Mechanistic Insight into the Catalytic Staudinger Ligation

Article abstract of DOI:10.1021/acs.orglett.8b04035

Organophosphorus-catalyzed Staudinger ligation between carboxylic acids and azides in the presence of phenylsilane reductant produces amides. NMR-based mechanistic investigations revealed that the catalytic Staudinger ligation does not proceed via reduction of phosphine oxide but rather via reduction of iminophosphorane, which can subsequently undergo several transformations to produce the amide product.

Full text of DOI:10.1021/acs.orglett.8b04035

Letter
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Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Mechanistic Insight into the Catalytic Staudinger Ligation
†
,†,§
Paul B. White,*,†,‡ Sjoerd J. Rijpkema,†,‡ Roderick P. Bunschoten, and Jasmin Mecinovic*
́
†Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands
§Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
S
* Supporting Information
ABSTRACT: Organophosphorus-catalyzed Staudinger ligation
between carboxylic acids and azides in the presence of
phenylsilane reductant produces amides. NMR-based mechanistic
investigations revealed that the catalytic Staudinger ligation does
not proceed via reduction of phosphine oxide but rather via
reduction of iminophosphorane, which can subsequently undergo
several transformations to produce the amide product.
rganophosphorus-mediated reactions have found a
O
widespread use in synthetic organic chemistry.1 Well-
established examples include the Wittig reaction, Mitsunobu
reaction, Appel reaction, Staudinger reduction, and Staudinger
ligation, which have enabled the transformations of many
common functional groups and greatly contributed to the
construction of complex molecules of biomedical importance.1
Recent efforts have demonstrated the development of catalytic
versions of these classic reactions along with related reactions.2
Organophosphorus catalysis typically requires the presence of
silane-based reducing agents involved in the chemoselective
reduction of phosphine oxides to phosphines during the
catalytic cycle.3
The Staudinger ligation has been of paramount importance
for examinations of various molecular and biomolecular
systems.4 The first catalytic Staudinger ligation was described
by Ashfeld et al. in 2012.2f The reported Ph3P-catalyzed
Staudinger ligation between carboxylic acids and azides in the
presence of phenylsilane led to the formation of a diverse set of
amides in very good yields.2f Limited mechanistic work
suggested that the catalytic reaction importantly relies on the
efficient PhSiH3-mediated reduction of Ph3PO to Ph3P, which
then enters a new catalytic cycle. Recently, Denton et al.
challenged this proposed mechanism by suggesting that the
organophosphorus-catalyzed reaction proceeds via an alter-
native pathway through in situ formation of silyl esters.5
Herein, we report advanced NMR spectroscopic studies on the
organophosphorus-catalyzed Staudinger ligation that enables
the elucidation of the most plausible mechanism. Our
mechanistic studies suggest that (1) Ph3PO reduction is
kinetically unfeasible for being on-cycle and (2) reduction of
the iminophosphorane results in either unreactive silylamine
species or benzylamine, which reacts with benzoic acid to form
amide.
Figure 1. Time-course of the catalytic Staudinger ligation.
Ph3P 3 (0.1 equiv) and PhSiH3 4 (1.0 equiv) in anhydrous
toluene at 111 °C under argon led to an immediate (within 5
min) formation of benzylamine 5, iminophosphorane 6, silyl
ester 7, and two benzylamine-containing species 8 (minor) and
9 (major). Within 4 h, the starting azide 2 was fully consumed,
and the formation of the N-benzylbenzamide product 10 was
clearly observed. Both benzylamine-containing species were
still found after 4 h; the ratio, however, was reversed in favor of
8. A prolonged incubation (24 h) resulted in the disappearance
We initially carried out the time-course of the catalytic
Staudinger ligation and examined the formation of inter-
1
mediates and products by H and 31P NMR spectroscopy
(Figure 1 and Figures S1 and S2). Heating of benzoic acid 1
(1.0 equiv) and benzyl azide 2 (1.2 equiv) in the presence of
Received: December 18, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b04035
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of signals that belong to 8, 9, and 6 and in a substantial
increase in the formation of amide product 10.
were determined to be NHs (1H−15N HSQCED) (Figure
2C). A subsequent 1H−29Si HMBC revealed that the CH2 and
NH were connected to a 29Si nucleus at −34.12 ppm (8) and
−42.58 ppm (9) as well as the expected corresponding phenyl
groups (Figure 2D). Furthermore, the absence of any 1H cross
31P{1H} NMR spectra supported these findings and revealed
that Ph3PO 11 was not produced during the reaction (the
Ph3PO signal in 31P{1H} NMR spectrum derives from small
amounts present in the starting Ph3P 3) (Figure 1). Additional
31P{1H} NMR-based experiments demonstrated that PhSiH3
alone does not mediate reduction of Ph3PO to Ph3P within
limits of detection; the presence of benzoic acid, however,
increased the yield of 3 to 13% in 4 h (Figure S3). These
results suggest that it is unlikely that an efficient catalytic
Staudinger ligation proceeds via reduction of Ph3PO to Ph3P.
It is more likely that the majority of the amide product is
formed via a different pathway, as described below.
1
peaks at those 29Si shifts in the H−29Si HSQCED spectrum
revealed that 8 and 9 must be a quaternary silicon species
(Figure 2D). A third minor species was also observed in the 1H
spectrum at 4.17 ppm (Figure 2). Similar to 8 and 9, it was a
silylbenzylamine (δC = 45.00 ppm; δN = 31.44 ppm; δSi
=
−50.76 ppm) with an NH group; however, its low abundance
made the above analyses more challenging. Diffusion NMR
measurements estimated that the unknown intermediate was
∼1.72× heavier than 8 or 9 and thus is likely a bridging species
(Figure S4).
The unanswered question of how amide is formed led us to
investigate the two unknown compounds, 8 and 9, that are
present in high concentration from the beginning of the
reaction. The amount of these species decreased over time
with concomitant formation of amide 10, while the
concentration of amine 5 remained constant. Denton and
co-workers assigned these species as a silylated benzylamine
Partial structure fragments of the formula PhSi-
(Y)3−x(NHBn)x were drawn, and we hypothesized that Y
could be OBz or OH. Unfortunately, through-bond measure-
1
ments between the NH H and CO would be challenging
due to the number of bonds in between and through-space
measurements were difficult due to the overlap of BzO− with
free acid, toluene, Ph3PO, and PhSiH3. Therefore, 2,6-
dimethylbenzoic acid was employed to provide a spectral
handle via its unique methyl groups (Scheme 1). The reaction
1
1
based on comparison of H chemical shift and H−1H J-
couplings between the CH2 and NH of similar species from
literature.5 However, a more rigorous characterization was
required in order to unambiguously confirm these structures
and understand their role in the catalytic Staudinger ligation.
2D NMR analyses enabled the conclusive determination of
both structures: 8 as PhSi(OBz)(NHBn)2 and 9 as PhSi-
(OBz)2(NHBn) (Figure 2). The 1H−13C HSQCED spectrum
showed that both 8 and 9 CH2s were slightly shielded (13C:
45.33 ppm) from free benzylamine (13C: 46.43 ppm) (Figure
1
Scheme 1. NOE and H NMR Determination of 8′ and 9′
1
2A). The Hs exhibited a doublet splitting pattern distinct
from the singlets of benzylamine 5 or benzyl azide 2. A COSY
experiment (Figure 2B) revealed the coupling partner to be a
triplet at 1.79 and 2.27 ppm for 8 and 9, respectively, which
was performed under standard conditions and resulted in
nearly identical results as with BzOH. The resulting silylamine
doublets were selected for 1D NOESY experiments, which
revealed correlations to the acid methyls (Figure 2E).
Reciprocal NOEs were observed when selecting the methyl
1Hs. Integrating the singlet of the methyl group and the
corresponding doublet of the benzylamine conclusively
assigned the formulas PhSi(OBzMe2)(NHBn)2 (8′) and
PhSi(OBzMe2)2(NHBn) (9′) (Figure S5).
These structures are in line with our time-course data
(Figure 1); 9 predominantly appears at the early stage of the
reaction, when the amount of benzoic acid is high, whereas 8
becomes a dominant species during later stages of the reaction,
when an increasing amount of amine is produced. Within 30
min, >95% of the starting benzoic acid could be accounted for
as either part of the intermediates 8 and 9 or the product 10,
indicating the rapid reaction and seclusion of free benzoic acid
in the reaction mixture.
Since the formation of amide 10 coincided with the decay of
8 and 9, we were curious as to their formation, dynamics, and
reactivity (Figure 1). 1D EXSY (EXchange SpectroscopY)
spectra were acquired from catalytic reaction aliquots and
measured at 298 K where reactivity is halted (Figure S6). The
measurements revealed that the aminobenzyl moieties of 8 and
9 readily exchanged with each other as well as with free benzyl
amine (Scheme 2). Additionally, the unknown silylamine
species at 4.17 ppm underwent exchange with free benzyl
amine and 9, but not readily with 8. In the absence of free
amine, exchange between 8 and 9 was significantly retarded.
Figure 2. NMR spectroscopic characterization of intermediates 8 and
9.
B
DOI: 10.1021/acs.orglett.8b04035
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observing the reactivity of 6 with different components of the
reaction mixture. Addition of phenylsilane to 6 resulted in
reduction to the amine 5 and Ph3P as the sole products
(Scheme 3, Figure S8); no silylamine species were observed.
Scheme 2. Exchange of Intermediates 8 and 9
Scheme 3. Reaction of Iminophosphorane 6 with
Components of the Catalytic Staudinger Ligation
It was unclear whether or not 8 and 9 were off- or on-cycle
intermediates in the formation of the amide bond. This could
fortunately be probed by slightly altering the reaction
conditions. When substoichiometric equivalents of azide
(0.25 equiv vs BzOH) were used, the formation of 8 and 9
were avoided altogether. Furthermore, it was revealed that the
rate of amide formation was significantly faster; the same
quantity of amide (0.1 mmol) was produced in 1 h for the
substoichiometric condition compared to 4 h for the standard
conditions (Figure 3). This comparative time-course demon-
Addition of benzoic acid to 6 resulted in its immediate
protonation (6H+), as determined by a downfield shift in the
31P{1H} spectrum from 5.9 to 36.8 ppm; however, the 1H shift
of the CH2 did not visibly change (Figure S9). 31P{1H} spectra
acquired during the catalytic reaction do not reveal 6H+,
implying it is a highly reactive species (Figure 1). Interestingly,
without any other additives, 6H+ spontaneously formed amide
10 and Ph3PO in refluxing toluene, albeit very slowly (Scheme
3, Figure S9). However, in the presence of PhSiH3, 6H+
immediately (within 15 min) forms amine and Ph3P, instead of
amide and Ph3PO, and then progresses to form amide from the
reservoir of amine (Scheme 3).
In all cases, species 8 and 9 did not form directly from
reaction between 6H+ and other starting components in the
reaction. Therefore, we broadened our investigation to other
species present in the reaction mixture at the beginning.
Denton et al. identified and synthesized PhSiH2OBz (7) in
their mechanistic study, demonstrating its ability to form
amide in the presence of azide and phosphine catalyst.5
Following literature precedent, we synthesized 7 and then
introduced different components and intermediates. Excitingly,
the reaction between silyl ester 7 and iminophosphorane 6
afforded 8 (55%) and 9 (45%) after 3.5 h at room temperature
(Figure S10). Despite the highly reactive nature of silyl ester 7,
when reacted with benzyl amine 5, it only formed 40% of
amide product after 4 days at room temperature (Figure S11).
Free carboxylic acid and amine undergo phenylsilane-
mediated amidation in THF at room temperature.6 In line
with this finding, we observed that 58% of amide is formed in
toluene at 111 °C after 90 min (Figure S12 and Table S3). In
the absence of phenylsilane, the rate was drastically retarded,
yielding only 7.3% conversion after 24 h. Addition of catalytic
phosphine or phosphine oxide did not impact the rate or
results of the stoichiometric silane-mediated coupling; 77−
81% yields were observed after 24 h (Table S3).
Figure 3. Observation of rate inhibition by 8 and 9 when a
substoichiometric quantity (top) or a stoichiometric amount
(bottom) of benzyl azide 2 is used. Spectrum represents the reaction
at 1 h. Full time course is shown in Figure S7.
strates that, despite the lower starting azide concentration,
faster rates are obtained for amide formation under
substoichiometric conditions where 8 and 9 are not present
(Figure S7). These results suggest that 8 and 9 are off-cycle
intermediates that pool the reactive benzoic acid and
benzylamine components. A slow equilibrium is capable of
releasing these reagents as they are consumed to form the
amide likely via a phenylsilane-mediated process.
To better understand the formation of these silylamine
intermediates, we looked at the formation and reactivity of the
iminophosphorane 6 due to its role at converting azide into
amine-like species. Reaction between phosphine and azide
results in quantitative formation of 6 in less than 2 h at room
temperature and <30 min at 111 °C. We were interested in
With these observations in mind, a new catalytic cycle for
the Staudinger ligation can be proposed (Scheme 4). Azide 2
first reacts with the phosphine 3 to form the iminophosphor-
ane 6. Subsequent protonation of 6 is possible by benzoic acid
1; however, it is not observed in the catalytic reaction as the
subsequent reduction by phenylsilane 4 is significantly faster.
The reduction of 6H+ by phenylsilane 4 regenerates Ph3P 3
and produces amine 5. The amine 5 can then participate in
C
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several separate pathways simultaneously. First, it can react
with benzoic acid 1 and PhSiH3 4 to produce amide 10, as in
the stoichiometric reaction. Second, it can act as a base and
deprotonate benzoic acid 1. The benzoic acid 1 can then react
with PhSiH3 4 to form the silyl ester 7, which is observed at
the earliest time points of the reaction. The silyl ester can
subsequently react further with 6 to produce a family of off-
cycle silylbenzylamine intermediates, 8 and 9, which sequester
the acid and amine. Third, the amine 5 engages in a dynamic
equilibrium with 8 and 9 that causes the slow but eventual
release of free benzoic acid into solution. The acid and amine
then can subsequently react with the remaining phenylsilane to
form the amide product.
In summary, our NMR analyses demonstrated that the
catalytic Staudinger ligation does not proceed via phosphine
oxide but rather via iminophosphorane that upon reaction with
phenylsilane can undergo distinct pathways, including via off-
cycle silyl species, to produce the amide product. We envision
that our mechanistic work will contribute to development of
efficient catalytic Staudinger ligation under milder reaction
conditions.
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b04035.
NMR analyses (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: p.white@science.ru.nl.
*E-mail: mecinovic@sdu.dk.
ORCID
́
Jasmin Mecinovic: 0000-0002-5559-3822
Author Contributions
‡P.B.W. and S.J.R. contributed equally.
Notes
The authors declare no competing financial interest.
REFERENCES
■
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Tetrahedron Lett. 2018, 59, 59. (b) Xu, S.; He, Z. RSC Adv. 2013, 3,
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DOI: 10.1021/acs.orglett.8b04035
Org. Lett. XXXX, XXX, XXX−XXX