Direct Enamido C(sp2)?H Diphosphorylation Enabled by a PCET-Triggered Double Radical Relay: Access to gem-Bisphosphonates

Article abstract of DOI:10.1002/chem.202000517

Herein we report a novel and straightforward protocol for the construction of valuable gem-BPs by means of proton-coupled electron-transfer (PCET)-triggered enamido C(sp²)?H diphosphorylation. This reaction represents a rare example of realizing the challenging double C?P bond formation at a single carbon atom, thus providing facile access to a broad variety of structurally diverse bisphosphonates from simple enamides under silver-mediated conditions. Initial mechanistic studies demonstrated that the diphosphorylation involves two rounds of PCET-initiated radical relay process.

Full text of DOI:10.1002/chem.202000517

A Journal of
Accepted Article
Title: Direct Enamido C(sp2)-H Diphosphorylation Enabled by PCET-
triggered Double Radical Relay: Access to gem-Bisphosphonates
Authors: Hao-Qiang Cao, Hao-Nan Liu, Zhe-Yuan Liu, Bao-Kun Qiao,
Fa-Guang Zhang, and Jun-An Ma
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Direct Enamido C(sp2)-H Diphosphorylation Enabled by PCET-
triggered Double Radical Relay: Access to gem-Bisphosphonates
Hao-Qiang Cao,[a] Hao-Nan Liu,[a] Zhe-Yuan Liu,[a] Bao-Kun Qiao,[a] Fa-Guang Zhang,*[a] [b] and Jun-An
Ma*[a] [b]
[a]
H.-Q. Cao, H.-N. Liu, Z.-Y. Liu, Dr. B.-K. Qiao, Prof. Dr. F.-G. Zhang, and Prof. Dr. J.-A. Ma
Department of Chemistry, Tianjin Key Laboratory of Molecular Optoelectronic Sciences, and Tianjin Collaborative Innovation Centre of Chemical Science &
Engineering
Tianjin University
Tianjin 300072, P. R. of China
E-mail: zhangfg1987@tju.edu.cn, majun_an68@tju.edu.cn
Prof. Dr. F.-G. Zhang and Prof. Dr. J.-A. Ma
Joint School of NUS & TJU
[b]
International Campus of Tianjin University
Fuzhou 350207, P. R. of China
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Here we report a novel and straightforward protocol for the
construction of valuable gem-BPs by means of proton-coupled
electron
transfer
(PCET)-triggered
enamido
C(sp2)-H
diphosphorylation. This reaction represents a rare example of
realizing the challenging double C-P bond formation at a same carbon
atom, thus providing facile access to a broad variety of structurally
diverse bisphosphonates from simple enamides under silver-
mediated conditions. Initial mechanistic studies demonstrated that the
diphosphorylation involves two rounds of PCET-initiated radical relay
process.
Introduction
Geminal bisphosphonates (gem-BPs) are an important class of
compounds possessing the unique P-C-P moiety, and they are
stable analogues of naturally-occurring pyrophosphate (Figure
1).[1] Owing to their gifted bone affinity and specific inhibition for
FPPS (farnesyl pyrophosphate synthase), gem-BPs are currently
the most commonly used medicines in a variety of bone-relevant
diseases.[2] For instance, among them are several renowned anti-
osteoporosis drugs including clodronate, pamidronate, and
residronate (Figure 1, top).[3] Particularly, nitrogen-containing
gem-BPs have emerged as a significant type of highly potential
candidates to kill tumor cells for prevention and therapy of a series
of human cancers, and thus draw great interest in the past
decade.[4] However, their practical use for anticancer therapeutic
agents is often hampered due to poor cellular uptake, so there
has recently been considerable interest in developing more
lipophilic gem-BPs, as exemplified by representative solutions
such as replacing the hydroxyl “bone hook” at the geminal carbon
with simple hydrogen or lipophilic fluorine atom, introducing a long
carbon chain, or masking the negatively charge with pivoxil esters
(Figure 1, middle).[5] Beyond the important pharmacological roles,
gem-BPs have also been comprehensively exploited in
biomedical fields owing to their reliable metal-chelating ability.[6]
For example, the bone-seeking property of gem-BPs provides
promising opportunity to deliver medical targets specifically to
bone by versatile bisphosphonate conjugations
Figure 1. Representative biologically important molecules containing gem-
bisphosphonates.
(Figure 1, bottom).[7] Despite these impressive advances in gem-
BPs’ biological studies, the scarcity of reliable synthetic methods
to expand the structural diversity of gem-BPs has become the
major limiting factor of the impetus. Indeed, the majority of
conventional approaches mainly focused on the preparation of α-
hydroxyl or α-amino bisphosphonates (Scheme 1a).[8]
Alternatively, ionic C-C bond-forming transformations with
bisphosphonate
building
blocks,
such
as
vinylidenebisphosphonate ethyl ester (VBP)[9] and methylene-
bisphosphonate ethyl ester (MBP),[10] have proved to be valid
route to produce lipophilic gem-BPs (Scheme 1b), but the utility is
still largely restricted due to limited substrate scope, poor
selectivity, and tedious pre-synthesis of the bisphosphorous
reagents. In particular, the synthesis of tetra-substituted vinyl
gem-BPs has not been reported until now.[11] Therefore, the
development of general and efficient synthetic methods to rapidly
1
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produce versatile functionalized gem-BPs from simple chemical
entities is still highly desirable.
evaluated under the optimized conditions (Scheme 2). For
different phosphonate reagents, such as diethyl or dibutyl
phosphonates, and diphenylphosphine oxide, the corresponding
gem-bisphosphontaes 3b–3d were smoothly afforded in 70–82%
yields. Subsequently, enamide counterparts bearing a series of
different amino-protecting groups, including isopropyl, tert-butyryl,
benzoyl, and benzyloxycarbonyl, were all evaluated under the
standard conditions, and gave rise to the products 3e–3h in
moderate to high yields. As for aryl enamides, this transformation
could tolerate both electron-donating and electron-withdrawing
substituents, such as -Me, -OMe, -halogens, -OCOMe, -CF3, -CN,
and -CO2Me, irrelevant of their locating patterns on the phenyl
ring, thus delivering the desired β-amido vinyl bisphosphonates
3i–3e’ in 61–88% yields. Notably, compound 3v was analyzed
with single X-ray to unambiguously determine the molecular
structure, and other bisphosphonates are assigned by analogy.[18]
Furthermore, the generation of compound 3m possessing a long
alkyl chain in practical yield displays the potential utility of this
method in preparing lipophilic gem-BPs aiming for increased
biological activities. 2-naphthyl enamide was found to be suitable
reaction partner in this process (3e’). N-heterocycle-containing
bisphosphonates have emerged as the third-generation
candidates in searching for more effective drugs to treat bone-
related diseases.[2,4] In this context, a wide array of pyrrole,
thiophene, thiazole, pyridine, and para-diazine-derived enamides
were prepared and reacted with phosphonate 2a under identical
conditions. Pleasingly, the corresponding gem-BPs 3f’–3o’ were
readily provided in 61–81% yields, thereby allowing new
possibilities in achieving structurally diversified bisphosphonates.
In addition, alkyl-substituted enamides also proved to be
applicable in this protocol, furnishing 3p’ and 3q’ in decent
C-H phosphorylation has been recognized as a straightforward
approach to produce various organophosphorus compounds.[12]
Although powerful, all the precedented examples only focus on
mono-phosphorylation, while the more attractive C-H
diphosphorylation has not been realized until now, especially 1,1-
diphosphorylation at a same carbon atom.[13] Herein, we report a
major advance for synthesizing geminal bisphosphonates by
means of silver-mediated direct 1,1-diphosphorylation of
enamides (Scheme 1c).[14] By taking advantage of proton-coupled
electron transfer (PCET)[15]-triggered radical relay process,[16] this
study implemented the first example of two-fold C-P bond
formation from C(sp2)-H bond at a same carbon atom.[17] More
importantly, this reaction allows the efficient synthesis of a broad
range of fully functionalized β-amino vinyl gem-BPs, as well as
halogen, azirine, ketone, peptide, and alkyne-substituted ones,
thus considerably opening up new possibilities in expanding the
potential chemical space in this emerging field.
yields.[19]
Ultimately,
commercially
available
2-
acetamidoacrylates and N-vinylacetamide were treated with
phosphonate 2a under the optimal conditions, and produced
highly functionalized α-dehydroamino acids and β-dehydroamino
phosphoric acids derivatives 3r’–3t’ in 51–62% yields, providing
another clear benefit of this facile protocol.
To
demonstrate
the
scale-up
feasibility
of
this
diphosphorylation method, three representative examples (3a, 3d,
and 3k’) were prepared in gram-scale, all observed with
maintained good level of results compared with model reactions
(Scheme 3a). In particular, the reaction between enamide 1a and
phosphonate 2a was also operated at a scale of 10 grams, thus
leading to 21.9 grams of 3a in 75% yield in just 12 hours. It should
be noted that excess Ag2O and the remaining silver residue could
be recycled by simple operations (Scheme 3b).[20] The
reproduced Ag2O could still facilitate the diphosphorylation with
good activity, thus significantly improving the advantage of
economic practicality. The immense value of P-C-P skeleton has
been extensively demonstrated through its frequent presence in
various active pharmaceutical ingredients, but available methods
to achieve the structural diversity is still far from trivial. In this
context, a diverse array of synthetic transformations with the
obtained gem-BPs was further investigated. As illustrated in
Scheme 3c, the free amino bisphosphonates [4a (X-ray
confirmed) and 4b] and carbonyl bisphosphonates [6a (X-ray
confirmed) and 6b] were smoothly provided in good yields under
simple basic and acidic conditions, respectively.[18] More
importantly, the azirine-functionalized gem-BPs 5a and 5b were
afforded in high yields via I2-mediated cyclization, thus adding
another attractive handle to the central P-C-P motifs.
Scheme 1. Development of general synthetic means for the construction of
gem-bisphosphonates.
Results and Discussion
Extensive screening of various reaction parameters (see the SI
for details) concluded that the desired β-amino vinyl gem-
bisphosphonate 3a was afforded in 84% yield when phenyl
enamide 1a was reacted with diisopropyl phosphonate 2a in the
presence of silver oxide (Ag2O) at reflux for 12 h in acetonitrile.
The employment of Ag2O plays a critical role in this transformation,
as evidenced by the fact that almost no conversion was observed
when using other metal complexes [such as Mn(OAc)3] or silver
salts (including AgF, AgOAc, AgNO3, Ag2SO4, and Ag2CO3).
Moreover, attempts to reduce the amount of Ag2O turned out to
be unworkable, suggesting that the silver reagent may bear
multiple roles in the reaction process (vide infra). The substrate
scope of this C(sp2)-H diphosphorylation reaction was then
2
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Scheme 2. Substrate scope of silver-mediated direct gem-diphosphorylation of enamides. Reaction conditions: A mixture of enamide 1 (0.5 mmol), H-phosphonate
2 (1.1 mmol) and Ag2O (348 mg, 1.5 mmol) in CH3CN (10 mL) was reacted at reflux temperature for 12 hours; Yield of isolated product.
Furthermore, a series of halogen-substituted bisphosphonates
7a–7d, including -Cl, -Br, and -F, were all readily prepared by
means of electronic substitution transformations. Among them,
noteworthy is that the pyridine-containing compounds 6b and 7d
represent the dehydroxyl and fluorinated analogues of Risedronic
acid (drug for Paget's disease), respectively. Notably, the free
bisphosphoric acid 6c was obtained in 84% yield by simple
treatment of 6a with TMSBr. In addition, the practical applicability
is exemplified by the rapid preparation of several pharmaceutical-
relevant molecules with good efficiency, including 3u’-gem-BPs-
functionalized Celestolide derivative, 3v’-gem-BPs-functionalized
Gemfibrozil derivative, and 3w’-an analogue of Pregnane X
receptor agonist SR12813 (Scheme 3d).[21]
The presence of ester and amino groups in obtained BPs may
offer new opportunity for connecting to medically relevant targets.
As a proof of concept, the free acid-containing bisphosphonate 8a
was synthesized from compound 3s’ in good yield, and
subsequently coupled with phenylalanine to give peptide-
functionalized molecular 8b in 75% yield (Scheme 4a). More
importantly, we were pleased to find that the alkyne moiety could
also be easily introduced to free amino-BPs 4, thus allowing facile
click ligation of 9a–9c with Azidothymidine to give corresponding
triazole-connected BPs 10a–10c in high yields (Scheme 4b).
3
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Scheme 3. Scale-up experiments and further synthetic transformations.
the SI for details). Indeed, both isomers of mono-phosphorylation
intermediates Z-11a and E-11a were uneventfully converted to
bisphosphonate 3a in excellent yields (Scheme 5a). Remarkably,
an isomerization process of the C-C double bond was observed
during mechanistic studies.[22] For instance, the reaction between
Z-11a and diphenylphosphine oxide provided 3x’ in 65% yield,
whose stereochemistry has been confirmed by X-ray
crystallographic analysis. Subsequently, a group of N-protected
enamides, including -Me, -Bn, and -Boc, were prepared and
subjected to otherwise identical reaction conditions, while only the
mono-phosphorylation products 11b–11d were formed in
distinctly low yields (Scheme 5b). Reacting 11b–11d with
phosphonate reagent in a separated manner also turned out to be
no conversion at all. These results strongly suggest that the N-H
moiety may operate an essential role in initiating the reaction,
especially for the second C-P bond formation. The addition of a
radical scavenger (TEMPO) completely inhibited the
diphosphorylation (Scheme 5c). Notably, both radical-trapping
products 12a and 12b (X-ray confirmed) were obtained in a yield
of 45% and 67%, respectively.[23] These results clearly
demonstrate that the reaction could undergo in radical manner
and in-situ generated alkyl radical species might account for the
observed high reactivity of double C-P bond
Scheme 4. Connections of amino-BPs to phenylalanine and Azidothymidine.
A series of experiments were subsequently conducted to cast
some light on the mechanism of this novel gem-diphosphorylation
reaction. Monitoring the reaction by 31P-NMR and TLC suggested
that it may first undergo mono-phosphorylation and then
completed the reaction after the second C-P bond formation (see
4
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occur and accomplish another C-P bond formation, thus
ultimately providing the final gem-bisphosphonate product 3. It
should be noted that this study represents the first example to
successfully utilize PCET process for double C-H
functionalization.
Conclusion
In summary, a novel method for the efficient preparation of
valuable gem-bisphosphonates from readily accessible enamides
is described. The realization of this transformation hinges on
silver-mediated radical relay process involving PCET as the key
step, thus solving the challenging double C-P bond formation at a
same carbon atom. The good functional group compatibility and
versatile synthetic transformations render the facile preparation of
a wide range of highly functionalized gem-bisphosphonates under
mild conditions. Given the enormous significance of the P-C-P
backbones in biological and medical applications, the present
protocol will open up new possibilities in relevant fields.
Experimental Section
General procedure for silver-mediated direct diphosphorylation of
enamides. The mixture of enamide 1 (0.5 mmol, 1.0 equiv), Ag2O (1.5
mmol, 3.0 equiv), and H-phosphonate 2 (1.1 mmol, 2.2 equiv) in CH3CN
(10.0 mL) were added into a 25 mL schlenk flask equipped with a stirring
bar. The reaction was stirred at reflux temperature for 12 hours and
monitored by TLC. Then the reaction mixture was filtered through diatomite
(Put a layer of filter paper on the diatomite, and a silver residue filter cake
will be formed on the filter paper. Collect the silver residues for
regeneration and recycling). The filtrate was concentrated under reduced
pressure and subsequently purified by flash column chromatography on
silica gel with PE/EtOAc mixture (10/1–1/1 ratio). After removing the
solvent in vacuo, the desired compound 3 could be obtained.
Acknowledgements
This work was financially supported by the National Key Research
and Development Program of China (2019YFA0905100),
National Natural Science Foundation of China (Nos. 21772142,
21901181, and 21961142015), and Tianjin Municipal Science &
Technology Commission (19JCQNJC04700). We thank Prof
Guosheng Ding in the Analysis and Testing Center of Tianjin
University for NMR experiments.
Scheme 5. Mechanistic studies and proposed mechanism.
formation. Collectively, a plausible mechanism is depicted in
Scheme 5d based on the experimental clues and previous
precedents. In the presence of Ag2O, enamide 1 undergoes
proton-coupled electron transfer (PCET) process to give amidryl
radical I-1.[24] The silver oxide functions as both a mild oxidant and
a weak Brønsted base during this step, thereby explaining its
unique match for this transformation.[25] Then the N-centered
radical would quickly isomerize to a more stable C-centered
radical I-2.[26] At this stage, radical coupling between alkyl radical
I-2 and the in-situ formed P-centered radical gave rise to imine
intermediate I-3.[27] Isomerization of I-3 to mono-phosphorylation
product 11 is driven by the formation of intramolecular hydrogen
bond.[28] Likewise, a second round of radical relay process
consisting of PCET, radical transfer, and radical coupling, would
Keywords: radical relay • bisphosphonates • enamides • silver •
synthetic methods
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[28] The presence of hydrogen bonds in both mono-phosphorylation and
diphosphorylation products have been confirmed by the X-ray analysis
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products in ref 12m. See the SI for X-ray details.
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Direct double C-P bond formation at a same carbon atom in one-pot: By taking advantage of PCET-triggered radical relay
process, a new general method to versatile valuable functionalized gem-bisphosphonates is described.
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