Taming the Reactivity of Phosphiranium Salts: Site-Selective C-Centered Ring Opening for Direct Synthesis of Phosphinoethylamines

Article abstract of DOI:10.1002/anie.201916449

Advances in the field of phosphorus chemistry are documented, by revealing the synthetic utility of previously underutilized quaternary phosphiranium salts (QPrS) as three-chain-atom electrophilic building blocks. Notably, control of their challenging C-centered electrophilicity is disclosed with an expedient synthesis of tertiary β-anilino phosphines as a proof-of-concept.

Full text of DOI:10.1002/anie.201916449

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Accepted Article
Title: Taming the reactivity of Phosphiranium salts: Site-
selective C‑centered-Ring Opening for Direct Synthesis of
Phosphinoethylamines
Authors: Julien Gasnot, Clément Botella, Sébastien Comesse, Sami
Lakhdar, Carole Alayrac, Annie-Claude Gaumont, Vincent
Dalla, and Catherine Taillier
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10.1002/anie.201916449
Angewandte Chemie International Edition
Taming the reactivity of Phosphiranium salts: Site-selective
C-centered-Ring Opening for Direct Synthesis of
Phosphinoethylamines
Julien Gasnot,[a] Clément Botella,[a] Sébastien Comesse,[a] Sami Lakhdar,[b] Carole Alayrac,[b] Annie-
Claude Gaumont,[b] Vincent Dalla[a]* and Catherine Taillier[a]*
Abstract: This work documents advances in the field of phosphorus
chemistry, by revealing the synthetic utility of the heretofore under-
utilized quaternary phosphiranium salts (QPrS) as 3-chain atoms
electrophilic building blocks. Notably, the control of their challenging
C-centered electrophilicity is disclosed with as proof of concept an
expedient synthesis of tertiary -anilino phosphines.
nucleophile is known.[8] Oxygenated nucleophiles (H2O, MeOH,
EtOH) were exclusively used, which not surprisingly (vide supra)
led to complete P-selectivity. (Scheme 1, B). Interestingly, one
early report presented phosphiranes as potential precursors of
polyphosphine polymers using cationic initiation postulated to rely
on the formation of a transient phosphiranium intermediate. [6b] On
these grounds, we assumed that QPrS are attractive platforms to
become useful C-centered 3-chain atoms electrophilic building
blocks, by virtue of their broad potential for structural modification
and reactivity modulation. In practice, we anticipated that a
synergistic association of the required polarity inversion of the P-
C linkage to favour C-attack, coupled with an increased steric
constrain to prevent nucleophilic attack from occurring at
phosphorus, could be fashioned through proper handling of
sterics and electronics in a concerted way within the QPrS
structures. In this context, we report here preliminary successes
toward these aims, illustrated by the first examples of
intermolecular ring-openings of phosphiranium salts[9] with good
chemical efficiency and complete carbon selectivity using anilines
as a nucleophile component (Scheme 1, C).
The chemistry of 3-membered saturated rings containing one
heteroatom has been extensively studied and successfully
exploited in many valuable transformations for the rapid and
atom-economical access to a wide array of functionalized building
blocks. Ring-opening reactions dominate the chemistry of these
entities, with epoxides and aziridines as leading examples, and
have amply contributed to make them highly valuable and popular
synthetic intermediates.[1] Nucleophilic attack is routinely
occurring selectively on the ring carbons due to polarization of the
C-heteroatom bond, but nonetheless activation of the
heterocycles is often required to promote the desired ring
cleavage (Scheme 1, A). As seen in the aziridine series,
introduction of an electron withdrawing group on nitrogen or
quaternarization leading to aziridinium ion intermediates were
often used as efficient activation modes to improve reactivity and
scope,[2] by weakening the C-N bond by accentuating charge
separation with concomitant increase of the ring carbons
electrophilicity. Despite an obvious structural analogy, 3-
membered phosphorus analogues have barely been involved in
similar transformations, and the site-selective ring opening of
phosphirane derivatives at carbon for direct incorporation of
phosphino ethylene units into molecules still remains a challenge
(Scheme 1, A). This is largely correlated with their relative
instability, susceptibility to oxidation, and polarity inversion of the
C-P bond which inherently places electrophilicity on
phosphorus.[3]-[6] Quaternary phosphiranium salts (QPrS) have
long remained elusive species which were mostly described as
transient intermediates postulated on the basis of analytical
data.[7] The first example of an isolated and fully characterized
QPrS dates back to 1995, and as far as we are aware, only a
single report discussing its ring-opening with an external
Scheme 1. Nucleophilic ring-opening of nitrogen and phosphorus 3-membered
onium ions.
[a]
Dr. J. Gasnot, C. Botella, Dr. S. Comesse, , Prof. V. Dalla, Dr. C.
Taillier Normandie Univ., URCOM, UNIHAVRE, FR 3032, EA 3221
25 rue Philippe Lebon, BP 540, 76058 Le Havre (France)
E-mail: vincent.dalla@univ-lehavre.fr
We
began
our
investigations
with
the
model
methylphosphiranium triflate salt 1a.[10],[11] To alleviate any P
affinity issues expressed by the oxygen nucleophiles,[8] we
primarily focused our attention on amino derivatives as a
nucleophile (Scheme 2). Subjecting phosphiranium salt 1a to an
array of primary and secondary amines under various reaction
conditions surprisingly either let 1a untouched, or led to the
E-mail: catherine.taillier@univ-lehavre.fr
[b]
Dr. S. Lakhdar, Dr. C. Alayrac, Prof. A.-C. Gaumont
Normandie Univ., LCMT, ENSICAEN, UNICAEN, CNRS, 6,
Boulevard Marechal Juin, 14000 Caen (France)
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201916449
Angewandte Chemie International Edition
formation of phosphine oxide 5 that most likely results from
nucleophilic attack at P[8] and subsequent reaction with water.[12]
Use of the less nucleophilic aniline gave rise to a major advance
with smooth conversion of 1a and formation of a new major
product, which we isolated in pure form (84% yield), and
characterized as the desired -anilino phosphine 3a.[13] A second
product was also isolated in 6% yield and fully characterized as
the amino diphosphine 3a’ resulting from an additional opening of
the phosphiranium 1a by intermediate II. 3a’ could be
independently prepared and isolated in a synthetically useful yield
of 50% by iterative ring-openings (cond. B). Efforts were
undertaken to further optimize the reaction, but the original
conditions [Cond. A: phosphiranium 1a (1 equiv), aniline 2a (1
equiv), CDCl3, 50 °C] remained the best for optimal yield and
selectivity of 3a.[14]
Scheme 3. Nucleophilic ring-opening of phosphiranium cation 1a with aniline
derivatives.
Using standard conditions at 50°C, N-alkyl secondary anilines
2h-2k gave the corresponding adducts 3h-3k in an uniform and
decent range of yields (44-66%). The data recorded
throughout this preliminary set of results demonstrate that both
sterics and electronics contribute strongly and almost equitably
to reaction rates. As a matter of fact, N-methyl aniline 2h and
its electron-rich 4-methoxy analog 2g comparatively reacted
about 2.5 to 3.5 times slower than their parent primary
congeners 2a and 2c (16 h versus 4.5 h - 6 h). Similarly
reactions with N-benzyl aniline 2k and the deactivated N-
methyl aniline 2j required further increase of the reaction times
(respectively 36 h and 11 d) to reach full conversion. These
two amines could, however, be converted within standard
reaction time (16 h) by slightly increasing temperature to 80°C,
with only little erosion on products yields (3j, 51% versus 66%
and 3k, 34% versus 44%).
Modulations of the quaternarizing group R, the arylphosphine
group, or the nature of the counteranion, which all are key
structural elements within the QPrS structures, [9],[16] were next
scrutinized (Scheme 4). Interestingly, both phosphiranium
triflate 1a and tetrafluoroborate 1b salts exhibited identical
outcomes under the optimal reaction conditions with aniline 2a
[2a (1 equiv), CDCl3, 50 ºC, 6.5 h → 3a, 84% and 85%
respectively], thus arguing for marginal counteranion effect in
this specific case. Furthermore, identical yields of the β-amino
phosphine 3a could also be recorded on application of step-
economical one-pot quaternarization/ring-opening sequences
starting from the parent mesitylphosphirane and using either
MeOTf or Me3O.BF4 as methylation agents (see footnote d in
Scheme 4).
Scheme 2. Nucleophilic ring-opening of phosphiranium cation 1a
The substrate scope for the ring opening of QPrS 1a was
examined using a variety of aniline derivatives (Scheme 3).
Smooth reactions proceeded with primary anilines 2a-2e,
providing the corresponding -amino phosphines 3a-3e. The
electronic nature of the substituents on the aromatic ring as well
as the steric environment around nitrogen clearly proved to
greatly influence reaction kinetics. Reactions indeed took place
over an important time range (from 4.5 h for the electron rich
aniline 2c to 4-5 days for bulky (2c) and electronically deactivated
anilines 2d and 2e). However, these structural variations did not
alter chemical efficiency dramatically, and the desired adducts 3a-
3e were isolated in a homogeneous range of 59-84% yield. Small
portions of the corresponding di-addition products 3’ were
typically observed in these reactions, although it should be
mentioned that their formation was limited or even suppressed
when using electron-poor anilines (see p-NO2 3d). As an
embodiment of the prospective synthetic utility of the method, two
bis-phosphinoethylanilines 3f and 3g with multiple sites for
potential metal coordination.[15] were easily prepared in
synthetically useful yields using dianiline nucleophiles 2f and 2g
(72% and 41% yields respectively).
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10.1002/anie.201916449
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the corresponding ring-opened products 9b and 9c, within 2.5
h and 36 h respectively. However, this increase in reactivity
caused an alteration of the ring-opening selectivity, which
resulted in moderate yields for the phosphinoethylamine
products 9a-9c (38-49%).[18]
The challenging ring-openings of phosphiranium methylene
esters 1h-1j were finally tested with anilines 2a-2b and 2h to
probe the influence of an electron-withdrawing group on both
reactivity and regioselectivity. As shown by the formation of
phosphinoethyl anilines 10a-10c in the preliminary reactions of
1h-1i with 2a, the C-centered ring-opening still prevailed. In
fact, these densely functionalized ester-containing substrates
were found to exhibit similar reactivity profile to P-diaryl
phosphiranium 1g, with ring-openings proceeding at ambient
temperature to give products 10a-10c in moderate yields (27-
48%). Hypothesizing that the observation of substantial
amounts of side products may to some extent reflect site
selectivity issues (competition C vs P),[19] we next evaluated
combination of bulkier reaction partners such as QPrS 1i, 1j
and anilines 2b, 2h. As anticipated and delightfully, yield
enhancements were observed for the corresponding β-
aminophosphines 11a-11c and 12a-12c which were isolated in
33%-88%.[20]
Scheme 4. C-centered ring-opening of phosphiranium cations 1a-1j[a]
.
Influence of steric factors on the reaction selectivity was next
evaluated with QPrS 1c and 1d respectively equipped with the
bulky supermesityl or the simplest phenyl substituents on P.
Reaction of the latter with aniline at 50 °C only led to side-
products.[17] In contrast, the hindered substrate 1c underwent
a slow (4 d at 50 °C) but productive transformation to afford the
corresponding ring-opened product 7a in a modest yield of
34%. Running the reaction at 80 °C again provided spectacular
inputs, with clear reaction kinetic and yield enhancements (16
h, 77%). The P-allyl and P-benzyl QPrS 1e, 1f demonstrated a
spectacular increase in reactivity on reaction with aniline 2a,
yielding in a room temperature process adducts 8a and 8b in
high yields (78% and 71 % over 2 steps).[16b]
Scheme 5. Mechanistic investigations.
Finally, experiments to gain mechanistic insights into the C-
centered ring opening of QPrS 1a were realized (Scheme 5).
Since nucleophilic attack of 1a should produce a transient
protio-anilinium entity with underlying leaving group ability, the
hypothesis of a reversible ring-opening operating under
thermodynamic control was surveyed. Cross-over experiments
reacting the protiophosphonium intermediate II (resulting from
a first ring-opening of 1a with aniline 2a) with either p-methoxy
aniline 2c or 3,5-diCF3 aniline 2e were performed. Neither
formation of scrambling products 3c or 3e nor back reversion
to phosphiranium 1a were observed, thus excluding the
The
substrate
scope
was
further
extended
to
P-diarylphosphiranium salt 1g. This latter also exhibited an
increased reactivity, since only 3 h at 50 °C (vs 6 h in the case
of the model QPrS 1a) was required for full conversion in
reaction with aniline 2a, to give the corresponding ring-opened
product 9a as an inseparable mixture of mono- and di-addition
products in a combined isolated yield of 48% (ratio = 82:18).
This higher reactivity was further exemplified in room
temperature reactions with N-methyl aniline 2h and the
electron-poor aniline 2e (which both normally retard the ring-
opening, see Scheme 3). Both reactions led to the formation of
occurrence of
a reversible process. Otherwise, when
evaluating the scope of the reaction, we occasionally observed
significant influence of the phosphiranium counteranion on the
reaction rates (results not shown). We first postulated a
possible template effect exerted by the sulfonate group[21]
assisting proton transfer from aniline on the forming phosphine
during ring-opening. Test reactions with aniline-d7 2a-d7 and
aniline-d5 2a-d5 were thus realized. In both cases, formation of
the NH product 3a-d5 was obtained, revealing a H/D exchange
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10.1002/anie.201916449
Angewandte Chemie International Edition
[W(CO)5] ring-openings, see : A. Marinetti, F. MatheyTetrahedron 1989, 45,
3061. b) For an example of phosphirane cationic ring-opening
polymerisation, see: S. Kobayashi, J.–I. Kadokawa, Macromolecular
Rapid Communications 1994, 15, 567. c) For some examples of
theoretical and experimental studies on phosphirane derivatives ring-
openings, see: M. L. Coote, J. L. Hodgson, E. H. Krenske, B. E. Wild
Heteroatom Chem. 2007, 18, 118; M. L. Coote, E. H. Krenske, I. Maulana,
J. Steinbach, B. E. Wild Heteroatom Chem. 2008, 19, 178.
during the process. A rather surprising acceleration was also
observed with respect to the benchmark reaction, whether
starting from the triflate salt 1a or the tetrafluoroborate salt 1b.
These results thus suggest that proton transfer from the
developing anilinium ion onto the nascent phosphine is not
involved in the rate determining step, thereby arguing for a
SN2-type mechanism.[22] Further studies aiming to clarify this
assumption are currently ongoing in our laboratory.
[7]
[8]
a) N. J. Lawrence, F. Muhammad J. Chem. Soc., Chem. Commun. 1993,
1187; b) N. J. Lawrence, F. Muhammad, Tetrahedron 1998, 54, 15345; and
ibid. 15361 ; c) S. Krupski, G. Kehr, C. G. Daniliuc, G. Erker Chem.
Commun. 2016, 52, 2695 and references cited.
In conclusion, the underlying C-centered electrophilicity of
phosphiranium ions has been tamed for the first time. Anilines
were identified to exhibit the suitable balance of the key
nucleophilicity, pKa and size attributes required to properly
control site selectivity in the ring opening of QPrS. This
resulted in the production of -aminophosphines in fair to good
a) D. C. R. Hockless, M. A. McDonald, M. Pabel, S. B. Wild J. Chem. Soc.,
Chem. Commun. 1995, 257; b) D. C. R. Hockless, M. A. McDonald, M.
Pabel, S. B. Wild J. Organomet. Chem. 1997, 529, 189; c) For another recent
example of isolated QPrS, see: a) A. Ficks, I. Martinez-Botella, B.
Stewart, R. W. Harrington, W. Clegg, L. J. Higham Chem. Commun.
yields, in
a straightforward and reliable fashion which
2011, 47, 8274.
complements the few existing routes to these synthetically
useful molecules. Beyond the few examples described in this
preliminary study, we expect that these results will inspire
future discoveries to contribute making QPrS with similar
stability and steric features a popular platform for common use
in organic synthesis, e.g. to produce dedicated targets, useful
building blocks as well as potential P,N-tools for catalysis.
[9]
J. Gasnot, C. Botella, S. Comesse, S. Lakhdar, C. Alayrac, A.-C.
Gaumont, V. Dalla, C. Taillier, Synlett, 2020, DOI: 10.1055/s-0040-
1708000.
[10] The model QPrS substrate 1a was obtained by alkylation of the relatively
stable parent mesityl phosphirane with methyl triflate. See SI and
reference in footnote 9 for details.
[11] QPrS 1a was identified in a preliminary study as presenting the required
balance of reactivity/stability for easy handling.
[12] (a) No trace of the desired -amino phosphines 3 was detected in any
cases; (b) The full scope of nucleophiles tested is given in the SI.
[13] Formation of the protonated intermediate II was first observed, as
confirmed by 31P NMR analysis of the crude mixture which gave a broad
1
signal at -14.1 ppm and a large J(H-P) coupling constant (J =516 Hz).
Acknowledgements
Filtration of the crude mixture over basic Al2O3 was next performed to
release the expected phosphinoethyl amine 3a as the major product (in
mixture with the bis-(phosphinoethyl) amine 3a’, 3a/3a’ = 93:07).
[14] a) The full optimization study is given in the SI; b) It should be noted that
identical results in terms of rate and chemical yields were equally
obtained using CDCl3 or CHCl3. Consequently, CDCl3 was chosen as
solvent of choice for NMR monitoring.
We gratefully acknowledge the region Haute-Normandie, the
réseau CRUNCH for grants to JG and CB. JG also thanks the
University Le Havre Normandie for financial support.
Keywords: Phosphiranium ions, Nucleophilic ring-opening, Site-
[15] For representative examples of P,N- and P,N2-ligands, see: a) M.
P. Carroll, P. J. Guiry Chem. Soc. Rev. 2014, 43, 819; b) W. Li, J. Zhang
Chem. Soc. Rev. 2016, 45, 1657; c) For a representative example, see :
J. D. G. Correia, A. Domingos, I. Santos Eur. J. Inorg. Chem. 2000, 1523.
[16] a) The corresponding QPrS substrates 1b-1g were obtained from their
parent phosphiranes (Conditions A-E, Scheme 4) - See SI for details; b)
A sequential one-pot triflation/alkylation protocol was applied. For the
formation of the sensitive triflate intermediate, see: E. J. Corey, C. J.
Helal Tetrahedron Lett. 1996, 37, 5675.
selectivity, Steric protection, Phosphinoethyl amines,
[1]
a) Aziridines and epoxides in organic synthesis Yudin, A. K. Ed. Wiley-
VCH, Weinheim, 2006 ; b) W. H. Pearson, B. W. Lian, S. C. Bergmeier
In Comprehensive Heterocyclic Chemistry II; A. R. Katritzky, C. W. Rees,
E. F. V. Scriven, Eds.; Pergamon Press: Oxford, 1996; Vol. 1A, Chapter
1, p. 1; c) I. Erden In Comprehensive Heterocyclic Chemistry II; A. R.
Katritzky, C. W. Rees, E. F. V. Scriven, Eds.; Pergamon Press: Oxford,
1996; Vol. 1A, Chapter 3, p. 97.
[17] a) The major product formed in the reaction of phosphiranium 1d was
found to be phosphine oxide 5 which most likely results from P-addition
of either aniline 2a or water traces. b) For similar steric effects observed
on the site-selectivity of a C-centered ring opening of epi-selenonium
ions, see: A. Toshimitsu, K. Nakano, T. Mukai, K. Tamao J. Am. Chem.
Soc. 1996, 118, 2756.
[2]
[3]
S. Stanković, M. D'hooghe, S. Catak, H. Eum, M. Waroquier, V. Van
Speybroeck, N. De Kimpe, H.-J. Ha Chem. Soc. Rev. 2012, 41, 643.
a) F. Mathey. Chem. Rev. 1990, 90, 997; b) L. D. Quin, in A Guide to
Organophosphorus Chemistry (Ed.: L. D. Quin), John Wiley Sons, New
York, 2000, pp. 234–241; c) F. Mathey, M. Regitz, in Phosphorus-Carbon
Heterocyclic Chemistry: The Rise of a New Domain (Ed.: F. Mathey),
Elsevier Science, Amsterdam, 2001, pp. 17–55.
[18] In full accordance with our earlier observation (see Scheme 3), formation
of the corresponding di-addition products was marginal in the reactions
of P-diaryl phosphiranium 1g with anilines 2e and 2h.
[4]
[5]
[6]
Phosphiranes are described to be moderately stable species that could
lead to ring-fragmentation reactions or rearrangements. For theoretical
studies, see: a) J. A. Boatz, M. S. Gordon, J. Phys. Chem. 1989, 93,
3025; b) Nguyen, M. T.; Landuyt, L.; Vanquickenborne, L. G., J. Chem.
Soc, Faraday Trans. 1994, 90, 1771.
[19] An increased instability of this series of phosphiranium salts was also
observed. As a consequence, storage of the salts 1h-1j should be limited
to only a few days, even at -20 °C.
[20] Ratios of mono- and di-addition products not shown - See SI for details.
[21] For leading reviews showcasing counterions templating effect, see: a) H.
Xu, S.-J. Zuend, M. G. Woll, Y. Tao, E. N. Jacobsen Science 2010, 327,
986; b) M. Jia, M. Bandini, ACS Catal. 2015, 5, 1638.
Phosphorus and carbon atoms bear significant positive and negative
partial charges respectively. a) D. Gonbeau, G. Pfister-Guillouzo, Inorg.
Chem. 1987, 26, 1799; b) Dobbs, K. D.; Boggs, J. E.; Barron, A. R.;
Cowley, A. H., J. Phys. Chem. 1988, 92, 4886; c) S.-W. Wang, W. Liu,
R. H. Colby Chem. Mater. 2011, 23, 1862.
[22] For a relevant kinetic isotope effects study involving deuteriated aniline
nucleophiles, see : I. Lee, H. J. Koh, B-S. Lee, H. W. Lee, J. Chem. Soc.
Chem. Commun. 1990, 335.
Only rare examples of three-membered phosphorus ring opening were
reported: a) For some examples of phosphirane-tungsten complexes
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COMMUNICATION
Dr. Julien Gasnot, Clément Botella, Dr.
Sébastien Comesse, Dr. Carole Alayrac,
Dr. Sami Lakhdar, Prof. Annie-Claude
Gaumont, Prof. Vincent Dalla and
Dr. Catherine Taillier
Page No. – Page No.
Text for Table of Contents
Taming the reactivity of
Phosphiranium salts: Site-selective
C-centered-Ring Opening for Direct
Synthesis of Phosphinoethyl Amines
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