Synthesis of α-Aminophosphonates by Umpolung-Enabled Cu-Catalyzed Regioselective Hydroamination

概要

Title

Synthesis of α-Aminophosphonates by UmpolungEnabled Cu-Catalyzed Regioselective
Hydroamination

Author(s)

Nakamura, Shogo; Nishino, Soshi; Hirano, Koji

Citation

Journal of Organic Chemistry. 2023, 88(2), p.
1270-1281

Version Type AM
URL

https://hdl.handle.net/11094/92683

rights

© 2023 American Chemical Society.

Note

Osaka University Knowledge Archive : OUKA
https://ir.library.osaka-u.ac.jp/
Osaka University

Synthesis of a-Aminophosphonates by UmpolungEnabled Cu-Catalyzed Regioselective Hydroamination
Shogo Nakamura,† Soshi Nishino,† and Koji Hirano*,†,‡
†

Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka 565-

0871, Japan
‡

Innovative Catalysis Science Division, Institute for Open and Transdisciplinary Research Initiatives

(ICS-OTRI), Osaka University, Suita, Osaka 565-0871, Japan
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if required
according to the journal that you are submitting your paper to)
k_hirano@chem.eng.osaka-u.ac.jp

O
(EtO)3Si H
P(OR)2 +
BzO NR’2
H
Cu

*

O
P(OR)2

NR’2
34 examples
up to 99% yield, 99:1 er

application to silylamination
PhMe2Si
Ph

O
P(OEt)2
NBn2

52%, 12:88 dr

A copper-catalyzed regioselective hydroamination of a,b-unsaturated phosphonates has been developed
to form corresponding a-aminophosphonates of interest in medicinal chemistry.

The introduction of an

umpolung, electrophilic amination strategy with the hydroxylamine derivative is the key to achieving the
a-amination regioselectivity, which is otherwise difficult under the conventional nucleophilic

1

hydroamination conditions with the parent amine.

Asymmetric synthesis with a chiral bisphosphine

ligand and application to a related silylamination reaction are also described.

2

An a-aminophosphonic acid is a phosphorus analogue of a-amino acid and frequently found in
bioactive molecules and pharmaceutical agents, as exemplified by alafosfalin, prodipine, and
incadronate.1

Accordingly, such a structural motif has great potential in medicinal and pharmaceutical

applications, and several preparative methods thus have been developed by synthetic chemists.2

The

aza-Michael reaction of readily available a,b-unsaturated phosphonates with NH amines also seems to be
a concise approach to the targeted molecule.

However, due to their inherent polarization of the C=C

bond, the product obtained is not the desired a-aminophosphonate but the regioisomeric baminophosphonate (Scheme 1a).3

On the contrary, we recently reported the copper-catalyzed

regioselective hydroamination4 reaction of a,b-unsaturated esters with the hydrosilane and
hydroxylamine to deliver the corresponding a-amino acid with high a-amination selectivity.5

The key

to success is the polarity inversion (umpolung)6 concept using the nucleophilic hydride (hydrosilane) and
electrophilic amino source (hydroxylamine).7

Because of our continuing interest in this chemistry, we

have now developed a copper-catalyzed umpolung-enabled regioselective hydroamination of a,bunsaturated phosphonates, giving the a-aminophosphonates in good yields (Scheme 1b).

By using a

suitable ancillary chiral bisphosphine ligand, the asymmetric induction can also form the enantioenriched
a-aminophosphonate.

Additionally, the use of a silylborane instead of the hydrosilane enables the

regioselective silylamination8 reaction.

Detailed optimization studies and the substrate scope are

described herein.

3

Scheme 1. Approaches to Aminophosphonic Acids from a,b-Unsaturated Phosphonates and
Amines
a) aza-Michael reaction with NH amines

δ+ δ–

O
P(OR)2

+

δ+

δ–

base or no catalyst

H NR’2

O
P(OR)2

R’2N
H

β-aminophosphonates
b) umpolung hydroamination with hydrosilanes and hydroxylamines (this work)

δ+

O
P(OR)2

δ–

δ–
(EtO)3Si H
+

cat. Cu/L

H

δ+

*

BzO NR’2

O
P(OR)2
NR’2

α-aminophosphonates

We began our optimization studies with b-phenethyl-a,b-unsaturated phosphonate 1a, O-benzoyl-N,Ndibenzylhydroxylamine (2a), and (EtO)3SiH to identify the suitable copper catalyst, ligand, additives, and
solvent.

After the extensive screening, we found that by using a combination of a

Cu(OAc)2•H2O/DPEphos catalyst and a CsOPiv additive, the reaction proceeded smoothly in 1,4-dioxane
even at room temperature to deliver the desired a-aminophosphonate 3aa in 92% isolated yield with
exclusive a-amination regioselectivity (Scheme 2).

Some observations in optimization studies are noted.

Several monodentate and bidentate phosphine ligands showed moderate to good performance, but no
reaction occurred in the absence of phosphine ligands or Cu salts.
indispensable but remarkably increased the reaction efficiency.

The CsOPiv additive was not

The yield of 3aa was less dependent on

the leaving group of the amine, and thus, the most readily available benzoyl derivative, 2a, was employed
as the optimal amination reagent (see the Supporting Information for more details).

Scheme 2. Optimal Conditions for Cu-Catalyzed Regioselective Hydroamination of 1a with
(EtO)3SiH and 2a.

4

Ph

O
P(OEt)2 +
1a (0.25 mmol)

(EtO)3Si H +
(3.0 equiv)

Cu(OAc)2•H2O (12 mol %)
DPEphos (12 mol %)
CsOPiv (3.0 equiv)
1,4-dioxane, rt, 18 h

BzO NBn2
2a (1.5 equiv)
H

Ph

O
P(OEt)2

NBn2
3aa 92%

O
Ph2P

PPh2
DPEphos

Under the conditions described in Scheme 2, we investigated the scope of a,b-unsaturated phosphonates
1 and hydroxylamines 2.

The structures of representative products 3 are shown in Figure 1.

In addition

to the primary alkyl substituents (3aa and 3ba), the more congested cyclopropyl- and cyclohexyl
substituents were well tolerated under the standard conditions (3ca and 3da, respectively).

The copper

catalysis was compatible with a wide range of functional groups, including benzyl ether, acetal, silyl ether,
ester, Boc-protected amine, and alkyl bromide (3ea–ja, respectively).

Aromatic substrate 1k was also

amenable to the hydroamination to form the corresponding a-aminophosphonate 3ka with high
regioselectivity (>20/1 in the crude mixture).

Moreover, the electron-rich (3la), electron-deficient

(3ma), halogenated (3na), higher-fused (3oa), and heteroatom-incorporated (3pa and 3qa) aromatic rings
all were accommodated to deliver the targeted hydroaminated products in good yields.
hydroxylamines was also substantially broad.

The scope of

Both acyclic (3ab–ad) and cyclic (3ae–ah) amines were

coupled with a,b-unsaturated phosphonate 1a to furnish the hydroaminated products in good yields.
Notably, the antidepressant drug, nortriptyline, was also successfully conjugated with 1a, and the
corresponding complex a-aminophosphonate 3ai was obtained in 84% yield.

5

phosphonate scope
H

O
P(OEt)2

Ph

H

NBn2
3aa 92% (99%)a
H

NBn2

3ba 86%

3ca 48%

3da 88%

H

H

NBn2

hydroxylamine scope
H
O
P(OEt)2
Ph
N
Bn
Me
O
P(OEt)2

Ph

H

Ph
Et

O
P(OEt)2

N

O

H

Ph

3ka 74%
H

MeO

H

3af 80%

H

O
P(OEt)2

Ph

Me
H

NBn2

N

O
P(OEt)2

Ph

3ad 76%

N

O
P(OEt)2

Ph

N

N

N
3ag 73%
Boc

S

3ah 81%

3ai 84%
from Nortriptyline

Figure 1. Structures of a-aminophosphonates 3 synthesized by Cu-catalyzed hydroamination.
yields are given.

O
P(OEt)2

3qa 67%

3pa 63%

O
P(OEt)2

O
P(OEt)2
NBn2

O
P(OEt)2
NBn2

S

3oa 70%
H

H

O
P(OEt)2

Et

N
3ae 82%

O
P(OEt)2

N

O
P(OEt)2

Ph

N

H

NBn2

3ac 79%
H

NBn2

NBn2

H

O
P(OEt)2

MOMO

3ja 74%

3na 71%

O
P(OEt)2

H

3fa 75%

O
P(OEt)2 Br

NBn2

Br

H

3ab 81%
H

H

3ma 62%

3la 83%

O
P(OEt)2

3ea 65%

3ia 92%

O
P(OEt)2
NBn2

F

O

NBn2

3ha 75%

O
P(OEt)2

Ph

NBn2

NBn2

3ga 81%

MeO

O
BocN
P(OEt)2

PivO

H

O
P(OEt)2

NBn2

NBn2

H

H

O
P(OEt)2

NBn2

O
P(OEt)2

TBSO

H

O
P(OEt)2

Isolated

Reaction conditions: Cu(OAc)2•H2O (0.030 mmol), DPEphos (0.030 mmol), 1 (0.25

mmol), (EtO)3SiH (0.75 mmol), 2 (0.38 mmol), CsOPiv (0.75 mmol), 1,4-dioxane (1.0 mL), rt, 18–36 h.
a

On a 1.0 mmol scale.

The umpolung-enabled copper-catalyzed hydroamination protocol could also be applied to the b,bdisubstituted a,b-unsaturated phosphonates (Scheme 3).

In this case, the asymmetric synthesis was

possible by using the (R)-DM-SEGPHOS ligand, and the corresponding enantioenriched aaminophosphonates were formed with high enantioselectivity.

For example, b-methyl-b-phenyl

phosphonate 1r was converted to optically active 3ra in 79% yield with a 99/1 enantiomeric ratio (er).
Unfortunately, the point chirality at the a-position was not controlled well, and the diastereomeric ratio
was thus low (41/59 dr).

However, both diastereomers could be separated from each other and isolated

in stereochemically pure forms by chromatographic purification.

Additionally, the benzyl group on

6

nitrogen could be readily deprotected under the standard hydrogenolysis conditions using Pd(OH)2 to
deliver the optically active primary a-NH2 phosphonate (see the Experimental Section for details).

The

asymmetric copper catalysis was tolerant of the electronically diverse aryl groups at the b-position, such
as methoxy-, trifluoromethyl-, and bromo-substituted phenyl rings (3sa–ua, respectively).

Naphthalene

Furthermore, the b-ethyl-b-

and pyridine were also viable substituents (3va and 3wa, respectively).

phenyl- and b,b-dialkyl-substituted phosphonates underwent the enantioselective hydroamination to
The absolute configuration at the b-

afford 3xa and 3ya, respectively, with high enantioselectivity. ...

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