Biphilic organophosphorus catalysis: Regioselective reductive transposition of allylic bromides via PIII/PV redox cycling

Article abstract of DOI:10.1021/jacs.5b01899

We report that a regioselective reductive transposition of primary allylic bromides is catalyzed by a biphilic organophosphorus (phosphetane) catalyst. Spectroscopic evidence supports the formation of a pentacoordinate (σ⁵-P) hydridophosphorane as a key reactive intermediate. Kinetics experiments and computational modeling are consistent with a unimolecular decomposition of the σ⁵-P hydridophosphorane via a concerted cyclic transition structure that delivers the observed allylic transposition and completes a novel P^III/P^V redox catalytic cycle. These results broaden the growing repertoire of reactions catalyzed within the P^III/P^V redox couple and suggest additional opportunities for organophosphorus catalysis in a biphilic mode.

Full text of DOI:10.1021/jacs.5b01899

Communication
pubs.acs.org/JACS
Biphilic Organophosphorus Catalysis: Regioselective Reductive
Transposition of Allylic Bromides via PIII/PV Redox Cycling
Kyle D. Reichl, Nicole L. Dunn, Nicholas J. Fastuca, and Alexander T. Radosevich*
Department of Chemistry, The Pennsylvania State University, University Park, Pennsylvania 16802, United States
S
* Supporting Information
ABSTRACT: We report that a regioselective reductive
transposition of primary allylic bromides is catalyzed by a
biphilic organophosphorus (phosphetane) catalyst. Spec-
troscopic evidence supports the formation of a penta-
coordinate (σ5-P) hydridophosphorane as a key reactive
intermediate. Kinetics experiments and computational
modeling are consistent with a unimolecular decom-
position of the σ5-P hydridophosphorane via a concerted
cyclic transition structure that delivers the observed allylic
transposition and completes a novel PIII/PV redox catalytic
cycle. These results broaden the growing repertoire of
reactions catalyzed within the PIII/PV redox couple and
suggest additional opportunities for organophosphorus
catalysis in a biphilic mode.
hosphorus-based compounds figure prominently in a range
Pof catalytic applications. Apart from their role as supporting
ligands in transition metal chemistry,1 tricoordinate phosphorus
compounds comprise a well-known class of nucleophilic
catalysts,2 wherein neutral tricoordinate (σ3-P) phosphines
(Figure 1A) behave as electron-pair donors with respect to
electron-deficient substrates to elicit catalysis via tetracoordinate
(σ4-P+) phosphonium intermediates. More recently, the
potential of Lewis acidic σ4-P+ cations themselves to behave as
catalysts in an electrophilic mode via intermediate pentacoordi-
nate (σ5-P) phosphoranes has been demonstrated (Figure
1B).3−5 Herein, we demonstrate a biphilic6 mode of organo-
phosphorus catalysis that unifies both nucleophilic (donor) and
electrophilic (acceptor) reactivities at a single phosphorus center.
Specifically, we show that a small-ring phosphacycle catalyzes the
regioselective transpositive reduction of allylic bromides in a
manner that involves interconversion of well-characterized σ3-P,
σ4-P+, and σ5-P species (Figure 1C). Taken together with
ongoing work in the area of phosphine oxide redox catalysis,7
these results further solidify the viability of the PIII/PV oxidation
state couple in catalytic chemistry8 and portend new develop-
ments in biphilic organophosphorus catalysis that leverage the
unique reactivities of σ5-P phosphoranes.9
Figure 1. Modes of organophosphorus catalysis.
outcome (and by analogy to reduction of related σ4-P+
cations14), the possible intervention of σ5-P hydridophosphorane
intermediates was posited by Gallagher,15 although direct
experimental evidence for this proposed pathway has not been
reported.
On the basis of the aforementioned stoichiometric precedent,
this allylic reduction presented itself as an appealing platform by
which to test emerging hypotheses regarding the design features
requisite for biphilic organophosphorus catalysis.16 In contrast to
the regiospecific transposition of the corresponding stoichio-
metric reduction (Figure 1C), catalytic loading (10 mol %) of
triphenylphosphine-derived ion 617 in the reduction of cinnamyl
bromide (3) with LiAlH(OtBu)3 delivers products 4:5 in a 18:82
ratio (Table 1, entry 2); this γ/α-selectivity ratio deviates only
It is known from the work of van Tamelen10 and Nojima11 that
stoichiometric reaction of allylic phosphonium cations (e.g., 1,
Figure 1C, bottom) with metal hydrides results in reductive
deallylation of the σ4-P+ cation to the corresponding σ3-P
phosphine.12 With respect to the allylic moiety, the reduction is
regiospecific; alkenes 2 resulting from allylic transposition (i.e., γ-
reduction) are the sole products observed under these
stoichiometric conditions.13 On account of this regiochemical
Received: February 20, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b01899
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Journal of the American Chemical Society
Communication
Table 1. Effect of Organophosphorus Catalyst on
Regioselectivity of Transpositive Allylic Reduction
a
chemistry by Westheimer22 and Hudson;23 namely, the strain
accrued to the σ4-P+ phosphetanium 12 minimizes the geometric
reorganization (and by consequence the free energy) necessary
to access a presumed σ5-P hydridophosphorane. As has been
noted by Hoz,24 molecular orbital electronic effects may also play
a significant role in the rate accelerations in small-ring systems.
Assessment of the phosphetane-catalyzed allylic reduction
with respect to a panel of sterically and electronically varied allylic
bromides are collected in Table 2. On a 1 mmol scale, good yield
b
c
c
entry
R3P
yield
ratio (4:5)
1
2
3
4
5
6
7
8
9
none
6
80
78
9:91
18:82
11:89
19:81
54:46
94:6
7
85
8
95
9
95
10
96
d
10
e
100
81
98:2
10
88:12
11
96
91:9
b
Table 2. Assessment of Phosphetane-Catalyzed Allylic
a
a
See Supporting Information for full experimental details. See ref 17.
The combined yield and ratio of 4 and 5 were determined by GC
analysis (dodecane internal standard). Neutral trivalent 10 as catalyst.
10·HBF4 salt as precatalyst.
Reduction
c
d
e
marginally from an uncatalyzed control reduction (entry 1).
Evidently, direct uncatalyzed reduction of 3 with LiAlH(OtBu)3
outcompetes notional biphilic catalysis by triphenylphosphine.
Following on Gallagher’s hypothesis and abundant precedent
demonstrating enhanced electrophilic reactivity of cyclic
phosphorus-based compounds compared to their acyclic
congeners,18 the conversion σ4-P+ → σ5-P was targeted for
acceleration. While neither dibenzophosphole 8 nor phospho-
lane 9 derivatives (proven catalyst motifs in several catalytic PIII/
PVO redox methods)19 satisfactorily alter the reduction
outcome, catalytic loading of phosphonium salt derived from a
four-membered phosphetane 1020,21 delivers reduction products
with excellent γ/α-selectivity. Specifically, dropwise addition of
LiAlH(OtBu)3 (2.5 equiv, 0.42 M in THF) to a 90 °C mixture of
3 and 10 mol % of allylated 10 in toluene over 15 h results in a
combined 96% yield of reduction products as a 94:6 ratio in favor
of the γ-reduction product 4. Use of neutral trivalent
phosphetane 10 provides similarly high selectivity (entry 7),
while the corresponding HBF4 salt results in a slightly diminished
4:5 ratio (entry 8).The identity of the exocyclic P-substituent has
only a minor effect on the observed product ratio (compare
entries 6 and 9), indicating the dominant role of the phosphetane
moiety in controlling the reactivity.
Stoichiometric competition experiments confirm the en-
hanced reactivity of the strained phosphonium salts derived
from four-member phosphacycle 10 toward hydridic reduction.
In the reaction of an equimolar mixture of cinnamylphos-
phetanium salt 12 and cinnamyl bromide 3 with limiting
LiAlH(OtBu)3 (eq 1), it is 12 that is preferentially reduced as
inferred from the product distribution determined by GC.
Similarly, by monitoring the 31P NMR spectra of the reaction of
an equimolar mixture of 14 and acyclic phosphonium 13 (eq 2),
we estimate a rate difference of >20 in favor of the
phosphetanium 14. Qualitatively, these outcomes conform to
strain/acceleration arguments advanced in organophosphorus
a
See Supporting Information for full experimental details. Isolated
yields are reported unless otherwise stated. Ratios (γ:α) determined by
b
1H NMR integration unless otherwise stated. Determined by GC
c
analysis. Reaction time 10 h due to thermal instability of substrate.
d
e
f
TBDPS = tert-butyldiphenylsilyl. TBS = tert-butyldimethylsilyl. d.r.
and relative stereochemistry of major isomer determined after TBS
deprotection.
and selectivity for the transposed reduction product is observed
for γ-alkyl substituted substrates (Table 2A). Regioselective
reductive transposition also deconjugates styrenyl and dienyl
substrates with high selectivity (Table 2B). Similarly, sterically
encumbered allylic bromides are converted with high selectivity
to the contrasteric γ reduction products (Table 2C). Additional
examples can be found in the Supporting Information (SI)
(Table S3). In all instances, control reductions conducted in the
absence of the phosphetane catalyst favored direct α-reduction
B
DOI: 10.1021/jacs.5b01899
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Journal of the American Chemical Society
Communication
products, confirming that the γ selectivities reported in Table 2
are in fact due to the action of the catalyst.
Stoichiometric isotopic labeling experiments designed to
establish the provenance of the newly formed γ-allylic C−H
were conducted. Treatment of 15 with LiAlD4 results in
formation of 16-dγ (eq 3), where deuterium is incorporated
−75.4 ppm, d, J = 258 Hz, Figure 2B), whose chemical shift and
multiplicity are consistent with formulation as a σ5-P hydrido-
phosphorane.26 This assignment is further supported by the
observation that treatment of the saturated σ4-P+ hydro-
cinammylphosphetanium ion 18 with LiAlH4 (eq 6) yields an
isolable species (19) with similar spectral characteristics (δ −80.4
ppm, d, J = 248 Hz). Subsequent warming of the NMR solution
containing 17 results in clean conversion to σ3-P phosphetane 10
(δ +25.1 ppm, Figure 2C) without the intervention of any
observable intermediates. Overall, the conversion of 12 → 10
proceeds with retention of configuration at phosphorus. We
tentatively assign a trigonal bipyramidal stereochemistry
depicted as 17 that minimizes both repulsive steric interactions
(i.e., the large gem-dimethyl group is equatorial and the small
hydride is apical) and phosphetane ring strain; this assignment
conforms to the results of DFT modeling (see Figure S2 in SI).
The kinetics of the process σ5-P → σ3-P (i.e., 20 → 10) were
monitored by VT-NMR over the temperature range −70 °C < T
< −45 °C for the parent allyl system (eq 7), permitting extraction
exclusively at the γ-position.11 Complementarily, treatment of
15-d2α with LiAlH4 results in formation of 16-d2α without loss or
scrambling of the geminal deuterium labels (eq 4), indicating the
phosphetanium salt is not deprotonated during the course of the
reaction.
In accord with Gallagher’s proposal and consistent with the
notion of biphilic catalysis in this system, in situ spectral data
reveal the intermediacy of a σ5-P hydridophosphorane species in
the reductive deallylation of σ4-P+ cinammylphosphetanium ion
12 to σ3-P phosphetane 10 (eq 5).25 When monitored by 31P
of the activation parameters by Eyring analysis (ΔH‡ = +15.2(8)
kcal·mol−1, ΔS‡ = −3(4) cal·mol−1 K−1). DFT calculations
(M06-2X/6-311++G(2d,2p)) provide further data regarding the
conversion 20 → 10. Structure 21 (Figure 3) represents the
NMR, reaction of 12 (δ +48.5 ppm, Figure 2A) with LiAlH4 at
−70 °C results in formation of a new phosphorus species 17 (δ
Figure 3. Computational modeling of the conversion σ5-P → σ3-P
[M06-2X/6-311++G(2d,2p)]. (A) Enthalpy (free energy) for pathway
in kcal/mol. (B) Optimized σ5-P hydridophosphorane structure 21. (C)
Optimized transition state structure TS.
global minimum for the suite of polytopal isomers of the σ5-P
hydridophosphorane in which the phosphetane ring spans one
apical and one equatorial site of a phosphorus-centered trigonal
bipyramid.27 The lowest energy pathway connecting
hydridophosphorane 21 and phosphetane 22 transits via a single
first-order saddle point, whose structure (TS) involves
concomitant P−Cα bond cleavage (2.29 Å) and direct transferal
of H from P to Cγ (d(P−H) 1.64 Å, d(H−Cγ) 1.62 Å). With
respect to geometry, TS is best described as a distorted square
pyramid about phosphorus with the P-phenyl moiety occupying
Figure 2. In situ 31P NMR spectra for the reaction shown in eq 5. (A)
Initial spectrum of phosphetanium 12. (B) Spectrum recorded at −70
°C immediately following addition of LiAlH4 showing formation of 17.
(C) Spectrum recorded after warming reaction to −30 °C showing
formation of 10. Units are ppm relative to 85% H3PO4 external standard.
C
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Journal of the American Chemical Society
Communication
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the apical site, and both the four-membered phosphetane and
five-membered envelope-like cycle spanning cis-basal positions.
The computed ΔH‡ (11.9 kcal/mol) is in good agreement with
the experimental value, and the cyclic nature of transition
structure TS is consistent with the negative value of the
experimentally determined activation entropy. We note that this
proposed mechanism via the five-center, six-electron transition
structure of TS bears a formal orbital equivalency with well-
known hydrocarbon-based pericyclic group transfer reactions28
(e.g., ene/retro-ene reactions29).
In summary, we have demonstrated a regioselective reductive
transposition of allylic bromides catalyzed by a small-ring
phosphacycle. The experimental and computational results
implicate the operation of a PIII/PV mechanistic pathway that
involves the interconversion of discrete, observable σ3-P, σ4-P+,
and σ5-P species. We note that the phosphetane-catalyzed allylic
reduction represents a phosphacatalytic complement to known
stoichiometric diazene-mediated30 and catalytic Pd π-allyl31
reduction protocols. The biphilic organophosphorus catalysis
demonstrated here presents reactivity that merges archetypal
nucleophilic and electrophilic manifolds; additional studies, both
synthetic and mechanistic, that probe this reactivity are currently
underway.
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(17) The σ4-P+ allylphosphonium salts derived from 6−11 are
conveniently manipulated air stable solids that liberate the correspond-
ing free σ3-P phosphines in solution by reduction with loss of propene.
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G.; Bergesen, K.; Juvvik, P.; Thelin, H.; Sjoberg, B.; Larsen, E. Acta
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̈
ASSOCIATED CONTENT
* Supporting Information
Synthetic procedures, spectral characterization data, kinetics
data, Cartesian coordinates for stationary points. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
S
(19) (a) O’Brien, C. J.; Tellez, J. L.; Nixon, Z. S.; Kang, L. J.; Carter, A.
L.; Kunkel, S. R.; Przeworski, K. C.; Chass, G. A. Angew. Chem., Int. Ed.
2009, 48, 6836. (b) van Kalkeren, H. A.; Leenders, S. H. A. M.;
Hommersom, C. R. A.; Rutjes, F. P. J. T.; van Delft, F. L. Chem.Eur. J.
2011, 17, 11290. (c) O’Brien, C. J.; Lavigne, F.; Coyle, E. E.; Holohan, A.
J.; Doonan, B. J. Chem.Eur. J. 2013, 19, 5854.
AUTHOR INFORMATION
Corresponding Author
*radosevich@psu.edu
Notes
■
(20) Phosphetane 10 was prepared on gram scale via McBride reaction
of PhPCl2, tert-butylethylene, and AlCl3 according to: Cremer, S. E.;
Chorvat, R. J. J. Org. Chem. 1967, 32, 4066.
(21) Marinetti, A.; Carmichael, D. Chem. Rev. 2002, 102, 201.
(22) Westheimer, F. H. Acc. Chem. Res. 1968, 1, 70.
The authors declare no competing financial interest.
(23) Hudson, R. F.; Brown, C. Acc. Chem. Res. 1972, 5, 204.
(24) Sella, A.; Basch, H.; Hoz, S. J. Am. Chem. Soc. 1996, 118, 416.
(25) The BPh4 counterion was required for low temperature
ACKNOWLEDGMENTS
■
−
Financial support was provided by the Pennsylvania State
University and the NIH (GM114547). A.T.R. gratefully
acknowledges early career support from the Alfred P. Sloan
Foundation.
solubility of phosphonium 12 in THF.
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(27) See SI for full details.
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DOI: 10.1021/jacs.5b01899
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