (54 mL, 5–6M in
nonane), CuI (0.03 mmol), DCE (0.5 mL).
[b]
1
Isolated yields are based on amines, and H NMR yields
using an internal standard are given in parentheses.
NR=no reaction.
Scheme 3. Proposed mechanism for the phosphorylation of
glycine derivatives.
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Acknowledgements
The authors acknowledge the Canada Research Chair Foun-
dation (to C.-J. Li), the CFI, FQRNT Center for Green
Chemistry and Catalysis, NSERC, and McGill University for
financial support. HZ and YL acknowledge the financial sup-
port of universities and principals overseas study plan in
Jiangsu province for outstanding young and middle-aged
teachers, China.
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6 Phosphorylation of Glycine Derivatives via Copper(I)-
3
À
Catalyzed Csp H Bond Functionalization
Adv. Synth. Catal. 2016, 358, 1 – 6
Huizhen Zhi, Sosthene Pierre-Marie Ung, Yun Liu,
Liang Zhao, Chao-Jun Li*
Adv. Synth. Catal. 0000, 000, 0 – 0
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