Bismuth(III)-Catalyzed Sequential Enamine-Imine Tautomerism/2-Aza-Cope Rearrangement of Stable β-Enaminophosphonates: One-Pot Synthesis of β-Aminophosphonates

Article abstract of DOI:10.1021/acs.orglett.0c00796

A novel catalytic tautomeric transformation of a β-enaminophosphoryl and 2-aza-Cope rearrangement sequence has been successfully applied to the one-pot synthesis of β-aminophosphonates with high efficiency and good tolerance. In this tandem reaction, Bi(OTf)₃ exhibits unique activities and promotes both of enamine-imine tautomerism and 2-aza-Cope rearrangement.

Full text of DOI:10.1021/acs.orglett.0c00796

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Letter
Bismuth(III)-Catalyzed Sequential Enamine−Imine Tautomerism/2-
Aza-Cope Rearrangement of Stable β‑Enaminophosphonates: One-
Pot Synthesis of β‑Aminophosphonates
Ming Jin, Shi-fu Yin, and Shang-Dong Yang*
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sı Supporting Information
ABSTRACT: A novel catalytic tautomeric transformation of a β-enaminophosphoryl and 2-aza-Cope rearrangement sequence has
been successfully applied to the one-pot synthesis of β-aminophosphonates with high efficiency and good tolerance. In this tandem
reaction, Bi(OTf) exhibits unique activities and promotes both of enamine−imine tautomerism and 2-aza-Cope rearrangement.
3
1
β-Aminophosphonic acids, as “phosphorus analogues” of the
catalyzed asymmetric proton transfer reaction in metastable
12
corresponding amino acids, have widespread applications as
antibacterial agents, enzyme inhibitors, haptens for catalytic
phosphonate antibodies, and anti HIV agents (Figure 1, A).
However, only limited catalytic methods have been
established for their preparation. The exploration of novel
and versatile protocols which allow easy access to the β-
aminophosphonate precursors is in high demand. From the
perspective of synthetic potential, catalytic tautomerization of
enamines, displaying the practicality of acid-mediated
tautomerization of simple enamines to imines. In addition,
2
3
4
5
13
Hantzsch ester has been widely applied as a hydrogen donor
6
in several transformations, and enamine−imine tautomerism
resulting in aromatization is the key to its reactivity. At present,
the catalytic transformation of in situ tautomerization of β-
enaminophosphoryl species to active imine intermediates is
still a challenging process due to the highly stable conjugated
NH-CC−PO structures. Herein, we have achieved an
efficient method for the synthesis of β-aminophosphonates
from β-enaminophosphonates by a bismuth-catalyzed tandem
enamine−imine tautomerization and 2-aza-Cope rearrange-
7
β-enaminophosphoryl to produce active imine intermediates
which can go through further functionalizations would provide
a concise and general access to β-aminophosphonates. Over
the past two decades, a variety of strategies have been
developed to drive the tautomerization of enamines to imines
in catalytic transformations (Figure 1, B). For example, in
006, Nagy and Fabian conducted a theoretical study of enol
imine−enaminone tautomeric equilibria and found the
tautomeric preference changes due to solvent-dependent
14−16
ment
sequence (Figure 1, C).
At the outset, α-phosphoryl formaldehyde 1A and
homoallylic amine 2a were applied as the model substrates
for the tandem reaction (for details, see Supporting
Information Table S1). To our delight, the desired product
2
8
2+
3A was detected when Bi(OTf) was chosen as the catalyst,
3
hydrogen bond interactions. In a host−guest system, Zn
albeit in trace yield. Taking into consideration that the effect of
steric hindrance was very crucial for the 2-aza-Cope rearrange-
ment step in the formation of the six-membered ring chair
transition state, we replaced 1A (R = Ph) with a more flexible
phosphonate 1a (R = OEt). As a result, this change increased
selectively interacts with anthracenone compounds and
induces a metal-mediated imine−enamine tautomerization
process, which contributes to the development of a new
9
fluorescence detection method. Moreover, highly Lewis acidic
B(C F ) can react with equivalent amounts of NH hetero-
6
5 3
cycles to form stable adducts which are useful intermediates in
1
0
11
Received: March 2, 2020
synthesis. Metal ligand cooperation (MLC) catalysis is a
new method to drive the tautomerization process, allowing for
higher catalytic performance. This strategy has inspired
11b
Milstein and co-workers to design new PNN-Ru catalysts
for efficient borrowing hydrogenation reactions. More recently,
Luan and co-workers have developed a chiral phosphoric acid
©
XXXX American Chemical Society
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A
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transition metals including platinum, palladium, rhodium,
iridium, and ruthenium complexes. However, metal salts such
as bismuth, tungsten, and tin were proven to be effective
catalysts. On the basis of these preliminary results, Bi(OTf)3
was chosen as the catalyst for further optimization.
Thereafter, we further investigated the reaction conditions
for details, see Supporting Information Table S2). At first, the
(
temperature was evaluated (entries 1−5). The yield decreased
with decreased temperature, and no product was detected
below 80 °C. A variety of solvents were then screened at 90 °C
(
entries 6−13). The reaction did not work in solvents such as
CH CN, dioxane, and DMAc. Comparatively, the yield was
3
improved to 61% with DCE as the solvent. The effects of
antagonistic anions were also investigated through the
combination of BiI with different silver salts (entries 14−
3
2
6). AgPF and AgNTf showed comparable performance,
6 2
whereas a sharp decline in yield was observed with AgBF4
additive. Interestingly, the yield increased when the catalyst
loading was decreased from 15 to 5.0 mol % (entries 27−29).
A diminished yield was observed when the catalyst loading was
reduced to 2.5 mol % (entry 30). Then, a secondary
investigation on temperature was conducted (entries 31−34)
and the yield was further improved to 76% at 100 °C (entry
3
2). Elevated or reduced concentrations gave no improved
results (entries 35−36). An enantioselective variant could not
be achieved despite the employment of a variety of chiral
ligands.
With the optimal conditions in hand, we set out to explore
the scope of this transformation (Scheme 1). Substituents in
the phosphonyl group were investigated, giving good reactivity
in each case (3a−3c, 56−72% yields). It should be noted that
both diastereoisomers of 3c were isolated by column
chromatography on silica gel. The relative configuration was
confirmed by 2D-NOESY analysis, and two isomers were
described as (±)-erythro-3c′ and (±)-threo-3c′′ (see the SI
for details). Substrates with ortho-I or ortho-Cl in the phenyl
groups were well tolerated, albeit in lower yields (3d and 3e,
5
2−54% yields). Compound 2f with a (p-CF )C H group
3
6
4
also worked well, giving the product in a satisfactory yield (3f,
8% yield). In addition, 2g bearing a phenolic hydroxyl group
Figure 1. Bioactive β-aminophosphonic acids and strategy for
enamine−imine tautomerization.
6
could also serve as a reaction partner; however, the two
isomers failed to be isolated by column chromatography (3g,
4
0% yield). When the phenolic hydroxyl group was protected
the yield of the corresponding product 3a to 55% (Figure 2a).
As indicated by Figure 2b, the phosphonate group is more
favorable to formation of the six-membered ring transition
state. Encouraged by these results, Brønsted acids and other
metal catalysts were examined. Chiral phosphonic acids and D-
camphorsulfonic acid failed to promote the reaction, as did
with a TBS group, the reaction still proceeded smoothly with
the protecting group unaffected (3h, 50% yield). Monosub-
stituted phosphonyl formaldehyde 1i gave a moderate yield
(
3i, 51% yield), which may derive from more flexible
configuration of the corresponding imine intermediate. At
this stage, we turned our attention to more general substrates,
and a variety of alkyl-substituted α-phosphonyl formaldehydes
were tested in the reaction. These reactions all worked
smoothly to provide the corresponding β-aminophosphonates
with satisfying yields (3j−3o, 69−75% yields). No isomer-
ization of the olefin or ring-opening of the cyclopropane was
observed (3j−3k, 3o), indicating excellent tolerance of this
bismuth catalysis. Notably, threo-isomers were the major
products in the reaction, and the ratio of threo- to erythro-
isomer varied from 1.3:1 to 2.8:1 with the change of substrates.
However, the reaction did not work with substrates 1r and 1q,
possibly due to the coordination of nitrile group to the bismuth
catalyst and the strong conjugation of the aryl group. In
addition, the reaction was incompatible with amines 2b−2d. A
possible reason may be that the spatial configurations are
Figure 2. Preliminary results on the tandem reaction.
B
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Letter
Scheme 1. Reaction Scopea,b
Scheme 2. Synthetic Applications
Scheme 3. Mechanism Investigation
a
Bi(OTf) (0.01 mmol), 1a−1o or 1q−1r (0.10 mmol), 2a−-2d
3
(
0.11 mmol), 4 Å MS (50 mg), DCE (1.0 mL), under argon at 100
b c
°C for 60 h. Yield of isolated product. Two diastereomers were not
isolated by column chromatography on silica gel, and the ratio was
determined by 31PNMR analysis.
(
Schemes 3b). These results indicated that Bi(OTf) was very
3
changed with different amine substrates, disfavoring the 2-aza-
Cope rearrangement processes any further.
effective in prompting the 2-aza-Cope rearrangement process.
To further investigate the action of Bi(OTf) in the reaction,
3
Having establishing the reaction scope, we started to explore
the utilities of this method in synthesis. As demonstrated in
Scheme 2a, removal of protecting groups in 3h′′ was
performed with high efficiency, and the corresponding amine
control reactions of 1o and 2a were done under bismuth
catalysis, whereas no product was detected without Bi(OTf)3
and only enamine intermediate C was isolated (Schemes 3c
and 3d), which shows that Bi(OTf)3 could drive the
tautomerization of β-phosphorylenamine toward β-phosphoryl
imine and also benefit the subsequent 2-aza-Cope rearrange-
ment process. In addition, monodeuterated product [D]-3o,
which was generated from the 2-aza-Cope rearrangement of
the corresponding imine intermediate, was detected from the
deuterium-labeling experiment of enamine C in the presence of
4
h was obtained in excellent yield. Compound 5i, the
17
precursor of a bioactive molecule, could be easily accessed
from simple starting materials with the assistance of this
bismuth-mediated tandem reaction (Scheme 2b). Significantly,
the current bismuth-catalyzed enamine to imine tautomeriza-
tion can also cooperate with a successive transfer hydro-
genation process, delivering 3B in 94% yield through a one-pot
operation (Scheme 2c).
10 equiv of D O (Scheme 3e), indicating that a proton transfer
2
type tautomerization of enamine C took place in the reaction.
Subsequently, mechanistic experiments were conducted to
obtain more details on this transformation. To verify the role
of bismuth catalyst in the reaction, a series of control
experiments were performed. The reaction of 1p and 2a
In conclusion, Bi(OTf) acts as a sequential catalyst and
3
promotes both of the two key steps in the tandem reaction:
enamine−imine tautomerism and 2-aza-Cope rearrangement
of imine intermediate generated in situ.
14,18
proceeded in the absence of Bi(OTf) at 100 °C to only
On the basis of these results and previous reports,
a
3
observe the 9% NMR yield (Schemes 3a). However, the yield
was greatly increased to 44% with Bi(OTf)3 as catalyst
plausible reaction pathway was proposed (Scheme 4). Initially,
aldehyde 1 and amine 2a were condensed to provide the
C
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Scheme 4. Mechanistic Rationale
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We are grateful to the NSFC (No. 21532001) and the
International Joint Research Centre for Green Catalysis and
Synthesis, Gansu Provincial Sci. & Tech. Department (No.
2016B01017), for financial support.
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Shang-Dong Yang − State Key Laboratory of Applied Organic
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State Key Laboratory for Oxo Synthesis and Selective
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Ming Jin − State Key Laboratory of Applied Organic Chemistry,
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Shi-fu Yin − State Key Laboratory of Applied Organic
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