Tri(1-adamantyl)phosphine: Expanding the Boundary of Electron-Releasing Character Available to Organophosphorus Compounds

Article abstract of DOI:10.1021/jacs.6b03215

We report here the remarkable properties of PAd₃, a crystalline air-stable solid accessible through a scalable S_N1 reaction. Spectroscopic data reveal that PAd₃, benefiting from the polarizability inherent to large hydrocarbyl groups, exhibits unexpected electron releasing character that exceeds other alkylphosphines and falls within a range dominated by N-heterocyclic carbenes. Dramatic effects in catalysis are also enabled by PAd₃ during Suzuki-Miyaura cross-coupling of chloro(hetero)arenes (40 examples) at low Pd loading, including the late-stage functionalization of commercial drugs. Exceptional space-time yields are demonstrated for the syntheses of industrial precursors to valsartan and boscalid from chloroarenes with ～2 × 10⁴ turnovers in 10 min.

Full text of DOI:10.1021/jacs.6b03215

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Communication
Tri(1-adamantyl)phosphine: Expanding the Boundary of Electron-
Releasing Character Available to Organophosphorus Compounds
Liye Chen, Peng Ren, and Brad P. Carrow
J. Am. Chem. Soc., Just Accepted Manuscript • Publication Date (Web): 10 May 2016
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Tri(1-adamantyl)phosphine: Expanding the Boundary of Electron-
Releasing Character Available to Organophosphorus Compounds
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Liye Chen, Peng Ren,and Brad P. Carrow*
Department of Chemistry, Princeton University, Princeton, NJ 08544, United States
Supporting Information Placeholder
increased
αꢀcarbon branching in the homoleptic series
ABSTRACT:We report here the remarkable properties
of PAd3, a crystalline airꢀstable solid accessible through
a scalable SN1 reaction. Spectroscopic data reveal that
PAd3, benefiting from the polarizability inherent to large
hydrocarbyl groups, exhibits unexpected electron releasꢀ
ing character that exceeds other alkylphosphines and
falls within a range dominated byNꢀheterocyclic carꢀ
benes. Dramatic effects in catalysis are also enabled by
P{C[(H)3ꢀn(CH3)n]}3 (n = 0ꢀ3) can be seen in Figure 1a
(open circles).Tolman rationalized such a trend as arisꢀ
ing from steric repulsion of larger substituents, whichraꢀ
ises the HOMO energy as phosphorus adopts a more
planar geometry (Figure 1b). However,a curious enꢀ
hancement in donor strengththat is not readily explained
by geometric effects is evident for phosphines that posꢀ
sessalkyl substituents at the more distant βꢀposition(e.g.
PBu3 and PCy3) rather thanβꢀmethylgroups (e.g. PEt3
and P(iꢀPr)3).We report here the first synthesis of tri(1ꢀ
adamantyl)phosphine (PAd3), which appears to capitalꢀ
ize on this effect more than existing phosphinesto access
electronꢀreleasing properties exceeding a boundary for
organophosphines that has persisted over many decꢀ
ades.11
PAd3duringSuzukiꢀMiyaura
reactions
of
chloꢀ
ro(hetero)arenes (40 examples) at low Pd loading, inꢀ
cluding the lateꢀstage functionalization of commercial
drugs. Exceptional spaceꢀtime yieldsare demonstrated
for the syntheses of industrial precursors to valsartan and
boscalid from chloroarenes with ca. 2 × 104 turnoversin
10 min.
a)Tolman electronic parameter of PR3.a
b) (∠C–P–C) in PR3.
b
∑
The capacity of ancillary ligands to tune the activity,
selectivity, and stability of homogeneousmetal cataꢀ
lystshas played a central role in the development of
many modern synthetic methods.1Phosphines constituteꢀ
one of the most utilized among various ligand types due
in large part to thesensitivity of the electron density and
steric environment about phosphorus towardssubstituent
perturbations. The many areas of synthetic chemistrythat
utilize organophosphines,including emerging fieldssuch
as organocatalysis,2bioorthogonal reactions,3 nanoꢀ
materials,4 polymerization,5and frustrated Lewis
pairs,6could thus benefit from expansion of accessible
stereoelectronic properties beyond classical boundaries.
Several recent discoveries that highlight this potential
include Alcarazo’s phosphine cations’ ability to greatly
Figure 1.Examples of β–substituenteffects on the (a) TEꢀ
Pand (b) geometry of homoleptic phosphines. aχ = νCO(A1)–
2056.1 cmꢀ1 for Ni(CO)3(PR3). From solidꢀstate data for
b
accelerate
π
ꢀacid catalysis,7Radosevich’s Tꢀshaped
Au(PR3)Cl.12
phosphines’ oxidative additions,8and Dielmann’s imidꢀ
azolinꢀ2ꢀylidenaminophosphines’ reversible CO2 fixaꢀ
tion.9
Numerous syntheses of phosphines with two 1ꢀ
adamantyl (Ad) substituents have been developed, many
of which have found wide success in catalyꢀ
sis.13Installation of a third hindered Adgroup, however,
has remained challenging. In fact, any triꢀtertꢀ
alkylphosphine for which all βꢀcarbon positions are alꢀ
kyl rather than methyl groupsisto the best of our
knowledge unprecedented. We found that reaction of
Another enabling aspect of organophosphine chemisꢀ
try has been the development of quantitative descriptors
oftheir electronicand steric properties such as Tolman’s
electronic parameter (TEP) and cone angle, respectiveꢀ
ly,10which aids both inmechanistic understanding and
predictionof reactivity. A typical response of the TEP to
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ClPAd2 and AdMgBr in the presence of a CuI/LiBr cataꢀ
1),PAd2(nꢀBu) (νCO1956.9 cmꢀ1), or PCy3 (νCO1958.7 cmꢀ
lyst14 led to complete consumption of the electrophile
over 15 h but gave only trace amounts of PAd3 (1). This
is consistent with a nonꢀcatalyzed SN2 route attempted
by Whitesides.15An alternative strategy (Scheme 1a) to
forge the final hindered P–C bond in PAd3 that proved
surprisingly facile involved instead an SN1 reaction
withAd cation.16,17A mixture of the commercial reagent
HPAd2,AdOAc (1.1 equiv), and Me3SiOTf (1.2 equiv)
cleanly generated protonated PAd3 over 24 h at rt. Neuꢀ
tralization of 1.HOTf with Et3Nformed a colorless preꢀ
cipitate, pure PAd3, that was simplyfilteredunder air in
good yield (63 %)on a multiꢀgram scale. We were surꢀ
prised to then discover that negligible oxidation of solid
PAd3occurred during storage under air over a period of
three months as determined from periodic analysis of
aliquots by 31P NMR spectroscopy.18 This behavior conꢀ
trasts starkly with many other alkylphosphines that are
airꢀsensitive and in the case of P(tꢀBu)3, pyrophoric.
1) all exhibit distinctly higher frequencies indicative ofꢀ
reduced electron releasing ability of these compared to
PAd3.25 The TEP for PAd3(2052.1 cmꢀ1), indirectly calꢀ
culated from the relationship between νCO for
Ni(CO)3(L) and Rh(acac)(CO)(L) complexes (Figure
S5),26 is significantly red shifted compared to P(t-
Bu)3(2056.1cmꢀ1) and other alkylphosphines.10a,10c In
fact, PAd3approachesarange typical ofNꢀheterocyclic
carbenes(e.g. IPr; 2051.5 cmꢀ1)27 that are generally reꢀ
garded as superiorσ donors to transition metꢀ
als.28Additional theoretical and experimental data that
corroborate this spectroscopic datainclude ahigher calcuꢀ
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lated HOMO energyfor PAd3(+0.20 eV)relative to P(t-
THF
Bu)3, a larger pKα
of the conjugate acid of
PAd3(11.6)compared to P(t-Bu)3(10.7),29and a smallꢀ
er1J(31Pꢀ77Se)coupling constant forAd3PSe (669.9 Hz)
than for(tꢀBu)3PSe (688.2 Hz).30
Several effectswere considered that might account for
the unique electronic properties of PAd3. The average
Cα–Cβbond length of PAd3 in 2 (1.551(4) Å) is slightly
longer than the average Cβ–Cγ and (1.537(4) Å)andCγ–
Cδ (1.530(4)Å) bond lengths, respectively. A hyperconꢀ
jugative effect would be expected to contract the Cα–
Cβbonds,31 which is clearly not the case.The sum of the
C–P–Cangles about PAd3(332.6(4)°) determined from
solid state data for2 areslightlylesscomparedto P(tꢀ
Bu)3inthe analogous gold complex (335(3)°).12aThe C–
P–Cangles in 4andthe known complex Pd[P(t-
Bu)3](Ph)(Br) are also similar.20These data show that
planarization of phosphorus also does not account for
the properties of PAd3. However,London dispersion
could explainthe slight contraction of theC–P–Cbond
angles in PAd3,11and this possibility led us to further
consider van der Waals forces.11,32The larger Taft polarꢀ
izability parameter (σα) of Ad(– 0.95) compared to tꢀ
Bu(– 0.75) indicates the former is better able to facilitate
electron donation from phosphorus by stabilizing a more
polarizedP−M dative bond.33In fact, a general correlaꢀ
tion is observed between σαand the TEP of a series of
homoleptic alkylphosphines(Eq 1). Thiscorrelation sugꢀ
gests to us that van der Waals forces mightaccount for
Scheme 1. Synthesis and properties of PAd3 (1).
Comparison ofthe Charton steric parameter (υ) for the
Adgroup (1.33) compared to, for instance, a tꢀBu group
(1.24) intuitively suggests that PAd3 should be more steꢀ
rically hindered than other trialkylphosphines.19We thus
synthesized (PAd3)AuCl (2) (Scheme 1b) and the airꢀ
stable cationic complex 4, prepared in one step by coorꢀ
dination of 1 to palladacycle 3(Scheme 1c),20to quantitaꢀ
tively establish the steric properties of PAd3.Thecone
angle (θ) calculated from the solid state structure of
2(179°) is similar to the reported value for P(tꢀBu)3
(182°).10b Similarly, the buried volume parameter
(%Vbur) of PAd3in 2 (40.5) calculated using the Samꢀ
bVca program21is close to that for P(tꢀBu)3(40.0) in an
analogous gold complex.10b,22Values for PAd3 in4(40.3)
versus P(tꢀBu)3 inPd[P(tꢀBu)3](Ph)(Br) (39.3)23 are also
similar. We thus conclude PAd3and P(tꢀBu)3are best deꢀ
scribed as isosteric, which contrasts common proposals
about the differences of Adꢀ and tꢀBuꢀphosphine congeꢀ
ners.24
the trendthatphosphines possessing largeβꢀalkyl groupꢀ
sare more electronꢀreleasing thanthe
β
ꢀmethyl analogues
(Figure 1a).11
2
ꢁ
ꢂ ꢁ
ꢂ
ꢀCO A1 = 20.234×σα + 2071.5; R = 0.995 (1)
Because transition states are generally more polarizaꢀ
ble than are ground states,34 we wanted to assess effects
ofPAd3within a catalytic manifold. We chose as a chalꢀ
lenging test case the room temperature SuzukiꢀMiyaura
crossꢀcoupling (SMC) of pꢀchloroanisole (0.50 mmol),
1ꢀnapthylboronic acid (0.55 mmol) and KOH (1.1
mmol) in the presence of palladacycle 3 and a phosphine
(0.05 mol% Pd; L:Pd = 1:1 in all cases) in THF/toluene
(Eq2). The use ofP(tꢀBu)3, PAd2(nꢀBu), or PCy3, each of
whichis used extensively for SMC,35led to low
yields(<10%) of 1ꢀ(pꢀanisyl)naphthalene (6)over 8 h
The electronic properties of PAd3 (Scheme 1d) were
next established from the carbonyl stretching frequency
of 5 (νCO 1948.3 cmꢀ1), which occurs at a uniquely low
frequency among alkylphosphines. Analogous Rh comꢀ
plexes (S3ꢀS5) ligated by P(t-Bu)3(νCO1956.4 cmꢀ
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(Figure 2).In contrast, the reaction catalyzed by the Lastly, we broadenedour investigation of the SMCto
1
combination of 3 and PAd3 under identical conditions
proceeded to 99% yield within 4 h. The yield of 6 at 10
min (99%) using0.25 mol%3 and 0.5 mol%
PAd3corresponds to a turnover frequency (TOF) of 1.2 ×
104 hꢀ1 at rteven with this quintessential deactivated subꢀ
strate for SMC; an analogous reaction using P(tꢀBu)3was
slower andstalled at ca. 33% yield (Figure S3). The reacꢀ
tivity of 3 and PAd3 compared favorably even headꢀtoꢀ
head againststateꢀofꢀtheꢀart precatalystssuch as SPhosꢀ
Pd G2, XPhosꢀPd G3, and PEPPSIꢀIPr.36Note that these
data only sample the ensemble of ligand effects on cataꢀ
lyst initiation, innate reactivity, and stabilitythat affect
the overall catalyst performance.We do believe the high
reactivity of the PAd3ꢀPd catalyst in this SMC reflects
the donicity and polarizability of PAd3, but a related
PAd3ꢀPd complex (S1) was also found to beverystable
towards cyclometalation (Figure S1). Thus,catalyst staꢀ
bility differences might also contribute to these observaꢀ
tions.
establish if PAd3ꢀPd catalysts might be broadly applicaꢀ
ble at low Pd loading (≤0.1 mol%),37 which is desirable
for industrial applications yet remains challenging using
chloroarenes.38A limited selection of solvents (THF, tolꢀ
uene, or nꢀBuOH) and bases (K3PO4 or K2CO3) using
4as catalyst was sufficient to achieve high yields across
40 diverse combinations of chloro(hetero)arene and orꢀ
ganoboronic acid. Representative examples are shown in
Scheme 2 with the remainder listed in the Supporting
Information (Figure S4). Complex 4 retained high activiꢀ
ty in the presence of Nꢀheteroaryl substrates including
pyridine, pyrrole, pyrazine,pyrimidine, isoxazole, triaꢀ
zine, and thiadiazole fragments giving high yields within
1ꢀ12 h using 0.05ꢀ0.1 mol% Pd. Products from reactions
with organoboron compounds that are notoriously sensiꢀ
tive to protodeboronation such as 2ꢀpyrrolyl, 2ꢀfuryl,2ꢀ
thienyl, and 2,6ꢀdifluorophenyl boronic acids alꢀ
soformed in high yields even at low catalyst loadꢀ
ings.39Reactions that formed industrial precursors (7,
8)to valsartan and boscalid proceeded to high yield (95ꢀ
97 %) within 10 minat 100 ºC using 0.005 mol%
Pd.37bThese turnover numbers (TON) of ca. 2 × 104 and
exceptionalTOFsexceeding1 × 105hꢀ1 highlight that high
spaceꢀtime yield are accessible using less reactive chloꢀ
roarenes and low Pd loading. High TON within1ꢀ5 h are
also observed for reactions of Nꢀheterocycles (9ꢀ11).
Lastly, functionalization by SMC of the C–Cl bond in
haloperidol, fenofibrate, montelukast, glibenclamide,
and 5ꢀRꢀrivaroxaban with methyl, cyclopropyl, hetꢀ
eroaromatic, or fluoroaromatic fragments occurred in
uniformly good yields (65ꢀ92%). We were very encourꢀ
aged by the observations that PAd3, a simple compound
readily prepared from inexpensive reagents, engenders
catalytic properties rivaling some of the most important
methods developed for SMC reactions.
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Figure 2.Yield of 6 from reactions in Eq 2.L/Pd = 1 in all
cases.
Scheme 2. Illustrative examples of 4 as a general cat-
alyst for Suzuki-Miyaura coupling of chlo-
ro(hetero)arenes.a
The stark contrast of the catalytic effects of PAd3 verꢀ
sus, for instance, PAd2(nꢀBu)in this SMC is surprising
given the structural similarities.We considered that Tolꢀ
man’s proposal of substituent additivity (Eq 3)10acould
be used toevaluateif in fact the number of Ad groups
exerts a proportional effect on the phosphine properties.
We thus determinedχAd (Eq 4) in PAd3 (− 1.3 cmꢀ1),
PAd2(nꢀBu)(− 0.20 cmꢀ1), and PAd2Bn(−1.0cmꢀ1) using
knownχRand TEP values.10a The variance in χAd indiꢀ
cates that, contrary to Tolman’s proposal,10cthe influence
of the Ad group is actually dependent on the exact phosꢀ
phine structureand also that phosphorus apparently gains
more electron density per Ad group in the case of PAd3.
ꢇ
ꢀ1
ꢄ
ꢁ
ꢂ
ꢀCO A1 ꢃ 2056.1 cm = = ꢅ ꢄꢆ (3)
ꢆꢈꢉ
(ꢄ ꢃ ꢄR)
ꢁ
ꢂ
2
For P Ad R:ꢄ =
(4)
Ad
2
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Notes
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The authors declare the following competing financial inꢀ
terest: a patent application was filed by Princeton Universiꢀ
ty.
5
ACKNOWLDEGMENT
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9
Financial support was provided by Princeton University.
We thank Long Wang for efforts to characterize complexes
of 1.
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aSee Supporting Information for 28 additional examples
and full experimental details. bYield determined by NMR.
In conclusion, a facile and scalable synthesis of PAd3
has been developed. Spectroscopic data reveal PAd3is
significantly more donating than P(tꢀBu)3, thus redefinꢀ
ing the limit of electronꢀreleasing characteraccessible to
alkylphosphines that has persisted for half a centuꢀ
ry.Preliminary investigations to establish how the elecꢀ
tronic properties and chemical stabilityof PAd3might be
leveraged revealedthat a PAd3ꢀpalladacyclecatalyzes
SuzukiꢀMiyaura coupling of chloro(hetero)arenes with
exceptionalTOF and high TON. A strong correlation
between the Tolman electronic and Taft σαparameterꢀ
sargues the special properties of PAd3originate from the
substantialpolarizabilityinherent to large hydrocarbyl
groups like adamantyl. These results support the hypothꢀ
esis that access to phosphine steric or electronic properꢀ
ties beyond historical limits can enableunique reactivity
in catalysis and also contribute to a growing number of
examples for whichweak van der Waals forces can in
fact contribute significantly to both structure and reacꢀ
tivity.11
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711; (b) AgnewꢀFrancis, K. A.; Williams, C. M. Adv. Synth. Catal.2016,
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ASSOCIATED CONTENT
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charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
bcarrow@princeton.edu
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e.g. Drug Functionalization:
v. electron-rich,
yetair stable
Catalytic Effects:
Unparalleled Rates
(up to 105 h-1 for Ar-Cl)
Broad Compatibility
(40 examples)
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