Direct transformation of amides into α-amino phosphonates via a reductive phosphination process

Article abstract of DOI:10.1021/ol4019419

The first general method for the reductive phosphination of amides in one pot has been developed. The reactions described provide a novel access to α-amino phosphonates in good to excellent yields, cover a broad scope of substrates such as secondary and tertiary amides, and do not require a low temperature.

Full text of DOI:10.1021/ol4019419

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Direct Transformation of Amides into
r‑Amino Phosphonates via a Reductive
Phosphination Process
Yuzhen Gao,† Zhongbin Huang,† Rongqiang Zhuang,† Jian Xu,† Pengbo Zhang,†
Guo Tang,*,† and Yufen Zhao†,‡
Department of Chemistry, College of Chemistry and Chemical Engineering, and the Key
Laboratory for Chemical Biology of Fujian Province, Xiamen University, Xiamen,
Fujian 361005, China, and Key Laboratory of Bioorganic Phosphorus Chemistry and
Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, China
t12g21@xmu.edu.cn
Received July 10, 2013
ABSTRACT
The first general method for the reductive phosphination of amides in one pot has been developed. The reactions described provide a novel
access to R-amino phosphonates in good to excellent yields, cover a broad scope of substrates such as secondary and tertiary amides, and do not
require a low temperature.
R-Amino phosphonates have played an increasingly
important role in a variety of areas such as medical
chemistry and biologicals,1 herbicides,2 and fungicides.3
Despite more than 60 years of effort and the develop-
ment of numerous methods, organic chemists continue to
search for more straightforward ways to make R-amino
phosphonates. Among them, the Pudovik reaction4 and
the KabachnikÀFields reaction5 emerged as the most
widely adopted protocols (Scheme 1). The nucleophilic
additionreactionof phosphites withimines isanimportant
general method for the formation of the NÀCÀP bonds,
which is usually promoted by Lewis bases and acids
following the pioneering work of Pudovik.4 However,
these generate good yields of R-amino phosphonates only
if an imine is employed as a conjugated system.6 The
KabachnikÀFields reaction is a three-component reaction
of an amine, an aldehyde, and a dialkyl phosphite, lead-
ing to the formation of R-aminophosphonic acid esters.
† Xiamen University.
‡ Tsinghua University.
(1) (a) Bonarska, D.; Kleszczynska, H.; Sarapuk, J. Cell. Mol. Biol.
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r
10.1021/ol4019419
XXXX American Chemical Society

the amide group is relatively inert to reduction and direct
nucleophilic addition.14 Traditionally, before nucleo-
philic addition, preactivation of amides is required.15 The
most popular reductant is lithium aluminum hydride
which has poor selectivity, and many more groups may
be reduced. Recently, the research groups of Belanger16
and Huang15e reported the triflic anhydride activated
reductive alkylation of amides into amines respectively.
Moreover, Gunda I. Georg et al. reported the use of
Schwartz’s reagent (Cp2ZrHCl) to reduce amides to the
corresponding aldehydes and its mechanism was dis-
cussed.18 Additionally, Noritaka Chida et al. demon-
strated the use of reactive nucleophile DIBAL17 and
Cp2ZrHCl19 to directly transform amides into amines
by reductive alkylation using organic metallic reagents
as the nucleophiles. However, the reaction conditions
were harsh. Based on these considerations, it would be
particularly interesting and valuable to develop the
reductive phosphorus nucleophilic addition reaction of
amides undermild conditions, which has not been reported
so far. We envisioned that reduction of the amide carbonyl
using the Schwartz reagent might help us to achieve this
goal.
Our continued interest in PÀC formations recently20
prompted us to explore the possibility of the phosphina-
tion of inert amide carbonyls promoted by Cp2ZrHCl for
the preparation of R-amino phosphonates (Scheme 1).
Compared with the aldehydes and imines, the amides are
readily available, highly stable, and less toxic. Direct
condensation of simple H-phosphonates with amides is
found to be a more interesting and valuble route than those
reactions using aldehydes and imines as the reagents.
We began our investigations with the examination of
the reaction of N-benzylbenzamide (1a) with diethyl
H-phosphonate (2a) and Cp2ZrHCl. At the outset, the
reaction was carried out in THF. The choice of tempera-
ture is critical for the reaction (entries 1À3). At room
temperature, product 3a was detected in only 14% yield
(Table 1, entry 1). The reaction also proceeded slowly at
40 °C, giving a 78% yield (entry 2). However, when the
temperature was raised to 60 °C for 12 h, the phosphina-
tion of amide led to 3a in 97% yield (entry 3). The choice of
Scheme 1. Synthetic Routes to R-Amino Phosphonates
The important advantages of the method include the fact
that it is a single-stage process and the availability of the
starting compounds. Recently, great efforts have been
made to develop the Lewis acid catalytic,7 catalyst-free,8
and asymmetric9 synthesis of R-amino phosphonates
involving the condensation of H-phosphonates with
aldehydes or imines, along with the use of microwave
techniques.10 Although these methods are very mature, the
range of starting materials is limited to aldehydes or imines. In
2009, Shipman and co-workers developed a “one-pot” syn-
thesis of R-amino phosphonates from methyleneaziridines.11
In addition, in 2010 Ofial et al. discovered that C(sp3)ÀH
bonds in the R-position to nitrogen of N,N-dialkylanilines
could be activated for a subsequent CÀP bond forma-
tion.12 R-Amino phosphonate could be also obtained by
the oxidation of benzyl alcohol in the presence of aniline
and dimethyl phosphite, but only one example was re-
ported by the Fan group.13 Unfortunately, only the special
starting materials such as aromatic amines and methyle-
neaziridines were investigated in recent years. Conse-
quently, the development of a general and direct method
for the transformation of other functional groups such as
amides into R-amino phosphonates is highly desirable in
synthetic organic chemistry.
Amides as a class of readily available compounds are
pervasive in nature. Owing to their resonance stabilization,
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1593. (c) Zhang, J.; Cui, Z.; Wang, F.; Wang, Y.; Miao, Z.; Chen, R.
Green Chem. 2007, 9, 1341–1345.
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4501–4504. (b) Belanger, G.; O’Brien, G.; Larouche-Gauthier, R. Org.
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2005, 1393–1396. (b) Kaboudin, B.; Nazari, R. Tetrahedron Lett. 2001,
42, 8211–8213. (c) Yadav, J. S.; Reddy, B. V. S.; Madan, C. Synlett 2001,
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74, 3573–3575.
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1667–1676.
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B
Org. Lett., Vol. XX, No. XX, XXXX

Table 1. Optimization of Reaction Conditionsa
Table 2. Direct Transformation of Secondary Amides into
R-Amino Phosphonatesa
entry
solvent
T (°C)
yield (%)
1
THF
rt
14
2
THF
40
60
60
100
60
110
60
80
40
80
80
78
3
THF
97
4
dioxane
dioxane
toluene
toluene
DCE
62
5
88
6
21
7
75
8
64
9
DCE
91b
10
10
11
12
CH2Cl2
CH3CN
DME
trace
75
a Reaction conditions: 1a (0.3 mmol) and 2a (0.36 mmol), Cp2ZrHCl
(0.66 mmol), solvent (3 mL), under nitrogen for 12 h in a Schlenk tube.
Yields were determined by 31P NMR. b The reaction time is 24 h.
solvent is also very important. Like THF, 1,4-dioxane is
also a suitable solvent for this reaction. At 60 °C for 12 h,
only a 62% yield was obtained (entry 4). When the
temperature was raised to the refluxing temperature, the
yield could reach 88% (entry 5). When the reaction was
performed in toluene, CH2Cl2, or CH3CN, a much lower
yield was obtained at its refluxing temperature. The reac-
tion conducted in 1,2-dichloroethane (DCE) at 60 °C led
to a moderate yield. Further screening indicated that
raising the temperature to 80 °C and prolonging the time
to 24 h resulted in a satisfactory yield (entry 9).
Having the optimal conditions in hand, we next
examined the reactions of various amides with diethyl
H-phosphonate to understand the scope of the reaction
(Table 2). A variety of secondary amides, including aroyl
(Table 2, 3aÀ3k, 3mÀ3p, 3s), alkanoyl (Table 2, 3q, 3r),
and alkenoyl (Table 2, 3l) amides, were transformed into
the corresponding R-amino phosphonates in good to ex-
cellent yields. The substituted benzoyl group with electron-
withdrawing nitro group and electron-donating methoxyl
group also reacted smoothly with H-phosphonate result-
ing in products 3c and 3d in 88% and 92% yield, respec-
tively. Although nitro functionalities are easily reduced,
they were maintained and the reaction indicated excep-
tional chemoselectivity (3c). Halogen atoms such as fluoro
and chloro on the aromatic ring (3e, 3f, 3i) and alkyl
chloride (3o) were unaffected under the present reaction
conditions. Heteroaromatic compounds can also partici-
pate in the R-amino phosphination in a slightly lower yield
due to a potential interaction between zirconium and the S,
N atoms (3j, 3k). It should be noted that the reaction
of R,β-unsaturated amides led to a highly selective 1,2-
addition and giving a 78% yield (3l), whereas amides
a Conditions: treatment of 1a (0.3 mmol) in anhydrous THF (3 mL)
with Cp2ZrHCl (0.66 mmol) under nitrogen which was stirred at rt,
and then 2a (0.36 mmol) was added until the suspension cleared (about
5À15 min); the mixture was stirred at 60 °C for about 12 h in a Schlenk
tube. b Cp2ZrHCl (1.2 equiv).
Org. Lett., Vol. XX, No. XX, XXXX
C

The H-phosphonate reaction was also successfully
applied to dibenzyl, diisopropyl, and dimethyl H-phos-
phonates and H-phosphonates containing acetals in sat-
isfactory yields in addition to diethyl H-phosphonate,
indicating that the reactivities of these dialkyl phospho-
nates are almost independent of the alkyl moieties (3a,
3xÀ3z, 3aa). The acetal group was well tolerated in the
reaction (3aa), but the yield was affected by the steric
hindrance.
Scheme 2. Possible Mechanism
Based on the above experiment results and previous
reports,18b,20 a plausible reaction mechanism could be
proposed in Scheme 2. By treatment of amide with
Cp2ZrHCl, two possible intermediates I and II were
formed and subsequently reacted with H-phosphonate to
produce the corresponding R-amino phosphonates.
In conclusion, the first general method for the reductive
phosphination of amides using the Schwartz reagent in one
pot has been developed. The reactions described provide a
novel access to R-amino phosphonates in good to excellent
yields, cover a broad scope of substrates such as secondary
and tertiary amides, and do not require a low temperature.
Moreover, the amides are highly stable, easily available,
and versatile. Further application of this method toward
the synthesis of biologically active molecules is in progress.
containing a terminal double bond and terminal triple link
did not allow us to isolate the expected product. Similarly,
when the amides contain a hydroxyl, no product could be
detected, probably because Cp2ZrHCl could be inacti-
vated by the active hydrogen.
Phosphination of aliphatic amides also gave excellent
results (3nÀ3p), whereas aliphatic aldimine compounds
that react with phosphite often yield R-amino alkylpho-
sphonates in very low yields by the Pudovik reaction.
Benzyl (3aÀ3i), phenyl (3t), n-alkyl (3l, 3m), and sec-alkyl
(3j, 3k) groups on the nitrogen atom of the secondary
amides did not influence the reaction efficiency.
Only 1.2 equiv of Cp2ZrHCl was needed when tertiary
amides were used as reactants. The reductive phosphor-
ylation of tertiary amides also resulted in the formation of
tertiary R-aminophosphonate in 72À91% yields (3tÀ3w).
Dimethylformamide (DMF) reacted with H-phosphonate
to afford 3t in high yield. Diisopropyl amide reacted
for 12 h. providing 62% of the desired product (3w).
The above results show that steric hindrance on the
amine portion of the carboxamide is the cause of the lower
yields.
Acknowledgment. We acknowledge financial support
from the Chinese National Natural Science Foundation
(21173178, 21232005), the National Basic Research Pro-
gram of China (2012CB821600), and the Program for
Changjiang Scholars and Innovative Research Team in
University. We are grateful to Prof. Dr. D. M. J. Lilley
from University of Dundee for valuable discussions on this
paper.
Supporting Information Available. General experimental
procedure and characterization details. This material is
available free of charge via the Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX