Investigation of reactive intermediates and reaction pathways in the coupling agent mediated phosphonamidation reaction

Article abstract of DOI:10.1002/ejoc.201501244

The preparation of carboxamides through the coupling agent mediated reaction of carboxylic acids and amines is one of the most frequently employed reaction types of modern organic synthesis and has largely replaced older methods of amide formation based on reactive acyl chloride intermediates. However, the preparations of analogous phosphonamidates still rely on the use of phosphonochloridate intermediates - a method that is incompatible with sensitive functional groups. Herein, we present a comprehensive study in which different coupling agents are tested in the phosphonamidation reaction. The procedures, parallel to those typically applied to the preparation of carboxamides, were generally unsuccessful with regard to the coupling reactions of monoesters of phosphonic acids and amines, with the exception of those mediated by (benzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyBOP). The implementation of a preactivation period in the absence of the amine coupling partner allowed for efficient phosphonamidate formation with coupling agents such as (1-cyano-2-ethyoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU), [ethyl cyano(hydroxyimino)acetato-O²]tri-1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), dicyclohexyl carbodiimide (DCC), N,N′-diisopropylcarbodiimide (DIC), and N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate (HBTU). The reactive intermediates observed by ³¹P NMR analysis were individually synthesized and examined to understand their influence on the reaction. A phosphonamidation reaction that uses (1-cyano-2-ethyoxy-2-oxoethylideneaminooxy)dimethylamino-morpholino-carbenium hexafluorophosphate (COMU) to mediate the coupling of monoalkyl esters of phosphonic acids and amines was developed. A preactivation period without the amine was needed to obtain the product. Using this step allowed for other coupling agents to be successfully used in the reaction.

Full text of DOI:10.1002/ejoc.201501244

DOI: 10.1002/ejoc.201501244
Full Paper
Phosphonamidation Reactions
Investigation of Reactive Intermediates and Reaction Pathways
in the Coupling Agent Mediated Phosphonamidation Reaction
Kim Alex Fredriksen[a] and Mohamed Amedjkouh*[a]
Abstract: The preparation of carboxamides through the coup- acids and amines, with the exception of those mediated by
(benzotriazol-1-yloxy)tripyrrolidinophosphonium
hexafluoro-
ling agent mediated reaction of carboxylic acids and amines is
one of the most frequently employed reaction types of modern
organic synthesis and has largely replaced older methods of
amide formation based on reactive acyl chloride intermediates.
However, the preparations of analogous phosphonamidates still
rely on the use of phosphonochloridate intermediates – a
method that is incompatible with sensitive functional groups.
Herein, we present a comprehensive study in which different
coupling agents are tested in the phosphonamidation reaction.
The procedures, parallel to those typically applied to the prepa-
ration of carboxamides, were generally unsuccessful with re-
gard to the coupling reactions of monoesters of phosphonic
phosphate (PyBOP). The implementation of a preactivation pe-
riod in the absence of the amine coupling partner allowed for
efficient phosphonamidate formation with coupling agents
such as (1-cyano-2-ethyoxy-2-oxoethylideneaminooxy)dimeth-
ylamino-morpholino-carbenium hexafluorophosphate (COMU),
[ethyl
cyano(hydroxyimino)acetato-O2]tri-1-pyrrolidinylphos-
phonium hexafluorophosphate (PyOxim), dicyclohexyl carbo-
diimide (DCC), N,N′-diisopropylcarbodiimide (DIC), and
N,N,N′,N′-tetramethyl-O-(1H-benzotriazol-1-yl)uronium
fluorophosphate (HBTU). The reactive intermediates observed
by 31P NMR analysis were individually synthesized and exam-
ined to understand their influence on the reaction.
hexa-
Introduction
cised when preparing lower molecular weight phosphonochlor-
idates to avoid the formation of highly neurotoxic substances,
structurally similar to chemical warfare agents.[3]
Amide bond-forming reactions are among the most important
tools in a synthetic organic chemist's toolbox. Carboxamides
are, by far, the most studied among the different classes of
amides and are frequently encountered in organic compounds
that range from complex natural products to high-strength pol-
ymer fibers. Unlike the rapidly interconverting, pseudoplanar
geometry of carboxamides, the geometry of phosphonamid-
ates, in which the nitrogen atom is bonded to a phospho-
rus(V) instead of a carbon atom, is tetrahedral, making the
phosphorus atom a stereogenic center. Phosphonamidates
have attracted interest in various areas of organic chemistry for
their potential as structural scaffolds in medicinal chemistry,
and in many cases, the tetrahedral geometry around the phos-
phorus atom is of key importance.[1] The commonly employed
strategy for the formation of such phosphonamidates involves
the aminolysis of phosphonochloridates, which in turn are avail-
able from either phosphonates (mono- or diesters of phos-
phonic acid) or phosphites (Scheme 1).[1d,2] Although this strat-
egy has been successfully used to prepare phosphonochlor-
Scheme 1. Preparation of phosphonamidates by employing phosphono-
chloridates.
Phosphonamidates can also be prepared from phosphor-
idates from simple starting materials, the reaction conditions us(III) species through a late-stage oxidation to give phosphor-
are commonly incompatible with sensitive functional groups or us(V).[4] Reports detailing phosphonamidate formation medi-
labile stereogenic centers. In addition, caution must be exer- ated by coupling agents are scarce. To the best of our knowl-
edge, Burger and Anderson reported in as early as 1957 the
[a] Department of Chemistry, University of Oslo,
first successful coupling agent mediated phosphonamidation
reaction between monoesters of phosphonic acids and amines
Postboks 1033, Blindern, 0315 Oslo, Norway
E-mail: mamou@kjemi.uio.no
http://www.mn.uio.no/kjemi
Supporting information for this article is available on the WWW under
by using dicyclohexyl carbodiimide (DCC) as the coupling
agent.[5] Nevertheless, this report appears to have been over-
http://dx.doi.org/10.1002/ejoc.201501244.
looked by most researchers in the field, which may partly ex-
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plain the lack of successful phosphonamidation reactions. Re- investigating the scope and limitations of the described meth-
grettably, we became aware of this article at a late stage of ods. This observation prompted us to undertake a systematic
our study. In Burger and Andersons work, DCC was reportedly study of the phosphonamidate coupling reaction to gain in-
capable of generating activated species such as pyrophosphon- sight into its key features and reactive intermediates that are
ates, and notably, the order of addition of the reagents was involved in its mechanism. Furthermore, these results would
found to be critical.[6] Years later, and perhaps unaware of the benefit the development of a more general protocol for the
work by Burger and Andersons,[5] Imoto and co-workers were synthesis of phosphonamidates by using standard peptide
unsuccessful in their attempt to use DCC to facilitate a phos- coupling reagents.
phonamidation reaction.[7] Martell and co-workers experienced
similar difficulties with the use of DCC to mediate a P–N bond
formation.[8]
With the introduction of tris(alkylamino)phosphonium coup-
ling agents, Dumy and co-workers demonstrated that both
Results and Discussion
(benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexa-
fluorophosphate (BOP) and (benzotriazol-1-yloxy)tripyrrolidino-
phosphonium hexafluorophosphate (PyBOP) could facilitate a
phosphonamidation reaction.[9] Coste and co-workers adopted
their method a few years later in a publication primarily di-
rected towards the synthesis of mixed phosphonates.[10] Nota-
bly, the approach shared by the two reports, encompasses a
narrow substrate scope, and only four products were isolated
in the moderate yields of 60–65 %.
In the context of solid phase synthesis, another successful
P–N bond formation mediated by N,N′-diisopropylcarbodiimide
(DIC), also a carbodiimide coupling agent, in the presence of
1-hydroxy-7-azabenzotriazole (HOAt) as an additive has been
reported by Kitamura and Ishibashi.[11] Notably, their attempts
to use PyBOP among other coupling agents gave poor re-
sults.[12]
In the course of our studies, we examined several types of
coupling agents in the phosphonamidation reaction between
monoalkyl esters of benzylphosphonic acid and amines, includ-
ing carbodiimides DCC and DIC[13] and the 1-hydroxybenzotri-
azole (HOBt)-based coupling agents PyBOP and N,N,N′,N′-tetra-
methyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate
(HBTU)[14] as well as [ethyl cyano(hydroxyimino)acetato-O2]tri-
1-pyrrolidinylphosphonium hexafluorophosphate (PyOxim), and
(1-cyano-2-ethyoxy-2-oxoethylideneaminooxy)dimethylamino-
morpholino-carbenium hexafluorophosphate (COMU),[15] – two
recently reported coupling agents based on ethyl 2-cyano-2-
(hydroxyimino)acetate (Oxyma, Figure 1).[16] The initial phos-
phonamidation reactions were carried out with readily available
starting materials in procedures that are typically employed for
analogous carboxylic acids.
To our surprise, only PyBOP efficiently mediated the conver-
It is surprising to observe the limited number of successful sion of phosphonic acid derivative 1a into the corresponding
coupling agent mediated preparative methods for phosphona- product, whereas the reactions with the other coupling agents
midates in the literature. The few available reports appear to resulted in either trace amounts of product or no conversion
have focused on the synthesis of target molecules rather than (Table 1).
Figure 1. Coupling agents and additives investigated in this work.
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Table 1. Screening of coupling agents in the phosphonamidation reaction by
using literature procedures.
Oxim (Table 1, Entry 7) as an alternative to COMU (Table 1,
Entry 6) to investigate whether the outcome of these reactions
could be affected by the choice of the activator group (i.e.,
phosphonium vs. guanidinium/uronium) rather than by the
identity of the leaving group [OBt or Oxyma anion, Figure 1].
PyOxim and PyBOP are both activated by the tripyrrolidino-
phosphonium group, but they were expected to generate dif-
ferent activated phosphonates after the initial activation steps.
PyBOP should give OBt-phosphonate 3a and 3b, and PyOxim
is expected to give Oxyma-phosphonate 4 (Figure 2).[19] This
change, however, had no significant effect on the outcome of
the phosphonamidation reaction, and the result obtained by
PyOxim was comparable to that with COMU (Table 1, Entries 6
and 7). This indicates that the structure of the activator group
alone cannot fully explain the results presented in Table 1. As
for the DCC- and DIC-mediated phosphonamidation reactions,
no product formation was observed in either the presence or
absence of HOBt.[20]
Entry
Coupling agent
[1.15 equiv.]
Additive
[0.5 equiv.]
Conversion [%][a]
1[b]
2
3
PyBOP
HBTU
DCC
–
–
–
>95
trace
0
4
DIC
–
0
5
DCC
COMU
PyOxim
HOBt
–
–
0
6[b]
7
trace
trace
[a] Conversion was measured by 31P NMR analysis of the crude reaction mix-
ture. [b] Similar results were obtained when cyclohexylamine was replaced
with BnNH2.
Notably, in the attempted COMU-mediated coupling reac-
tion, the major isolated product was stable guanidinium salt 6
rather than phosphonamidate 2. The direct reaction between
the coupling agent and the amine had occurred instead
(Scheme 2).[17] The extent of formation of this byproduct sug-
gests that the amine is significantly more reactive than phos-
phonic acid derivative 1a towards COMU.
Figure 2. Different activated phosphonates; OBt = benzotriazolyl)oxy).
As our initial results suggest, the structures of both the acti-
vator and leaving groups of the coupling agents are important,
but their roles are not easily rationalized. In this context, it is
important to acknowledge that the development of coupling
agents has focused on amidation reactions of carboxylic acids
and not of other acids, such as phosphonic acids. Phosphonic
acids are stronger acids than their carboxylic acid counterparts,
and subsequently the phosphonic acid anion formed upon de-
protonation should be less nucleophilic than a carboxylate. In
addition, the phosphonic acid anion is sterically congested,
which may contribute to its low nucleophilicity.[21]
The inability of most of the examined coupling agents to
facilitate the phosphonamidation reaction led us to investigate
the reaction further. Thus, we sought to explore the possibility
of using a non-hydroxybenzotriazole-based coupling agent to
facilitate the reaction because of the intrinsic risks associated
with this class of compounds.[22] Both COMU and PyOxim fulfill
this requirement, as their structures contain the less hazardous
Oxyma oxime (Figure 1).[16]
Scheme 2. A preactivation strategy was necessary to avoid the side reaction
between the amine and COMU.
We were intrigued by the apparent significance of the activa-
tor group (i.e., phosphonium, guanidinium, and uronium) of a
given coupling agent on the outcome of the reaction and espe-
cially by the difference in the results obtained by PyBOP
(Table 1, Entry 1) and HBTU (Table 1, Entry 2).[18] After the initial
To avoid the aforementioned unproductive side reaction be-
activation steps, both PyBOP and HBTU should give rise to the tween COMU and the amine, we opted for a preactivation strat-
same benzotriazolylphosphonates 3a and 3b (Figure 2), which egy, in which phosphonic acid derivative 1a, the base, and
in turn should undergo aminolysis to furnish phosphonamidate COMU were stirred for 3 h prior to the aminolysis (Scheme 2).
2. Notably, only PyBOP gave the product in appreciable yields, This approach increased the conversion of 1a into product 2
and, therefore, the difference in the outcome of the two reac- from the trace amounts obtained by the original procedure to
tions may indicate a mechanistic difference in the activation 69 % with the preactivation strategy, as measured by 31P NMR
steps. In light of this observation, we decided to evaluate Py- analysis of the crude reaction mixture (Scheme 2).
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In the 31P NMR spectrum of the reaction mixture from the version of 5 into both product 8 and anion 1b was observed.
preactivation step, three main species along with unconsumed Product 8 was afforded in 74 % conversion from 5. Thus, to
starting material were observed (Scheme 3). The signals were achieve high conversion into the desired product, it was neces-
confirmed to stem from Oxyma-phosphonate 4 and a diastereo- sary to limit the formation of pyrophosphonates 5a and 5b
meric mixture of pyrophosphonates 5a and 5b by comparison during the preactivation step. This is important because anion
of the spectroscopic data with that of separately synthesized 1b, which is produced from the aminolysis reaction of pyro-
material. Compounds 4, 5a, and 5b could be synthesized sepa- phosphonates 5a and 5b, is significantly less reactive towards
rately by adding either Oxyma/Et3N or phosphonic acid deriva- COMU than the amine. This leaves most of anion 1b unable to
tive 1a/Et3N to freshly prepared batches of phosphono- reactivate, as the coupling agent is irreversibly consumed by
chloridate 7 (Scheme 3).
the formation of guanidinium salt 9 (Scheme 4).
In a control experiment, we could demonstrate that pyro-
When the preactivation protocol was attempted with PyBOP
phosphonates 5a and 5b were capable of undergoing an ami- instead of COMU, a higher concentration of pyrophosphonates
nolysis reaction with both cyclohexylamine and BnNH2 in the 5a and 5b relative to the activated phosphonate (i.e., 4 or 3a)
absence of a coupling agent, additive, or base to generate was measured. When PyBOP was used, the ratio of 5a/5b was
phosphonamidates 2 and 8 with 42 % conversion and the si- approximately 1:1 prior to the aminolysis compared to a ratio
multaneous release of anion 1b. This control experiment was of 1:0.8 with COMU. However, a significant amount of uncon-
deemed necessary for our study because of the existence of sumed starting material was observed in the crude reaction
contradicting reports with regard to the reactivity of other pyro- mixture with COMU, which suggests that a longer preactivation
phosphonates towards amines.[23] When Oxyma-phosphonate period is required. Unlike the phosphonamidation reaction me-
4 was subjected to an aminolysis reaction with BnNH2, full con- diated by COMU, the resulting preactivation mixture that con-
Scheme 3. All reactive intermediates observed in the crude mixture of the preactivation step were synthesized separately to confirm their presence in the
reaction mixture and map their reactivity in the phosphonamidation reaction.
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Scheme 5. PyBOP is more capable than COMU of converting the pyrophos-
phonates into product during the aminolysis step of the reaction.
Scheme 4. During the preactivation period, the formation of pyrophosphon-
ates 5a and 5b is undesired when using COMU. Upon aminolysis, 5a and 5b
release anion 1b, which has a low rate of reactivation compared to its rate
of formation of guanidinium salt 9.
an aminolysis reaction with BnNH2, which afforded product 8
in 42 % conversion. These experiments demonstrate that both
coupling agents facilitate the phosphonamidation reaction of
anion 1b after the initial aminolysis step of pyrophosphonates
5a and 5b.
In an effort to reduce the formation of pyrophosphonates
during the preactivation step of the COMU-mediated phos-
phonamidation reaction, several changes to the original reac-
tion conditions were explored. During the first step of the
COMU-mediated coupling of phosphonic acid derivative 1a, ac-
tivated phosphonate 11, for the sake of this discussion, can
proceed to react by two pathways, A or B (Scheme 6).
By starting from 11, the ratio of formation of Oxyma-phos-
tained PyBOP efficiently converted a majority of the reactive
intermediates into product, without the side reaction between
the amine and the coupling agent (Scheme 5).
The difference in reactivity between COMU and PyBOP to-
wards the amine could be demonstrated by a series of control
experiments, in which BnNH2 was added to a solution of equi-
molar amounts of pyrophosphonates 5a and 5b, Et3N, and the
respective coupling agent. The ratio between the product and
anion 1b was determined by 31P NMR analysis. In the presence
of 2 equiv. of BnNH2, a second aminolysis step is possible if the
coupling agent is able to reactivate anion 1b, which is released phonate 4 relative to pyrophosphonates 5a and 5b is expected
from the aminolysis reaction of pyrophosphonates 5a and 5b. to depend on the relative concentration of the Oxyma anion
An investigation into the ability of both COMU and PyBOP to and that of anion 1b. As the Oxyma anion is released into solu-
reactivate anion 1b after the initial aminolysis step was per- tion as COMU is consumed, its concentration is negligible at
formed. For this second aminolysis to operate, anion 1b would the beginning of the reaction compared to that of anion 1b.
need to be more reactive than the amine towards the coupling During this period, Pathway B, which leads to pyrophosphon-
agent. When 1 equiv. of COMU and Et3N were added together ates 5a and 5b, is considered the dominant pathway until the
with pyrophosphonates 5a and 5b, a conversion of 53 % was concentration of the Oxyma anion increases. Thus, we sought
achieved, whereas the combination of 5a and 5b with PyBOP to change the reaction conditions to favor Pathway A. This
and Et3N resulted in an increased conversion of 82 %. In a previ- pathway should be favored if additional Oxyma is added prior
ous experiment, we subjected pyrophosphonates 5a and 5b to to the preactivation period or by changing the order of addition
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concentration of Oxyma relative to phosphonic acid derivative
1a during the preactivation period, a solution of 1a and Et3N
was added dropwise (0.4 mmol h–1 by an automated syringe
pump) to a solution of COMU and Oxyma (Method C, Table 2,
Entry 4). This improved the conversion from 75 to 89 % when
cyclohexylamine was the substrate. A virtually identical result
was observed when a solution of Oxyma, 1a, and Et3N was
added dropwise to COMU.
When COMU was replaced with PyOxim (Table 2, Entry 5), a
decrease was observed for the conversion. To further investi-
gate whether the presence of 0.5 equiv. of Oxyma had any ef-
fect on the outcome of the reaction under Method C, experi-
ments were conducted in the absence of Oxyma (Table 2, En-
tries 6 and 7). In both experiments, the lack of added Oxyma
resulted in a reduced conversion, and thus supports our claim
that a higher concentration of Oxyma during the preactivation
step is beneficial.
Among the amines evaluated, primary amines normally re-
sulted in conversions between 85 and 91 % with a few excep-
tions, such as allylamine and glycine ethyl ester hydrochloride
(Table 3, Entries 8 and 10). The COMU-mediated coupling reac-
tions with secondary amines, however, were less successful
(Table 3, Entries 1, 11, 13, and 14) and afforded significantly
lower conversions that those with the primary amines.
Because the 31P NMR analysis of the crude reaction mixture
from the preactivation step shows significant formation of ac-
tive phosphonate 4, we suspect that the reduced conversions
for the reactions with secondary amines results from events
occurring during the aminolysis of 4. This was confirmed by
two separate experiments, in which activated phosphonate 4
was subjected to an aminolysis reaction with BnNH2 and mor-
pholine. The BnNH2 reaction reached 74 % conversion, whereas
the reaction with morpholine reached 42 % conversion.
Scheme 6. During the preactivation steps, activated phosphonate 11 can
proceed to react by two pathways, A or B. The relative concentration of anion
1b and Oxyma is thought to determine which pathway is preferred.
of the reactants. The results of these changes are displayed in
Table 2.
Table 2. A comparison of the conversions obtained when varying the method
and reagents of the phosphonamidation reaction.
Despite our efforts, we were unable to isolate any byprod-
ucts from the crude mixture for the reaction between 4 and
morpholine, which could suggest a possible mechanism for the
decomposition of activated phosphonate 5 into starting mate-
rial 1b. PyBOP (Table 3, Entries 4, 12, and 16), on the other hand,
achieved complete conversion of both primary and secondary
amines without special considerations, such as the need for pre-
activation or the dropwise addition of the reagents. A reduced
conversion into the product was only observed in the reaction
with allylamine (Table 3, Entry 9).
Differences were observed by changing the alkoxy group of
1a as in the methyl or isopropyl ester of benzylphosphonic acid.
The isopropyl and ethyl esters of benzylphosphonic acid gave
comparable results, whereas the corresponding methyl deriva-
tive displayed a reduced stability, which was evident in the
preactivation step by the presence of two additional byprod-
ucts.
Entry
Method
Coupling agent
[1.5 equiv.]
Additive
[0.5 equiv.]
Conversion [%][a]
1
2
3
4
5
6
7
A[b]
B[c]
B[c]
C[d]
C[d]
C[d]
C[d]
COMU
COMU
COMU
COMU
PyOxim
COMU
PyOxim
–
–
trace
69
75
89
72
Oxyma
Oxyma
Oxyma
–
75
19
–
[a] Percent conversion was determined by 31P NMR analysis of the crude
reaction mixture. [b] Standard conditions were employed for Method A.[15b]
[c] Preactivation for Method B: coupling agent (1.5 equiv.), additive (0 or
0.5 equiv.), phosphonic acid derivative 1a, and Et3N (2.15 equiv.) were mixed
for 2 h before the amine was added. [d] Preactivation Method C: dropwise
addition of phosphonic acid derivative 1a and Et3N (2.15 equiv.) into a solu-
tion of COMU or PyOxim (1.5 equiv.) and Oxyma (0.5 equiv.) in CH2Cl2. After
approximately 5.5 h, the amine was added dropwise over 2 h.
With the knowledge acquired from coupling reactions with
COMU, we wanted to investigate whether a coupling reaction
with HBTU could be improved by applying the same modifica-
tions as described earlier (Table 4).
In the presence of 1 equiv. of Oxyma during the preactiva-
When HBTU and phosphonic acid derivative 1a were sub-
tion step, we observed a slight increase in the conversion from jected to the preactivation conditions for 1.5 h and subse-
69 to 75 % (Method B, Table 2, Entry 3). To further increase the quently treated with cyclohexylamine, a 42 % conversion into
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Table 3. A comparison of the conversions obtained when varying the method
and reagents of the phosphonamidation reaction.
Table 4. A comparison of the conversions obtained when varying the method
and reagents of the HBTU-mediated phosphonamidation reaction.
Entry
Method
Coupling agent
[2.0 equiv.]
Additive
[0.5 equiv.]
Conversion [%][a]
1
2
3
4
A[b]
B[c]
C[d]
C[d]
HBTU
HBTU
HBTU
HBTU
–
–
0
42
0[e]
36
HOBt
–
[a] Conversions were determined by 31P NMR spectroscopic analysis. [b] The
standard literature procedure was employed. [c] Preactivation for Method B:
HBTU (2.0 equiv.), phosphonic acid derivative 1, and Et3N (2.15 equiv.) were
mixed for 2 h before the addition of cyclohexylamine. [d] Preactivation
Method C: dropwise addition of acid derivative 1 and Et3N (2.15 equiv.) into
a solution of HBTU (2 equiv.) and the additive (0 or 0.5 equiv.) in CH2Cl2. After
approximately 5.5 h, the cyclohexylamine was added dropwise over 2 h.
[e] The yield is likely the result of hydrolysis of the activated species from the
wet HOBt.
By applying the preactivation strategy to DCC- and DIC-me-
diated phosphonamidation reactions, we were able to obtain
product 2 with acceptable conversions (Table 5, Entries 3 and
4). Notably, the addition of Oxyma to the preactivation mixture
significantly improved the conversion into the product (Table 5,
Entries 5, 6, and 7). No differences were observed when the
reaction solvent was changed to MeCN.
Table 5. A comparison of the conversions obtained when varying the method
and reagents of the carbodiimide mediated phosphonamidation reaction.
Entry
Method
Coupling agent
[1.5 equiv.]
Additive
[1.0 equiv.]
Conversion [%][a]
[a] Conversion was determined by 31P NMR spectroscopic analysis. [b] Yields
were determined after column chromatography and Kugelrohr distillation.
[c] Preactivation for Method A: dropwise addition of the phosphonic acid
derivative and Et3N (2.15 equiv.) into a solution of COMU (1.5 equiv.) and
Oxyma (0.5 equiv.) in CH2Cl2. After approximately 5.5 h, the amine was added
dropwise over 2 h. [d] PyBOP (2.0 equiv.) was used under the literature condi-
tions.[9] [e] Et3N (3.15 equiv.) was used.
1
2
3
4
5
6
7
A[b]
A[b]
B[c]
B[c]
B[c]
B[c]
C[d]
DCC
DIC
DCC
DIC
DCC
DIC
DIC
–
–
–
–
0
0
50
50
74
74
78
Oxyma
Oxyma
Oxyma
[a] Conversions were determined by 31P NMR spectroscopic analysis of the
crude reaction mixture. [b] Standard liquid-phase conditions were employed.
[c] Preactivation for Method B: DCC or DIC (1.5 equiv.), phosphonic acid deriv-
ative 1, Oxyma (0 or 1.0 equiv.), and Et3N (2.15 equiv.) were mixed for 0.5 h
before cyclohexylamine was added. [d] Preactivation Method C: dropwise
addition of acid derivative 1 and Et3N (2.15 equiv.) into a solution of DIC
(2 equiv.) and additive (1.0 equiv.) in CH2Cl2 or MeCN. After approximately
5.5 h, the cyclohexylamine was added dropwise over 2 h.
the product was observed by 31P NMR analysis (Table 4, En-
try 2). Analysis of the crude reaction mixture from the preactiva-
tion step showed only pyrophosphonates 5a and 5b and no
activated phosphonate, as expected from the previous experi-
ments with COMU and PyBOP. The presence of 0.5 equiv. of
HOBt during the preactivation step combined with the slow
addition of the reagents surprisingly gave only anion 1b
(Table 4, Entry 3). It is most likely that the water from the wet
In examples where no preactivation strategy was employed,
HOBt together with the Et3N caused the reactive intermediates no conversion into the product was observed (Table 5, Entries 1
to hydrolyze into the starting material.
and 2). These observations are in agreement with previous find-
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was stirred for an additional 3 h, and then the volatiles were re-
moved under reduced pressure. Analysis of the crude mixture by
31P NMR analysis was used to determine the conversion into the
product. The crude mixture was diluted with CH2Cl2 (30 mL), and
the resulting solution was washed with water (5 × 10 mL), dried
with anhydrous Na2SO4, filtered, and concentrated under reduced
pressure. The crude residue was purified by column chromatogra-
phy [2.5 cm (diameter) × 10 cm (height of silica); CH2Cl2/MeOH/
Et3N, 100:0:0 to CH2Cl2/MeOH/Et3N, 100:1:0.5; see Supporting Infor-
mation for additional details]. The product fraction overlapped with
that of N,N-dimethylmorpholino-urea, which was later removed by
kugelrohr distillation (125 °C, 6–9 Torr, 2 h, product stays, urea is
removed).
ings of carbodiimide-mediated phosphonamidation reactions
that show the order of addition of reagents is crucial to obtain
significant conversion into product. As mentioned above, this
had already been established in 1957 by Burger and Ander-
son[5] and implemented, but not specifically discussed, by Ishi-
bashi and Kitamura in 2009.[11]
Conclusions
Herein, we have presented a comprehensive study of the coup-
ling agent-mediated phosphonamidation reaction by primarily
using the non-hydroxybenzotriazole-based coupling agents
COMU and PyOxim to mediate the coupling of monoesters of
phosphonic acids and amines. The realization that the reaction
required a preactivation period without the amine coupling
partner was of crucial importance, as the amine irreversibly con-
sumes the coupling agent in an unproductive pathway. The
implementation of this preactivation step allowed for successful
phosphonamidate reactions that used other well-established
coupling agents such as DIC, DCC, and HBTU. All major reactive
intermediates that were observed during the preactivation pe-
riod of the COMU-mediated phosphonamidation were synthe-
sized separately to confirm their identity and evaluate their re-
activity. Furthermore, by limiting the formation of pyrophos-
phonates in the preactivation step and assuring a low concen-
tration of the phosphonic acid derivative relative to that of the
coupling agent and Oxyma, we have shown that a higher con-
version into the desired phosphonamides can be achieved. Em-
ploying this strategy, we were able to obtain comparable results
to those obtained by the hydroxybenzatriazole-based coupling
agent PyBOP in the reaction of the phosphonic acid derivative
and several primary amines. A decrease in the conversion into
the phosphonamides was observed with secondary amines,
which was traced back to the aminolysis of the Oxyma-phos-
phonate. No byproducts could be isolated to account for the
low conversion into the product. When the monomethyl ester
of benzylphosphonic acid was used, a similar reduction in the
yield was observed. Analysis of the crude reaction mixture from
the preactivation step showed that the reduced conversion
could be traced back to byproducts that originated from the
preactivation step rather than the aminolysis of the activated
phosphonate, as was observed in the case of secondary amines.
Supporting Information (see footnote on the first page of this
article): Syntheses of relevant compounds and experimental setup.
Acknowledgments
This work was supported by the Research Council of Norway
(KOSK II program, grant number 206970) and the University of
Oslo.
Keywords: Synthetic methods · Phosphonamidation ·
Reaction mechanisms · Reactive intermediates · Phosphorus ·
Amines
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Experimental Section
COMU-Mediated Phosphonamidation Procedure for Com-
pounds 2, 8, and 12–22: COMU (650 mg, 1.5 mmol) and Oxyma
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stir bar, and CH2Cl2 (dried, 1 mL) was added. The heterogeneous
mixture was then added dropwise (0.9 mL h–1 by using an auto-
mated syringe pump) to a solution of the monoalkyl ester of benz-
ylphosphonic acid (1 mmol) and Et3N (0.3 mL, 2.15 mmol) in CH2Cl2
(2 mL) with vigorous stirring. The resulting mixture was aged for
an additional 2 h to primarily afford the corresponding Oxyma-
phosphonate with trace amounts of the pyrophosphonates and the
anion of the phosphonic acid derivative. The solution of the amine
(2 mmol) dissolved in CH2Cl2 (0.5 mL) was then added dropwise (by
using an automated syringe pump) over 1 h. The reaction mixture
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[19] No investigation has been carried out to investigate whether OBt-phos-
phonate 4a or 4b is the predominant species observed. Because of the
oxophilic nature of phosphorus, however, we believe that structure 4a
is most relevant.
[20] The solution to this problem was described by Burger and Anderson.
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[17] This observation is similar to what Burger and Anderson observed in
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79, 3575–3579.
Received: September 28, 2015
Published Online: December 9, 2015
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