3-Imidoallenylphosphonates: In Situ Formation and β-Alkoxylation

Article abstract of DOI:10.1021/acs.orglett.5b03314

3-Imidoallenylphosphonates, allenes bearing both an electron-withdrawing and -donating group, were isolated for the first time. An alkoxy substituent was introduced into these unprecedented intermediates in a one-pot approach, yielding β-functionalized am

Full text of DOI:10.1021/acs.orglett.5b03314

Letter
pubs.acs.org/OrgLett
3‑Imidoallenylphosphonates: In Situ Formation and β‑Alkoxylation
Jan K. E. T. Berton, Thomas S. A. Heugebaert, Wouter Debrouwer, and Christian V. Stevens*
SynBioC Research Group, Department of Sustainable Organic Chemistry and Technology, Faculty of Bioscience Engineering, Ghent
University, Coupure Links 653, B-9000 Ghent, Belgium
*
S Supporting Information
ABSTRACT: 3-Imidoallenylphosphonates, allenes bearing
both an electron-withdrawing and -donating group, were
isolated for the first time. An alkoxy substituent was introduced
into these unprecedented intermediates in a one-pot approach,
yielding β-functionalized aminophosphonates in excellent
yields and short reaction times. The mechanistic insights
gained are important additions to the domain of allene chemistry. Addition of biologically important molecules, including
monoglycerides, amino acids, and nucleosides, proves the general applicability of the developed method.
llenes are highly interesting building blocks, displaying a
broad range of reactivities owing to their unique molecular
Scheme 1. Approaches for the Synthesis of
Aminoallenylphosphonates
A
1
,2
3,4
structure of cumulated double bonds. Like alkynes, they are
excellent substrates for transition-metal-catalyzed cycloisomeri-
5
zations and readily participate in cycloadditions. They are,
however, often underused because of their supposedly low
stability. Amino-substituted allenes react with alcohols, thiols,
6
and secondary amines to give 1,2-adducts and react in [2 + 2] or
7
[
2 + 4] cycloadditions. These electron-rich allenamines,
however, are difficult to handle. They tend to polymerize even
8
at low temperatures and are sensitive to moisture. Amido-
allenes, being less electron-rich, are more stable and display
enamide reactivity. For instance, they are hydroaminated
9
through Lewis acid activation of the proximal double bond or
undergo alkoxylation at the α- or γ-position, but usually not at the
1
0
β-position. On the other hand, nucleophilic addition to
acceptor substituted allenes usually takes place at the β-position
yielding either the nonconjugated (kinetic control) or the
conjugated (thermodynamic control) product. In this work we
explored the unique reactivity pattern of allenylphosphonates
bearing an imide N-substituent. As part of our continuing interest
11−15
in phosphonylated N-containing compounds,
we inves-
tigated the one-pot synthesis and conversion of these previously
unreported 3-imidoallenylphosphonates 8 (Scheme 1b). The
first synthesis of allenylphosphonates was reported simulta-
neously by Mark and Boisselle, employing a [2,3]-sigmatropic
there is no further information on the synthesis or reactivity of 3-
22,23
aminoallenylphosphonates 8.
Aside from the mechanistic
interest, they are also precursors to γ-aminophosphonates.
Aminophosphonates are bioisosteres of amino acids and can act
as peptidomimetics in known antibacterial, antifungal, and
16,17
rearrangement of phosphonylated propargyl alcohols.
These
2
4
herbicidal agents. Allenes themselves can also play an
important role in the metabolic stability of pharmaceuticals.
Enprostil is a marketed prostaglandin analogue that is over 600
allenylphosphonates were readily activated by electrophiles to
18
produce oxaphospholenes through intramolecular cyclization.
Recently, the Fadel group reported the same sigmatropic
rearrangement for ynamido-alcohols, yielding the corresponding
times more potent than PGE in inhibiting gastric acid
2
25
19
secretion.
1
-sulfonamidoallenylphosphonates 2. They could be selec-
Our investigation started from phosphonylated propargyl-
amines 7a−b, which were easily prepared using an improved
literature procedure. Gao reported an elegant phosphonylation
tively reduced to α-vinylaminophosphonates 3, but also reacted
in a 5-endo-dig cyclization upon deprotection of the PMB-group
20
with CAN (Scheme 1a). Reaction with primary amines
21
produced phosphonylated imidazoles 5.
Phosphite addition to propyn iminium salts failed to produce
-aminoallenylphosphonates, and to the best of our knowledge,
Received: November 17, 2015
3
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03314
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of alkynes under a dry air atmosphere, but only on a 0.5 mmol
the nucleophile to the allene intermediate (entry 8). Increasing
the amount of KOtBu to 2 equiv gave complete reaction in no
more than 60 s (entry 9). We next investigated whether other
and eventually nonvolatilenucleophiles could be added. To
that end, a non-nucleophilic base, an aprotic solvent, and the use
of a stoichiometric amount of the nucleophile were required
26
scale and requiring 16 h. When scaling up the reaction we
found that also Glaser coupling occurred, which could be
suppressed by bubbling oxygen through the reaction mixture.
The phosphonylated alkynes 7a−b were obtained in high yields
on a 10 mmol scale in drastically shortened reaction times (see
Supporting Information). In preliminary experiments, phospho-
nylated N,N-di-Boc-propargylamine 7a was used as starting
material. At first, stoichiometric isomerization was evaluated with
(conditions A). Hence, K CO and THF were selected, using 1
2 3
equiv of EtOH as the nucleophile. The addition product 10 was
obtained as the single product, but full conversion required 8
days (entry 10). We reasoned that the limited solubility of the
2
7,28
organolithium bases (BuLi, LDA) in aprotic media.
However, the isomeric allenic products could not be detected
base hampered reaction progress. Thus, replacing K
Cs CO gave a completed reaction in only 40 min (entry 11).
NMR disclosed a Z-configuration of the olefin based on a 2.5%
NOE-enhancement of the vinylic proton when irradiating CH P.
CO with
3
35
2
29
(Table 1, entries 1−2).
2
3
Table 1. Optimization of Isomerization and Nucleophilic
Addition Conditions
2
No NOE-effects were observed between OCH and the vinylic
2
proton.
Next, we prepared a small library of derivatives. The addition
of primary, secondary, and tertiary alcohols was first evaluated
(
Scheme 2, compounds 9−11). As steric hindrance of the
introduced nucleophile increased, the transformation proceeded
more slowly, and in the case of t-BuOH, a complex mixture was
obtained. With i-PrOH, the addition product was still the major
product, along with some remaining alkyne and allene starting
material and a multitude of minor impurities. For volatile
nucleophiles, the nucleophile could be applied as the solvent
equiv
base
time
9/10
c
c
entry
base
BuLi
solvent
(min) t (°C) 8 (%)
(%)
1
2
3
4
5
6
1
dry Et O
60
180
60
30
5
−78
0
0
0
2
1
LDA
dry Et O
0
0
2
1
NaH
dry THF
dry THF
DMSO
rt
32
24
0
0
0.2
0.2
1
NaH
Δ
rt
0
(
conditions B). With EtOH, addition was rapid (60 s), and the
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
K CO
7
addition product 10 was isolated in 97% yield. The i-PrOH
derivative 11 could similarly be obtained in 94% yield. Upon
conducting the reaction in t-BuOH as a solvent, 82% conversion
to 9 was achieved after 3 h at 40 °C. Longer reaction times gave
secondary reactions that prevented isolation of 9. Other primary
alcohols such as n-BuOH and BnOH smoothly gave the desired
compounds 12 and 14 in yields around 90% (conditions A),
again without the need for purification. Phenol reacted rapidly to
give a mixture of two addition products 13a and 13b in a 6:1 ratio
and 90% yield. With the sterically demanding (−)-borneol as a
nucleophile, the intermediacy of the allene was illustrated once
again, but a conversion higher than 20% to the addition product
15 could not be achieved, nor could 15 be isolated. The presence
of an electrophilic group in the substrate, such as the aldehyde in
5-HMF (5-hydroxymethylfurfural), did not complicate matters
giving full conversion to 16 in 90% crude yield in 1 h. When
preparing an analytical sample, the removal of some minor
impurities required reversed phase flash chromatography causing
partial degradation, which has been previously observed in the
dry THF
dry THF
t-BuOH
t-BuOH
THF
1
rt
19
47
34
0
4
a
7
0.2
1
2
0
0
8
5
40
40
rt
25
100
100
100
9
2
1
b
10
1
1
8 days
40
0
2
3
b
1
1
Cs CO
2
THF
rt
0
3
a
equiv of t-BuOH added. 1 equiv of EtOH added. c31P NMR
conversion.
b
1
Accordingly, phthalimidoyl protected alkyne 7b was then used
exclusively, as the Boc-groups of alkyne 7a were not stable under
the previously applied conditions. Next, the isomerization using a
milder NaH or KOtBu aprotic system was investigated. Using a
stoichiometric amount of NaH, 32% of the starting material was
converted into the allene within 1 h, after which degradation
quickly occurred (entry 3). Using a catalytic amount of NaH led
to a lower conversion, while secondary reactions still occurred
30
(
entry 4). When performing the reaction in DMSO with KOtBu
31
36
as the base, 7% conversion to an addition product 9 was
observed (entry 5). Although allene 8b was not detected, this
addition product caught our interest given the position of the
isolation of related HMF derivatives. The coupling of two
allene moieties with ethylene glycol also proved to be easily
achievable as all of the starting material was converted into an
easily separable 91/9 mixture of bis-adduct 17a and monoadduct
17b. When water was evaluated as a nucleophile, the formation of
the corresponding ketone was expected, but we instead observed
formation of a complex reaction mixture, probably due to aldol-
type reactions.
3
2
double bond. Switching the solvent to THF and employing a
33
stoichiometric amount of base gave the allene intermediate 8b
and the addition product 9 together for the first time (entry 6).
Providing a proton source by adding 1 equiv of t-BuOH markedly
increased the conversion of the starting material, giving ∼50% of
the allene in only 2 min at 0 °C (entry 7). Longer reaction times
gave complex mixtures. Screening of different solvents in the
KOtBu/t-BuOH system revealed that conversion to allene 8b
was rapid but a conversion higher than 50% could not be
achieved (SI, Table 1), as alkyne 7b and allene 8b were most
likely in equilibrium. We then decided to scavenge the
intermediate allene 8b to obtain full conversion to the addition
product.
Finally, the addition of more complex and biologically relevant
molecules was investigated. Addition of DL-α-palmitin gave rise
to phospholipid-type product 18. Full conversion was obtained
in 30 min, resulting in four addition products (ratio 9:34:50:7 in
96% crude yield), which could not be separately isolated (see SI).
Addition of protected amino acids resulted in phosphono-
peptides 19 and 20. Phosphonopeptides often display important
biological activities. Bialaphos for instance is an antibacterial
24
Performing the addition in t-BuOH instead of adding just 1
equiv of t-BuOH as a proton source clearly drives addition of
metabolite, which also possesses strong herbicidal properties.
34
Adduct 19 was isolated in 63% yield as a 9/1 Z/E mixture. Partial
B
DOI: 10.1021/acs.orglett.5b03314
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Substrate Scope of Formation of β-Functionalized Aminophosphonates
a
Isolated yield and reaction time are indicated.
elimination of the addition product 19, giving 22 and 23, was
unavoidable, even when running the reaction at 0 °C, and
accounts for the slightly lowered yield in comparison to less
complex nucleophiles (Scheme 3).
detected in NMR experiments, only alkoxylation of isolated
allene 8b can unambiguously rule out Michael addition. To this
end, alkyne 7b was isomerized (Cs CO /THF; see SI) to the
2 3
allene 8b resulting in the first ever isolation of the 3-
imidoallenylphosphonate 8b in 16% yield. First, it was found
to be stable for several days, thus countering arguments that these
allenes display low stability. Second, allene 8b was indeed in
equilibrium with alkyne 7b, as 16% isomerization to 7b was
found under the same conditions.
Scheme 3. Elimination of the N-Z-L-Serine Methyl Ester
Addition Product
Most importantly, full conversion of allene 8b to allylphosph-
onate 27 in the presence of Cs CO and EtOH is compelling
2
3
evidence for the allene being the key intermediate in this one-pot,
two-step reaction. However, it is clear that product 28 can also be
produced from the addition to allene 8b (Scheme 4). Regardless
of the nucleophile adding across the C −C or the C −C double
Addition of N-Z-L-tyrosine methyl ester did not suffer from
this elimination reaction, as no acidic proton is present in the
tyrosine methyl ester. As was the case with the addition of
phenol, allylphosphonate 20a and vinylphosphonate 20b were
swiftly formed in a 6:1 ratio in 97% crude yield, after which the
regioisomers were separated from each other. The conformation
of 20b was confirmed to be Z, as a 2% NOE-effect was found on
α
β
β
γ
bond, the formation of a nonconjugated allyl anion, 24 or 26,
Scheme 4. Proposed Mechanism
the vinylic proton when irradiating NCH . Ultimately, the
2
addition of protected uridine was evaluated, as phosphono-
nucleosides such as tenofovir and adefovir are used in the
treatment of HIV. We were pleased to find that the uridine
addition product 21 could be isolated in 64% yield. For all of the
synthesized derivatives, addition selectively occurs at the central
C-atom. This illustrates that 3-imidoallenylphosphonates behave
as acceptor substituted allenes.
Finally, we investigated the mechanism of this alkoxylation
37
reaction. Michael addition to alkyne 7b would initially produce
vinylphosphonate 28 which can isomerize to yield the
allylphosphonate 27. Although vinylphosphonate 28 was never
C
DOI: 10.1021/acs.orglett.5b03314
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
results, owing to the unique orbital structure of allenes. These
nonconjugated anions either can be immediately protonated to
give 27 or 28 respectively or can rotate around their single bond,
forming the conjugated allyl anion 25. After protonation this can
lead again to the formation of either the allylphosphonate 27 or
the vinylphosphonate 28.
(5) Krause, N.; Winter, C. Chem. Rev. 2011, 111, 1994.
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(
(
(
1
(
5
During our syntheses we exclusively observed the formation of
allylphosponates 27, except for phenolic nucleophiles. In the case
of phenol addition at rt, a 6:1 27/28 ratio was found. When this
addition was repeated at 0 °C we found a 12:1 27/28 ratio. This
indicates either that the addition reaction is under kinetic control
or that Michael addition to alkyne 7b occurs (7b to 28) and is
suppressed at this lower temperature. Whatever the case, it was
shown that the pathway does not primarily pass over 28. Under
the applied conditions (rt, Cs CO ) 28 did not isomerize to 27.
Tamaru, Y. Org. Biomol. Chem. 2008, 6, 4105.
(11) Debrouwer, W.; Heugebaert, T. S.; Stevens, C. V. J. Org. Chem.
2
(
014, 79, 4322.
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J. Org. Chem. 2013, 78, 8232.
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03.
15) Moonen, K.; Van Meenen, E.; Verwee, A.; Stevens, C. V. Angew.
(
2
3
Furthermore, 27 was shown to be the thermodynamically more
stable product, as 28 was entirely converted to 27 upon 18 h of
reflux. Thus, the formation of 28 is not a part of the major
(
2
(
38
reaction pathway. This is in accordance with literature data, as
Chem., Int. Ed. 2005, 44, 7407.
addition of NaN to 3-phenylpropa-1,2-dienylphosphonate also
(16) Mark, V. Tetrahedron Lett. 1962, 3, 281.
(17) Boisselle, A. P.; Meinhardt, N. A. J. Org. Chem. 1962, 27, 1828.
3
gives the allylphosphonate, preserving the double bond
39
(
(
(
18) Macomber, R. S. J. Am. Chem. Soc. 1977, 99, 3072.
19) Gomes, F.; Fadel, A.; Rabasso, N. J. Org. Chem. 2012, 77, 5439.
20) Adler, P.; Gomes, F.; Fadel, A.; Rabasso, N. Eur. J. Org. Chem.
conjugated to the aromatic group.
In conclusion, the first synthesis of 3-imidoallenyl-
phosphonates was demonstrated. This transformation proceeds
via a prototropic rearrangement under very mild conditions, and
the imidoallenylphosphonate was isolated and characterized.
Moreover, it can be alkoxylated in a one-pot procedure in very
short reaction times in excellent chemical yields. The method is
applicable to an array of highly functionalized biologically
relevant nucleophiles, furnishing these adducts in moderate to
good yields. Purification on column was needed only in the case
of the more complex nucleophiles (15−21).
2
013, 2013, 7546.
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2
(
071.
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(24) Aminophosphonic and aminophosphinic acids: Chemistry and
Biological Activity; Kukhar, V. P., Hudson, H. R., Eds.; Wiley: Hoboken,
NJ, 2000.
(25) Carpio, H.; Cooper, G. F.; Edwards, J. A.; Fried, J. H.; Garay, G.
L.; Guzman, A.; Mendez, J. A.; Muchowski, J. M.; Roszkowski, A. P.; Van
Horn, A. R. Prostaglandins 1987, 33, 169.
ASSOCIATED CONTENT
Supporting Information
■
(26) Gao, Y.; Wang, G.; Chen, L.; Xu, P.; Zhao, Y.; Zhou, Y.; Han, L. J.
*
S
Am. Chem. Soc. 2009, 131, 7956.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b03314.
(27) Steinmetz, M. G.; Mayes, R. T. J. Am. Chem. Soc. 1985, 107, 2111.
(28) Doye, S.; Hotopp, T.; Wartchow, R.; Winterfeldt, E. Chem. - Eur. J.
1
998, 4, 1480.
Experimental details, product characterizations, and
spectral data (PDF)
(29) With BuLi the alkyne was dephosphonylated, while LDA attacked
the tBu-group producing the carbamic acid which cyclized to produce
the oxazolidinone.
(30) Sturtz, G.; Paugam, J. P.; Corbel, B. Synthesis 1974, 1974, 730.
AUTHOR INFORMATION
Corresponding Author
■
*
(31) Selling, H. A.; Rompes, J. A.; Montijn, P. P.; Hoff, S.; van Boom, J.
H.; Brandsma, L.; Arens, J. F. Recl. Trav. Chim. Pays-Bas 1969, 88, 119.
E-mail: chris.stevens@ugent.be.
2
3
(
32) A J coupling constant of about 20 Hz is typical for a PCsp
HP
Notes
fragment, indicating protonation of the carbon in α-position to the
phosphonate had occurred.
The authors declare no competing financial interest.
(
(
(
33) Lehrich, F.; Hopf, H. Tetrahedron Lett. 1987, 28, 2697.
34) Deutsch, E. A.; Snider, B. B. Tetrahedron Lett. 1983, 24, 3701.
35) It was noted that when a catalytic amount of Cs CO was used, full
ACKNOWLEDGMENTS
J.K.E.T.B. thanks Ghent Univeristy for financial support.
T.S.A.H. and W.D. thank the Research Foundation Flanders
■
2
3
conversion could not be obtained.
(36) Heugebaert, T. S. A.; Stevens, C. V.; Kappe, C. O. ChemSusChem
2015, 8, 1648.
(
FWO) for financial support for postdoctoral mandates. Prof.
Joseph J. Bozell (University of Tennessee, Knoxville) is thanked
for useful suggestions.
(37) Panarina, A. E.; Dogadina, A. V.; Ionin, B. I. Russ. J. Gen. Chem.
2
(
003, 73, 1729.
38) Moreover, it was shown that the addition was irreversible under
the applied conditions. No exchange of the alkoxy moiety was observed
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DOI: 10.1021/acs.orglett.5b03314
Org. Lett. XXXX, XXX, XXX−XXX