Lewis acid or alkyl halide promoted rearrangements of phosphor- and phosphinimidates to N,N-disubstituted phosphor- and phosphinamidates

Article abstract of DOI:10.1055/s-0030-1260141

In this paper, we describe the synthesis of N,N-disubstituted phosphor- and phosphinamidates via alkyl halide or Lewis acid catalyzed rearrangements of phosphor- or phosphinimidates. Furthermore, we introduce a novel one-pot procedure for the synthesis of N,N-disubstituted phosphoramidates which prevents the isolation of potentially explosive alkyl azide derivatives. In this reaction sequence, several alkyl halides are converted in situ into the corresponding azides and reacted with phosphites to generate phosphorimidates. Final addition of a catalytic amount of Lewis acid to the mixture affords the N,N-disubstituted phosphoramidates in good to excellent overall yields. 1 Introduction 2 Synthesis of N,N-Disubstituted Phosphor- and Phosphinamidates 2.1 Alkyl Halide Catalyzed Rearrangement of Phosphin- and Phosphorimidates 2.2 Lewis Acid Catalyzed Rearrangement of Phosphin- and Phosphorimidates 2.3 One-Pot Procedure for the Formation of N,N-Disubstituted Phosphoramidates from Alkyl Halides 3 Conclusion. Georg Thieme Verlag Stuttgart - New York.

Full text of DOI:10.1055/s-0030-1260141

FEATURE ARTICLE
2709
Lewis Acid or Alkyl Halide Promoted Rearrangements of Phosphor- and
Phosphinimidates to N,N-Disubstituted Phosphor- and Phosphinamidates
N, N-Dis
n
ubstitute
d
Ph
a
osphor- and Phos
W
phinamidates ilkening, Giuseppe del Signore, Wiebke Ahlbrecht, Christian P. R. Hackenberger*
Freie Universität Berlin, Institut für Chemie und Biochemie, Takustr. 3, 14195 Berlin, Germany
Fax +49(30)83852551; E-mail: hackenbe@chemie.fu-berlin.de
Received 4 May 2011; revised 7 July 2011
Traditionally, the synthesis of P(=O)–N containing phos-
phonamidates or phosphoramidates has found inspiration
in the classical strategies for the formation of amide
bonds, in which carboxylic acid derivatives are converted
Abstract: In this paper, we describe the synthesis of N,N-disubsti-
tuted phosphor- and phosphinamidates via alkyl halide or Lewis
acid catalyzed rearrangements of phosphor- or phosphinimidates.
Furthermore, we introduce a novel one-pot procedure for the syn-
thesis of N,N-disubstituted phosphoramidates which prevents the into activated esters before substitution with an amine nu-
isolation of potentially explosive alkyl azide derivatives. In this re-
cleophile occurs. Similarly, electrophilic phosphorus or
action sequence, several alkyl halides are converted in situ into the
phosphonic acid derivatives, in particular in the form of
corresponding azides and reacted with phosphites to generate phos-
the P(III) phosphorochloridites or P(V) phosphorochlori-
phorimidates. Final addition of a catalytic amount of Lewis acid to
dates, can react in a nucleophilic substitution reaction
the mixture affords the N,N-disubstituted phosphoramidates in
with amines, leading to the formation of a P–N bond.5 In
order to obtain phosphorus(V) phosphoramidates or phos-
good to excellent overall yields.
1
2
Introduction
phonamidates, the phosphorus(III) has to be oxidized af-
terwards (Scheme 1).6
Synthesis of N,N-Disubstituted Phosphor- and Phosphina-
midates
2.1
2.2
2.3
3
Alkyl Halide Catalyzed Rearrangement of Phosphin- and
Phosphorimidates
Lewis Acid Catalyzed Rearrangement of Phosphin- and
Phosphorimidates
One-Pot Procedure for the Formation of N,N-Disubstituted
Phosphoramidates from Alkyl Halides
Conclusion
1. base
R2
R2
O
O
R2
2. oxidation
R2
Cl
P
base
R1
P
R1
Cl + HN
R1
P
R1
N
HN
R1 R2
+
R1
R2
phosphoro-
chloridite
phosphoro-
chloridate
R1 = alkyl, aryl, O-alkyl, O-aryl
R
2 = alkyl, aryl
Key words: Staudinger reaction, phosphorimidate rearrangement,
phosphoramidates, phosphinamidate, one-pot procedure, Lewis
acid catalysis
Scheme 1 Traditional access to N,N-disubstituted phosphin-,
phosphon-, and phosphoramidates
An alternative route for the formation of P–N compounds
is offered by the Staudinger reaction between trivalent
phosphorus species and azides.7 Depending on the nature
of the phosphorus counterpart, different phosphorus com-
pounds became accessible (Scheme 2).8 In a widely ap-
plied synthetic transformation, the so called Staudinger
reduction, primary amines can be derived from azides via
hydrolysis of iminophosphoranes, which are formed by
Staudinger reaction of azides with phosphines.7 During
the hydrolysis, P–N bond cleavage occurs to form an
amine and a phosphine oxide. The replacement of at least
one of the alkyl or aryl substituents at the phosphorus by
an alkoxy group, can result in a different reaction pathway
causing formation of a P=O bond without corresponding
cleavage of the P–N bond. Thereby, phosphin-, phosphon-
or phosphoramidates become accessible and only acidic
conditions result in P–N bond cleavage.8
1
Introduction
Organic molecules containing a P(=O)–N bond are attrac-
tive targets in organic chemistry since they have found
widespread use in several areas of modern organic chem-
istry, including applications in catalytic transformations
as well as chemical biology. Phosphoric acid derivatives,
in particular, have been used in the area of asymmetric ca-
talysis and they are attracting increasing interest as
Brønsted acid or base catalysts and substantial progress
has been made concerning their catalytic ability.1 In the
domain of medicinal chemistry, phosphonamidates have
been used as surrogates for amide bonds in the synthesis
of pharmaceutically active peptide-based protease inhibi-
tors, since the P(=O)–NH moiety mimics the tetrahedral
transition state during amide bond hydrolysis.2 Similarly,
phosphoramidates have been used as analogues of phos-
phate esters in nucleotides3 or even in post-translationally
modified proteins.4
To date the Staudinger reaction has been the subject of
several hundreds of articles.8,9 The interest in this reaction
was additionally bolstered by the pioneering work of
Bertozzi and co-workers, who have identified the
chemoselective potential of the Staudinger reaction.
Hence, they have engineered a bioorthogonal Staudinger
ligation for the transformation of azides under physiolog-
SYNTHESIS 2011, No. 17, pp 2709–2720
Advanced online publication: 27.07.2011
DOI: 10.1055/s-0030-1260141; Art ID: T46511SS
© Georg Thieme Verlag Stuttgart · New York
x
x.
x
x
.
2
0
1
1

2710
I. Wilkening et al.
FEATURE ARTICLE
ical conditions in complex biomolecules.10 Recently, our In another synthetically useful reaction, phosphorimidates
group has used the Staudinger reaction of azides with can be N-alkylated by reaction with electrophiles to give
phosphites4 or silylated phosphinic acid esters or acids2 N,N-disubstituted phosphoramidates. These compounds
for chemoselective transformations. In the latter proto- can be regarded as protected secondary amines, which are
cols, phosphorimidates react with water and the nitrogen valuable building blocks in organic synthesis and in some
of the P=N bond is protonated to form a P(=O)–NH bond cases difficult to access.11–14 In order to avoid the afore-
(Scheme 2).
mentioned hydrolytic formation of N-monosubstituted
Biographical Sketches
Ina Wilkening studied Konrad Sandhoff under the the synthesis of P–N com-
chemistry at the Friedrich- supervision of Dr. Ute pounds by Staudinger reac-
Wilhelms Universität Bonn Schepers she moved to Ber- tions and their applications
and received her diploma in lin in 2007 to start her Ph.D. in peptide modifications at
2006. After her diploma under the direction of Prof. the Freie Universität Berlin.
work in the group of Prof. Christian Hackenberger on
Dr. Giuseppe Del Signore ty of Rome and his Ph.D. in dicinal chemistry depart-
was born in Rome. He re- 2003 at the RWTH Aachen. ment at Mercachem S.V.
ceived his M.Sc. in 1999 Currently, he is a senior sci-
from La Sapienza Universi- entist in the organic and me-
Dr. Wiebke Ahlbrecht ob- Prof. Christian Hackenberg- with Professor Dirk Menche
tained her diploma in chem- er she was involved in syn- at the University of Heidel-
istry from the Freie thetic
development
of berg on the total synthesis of
Universität Berlin in 2006. imide-amide rearrangement natural products.
During her diploma thesis to yield phosphoramides. In
under the supervision of 2010 she received her Ph.D.
Prof. Dr. Christian P. R. 2011 he was appointed as cluding the methodological
Hackenberger
chemistry in Freiburg and in bioorganic chemistry. He particular chemoselective
Madison/Wisconsin (M.Sc. has received several re- transformations, protein
studied associate professor for development of reactions, in
in 1999 with Samuel H. search awards, most recent- semi-synthesis, design of
Gellman). In 2003 he com- ly the Heinz Maier-Leibnitz multivalent scaffolds, cyclic
pleted his Ph.D. with Prize of the DFG, the proteins, biosynthesis of
Carsten Bolm at RWTH ADUC prize of the GDCh, sialic acids as well as the
Aachen. After postdoctoral and the Karl Winnacker structural and functional
research with Barbara Impe- Dozentenstipendium of the analysis of protein modifi-
riali (2003–2005) at MIT he FCI. The scientific research cations including signal
moved to the Freie Univer- interests of the Hackenberg- transduction and protein ag-
sität Berlin, where he first er group focus on various gregation.
led an Emmy Noether junior areas in organic chemistry
group from 2006–2010. In and chemical biology, in-
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

FEATURE ARTICLE
N,N-Disubstituted Phosphor- and Phosphinamidates
2711
STAUDINGER REACTION
(MECHANISM)
R2
R2
P
O
R2
R1
R2
P
R2
R2
phosphine (R2 = alkyl, aryl)
phosphite (R2 = O-alkyl)
STAUDINGER
REDUCTION
+
H2N
R2
P
R2
R1
R1
N3
1 = alkyl, aryl
primary
amine
phosphine(V)
oxide
R2
N
R
iminophosphorane
(R2 = alkyl, aryl)
phosphorimidate
(R2 = O-alkyl)
R1
H
O
R2
STAUDINGER-
PHOSPHITE
REACTION
R2
R2
R2
P
R2
N
H2O
R2 = O-alkyl
R1
+
HO-alkyl
N
P
N
N
– N2
phosphazide
phosphoramidate
Lewis acid
R2
R2
R2
aza-ylide
R1
or
Δ
P
N
via
R2
R1
O
R1
HN
‡
H+
PHOSPHORIMIDATE
REARRANGEMENT
R2
R1
R2
P
N
P
N
N
N
R3
R3
R2
R2
secondary
amine
N,N-disubstituted
phosphoramidate
four-membered
transition state
R
3 = alkyl
Scheme 2 Mechanism of the Staudinger reaction and possible reaction pathways, including Staudinger reduction, Staudinger–phosphite re-
action and rearrangements of phosphorimidates
phosphoramidates during the alkylation, strictly anhy- in high yields, as also verified by our own experience for
drous conditions have to be ensured.11 Challis and co- the reaction of benzyl azide (1a) with different phosphites
workers have pioneered a thermal rearrangement of phos- (Table 1, entries 1–3). Due to the efficiency of this trans-
phorimidates to phosphoramidates.12 The rearrangement formation, we decided to extend this methodology to dia-
proceeds via an intermolecular mechanism, in which one ryl phosphinimidates 5a–c obtained from Staudinger
imidate undergoes nucleophilic attack by the nitrogen of a reaction of benzyl azide (1a) with phosphinites
second imidate molecule. Additionally, the groups of (Scheme 3, Table 1, entries 4–6). To the best of our
Mapp13 and Batey1i have reported an intramolecular [3,3]- knowledge, the rearrangement of phosphinimidates 4 us-
sigmatropic rearrangement of allylic phosphorimidates as ing alkyl halide as catalysts has not been previously re-
a powerful tool for the synthesis of protected allylamines. ported. Furthermore, phosphinites are rarely used in
Another possibility to enhance the formation of N,N-di- Staudinger reactions because they are very prone to oxi-
substituted phosphoramidates is the use of catalysts, dation or hydrolysis and have to be kept under an argon at-
which accelerate the phosphorimidate rearrangement, e.g. mosphere. Three different diphenylphosphinites were
by addition of alkyl halides14 or Lewis acids.11,15
selected as model compounds to study the rearrangement
of phosphinimidates 4. Whereas methyl and ethyl diphe-
nylphosphinite are commercially available, benzyl diphe-
nylphosphinite was prepared from chlorodiphenyl-
phosphine and benzyl alcohol.17 As shown in Table 1, in
all cases the desired phosphinamidates 5a–c were accessi-
ble in high yields under reaction conditions similar to the
ones we used previously for the rearrangement of phos-
phorimidates 2a–c. However, a higher amount of alkyl ha-
lides was required, in particular when less reactive benzyl
diphenylphosphinite and ethyl diphenylphosphinite were
used.
In this article, we focus on the scope of alkyl halide and
Lewis acid catalyzed rearrangements of different P=N-
containing compounds, in particular phosphinimidates,
which can be obtained by reaction of azides with phos-
phinites. Additionally, we report our efforts to establish a
one-pot procedure for the formation of N,N-disubstituted
phosphoramidates from simple alkyl halides, thereby
avoiding the isolation of potentially explosive azides.
2
Synthesis of N,N-Disubstituted Phosphor-
and Phosphinamidates
2.2
Lewis Acid Catalyzed Rearrangement of
Phosphin- and Phosphorimidates
2.1
Alkyl Halide Catalyzed Rearrangement of
Phosphin- and Phosphorimidates
In a previous study, we used Lewis acids to induce the re-
arrangement of phosphorimidates 2 to obtain N,N-disub-
stituted phosphoramidates 3.11 We showed that the
reaction proceeded well with a variety of azides, in partic-
ular when the reaction was performed with boron trifluo-
ride–diethyl ether complex or trimethylsilyl triflate as the
Lewis acid catalyst. Now, we have further tested the scope
Alkyl halide promoted rearrangements of phosphorimi-
dates derived from the Staudinger reaction of azides with
phosphites, are already known in the literature
(Scheme 3).14,16 In these transformations, phosphorimi-
dates 2 require only low amounts of the alkyl halide spe-
cies to deliver the N,N-disubstituted phosphoramidates 3
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

2712
I. Wilkening et al.
FEATURE ARTICLE
R
O
P
R
R
R
O
P
O
R
R
O
R-X (cat.)
P(OR)3
– N2
R-X (cat.)
Bn
Ph2POR
– N2
O
R
N
BnN3
O
R
N
Ph
P
N
Ph
P
N
Bn
O
Bn
Bn
O
Ph
Ph
N,N-disubstituted
phosphoramidate
N,N-disubstituted
phosphinamidate
2a–c
1a
4a–c
X = I, Br
5a (R = Me)
5b (R = Et)
5c (R = Bn)
3a (R = Me)
3b (R = Et)
3c (R = Bn)
Scheme 3 Alkyl halide catalyzed rearrangement of phosphorimidates 2a–c and phosphinimidates 4a–c
Table 1 Staudinger Reaction and Alkyl Halide Catalyzed Rearrangement between Benzyl Azide and Different Phosphites and Phosphinites
Entry
1b
Phosphite or phosphinite Alkyl halide (mol%) Conditionsa
Solvent
benzene
Product
Yield (%)
90
P(OMe)3
MeI (5)
1. 80 °C, 2 h
2. 80 °C, 4 h
3a
2b
3b
4c
5c
6c
P(OEt)3
EtI (20)
1. 110 °C, 2 h
2. 110 °C, 4 h
toluene
benzene
benzene
toluene
benzene
3b
3c
5a
5b
5c
70
71
83
60
76
P(OBn)3
Ph2POMe
Ph2POEt
Ph2POBn
BnBr (25)
MeI (25)
EtI (20)
1. 80 °C, 2 h
2. 80 °C, 8 h
1. r.t., 20 min
2. 80 °C, 4 h
1. r.t., 20 min
2. 110 °C, 8 h
BnBr (25)
1. 80 °C, 2 h
2. 80 °C, 4 h
a 1. Imidate formation. 2. Rearrangement by addition of catalytic amounts of alkyl halides.
b General procedure I.
c General procedure II.
and also possible limitations of this transformation well tolerated under the reaction conditions (entries 5–7),
(Scheme 4). Originally, the rearrangement was performed including esters in the synthesis of the GlcNAc-phospho-
after formation of the phosphorimidate upon the addition ramidate 3h. On the other hand, when longer alkyl chains
of the Lewis acid at 80 °C. Here, we found that the product were tested, as for the reaction of benzyl azide (1a) with
3a was also formed at room temperature with 1 mol% of trioleyl phosphite, the rearrangement turned out to be less
catalyst added; however, longer reaction times were re- efficient; an inseparable mixture of N,N-disubstituted and
quired (Table 2, entry 1). In addition to trimethyl and tri- hydrolyzed compounds was obtained (data not shown).
ethyl phosphite also tributyl or triallyl phosphite could be
Next, we probed the Lewis acid catalyzed rearrangement
used in good overall yields to produce 3d and 3e with both
of phosphinimidates 4 (Scheme 5), which were obtained
Lewis acid catalysts (entries 2–4). We were also pleased
by Staudinger reaction of methyl diphenylphosphinite
to find that different functional groups on the azide were
with benzyl azide (1a) or phenyl azide (1e). For both
phosphinimidates 4a and 4d, the transfer of the methyl
group proceeded very well and delivered phosphinami-
dates 5a and 5d in 87% and 75% yields, respectively
(Table 3, entries 1 and 2). In contrast, the phosphinimidate
4b and 4e, derived from ethyl diphenylphosphinite and
azides 1a and 1e, reacted very slowly and even higher
amounts of catalysts delivered only moderate amounts of
phosphinamidates 5b and 5e (entries 3 and 4).
R1
R1
Lewis acid
R1
R2
R1
O
P
O
P
P(OR1)3
– N2
N3 R2
N
R2
O
N
O
O
O
R1
R1
1a (R2 = Bn)
2a,d–h
3a,d–h
N,N-disubstituted
phosphoramidate
1b (R2 = 4-O2NC6H4)
1c (R2 = 4-MeOC6H4)
1d (R2 = GluNAc)
R2
=
R1
Me
Me
=
R2
Bn
Bn
Bn
=
R1
Me
All
Bu
=
Similarly, the rearrangement of phosphinimidates 4c and
4f, derived from Staudinger reaction with benzyl diphe-
nylphosphinite turned out to be rather inefficient under the
standard protocol (Table 3, entries 5–10). Screening of
different aluminum- and boron-based Lewis acids did not
afford any improvement (data not shown). Apolar sol-
vents like toluene or xylene gave the highest but still mod-
3a
3d
3e
4-O2NC6H4
4-MeOC6H4
OAc
3f
3g
O
Me
3h
AcO
AcO
NHAc
Scheme 4 Lewis acid catalyzed rearrangement of phosphorimidates
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

FEATURE ARTICLE
N,N-Disubstituted Phosphor- and Phosphinamidates
2713
Table 2 Lewis Acid Catalyzed Rearrangement of Phosphorimidates 2a
Entry
1
Azide
Phosphiteb
P(OMe)3
BF3·OEt2 (mol%) Conditionsc
Product
Yield (%)
95
BnN3
1a
1
1
1
1d
1
1
1
1. 80 °C, 2 h
2. r.t., 16 h
3a
2
3
4
5
6
7
BnN3
1a
P(OAll)3
P(OBu)3
P(OBu)3
P(OMe)3
P(OMe)3
P(OMe)3
1. 80 °C, 2 h
2. 80 °C, 2 h
3d
3e
3e
3f
71
72
65
85
88
67
BnN3
1a
1. 80 °C, 5 h
2. 80 °C, 5 h
BnN3
1a
1. 80 °C, 5 h
2. 80 °C, 5 h
4-O2NC6H4N3
1b
1. 80 °C, 2 h
2. 80 °C, 2 h
4-MeOC6H4N3
1c
1. 80 °C, 2 h
2. 80 °C, 2 h
3g
3h
GlcNAcN3
1d
1. r.t., 16 h
2. r.t., 24 h
a General procedure III.
b All = allyl.
c All reactions were performed in benzene as solvent.
d TMSOTf.
Table 3 Induced Rearrangement of Phosphinimidatesa
Entry
1
Azide
Phosphinite
Ph2POMe
BF3·OEt2 (mol%) Conditionsa
Solvent
Product
Yield (%)
75
PhN3
1e
1
1. 80 °C, 2 h
2. 80 °C, 2 h
benzene
benzene
benzene
benzene
benzene
toluene
xylene
5d
5a
5e
5b
5f
2
3
BnN3
1a
Ph2POMe
Ph2POEt
Ph2POEt
Ph2POBn
Ph2POBn
Ph2POBn
Ph2POBn
Ph2POBn
Ph2POBn
1
1. 80 °C, 2 h
2. 80 °C, 2 h
87
36
51
25
20
13
30
30
40
PhN3
1e
5
1. 80 °C, 2 h
2. 80 °C, 16 h
4
BnN3
1a
10
10
20
40
20
20
20
1. 80 °C, 2 h
2. 80 °C, 24 h
5
PhN3
1e
1. 80 °C, 2 h
2. 80 °C, 2 h
6
PhN3
1e
1. 0 °C to r.t.
2. 80 °C, 5 h
5f
7
BnN3
1a
1. 0 °C to r.t.
2. 80 °C, 5 h
5c
5c
5c
5c
8
BnN3
1a
1. 0 °C to r.t.
2. 80 °C, 5 h
xylene
9
BnN3
1a
1. 0 °C to r.t.
2. 80 °C, 17 h
xylene
10
BnN3
1a
1. 0 °C to r.t.
2. 80 °C, 5 h
toluene
a General procedure IV.
b 1. Imidate formation. 2. Rearrangement under addition of catalytic amounts of Lewis acid.
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

2714
I. Wilkening et al.
FEATURE ARTICLE
R1
the solvent, which demands higher temperatures mainly
due to the low solubility of sodium azide. After refluxing
the reaction mixture for 24 hours, complete formation of
benzyl azide (1a) was observed by NMR. After refluxing
the reaction mixture for five hours with trimethyl phos-
phite and an additional three hours after addition of the
Lewis acid (10 mol%), the desired phosphoramidate 3a
was obtained in an excellent overall yield of 92%.
R1
R2
O
O
P
Ph2POR1
BF3⋅OEt2
N3 R2
N
R2
P
Ph
N
Ph
– N2
Ph
Ph
1a (R2 = Bn)
1e (R2 = Ph)
4
5
N,N-disubstituted
phosphinamidate
R2
Ph
Bn
Ph
=
R1
Me
Me
Et
=
R2
Bn
Ph
Bn
= =
R1
5d
5a
5e
5b
5f
5c
Et
Bn
Bn
In the case of activated bromides, like benzyl bromide
(6a) or cinnamyl bromide (6b) (entries 2 and 4), the reac-
tion proceeded in very high yields also without the addi-
tion of potassium iodide. Decreasing the amount of Lewis
acid catalyst from 10 mol% to 1 mol% led only to a yield
of 45% after three hours of rearrangement (entry 3). By re-
fluxing the reaction mixture for a further two days with
additional amounts of catalyst the reaction could be run to
completion (83%) with 17% hydrolyzed phosphoramidate
as a side product.
Scheme 5 Lewis acid induced rearrangement
erate yields (30–40%), and in all cases, significant
amounts of hydrolysis byproducts were observed.
2.3
One-Pot Procedure for the Formation of
N,N-Disubstituted Phosphoramidates from
Alkyl Halides
Besides benzyl bromide (6a) also normal primary bro-
mides could be used in the reaction sequence (entries 6–
10). Furthermore, alkyl mesylates and tosylates were tol-
erated, although with lower yields. Tertiary azides ob-
tained from the corresponding bromide like the malonic
acid derivative 6h could only be converted into the de-
sired phosphoramidates 3n to a very low extend, although
the formation of the azide and the phosphorimidate 2n
was quantitative. Nevertheless, the successive addition of
the Lewis acid did not lead to a satisfying rearrangement
and even after four days only 32% of the rearranged prod-
uct 3n was obtained with 35% of unreacted phosphorimi-
date 2n and 22% of hydrolyzed product being present.
This result may probably be attributed to the steric hin-
drance and to the strong electron-withdrawing effect of
the two ester groups which decrease the nucleophilicity of
the phosphorimidate nitrogen.
Azides are regarded as important compounds in organic
synthesis, in particular because of their high intrinsic re-
activity. Various methodologies for their synthesis exist
among which the nucleophilic substitution of a good leav-
ing group at sp3-hybridized carbons with inorganic azides
is probably the mostly widely applied method.18 Never-
theless, the isolation of azides, especially for derivatives
of low molecular weight, is not desirable due to their po-
tential explosive nature.18 Consequently, we aimed to de-
velop a procedure, in which isolation could be avoided by
performing the reaction as a one-pot process starting from
simple azide precursors. In the desired protocol
(Scheme 6), an alkyl or benzyl derivative with an appro-
priate leaving group should give a nucleophilic substitu-
tion with sodium azide, followed by Staudinger reaction
with the appropriate phosphite and final rearrangement af-
ter addition of the Lewis acid. Noteworthy, all the steps
should be carried out in one flask without isolation of any
intermediate species. It is important to note that for the
success of this one-pot protocol, full conversion of the
bromide to the corresponding azide is essential to avoid
side reactions: (1) the alkyl bromide may lead to forma-
tion of a phosphonate from the phosphite in an Arbuzov
reaction; and (2) alkylation of the intermediate phospho-
rimidate should be prevented. Also the addition of the
Lewis acid is a crucial factor, since incomplete consump-
tion of the phosphite would again lead to the formation of
a phosphonate, which cannot undergo the Staudinger re-
action.
1. NaN3 (1.2 equiv)
KI (4 mol%)
2. P(OMe)3 (1 equiv)
3. BF3⋅OEt2
O
P
R
N
O
R
X
MeCN, reflux, 22–46 h
Me
Me
Me
O
6a–h
X = Br, OMs, OTs
3a,g–n
Scheme 6 One-pot procedure towards N,N-disubstituted phosphor-
amidites
3
Conclusion
The one-pot reaction sequence was first tested with benzyl
bromide (6a) (Table 4, entry 1) as starting material, which
was reacted in acetonitrile with 1.2 equivalents of sodium
azide and a catalytic amount of potassium iodide. Usually,
nucleophilic substitution of benzyl bromides is performed
at room temperature in solvents like N,N-dimethylform-
amide or dimethyl sulfoxide, which are, however, not well
suited for the subsequent rearrangement, due to their hy-
droscopic nature and subsequent formation of the hydrol-
ysis byproduct.19 Consequently, we chose acetonitrile as
In summary, we have used the alkyl halide or Lewis acid
catalyzed rearrangement of phosphor- and phosphinimi-
dates for the formation of N,N-disubstituted phosphora-
midates and phosphinamidates. In these protocols
different alkyl substituents can be introduced at the nitro-
gen of the P(=O)–N bond in good to high yields. In addi-
tion, we have successfully introduced a one-pot procedure
for the formation of N,N-disubstituted phosphoramidates
without the intermediate isolation of alkyl azide deriva-
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

FEATURE ARTICLE
N,N-Disubstituted Phosphor- and Phosphinamidates
2715
Table 4 Reaction Scope of the One-Pot Processa
Entry
Bromide
Conditions
Phosphoramidate
Yield (%)
Me
NaN3, KI (4 mol%), MeCN, 80 °C, 24 h
P(OMe)3, MeCN, 80 °C, 5 h
O
P
Bn
BnBr
6a
1
92
N
O
BF3·OEt2 (10 mol%), MeCN, 80 °C, 3 h
Me
Me
O
3a
NaN3, MeCN, 80 °C, 24 h
P(OMe)3, MeCN, 80 °C, 5 h
BF3·OEt2 (10 mol%), MeCN, 80 °C, 5 h
BnBr
6a
2
3
3a
90
NaN3, KI, MeCN, 80 °C, 24 h
P(OMe)3, MeCN, 80 °C, 5 h
BF3·OEt2 (1 mol%), MeCN, 80 °C, 3 h
BF3·OEt2 (2 mol%), MeCN, 80 °C, 24 h
BF3·OEt2 (2 mol%), MeCN, 80 °C, 24 h
45b (3 h)
BnBr
6a
3a
78b (27 h)
83 (51 h)
Ph
O
P
1. NaN3, MeCN, 80 °C, 24 h
2. P(OMe)3, MeCN, 80 °C, 5 h
3. BF3·OEt2 (10 mol%), MeCN, 80 °C, 5 h
(E)-PhCH=CHCH2Br
6b
N
O
4
5
6
80
Me
Me
Me
O
3i
O
P
1. NaN3, KI (4 mol%), MeCN, 80 °C, 24 h
2. P(OMe)3, MeCN, 80 °C, 5 h
3. BF3·OEt2 (10 mol%), MeCN, 80 °C, 3 h
H2C=CHCH2Br
6c
N
O
51
Me
Me
Me
O
3j
Ph
O
P
1. NaN3, MeCN, 80 °C, 16 h
2. P(OMe)3, MeCN, 80 °C, 2 h
3. BF3·OEt2 (10 mol%), MeCN, 80 °C, 2 h
Ph(CH2)3Br
6d
£20b
N
O
Me
Me
Me
O
3k
3k
1. NaN3, MeCN, 80 °C, 24 h
2. P(OMe)3, MeCN, 80 °C, 5 h
3. BF3·OEt2 (10 mol%), MeCN, 80 °C, 5 h
Ph(CH2)3OMs
6e
7
8
50b
81
1. NaN3, KI (4 mol%), MeCN, 80 °C, 24 h
2. P(OMe)3, MeCN, 80 °C, 5 h
3. BF3·OEt2 (10 mol%), MeCN, 80 °C, 3 h
Ph(CH2)3Br
6d
3k
Me
O
1. NaN3, DMF, 60 °C, 16 h
2. P(OMe)3, DMF, 80 °C, 3 h
3. BF3·OEt2 (10 mol%), DMF, 80 °C, 12 h
N
Me(CH2)5Br
6f
P
9
40
61
O
O
Me
Me
3l
Me O
NaN3, KI (4 mol%), MeCN, 80 °C, 24 h
P(OMe)3, MeCN, 80 °C, 5 h
BF3·OEt2 (1 mol%), MeCN, 80 °C, 3 h
OTs
MeO
N
P
O
MeO
O
10
O
2
2
Me
Me
O
6g
3m
O
O
1. NaN3, KI (4 mol%), MeCN, 80 °C, 24 h
2. P(OMe)3, MeCN, 80 °C, 5 h
3. BF3·OEt2 (10 mol%), MeCN, 80 °C, 3 h
4. BF3·OEt2 (10 mol%), MeCN, 80 °C, 24 h
5. BF3·OEt2 (10 mol%), MeCN, 80 °C, 49 h
3b (3 h)
O
O
O
O
12b (27 h)
21b (51 h)
32b (100 h)
O
11
N
O
O
Me
P
Br
O
O
6h
Me
Me
3n
a General procedure V.
b Yield determined by 31P NMR.
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

2716
I. Wilkening et al.
FEATURE ARTICLE
der reduced pressure to give the crude product. Final purification by
flash column chromatography (EtOAc–hexane, 1:1) afforded the
pure product in 60–83% yield.
tives. Our future efforts are devoted to applying this meth-
odology to the synthesis of new derivatives in which the
biological potential of the phosphoramidate moiety is ful-
ly addressed.
Lewis Acid Induced Rearrangement of Phosphorimidates;
General Procedure III
In a 2-necked round-bottom flask the azide derivative was dissolved
in anhyd benzene (0.6 mmol/mL) and phosphite (1 equiv) was add-
ed. The mixture was refluxed at 80 °C for 2–5 h or stirred at r.t. for
24 h (see Table 2). After cooling to r.t. BF3·OEt2 (1 mol%) dis-
solved in anhyd benzene (50 mL) was added to the formed phospho-
rimidate and the rearrangement was allowed to proceed at 80 °C for
2–5 h or at r.t. for 16–24 h. The solvent was removed under reduced
pressure to give the crude product. Final purification by flash col-
umn chromatography [EtOAc–hexane, 3:1; for the sugar derivative
EtOAc–MeOH (0 to 5%)] afforded the pure product in 65–90%
yield.
All reagents, starting materials and solvents were purchased from
commercial suppliers and used without further purification if not
further mentioned. Methyl diphenylphosphinite and ethyl diphe-
nylphosphinite as well as dry solvents (MeCN, toluene, DMF) were
purchased from Acros Organics. Anhyd benzene and 3,4,6-tri-O-
acetyl-2-acetamido-2-deoxy-b-D-glucopyranosyl azide (1d) were
purchased from Sigma Aldrich. Flash chromatography was per-
formed on silica gel (Acros Silica gel 60 A, 0.035–0.070 mm). TLC
was performed on aluminum-backed silica plates (60 F254,
0.2 mm) which were developed using KMnO4 as visualizing agent.
1H, 13C, and 31P NMR spectra were recorded on a Jeol ECX/400,
Bruker AC 250 or AMX 500.
Lewis Acid Catalyzed Rearrangement of Phosphinimidates;
General Procedure IV
Benzyl Diphenylphosphinite
In a 2-necked round-bottom flask the azide derivative was dissolved
in anhyd benzene or toluene (0.6 mmol/mL) and phosphinite (1
equiv) was added slowly at r.t. or 0 °C (see Table 3). The mixture
was stirred at r.t. for 1–2 h or refluxed for 2 h and then BF3·OEt2
was added to the formed phosphinimidate. The rearrangement was
allowed to proceed at 80 °C for 2–24 h. The solvent was removed
under reduced pressure to give the crude product. Final purification
by flash column chromatography (EtOAc–hexane, 3:1) afforded the
pure product in 13–87% yield.
BnOH (0.518 mL, 541 mg, 5.00 mmol) was dissolved in Et2O
(25 mL) under an argon atmosphere. The soln was cooled to 0 °C
and Et3N (1.40 mL, 1.01 g, 10.0 mmol) and DMAP (61.0 mg,
0.599 mmol) in Et2O (5 mL) were added, followed by Ph2PCl
(0.895 mL, 1.10 g, 5.00 mmol). The mixture was allowed to warm
up to r.t. and after 90 min the precipitated salt was filtered off. The
solvent was removed under reduced pressure and benzyl diphe-
nylphosphinite was obtained as a colorless solid; yield; 1.30 g
(90%).17
1H NMR (250 MHz, CD3Cl): d = 4.93 (d, J = 9.10 Hz, 2 H, CH2),
One-Pot Procedure to N,N-Disubstituted Phosphoramidates;
General Procedure V
7.30–7.58 (m, 15 H, Ph).
31P NMR (202 MHz, CD3Cl): d = 114.48.
To a suspension of NaN3 (358 mg, 5.50 mmol), KI (33.0 mg,
0.199 mmol, 4 mol%), and MeCN (10 mL), the bromide
(5.00 mmol) was added. The mixture was refluxed for 16–30 h until
formation of the azide was complete. Afterwards P(OMe)3 (590 mL,
620 mg, 5.00 mmol) was added and the mixture was refluxed for an
additional 5 h and then BF3·OEt2 (10 mol%) in MeCN (500 mL) was
added. The rearrangement was complete after a further 3–51 h at
80 °C and the solvent was removed under reduced pressure. Final
purification by flash column chromatography (EtOAc–cyclohex-
ane, 2:1) afforded the pure product in 51–92% yield.
Tribenzyl Phosphite
PCl3 (0.437 mL, 687 mg, 5.00 mmol) was slowly added to a soln of
Et3N (2.09 mL, 1.52 mg, 15.0 mmol) in Et2O (120 mL). The mix-
ture was cooled to 0 °C and BnOH (1.55 mL, 1.62 mg, 15.0 mmol)
was added. The mixture was stirred at 0 °C for 1 h and left at r.t.
overnight. The precipitate was filtered and the solvent removed un-
der reduced pressure. The product was obtained as a colorless oil
and used without further purification; yield: 1.71 g (97%).19
1H NMR (400 MHz, CDCl3): d = 4.88 (d, J = 5.0 Hz, 6 H, CH2),
Dimethyl N-Benzyl-N-methylphosphoramidate (3a)
Prepared according to general procedure I or III from BnN3
(399 mg, 3.00 mmol) and P(OMe)3 (354 mL, 372 mg, 3.00 mmol);
yield: 619 mg (90%) (GPI) and 653 mg (95%) (GPIII). Alternative
according to general procedure V from BnBr (595 mL, 855 mg,
5.00 mmol) and P(OMe)3 (590 mL, 620 mg, 5.00 mmol) as a color-
less oil; yield: 1.05 g (92%).
1H NMR (400 MHz, CDCl3): d = 2.51 (d, J = 9.7 Hz, 3 H, NCH3),
3.68 (d, J = 11.0 Hz, 6 H, OCH3), 4.16 (d, J = 8.9 Hz, 2 H, CH2),
7.24–7.22 (m, 5 H, Ph).
7.40–7.25 (m, 15 H, Ph).
Alkyl Halide Catalyzed Rearrangement of Phosphorimidates;
General Procedure I
In a 2-necked round-bottom flask the azide derivative was dissolved
in anhyd benzene or toluene (see Table 1) (0.3 mmol/mL) and phos-
phite (1.0 equiv) was added. The mixture was refluxed for 2 h. After
cooling to r.t. the alkyl halide was added to the formed phosphorim-
idate and the rearrangement was allowed to proceed at 80 °C or
110 °C for 4–8 h. The solvent was removed under reduced pressure
to give the crude product. Final purification by flash column chro-
matography (EtOAc–hexane, 3:1) afforded the pure product in 70–
90% yields.
13C NMR (101 MHz, CDCl3): d = 33.1 (d, J = 3.8 Hz, NCH3), 53.0
(d, J = 5.0 Hz, CH2), 53.1 (d, J = 5.8 Hz, OCH3), 127.4, 128.2,
128.5, 137.8 (d, J = 4.6 Hz) (Ph).
31P NMR (162 MHz, CDCl3): d = 13.59.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H17NO3P: 230.0946;
Alkyl Halide Catalyzed Rearrangement of Phosphinimidates;
General Procedure II
In a 2-necked round-bottom flask the azide derivative was dissolved
in anhyd benzene or toluene (see Table 1) (0.3 mmol/mL) and phos-
phinite (1 equiv) was added slowly. The mixture was stirred at r.t.
for 20 min and only in case of benzyl diphenylphosphinite refluxed
for 2 h to form the phosphinimidate. The alkyl halide was added to
the formed phosphinimidate and the rearrangement was allowed to
proceed at 80 °C or 110 °C for 4–8 h. The solvent was removed un-
found: 230.0949.
Diethyl N-Benzyl-N-ethylphosphoramidate (3b)
Prepared according to general procedure I from BnN3 (399 mg,
3.00 mmol) and P(OEt)3 (514 mL, 487 mg, 3.00 mmol) as a color-
less oil; yield: 570 mg (70%).
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

FEATURE ARTICLE
N,N-Disubstituted Phosphor- and Phosphinamidates
2717
1H NMR (400 MHz, CDCl3): d = 1.02–1.06 (m, 3 H, NCH3), 1.28–
1.32 (m, 6 H, OCH3), 2.99–3.00 (m, 2 H, NCH2), 3.97–4.11 (m,
4 H, OCH2), 4.21 (d, J = 9.6 Hz, 2 H, CH2), 7.23–7.24 (m, 5 H, Ph).
13C NMR (101 MHz, CDCl3): d = 13.3 (d, J = 1.5 Hz, NCH3), 16.3
(d, J = 7.3 Hz, OCH3), 39.5 (d, J = 3.8 Hz, NCH2), 48.7 (d,
J = 5.0 Hz, CH2), 62.3 (d, J = 5.8 Hz, OCH2), 127.3, 128.3, 128.5,
138.3 (d, J = 3.8 Hz) (Ph).
N,N-Dibenzyl-P,P-diphenylphosphinic Amide (5c)
Prepared according to general procedure II or IV from BnN3
(266 mg, 2.00 mmol) and Ph2POBn (557 mg, 2.00 mmol) as a col-
orless solid; yield: 103–604 mg (13–76%).
1H NMR (250 MHz, CDCl3): d = 4.04 (d, J = 10.0 Hz, 4 H,
CH2Ph), 7.24–8.02 (m, 20 H, Ph).
13C NMR (500 MHz, CDCl3): d = 48.6 (d, J = 3.6 Hz, CH2Ph,
127.2, 127.8, 128.4, 128.7 (d, J = 12.5 Hz), 128.9, 131.4, 131.6,
131.6, 131.9 (d, J = 2.6 Hz), 132.7 (d, J = 9.3 Hz), 136.6 (d,
J = 3.6 Hz) (Ph).
31P NMR (162 MHz, CD3CN): d = 31.69.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C26H25NOP: 398.1668;
31P NMR (162 MHz, CDCl3): d = 10.79.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C13H23NO3P: 272.1416;
found: 272.1413.
Dibenzyl N,N-Dibenzylphosphoramidate (3c)
Prepared according to general procedure I from BnN3 (399,
3.00 mmol) and P(OBn)3 (1.06 g, 3.00 mmol). A second column
chromatography (CH2Cl2) gave the product; yield: 975 mg (71%).
1H NMR (250 MHz, CDCl3): d = 4.17 (d, J = 10.3 Hz, 4 H, NCH2),
5.09 (d, J = 11.8, 7.4 Hz, 2 H, OCH2), 5.18 (d, J = 11.8, 7.4 Hz,
2 H, OCH2), 7.25–7.39 (m, 20 H, Ph).
found: 398.1350.
Diallyl N-Allyl-N-benzylphosphoramidate (3d)
Prepared according to general procedure III from BnN3 (399 mg,
3.00 mmol) and triallyl phosphite (607 mg, 3.00 mmol) as a color-
less oil; yield: 655 mg (71%).
13C NMR (101 MHz, CDCl3): d = 48.4 (d, J = 7.8 Hz, NCH2), 68.1
(d, J = 9.8 Hz, OCH2), 127.4, 127.7, 128.2, 128.4, 128.5, 128.7,
136.5 (d, J = 5.9 Hz), 137.3 (d, J = 13.7 Hz) (Ph).
31P NMR (162 MHz, CDCl3): d = 10.91.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C28H29NO3P: 458.1880;
found: 458.1901.
1H NMR (400 MHz, CD3CN): d = 3.45 (dd, J = 11.6, 6.4 Hz, 2 H,
NCH2), 4.17 (d, J = 10.2 Hz, 2 H, CH2Ph), 4.41–4.56 (m, 4 H,
OCH2), 5.11 (ddd, J = 17.1, 1.4 Hz, 1 H, CH2), 5.17 (ddd, J = 10.2,
1.6, 0.5 Hz, 1 H, CH2), 5.21 (ddd, J = 10.5, 2.8, 1.4 Hz, 2 H, CH2),
5.33 (ddd, J = 17.2, 1.6 Hz, 2 H, CH2), 5.74 (ddt, J = 16.6, 10.2,
6.4 Hz, 1 H, CH), 5.88–6.01 (m, 2 H, CH), 7.26–7.37 (m, 5 H, Ph).
13C NMR (101 MHz, CD3CN): d = 48.3 (d, J = 4.6 Hz, NCH2),
49.3 (d, J = 5.0 Hz, CH2Ph), 68.0 (d, J = 5.3 Hz, OCH2), 118.2 (pt,
J = 2.8 Hz, CH2), 119.1 (pt, J = 4.3 Hz, CH2), 128.4, 129.4, 129.5
(Ph), 134.12 (m, CH), 134.91 (m, CH), 138.54 (d, J = 3.3 Hz, Ph).
N-Benzyl-N-methyl-P,P-diphenylphosphinic Amide (5a)
Prepared according to general procedure II or IV from BnN3
(399 mg, 3.00 mmol) and Ph2POMe (602 mL, 648 mg, 3.00 mmol);
yield: 800 mg (83%) (GPII) and 838 mg (87%) (GPIV). If neces-
sary, the compound was recrystallized (toluene–hexane) to obtain
the pure product as a colorless solid.
1H NMR (400 MHz, CD3CN): d = 2.46 (d, J = 10.7 Hz, 3 H,
NCH3), 4.09 (d, J = 8.5 Hz, 2 H, NCH2), 7.25–7.31 (m, 1 H, Ph),
7.33–7.43 (m, 4 H, Ph), 7.47–7.59 (m, 6 H, Ph), 7.84–7.92 (m, 4 H,
Ph).
13C NMR (101 MHz, CD3CN): d = 34.1 (d, J = 3.0 Hz, NCH3),
53.3 (d, J = 3.1 Hz, NCH2), 128.2, 129.0, 129.4, 129.7 (d,
J = 12.3 Hz), 132.9 (d, J = 2.5 Hz), 133.1, 134.1 (d, J = 9.1 Hz),
139.0 (d, J = 5.9 Hz) (Ph).
31P NMR (162 MHz, CD3CN): d = 9.03.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C16H23NO3P: 308.1410;
found: 308.1424.
Dibutyl N-Benzyl-N-butylphosphoramidate (3e)
Prepared according to general procedure III from BnN3 (399 mg,
3.00 mmol) and P(OBu)3 (812 mL, 751 mg, 3.00 mmol) as a color-
less oil; yield: 693 mg (65%) and 768 mg (72%).
1H NMR (400 MHz, CD3CN): d = 0.83 (t, J = 7.4 Hz, 3 H, CH3),
0.90 (t, J = 7.4 Hz, 6 H, CH3), 1.19 (tq, J = 15.0, 7.6 Hz, 2 H, CH2),
1.40 (m, 6 H, CH2), 1.55–1.64 (m, 4 H, CH2), 2.76–2.84 (m, 2 H,
NCH2), 3.83–3.99 (m, 4 H, OCH2), 4.17 (d, J = 10.4 Hz, 2 H,
CH2Ph), 7.22–7.36 (m, 5 H, Ph).
13C NMR (101 MHz, CDCl3): d = 13.8 (CH3), 14.0 (CH3), 19.0
(CH2), 20.1 (CH2), 30.1 (CH2), 32.5 (d, J = 7.0 Hz, CH2), 44.9 (d,
J = 3.9 Hz, NCH2), 49.2 (d, J = 4.9 Hz, CH2Ph), 66.1 (d,
J = 5.8 Hz, OCH2), 127.3, 128.4, 128.5, 138.4 (d, J = 3.1 Hz) (Ph).
31P NMR (162 MHz, CD3CN): d = 30.38.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H21NOP: 322.1355;
found: 322.1381.
Anal. Calcd for C20H20NOP: C, 74.75; H, 6.27; N, 4.36. Found: C,
74.87; H, 6.316; N, 4.366.
31P NMR (162 MHz, CD3CN): d = 10.85.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H35NO3P: 356.2349;
N-Benzyl-N-ethyl-P,P-diphenylphosphinic Amide (5b)
Prepared according to general procedure II or IV from BnN3
(399 mg, 3.00 mmol) and Ph2POEt (648 mL, 691 mg, 3.00 mmol)
as a colorless oil; yield: 604 mg (60%) (GPII) and 513 mg (51%)
(GPIV).
1H NMR (400 MHz, CD3CN): d = 0.97 (t, J = 7.1 Hz, 3 H, CH3),
2.86 (dq, J = 10.7, 7.1 Hz, 2 H, NCH2), 4.18 (d, J = 10.3 Hz, 2 H,
CH2Ph), 7.23–7.28 (m, 1 H, Ph), 7.31–7.36 (m, 2 H, Ph), 7.42–7.46
(m, 2 H, Ph), 7.46–7.55 (m, 6 H, Ph), 7.85–7.95 (m, 4 H, Ph).
13C NMR (101 MHz, CD3CN): d = 13.5 (d, J = 3.7 Hz, CH3), 40.5
(d, J = 3.5 Hz, NCH2), 49.1 (d, J = 3.6 Hz, CH2Ph), 128.1, 129.2,
129.3, 129.6, 129.7, 132.8 (d, J = 2.7 Hz), 133.2 (d, J = 9.1 Hz),
133.8 (d, J = 127.9 Hz), 139.1 (d, J = 4.5 Hz) (Ph).
found: 356.2356.
Dimethyl N-Methyl-N-(4-nitrophenyl)phosphoramidate (3f)
Prepared according to general procedure III from 4-nitrophenyl
azide (492 mg, 3.00 mmol) and P(OMe)3 (354 mL, 372 mg,
3.00 mmol) as a colorless solid; yield: 663 mg (85%).
1H NMR (400 MHz, CD3CN): d = 3.23 (d, J = 8.2 Hz, 3 H, NCH3),
3.69 (d, J = 11.5 Hz, 6 H, OCH3), 7.43 (d, J = 9.2 Hz, 2 H, Ph), 8.12
(d, J = 8.9 Hz, 2 H, Ph).
13C NMR (101 MHz, CD3CN): d = 36.5 (d, J = 3.7 Hz, NCH3),
54.1 (d, J = 5.3 Hz, OCH3), 120.0 (d, J = 4.6 Hz), 125.4, 143.1,
151.4 (d, J = 6.0 Hz) (Ph).
31P NMR (162 MHz, CD3CN): d = 7.59.
31P NMR (162 MHz, CD3CN): d = 29.81.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C21H23NOP: 336.1512;
found: 336.1543.
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

2718
I. Wilkening et al.
FEATURE ARTICLE
N-Ethyl-N,P,P-triphenylphosphinic Amide (5e)
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H14N2O5P: 261.0635;
found: 261.0657.
Prepared according to general procedure IV from PhN3 (357 mg,
3.00 mmol) and Ph2POEt (648 mL, 691 mg, 3.00 mmol) as a color-
less oil; yield: 347 mg (36%). In case of small amounts of Ph2POEt
in the product, analytical amounts phosphinamidate can be further
purified by HPLC as described above.
1H NMR (400 MHz, CD3CN): d = 1.01 (t, J = 7.1 Hz, 3 H, CH3),
3.43 (dq, J = 10.7, 7.1 Hz, 2 H, CH2), 7.01–7.08 (m, 1 H, Ph), 7.16–
7.24 (m, 2 H, Ph), 7.36–7.45 (m, 8 H, Ph), 7.87–7.95 (m, 4 H, Ph).
13C NMR (101 MHz, CD3CN): d = 15.1 (d, J = 3.0 Hz, CH3), 46.8
(d, J = 3.6 Hz, CH2), 126.4, 129.3 (d, J = 7.1 Hz), 129.4, 129.8,
132.5, 133.3 (d, J = 8.9 Hz), 133.7 (d, J = 129.3 Hz), 144.1 (d,
J = 1.3 Hz) (Ph).
Dimethyl N-(4-Methoxyphenyl)-N-methylphosphoramidate
(3g)
Prepared according to general procedure III from 4-methoxyphenyl
azide (447 mg, 3.00 mmol) and P(OMe)3 (354 mL, 372 mg,
3.00 mmol) as a colorless oil; yield: 647 mg (88%).
1H NMR (400 MHz, CDCl3): d = 3.10 (d, J = 9.0 Hz, 3 H, NCH3),
3.69 (d, J = 11.2 Hz, 6 H, POCH3), 3.76 (s, 3 H, OCH3), 6.79–6.85
(m, 2 H, Ph), 7.15–7.20 (m, 2 H, Ph).
13C NMR (101 MHz, CDCl3): d = 38.2 (d, J = 5.2 Hz, NCH3), 53.3
(d, J = 5.7 Hz, POCH3), 55.5 (OCH3), 114.4 (Ph), 125.6 (d,
J = 3.7 Hz), 137, 156.96 (d, J = 4.2 Hz).
31P NMR (162 MHz, CD3CN): d = 25.07.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C20H21NOP: 322.1355;
31P NMR (162 MHz, CDCl3): d = 9.83.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C10H17NO4P: 246.0890;
found: 322.1375.
found: 246.0868.
N-Benzyl-N,P,P-triphenylphosphinic Amide (5f)
Prepared according to general procedure IV from PhN3 (357 mg,
3.00 mmol) and Ph2POBn (877 mg, 3.00 mmol) as a colorless solid;
maximum yield: 288 mg (25%).
(2R,3S,4R,5R,6R)-5-Acetamido-3,4-diacetoxy-2-(acetoxymeth-
yl)-6-[(dimethoxyphosphoryl)(methyl)amino]tetrahydro-2H-
pyran (3h)
Prepared according to general procedure III from 2-acetamido-
3,4,6-tri-O-acetyl-2-deoxy-b-D-glucopyranosyl azide (50.0 mg,
0.134 mmol) and P(OMe)3 (15.0 mL, 16.0 mg, 0.134 mmol); for
solubility reasons benzene (1.5 mL) was used as solvent with addi-
tional MeCN (200 mL) to give the product as a white solid; yield:
37.1 mg (67%).
1H NMR (400 MHz, CD3CN): d = 1.90 (s, 3 H, CH3), 2.01 (s, 3 H,
CH3), 2.05 (s, 6 H, CH3), 2.63 (d, J = 9.2 Hz, 3 H, NCH3), 3.67 (d,
J = 11.3 Hz, 3 H, OCH3), 3.71 (d, J = 11.5 Hz, 3 H, OCH3), 3.87
(ddd, J = 10.1, 4.5, 3.6 Hz, 1 H, CH), 4.18 (m, 1 H, CH), 4.19 (d,
J = 1.1 Hz, 1 H, CH), 4.34 (dd, J = 10.0 Hz, 1 H, CH), 4.86 (dd,
J = 9.7, 8.9 Hz, 1 H, CH), 5.01 (dd, J = 9.8 Hz, 1 H, CH), 5.21 (dd,
J = 9.9 Hz, 1 H, CH).
13C NMR (101 MHz, CD3CN): d = 19.7 (CH3), 19.7 (CH3), 19.8
(CH3), 21.8 (CH3), 26.6 (d, J = 2.7 Hz, NCH3), 49.8 (d, J = 7.4 Hz,
C2), 52.5 (d, J = 4.8 Hz, OCH3), 52.7 (d, J = 4.9 Hz, OCH3), 62.3
(C6), 68.7 (C4), 73.2 (C3), 73.5 (C5), 85.1 (d, J = 6.8 Hz, C1),
169.9 (C=O), 170.4 (C=O), 170.7 (C=O), 171.1 (C=O).
31P NMR (162 MHz, CD3CN): d = 12.94.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C17H30N2O11P:
1H NMR (250 MHz, CDCl3): d = 4.59 (d, J = 9.1 Hz, 2 H, CH2),
6.86–7.39 (m, 15 H, Ph), 7.86–7.94 (m, 5 H, Ph).20
13C NMR (101 MHz, CDCl3): d = 54.8 (d, J = 3.1 Hz, CH2), 125.2,
127.1, 127.9, 128.1 (d, J = 4.6 Hz), 128.3, 128.4, 128.5, 128.7,
128.9, 131.5, 131.6 (d, J = 3.1 Hz), 132.6, 132.7 (d, J = 9.2 Hz),
137.5 (d, J = 4.6 Hz), 142.8 (Ph).
31P NMR (162 MHz, CDCl3): d = 27.38.
Dimethyl N-Cinnamyl-N-methylphosphoramidate (3i)
Prepared according to general procedure V from cinnamyl bromide
(985 mg, 5.00 mmol) as a pale-yellow oil; yield 1.02 g (80%).
1H NMR (400 MHz, CDCl3): d = 2.58 (d, J = 9.7 Hz, 3 H, NCH3),
3.63 (d, J = 11.1 Hz, 6 H, OCH3), 3.69 (ddd, J = 10.0, 6.5, 0.9 Hz,
2 H, NCH2), 6.07 (dt, J = 15.8, 6.6 Hz, 1 H, CH), 6.46 (d,
J = 15.9 Hz, 1 H, CH), 7.14–7.31 (m, 5 H, Ph).
13C NMR (101 MHz, CDCl3): d = 33.0 (d, J = 3.9 Hz, NCH3), 51.1
(d, J = 4.5 Hz, NCH2), 52.8 (d, J = 5.8 Hz, OCH3), 125.6 (d,
J = 3.6 Hz, CH), 126.2, 127.5, 128.4, (Ph), 132.7 (CH), 136.4 (Ph).
31P NMR (162 MHz, CD3CN): d = 13.45.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H19NO3P: 256.1097;
469.1582; found: 469.1598.
found: 256.1112.
N-Methyl-N,P,P-triphenylphosphinic Amide (5d)
Prepared according to general procedure IV from PhN3 (357 mg,
3.00 mmol) and Ph2POMe (602 mL, 649 mg, 3.00 mmol) as a col-
orless oil; yield: 691 mg (75%). The product contained small
amounts (~6%) of Ph2POMe and analytical amount can be further
purified by HPLC (0–5 min 100% H2O, 5–45 min 0% MeCN to
100% MeCN).
1H NMR (400 MHz, CD3CN): d = 3.02 (d, J = 9.9 Hz, 3 H, CH3),
6.97–7.03 (m, 1 H, Ph), 7.15–7.22 (m, 2 H, Ph), 7.33–7.39 (m, 2 H,
Ph), 7.38–7.49 (m, 6 H, Ph), 7.83–7.90 (m, 4 H, Ph).
13C NMR (101 MHz, CD3CN): d = 39.5 (d, J = 4.3 Hz, CH3),
125.4, 126.2 (d, J = 5.1 Hz), 129.5 (d, J = 12.5 Hz), 129.8, 132.7 (d,
J = 2.7 Hz), 133.3 (d, J = 9.1 Hz), 133.7 (d, J = 129.0 Hz), 147.2 (d,
J = 2.5 Hz) (Ph).
Dimethyl N-Allyl-N-methylphosphoramidate (3j)
Prepared according to general procedure V from allyl bromide
(434 mL, 605 mg, 5.00 mmol) as a colorless oil; yield: 457 mg
(51%).
1H NMR (400 MHz, CD3CN): d = 2.56 (d, J = 9.6 Hz, 3 H, NCH3),
3.54–3.60 (m, 2 H, CH2), 3.59 (d, J = 11.1 Hz, 6 H, OCH3), 5.17
(ddtd, J = 10.2, 1.8, 1.3, 0.6 Hz, 1 H, CH2), 5.22 (ddd, J = 17.2, 3.2,
1.6 Hz, 1 H, CH2), 5.79 (ddt, J = 17.1, 10.2, 6.1 Hz, 1 H, CH).
13C NMR (101 MHz, CD3CN): d = 33.4 (d, J = 3.9 Hz, NCH3),
52.3 (d, J = 4.6 Hz, NCH2), 53.3 (d, J = 5.5 Hz, OCH3), 117.7–
117.8 (m, CH2), 135.8–135.9 (m, CH).
31P NMR (162 MHz, CD3CN): d = 13.44.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C6H15NO3P: 180.0784;
found: 180.0782.
31P NMR (162 MHz, CD3CN): d = 25.45.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C19H19NOP: 308.1199;
found: 308.1223.
Dimethyl N-Methyl-N-(3-phenylpropyl)phosphoramidate (3k)
Prepared according to general procedure V from 3-phenylpropyl
bromide (754 mL, 995 mg, 5.00 mmol) as a colorless oil; yield:
104 mg (81%).
Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York

FEATURE ARTICLE
N,N-Disubstituted Phosphor- and Phosphinamidates
2719
1H NMR (400 MHz, CD3CN): d = 1.72–1.85 (m, 2 H, CH2), 2.58
(t, J = 7.9 Hz, 2 H, CH2), 2.59 (d, J = 9.7 Hz, 3 H, NCH3), 2.94–
3.04 (m, 2 H, CH2), 3.56 (d, J = 11.1 Hz, 6 H, OCH3), 7.12–7.31
(m, 5 H, Ph).
Nakashima, D.; Yamamoto, H. Angew. Chem. Int. Ed. 2008,
47, 2411. (e) Nakashima, D.; Yamamoto, H. J. Am. Chem.
Soc. 2006, 128, 9626. (f) Rueping, M.; Azap, C. Angew.
Chem. Int. Ed. 2006, 45, 7832. (g) Rueping, M.;
Ieawsuwan, W.; Antonchick, A. P.; Nachtsheim, B. J.
Angew. Chem. Int. Ed. 2007, 46, 2097. (h) Rueping, M.;
Nachtsheim, B. J.; Moreth, S. A.; Bolte, M. Angew. Chem.
Int. Ed. 2008, 47, 593. (i) Lee, E. E.; Batey, R. A. J. Am.
Chem. Soc. 2005, 127, 14887.
13C NMR (400 MHz, CD3CN): d = 30.8 (d, J = 2.6 Hz, CH2), 33.6
(CH2), 33.7 (d, J = 3.8 Hz, NCH3), 49.5 (d, J = 4.1 Hz, NCH2), 52.3
(d, J = 5.4 Hz, OCH3), 126.8, 129.3, 129.3, 143.2 (Ph).
31P NMR (162 MHz, CD3CN): d = 13.78.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C12H21NO3P: 258.1254;
found: 258.1283.
(2) (a) Wilkening, I.; del Signore, G.; Hackenberger, C. P. R.
Chem. Commun. 2011, 47, 349. (b) Bartlett, P. A.;
Marlowe, C. K. Biochemistry 1983, 22, 4618. (c) Jacobsen,
N. E.; Bartlett, P. A. J. Am. Chem. Soc. 1981, 103, 654.
(d) Mookhtiar, K. A.; Marlowe, C. K.; Bartlett, P. A.;
Vanwart, H. E. Biochemistry 1987, 26, 1962.
Dimethyl N-Hexyl-N-methylphosphoramidate (3l)
Prepared according to general procedure V from 1-bromohexane
(702 mL, 820 mg, 5.00 mmol) in DMF (10 mL) as a colorless oil;
yield: 447 mg (40%).
1H NMR (400 MHz, CDCl3): d = 0.83 (t, J = 6.7 Hz, 3 H, CH3),
1.24 (m, 6 H, CH2), 1.39–1.52 (m, 2 H, CH2), 2.59 (d, J = 9.9 Hz,
3 H, NCH3), 2.88–2.98 (m, 2 H, NCH2), 3.61 (d, J = 11.0 Hz, 6 H,
OCH3).
13C NMR (101 MHz, CDCl3): d = 14.1 (CH3), 22.7 (CH2), 26.3
(CH2), 28.1 (d, J = 2.6 Hz, CH2), 31.6 (CH2), 33.3 (d, J = 4.0 Hz,
NCH3), 49.2 (d, J = 3.8 Hz, NCH2), 52.9 (d, J = 5.7 Hz, OCH3).
31P NMR (162 MHz, CDCl3): d = 13.91.
(e) Radkiewicz, J. L.; McAllister, M. A.; Goldstein, E.;
Houk, K. N. J. Org. Chem. 1998, 63, 1419. (f) Grembecka,
J.; Mucha, A.; Cierpicki, T.; Kafarski, P. J. Med. Chem.
2003, 46, 2641. (g) Holden, H. M.; Tronrud, D. E.;
Monzingo, A. F.; Weaver, L. H.; Matthews, B. W.
Biochemistry 1987, 26, 8542. (h) Izquierdo-Martin, M.;
Stein, R. L. J. Am. Chem. Soc. 1992, 114, 1527.
(3) (a) Adelfinskaya, O.; Herdewijn, P. Angew. Chem. Int. Ed.
2007, 46, 4356. (b) Perrone, P.; Daverio, F.; Valente, R.;
Rajyaguru, S.; Martin, J. A.; Leveque, V.; Le Pogam, S.;
Najera, I.; Klumpp, K.; Smith, D. B.; McGuigan, C. J. Med.
Chem. 2007, 50, 5463. (c) Roman, C. A.; Balzarini, J.;
Meier, C. J. Med. Chem. 2010, 53, 7675. (d) Siddiqui, A.
Q.; McGuigan, C.; Ballatore, C.; Zuccotto, F.; Gilbert, I. H.;
De Clercq, E.; Balzarini, J. J. Med. Chem. 1999, 42, 4122.
(e) Tobias, S. C.; Borch, R. F. J. Med. Chem. 2001, 44, 4475.
(4) (a) Serwa, R.; Wilkening, I.; Del Signore, G.; Mühlberg, M.;
Claussnitzer, I.; Weise, C.; Gerrits, M.; Hackenberger, C. P.
R. Angew. Chem. Int. Ed. 2009, 48, 8234. (b) Böhrsch, V.;
Serwa, R.; Majkut, P.; Krause, E.; Hackenberger, C. P. R.
Chem. Commun. 2010, 46, 3176. (c) Serwa, R.; Majkut, P.;
Horstmann, B.; Swiecicki, J. M.; Gerrits, M.; Krause, E.;
Hackenberger, C. P. R. Chem. Sci. 2010, 1, 596. (d) Serwa,
R.; Swiecicki, J.-M.; Homann, D.; Hackenberger, C. P. R.
J. Pept. Sci. 2010, 16, 563. (e) Jaradat, D. M. M.; Hamouda,
H.; Hackenberger, C. P. R. Eur. J. Org. Chem. 2010, 5004.
(5) (a) Das, S.; Das, U.; Selvakumar, P.; Sharma, R. K.;
Balzarini, J.; De Clercq, E.; Molnar, J.; Serly, J.; Barath, Z.;
Schatte, G.; Bandy, B.; Gorecki, D. K. J.; Dimmock, J. R.
ChemMedChem 2009, 4, 1831. (b) Ramage, R.; Hopton, D.;
Parrott, M. J.; Richardson, R. S.; Kenner, G. W.; Moore, G.
A. J. Chem. Soc., Perkin Trans. 1 1985, 461.
HRMS (ESI-TOF): m/z [M + H]+ calcd for C9H23NO3P: 224.1410;
found: 224.1455.
Dimethyl N-{2-[2-(2-Methoxyethoxy)ethoxy]ethyl}-N-methyl-
phosphoramidate (3m)
Prepared according to general procedure V from 2-[2-(2-methoxy-
ethoxy)ethoxy]ethyl 4-toluenesulfonate (318 mg, 1.00 mmol),
P(OMe)3 (118 mL, 124 mg, 1.00 mmol), NaN3 (72.0 mg,
1.10 mmol), and KI (6.60 mg, 39.7 mmol, 4 mol%) in MeCN
(3 mL) with BF3·OEt2 (10 mol%) in MeCN (50 mL). Purification by
column chromatography (EtOAc to EtOAc–10% MeOH) gave the
product as a colorless oil; yield: 174 mg (61%).
1H NMR (400 MHz, CD3CN): d = 2.64 (d, J = 9.5 Hz, 3 H, NCH3),
3.14 (dt, J = 10.5, 5.7 Hz, 2 H, NCH2), 3.28 (s, 3 H, OCH3), 3.43–
3.46 (m, 2 H, CH2), 3.50–3.55 (m, 8 H, CH2), 3.59 (d, J = 11.1 Hz,
6 H, POCH3).
13C NMR (101 MHz, C6D6): d = 34.3 (d, J = 3.6 Hz, NCH3), 49.0
(d, J = 4.6 Hz, NCH2), 52.5 (d, J = 5.4 Hz, OCH3P), 58.7 (OCH3),
70.2 (d, J = 2.5 Hz, CH2), 70.6 (d, J = 1.3 Hz, CH2), 70.8 (CH2),
71.0 (CH2), 72.4 (CH2).
31P NMR (162 MHz, CD3CN): d = 13.66.
HRMS (ESI-TOF): m/z [M + Na]+ calcd for C10H24NNaO6P:
(6) (a) Popovici, C.; Ona-Burgos, P.; Fernandez, I.; Roces, L.;
Garcia-Granda, S.; Iglesias, M. J.; Ortiz, F. L. Org. Lett.
2010, 12, 428. (b) Ruiz-Gomez, G.; Iglesias, M. J.; Serrano-
Ruiz, M.; Garcia-Granda, S.; Francesch, A.; Lopez-Ortiz, F.;
Cuevas, C. J. Org. Chem. 2007, 72, 3790.
308.1233; found: 308.1240.
(7) Staudinger, H. Helv. Chim. Acta 1919, 2, 635.
(8) (a) Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48,
1353. (b) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L.
F. Tetrahedron 1981, 37, 437. (c) Gololobov, Y. G.;
Kasukhin, L. F.; Petrenko, V. S. Phosphorus, Sulfur Silicon
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Acknowledgment
The authors acknowledge financial support from the German Sci-
ence Foundation (Emmy-Noether program, HA 4468/2-1), the SFB
765, the Max-Buchner Stiftung, the Fonds der chemischen Industrie
(FCI) and the Boehringer-Ingelheim Foundation within the ‘Plus 3’
program.
(9) Kohn, M.; Breinbauer, R. Angew. Chem. Int. Ed. 2004, 43,
3106.
(10) (a) Lin, F. L.; Hoyt, H. M.; van Halbeek, H.; Bergman, R.
G.; Bertozzi, C. R. J. Am. Chem. Soc. 2005, 127, 2686.
(b) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007.
(c) Saxon, E.; Luchansky, S. J.; Hang, H. C.; Yu, C.; Lee, S.
C.; Bertozzi, C. R. J. Am. Chem. Soc. 2002, 124, 14893.
(11) Wilkening, I.; del Signore, G.; Hackenberger, C. P. R.
Chem. Commun. 2008, 2932.
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Synthesis 2011, No. 17, 2709–2720 © Thieme Stuttgart · New York