Expanding Ligand Space: Preparation, Characterization, and Synthetic Applications of Air-Stable, Odorless Di- tert-alkylphosphine Surrogates

alkylphosphine Surrogates

Research Article

Expanding Ligand Space: Preparation, Characterization, and

Synthetic Applications of Air-Stable, Odorless Di-tert-

Thomas Barber, Stephen P. Argent, and Liam T. Ball*

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ABSTRACT: The di-tert-alkylphosphino motif is common to many best-in-

class ligands for late-transition-metal catalysis. However, the structural

diversity of these privileged substructures is currently limited by the need to

manipulate highly toxic, highly reactive reagents and intermediates in their

synthesis. In response to this longstanding challenge, we report an umpolung

strategy for the synthesis of structurally diverse di-tert-alkylphosphine

building blocks via S 1 alkylation of in situ generated PH gas. We show

that the productswhich are isolated as air-stable, odorless phosphonium

saltscan be used directly in the preparation of key synthetic intermediates

and ligand classes. The di-tert-alkylphosphino building blocks that are

accessible using our methodology therefore enable facile expansion of extant

ligand classes by modiﬁcation of a previously invariant vector; we demonstrate that these modiﬁcations aﬀect the steric and

electronic properties of the ligands and can be used to tune their performance in catalysis.

KEYWORDS: phosphorus, phosphines, ligand synthesis, catalysis, cross-coupling

INTRODUCTION

Scheme 1. Occurrence, Conventional Synthesis, and

Proposed Synthesis of tert-Alkylphosphines

■

Advances in homogeneous transition-metal catalysis have been

underpinned by the rational design of sophisticated,

application-speciﬁc phosphine ligands. Sterically demanding,

electron-rich phosphines bearing tert-alkyl substituents have

emerged as especially privileged in polymerization, strong-

bond activation, and cross-coupling chemistries. While tri-

tert-alkylphosphines have huge historical and contemporary

signiﬁcance, structural modiﬁcation of this ligand class is

extremely challenging. In contrast, phosphines featuring two

tert-alkyl substituents share many of the desirable attributes of

their homoleptic counterparts but can be conveniently tuned

to meet reaction-speciﬁc demands through variation of the

third, unique substituent. As a consequence of this versatility,

the di-tert-alkylphosphino (DTAP) motif forms the basis of

−9

many current best-in-class ligands (Scheme 1A).

Despite the importance of DTAP motifs, the diversity in

their tert-alkyl substituents is extremely limited. Indeed, all

commercial phosphines featuring this substructure are based

on either tert-butyl or 1-adamantyl (Ad) substituents, with

just a handful of other examples documented in the patent and

primary literature. Further exploration of this privileged

region of ligand space is currently hampered by the practical

challenges associated with the synthesis of new DTAP building

Received: March 27, 2020

Revised: April 9, 2020

−

blocks. As a case in point, the conventional “P /C ” approach

to di-tert-alkylphosphines (Scheme 1B) involves manipu-

lation of highly hazardous, air-sensitive reagents and

intermediates over multiple steps, is redox-ineﬃcient, and is

XXXX American Chemical Society

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Scheme 2. Validation and Optimization of S 1 Alkylation of PH Gas Generated within a Two-Chamber Reactor System

Gas titration data are an average of two independent measurements and exhibit pseudo-ﬁrst-order kinetics (Scheme 2B, inset). S 1 alkylation

conditions unless stated otherwise: aqueous HCl (5.0 M, 10 equiv) added to Zn P (0.5 equiv) at RT in chamber 1 to generate 1 equiv of PH ;

R′OTf (1 equiv) added to tert-amyl-OR (6 equiv) at RT in chamber 2. Yields are of isolated, pure material; yields in parentheses were determined

by P NMR spectroscopic analysis vs internal standard. Using 3 equiv of tert-amyl acetate.

ultimately limited in scope by the diversity of the tert-

To explore the viability of this strategy, we ﬁrst conﬁrmed

alkylmetal reagents that are available.

that generation of PH₃from Zn₃P₂is indeed facile. As

determined by volumetric gas titration (Scheme 2B), complete

hydrolysis of Zn P occurs within 10 min of adding excess

−

We anticipated that an umpolung strategy (“P /C ”,

Scheme 1C) would provide unrivaled access to structurally

diverse DTAP building blocks and would eliminate the need

aqueous HCl. Under these conditions, gas evolution exhibits

pseudo-ﬁrst-order kinetics with an eﬀective half-life of 110 s

(Scheme 2B, inset), providing suﬃcient time for addition of

the acid before full gas pressure is achieved.

for wasteful redox adjustments at phosphorus. S 1 alkylation

would enable facile installation of sterically demanding

substituents and would open up a much wider pool of

−

alkylating agents than is available to the conventional P /C

Subsequently, we sought to identify conditions for S

alkylation of the ex situ generated PH gas (Scheme 2C). Prior

attempts to alkylate PH or its synthetic equivalents have

approach. In situ generation of both the P-nucleophile and the

C-electrophile would ultimately minimize the need to handle

reactive reagents and intermediates.

exploited S

neither of which allow installation of tert-alkyl substituents.

single example of S 1-type alkylation was recently reported by

Carrow, although a secondary phosphine nucleophilerather

than PH

was employed in order to generate the homoleptic

tertiary phosphine PAd As illustrated in entries 1−4, we

or hydrophosphination reactivity manifolds,

Herein we report realization of this umpolung approach to

secondary phosphine synthesis. By exploiting an S 1 manifold,

we demonstrate that di-tert-alkylphosphines can be prepared

selectively from readily available, bench-stable precursors. The

products are obtained as air-stable, odorless phosphonium salts

which can be isolated conveniently by ﬁltration. The DTAP

building blocks that are accessible in this way enable facile

expansion of extant ligand classes by modiﬁcation of a

previously invariant vector; we show that these modiﬁcations

aﬀect the steric and electronic properties of the new ligands

and can be used to tune their performance in catalysis.

found that a combination of tert-amyl alcohol or tert-amyl

methyl ether with either HOTf or TMSOTf failed to aﬀord

appreciable amounts of alkylphosphine products. While the

combination of tert-amyl acetate and HOTf proved similarly

unsuccessful (entry 5), the use of tert-amyl acetate and

TMSOTf resulted in high-yielding alkylation of PH (entry

). Notably, >95% of the phosphonium salt formed in this

way was recovered conveniently via precipitation and ﬁltration

in air. The isolated material proved to be a free-ﬂowing,

nonhygroscopic, and odorless solid that is soluble in organic

RESULTS AND DISCUSSION

■

Our proposed S 1 strategy (Scheme 1C) requires a synthon of

−

the type “HP ”. While phosphine gas (PH ) is an atom-

media and that can be stored on the bench for at least 1 year

economical and readily available synthetic equivalent to this

synthon, we were cognizant of the risks and practical

challenges associated with handling high-pressure, cylinderized

without noticeable degradation. Although the yield of 1a

suﬀered slightly when a lower stoichiometry of tert-amyl

acetate was employed (entry 7), these more economical

conditions proved generally applicable in subsequent studies

(vide infra).

PH₃. We therefore sought to generate the gas on demand

and in precise stoichiometries by protonolysis of a metal

phosphide. Speciﬁcally, we identiﬁed zinc phosphide (Zn P )

The conditions outlined in entries 6 and 7 of Scheme 2C

confer excellent selectivity for dialkylation, with neither mono-

as a convenient source of PH because, unlike other metal

phosphides, it is both bench-stable and cheap (£48/kg).

While Zn P can be stored and handled under an ambient

nor trialkylation products observed by P NMR spectroscopy.

This remarkable selectivity can be explained by considering the

atmosphere, it is readily protonolyzed to PH under acidic

diﬀerent basicities of primary, secondary, and tertiary

conditions. We anticipated that this reactivity could be

phosphines. The ﬁrst-formed primary phosphine is, presum-

ably, insuﬃciently basic to be fully protonated by the HOTf

coproduct. A second alkylation may therefore occur, aﬀording

a more basic secondary phosphine which is fully protonated

under the reaction conditions. This innate alkylation-depend-

exploited in the two-chamber “CO-ware” reactor system

developed by Skrydstrup, with PH generated in the ﬁrst

chamber from Zn P and consumed in the second chamber by

S_N1 alkylation (Scheme 2A).

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ent change in protonation state constitutes an eﬀective self-

regulation mechanism that prevents overalkylation and ensures

that the product is obtained as a stable, crystalline

Scheme 3. Synthesis of Di-tert-alkylphosphonium Salts via

S 1 Alkylation of PH Gas

phosphonium salt rather than an air-sensitive phosphine.

The optimized reaction conditions were applied successfully

to a range of diverse tert-alkyl esters (Scheme 3), thereby

providing convenient access to structurally unique di-tert-alkyl

phosphonium salts. All products were isolated as air-stable,

odorless solids on preparatively useful scales of up to 2.0 g.

Using this methodology, two homologous series featuring

increasing methylation at all C positions (1a−c: CMe Et,

CMeEt , and CEt ) or at a single C -position (1a,d,e: CMe Et,

CMe Pr, CMe Bu) of each tert-alkyl substituent were

prepared. We envisage that such facile access to series of

these types will enable the systematic variation of ligand

−

properties during catalyst development campaigns. Our P /C

approach also allows installation of substituents featuring steric

bulk distal to the phosphorus center (1f,g) and is compatible

with alkylating agents derived from both cyclic (1h−j) and

polycyclic (1k−m) alkanols. Notably, aryl bromides (1g) are

tolerated by our methodology, which illustrates its comple-

mentarity to conventional organometallic strategies. The ability

to incorporate this functionality provides a useful synthetic

handle that could ultimately be exploited for further

elaboration of the ligands.

As demonstrated for phosphonium salt 1k, esters other than

acetates can be used with no detriment to reaction eﬃciency.

In combination with the ready availability of tertiary alcohols

and their esters, this synthetic ﬂexibility increases the pool of

viable alkylating agents that can be employed in our

methodology. For example, salt 1f is prepared from papaya

isobutyrate, a commercial fragrance ingredient, whereas salt

m is derived from cedrol, which is produced on a kiloton

scale each year as the main component of cedar wood oil.

Notably, salt 1m is the ﬁrst example of a C-stereogenic di-tert-

alkylphosphine and is produced here as a single stereoisomer

from a cheap, chiral-pool alcohol.

Within the context of our proposed S 1 pathway, it is

essential that a carbocationic electrophile is accessible and that

it is suﬃciently long lived for bimolecular nucleophilic trapping

to compete with unimolecular elimination. Thusin addition

to tert-alkyl estersbenzhydryl acetate reacts cleanly to give

phosphonium salt 1n, whereas primary, secondary, and

conformationally constrained tertiary alkyl esters are unreactive

(

Scheme 3, bottom). In contrast, while tert-butyl acetate

ionizes eﬃciently, a well-documented and industrially

important E1/S 1 telomerization process competes with

trapping of the resulting carbocation by PH , aﬀording an

inseparable mixture of the desired di-tert-butylphosphonium

salt 1o and homologues 1p,q (Scheme 4A).

Deuterium labeling studies (Scheme 4B) provided further

evidence that the reaction progresses via a carbocationic

Conditions: aqueous HCl (5.0 M, 10 equiv) added to Zn P (0.5

equiv) at RT in chamber 1 to generate 1 equiv of PH ; TMSOTf (1

intermediate. Reaction of the isotopologous acetates d -2 and

equiv) added to ester (3 equiv; acetate ester unless stated otherwise)

at RT in chamber 2. Reactions were performed at a 1 mmol scale,

unless indicated otherwise; yields are of isolated, pure material.

d -2 with either PH or PD resulted in isotopic exchange at

the C positions, indicating that reversible elimination of the

carbocation to an alkene precedes nucleophilic trapping.

Moreover, the comparable extent of environment-weighted

Using 6 equiv of tert-alkyl acetate. Chamber 2 heated at 40 °C.

CH Cl (2 mL) added to chamber 2. Thermal ellipsoids are shown

at 50% probability; triﬂate counterion and hydrogen atoms bonded to

carbon are omitted for clarity.

exchange (ca 5%) at the β-methyl and β-methylene

substituents suggests that E1 elimination is equally statistically

likely to give the exo methylene or the internal alkene. In

contrast, the absence of deuterium incorporation at the γ-

methylene position implies that migration of the internal

alkene into conjugation with the phenyl ring is negligible.

Having identiﬁed general conditions for the preparation of

structurally diverse di-tert-alkyl phosphonium salts, we sought

to demonstrate their utility in ligand synthesis (Scheme 5). As

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Scheme 4. Evidence for an S 1 Mechanism

With ligand series 3 in hand, we sought to demonstrate that

the diﬀerent tert-alkyl substituents have a measurable eﬀect on

the electronic and steric properties of the phosphorus center

(

Scheme 6) and that these diﬀerences can have signiﬁcant

consequences for catalysis (Scheme 7).

Scheme 5. Di-tert-alkylphosphonium Salts as Convenient

Synthetic Surrogates for Secondary Phosphines in Common

P-Functionalization Reactions

Conditions: HCl in H O or DCl in D O (5.0 M, 10 equiv) added to

Zn P (0.5 equiv) at RT in chamber 1 to generate 1 equiv of PH or

PD ; TMSOTf (1 equiv) added to the ester (3 equiv) at RT in

chamber 2. Product distributions were determined by NMR

spectroscopic and mass spectrometric analysis of crude mixtures.

Pathway a: (1) DBU (1.2 equiv), THF, RT, 10 min; (2) BH ·SMe

(2 equiv), RT, 16 h. Pathway b: DBU (1 equiv), CCl , 50 °C, 27 h.

Pathway c: (1) K CO (3 equiv), MeOH, RT, 0.5 h; (2) H O (30%

aqueous; 2.5 equiv), RT, 2 h. Pathway d: (1) BnBr (1 equiv), K CO

(

3 equiv), toluene, 120 °C, 16 h; (2) BH ·SMe (2 equiv), RT, 2 h.

illustrated for 1c, treatment of the phosphonium salt with base

enables in situ release of the corresponding air-sensitive

secondary phosphine. This can then be exploited in conven-

tional P-functionalization chemistry, including (a) protection

as the phosphine−borane complex, (b) polarity inversion via

P-chlorination, (c) selective oxidation to the secondary

3 2

The ³¹P NMR chemical shifts for the free ligands 3 exhibit

the expected steric shielding eﬀect from increased substitution

at the C_βposition and correlate well against the group

contribution calculated for the individual tert-alkyl substitu-

phosphine oxide, and (d) S 2 alkylation to give an analogue

,31

of Beller’s cataXCium ABn ligand.

Our phosphonium salts

ents. Notably, however, this correlation does not hold for

can therefore be employed as convenient precursors to

versatile synthetic intermediates (via pathways a−c) or can

be converted directly to important ligand classes (via pathway c

or d). Notably, the synthesis of tertiary phosphines via

pathway d constitutes a low-cost and redox-eﬃcient route to

privileged DTAP-based ligands that entirely avoids the use of

PCl₃.

ligands in which the tert-alkyl groups feature two substituents

at the C position (3b,d,h,i). Following selenation, the one-

bond J_P₋_S_ecoupling constant was measured as an indicator of

the net electron-donating ability of each ligand (Scheme 6B).

While some caution must be exercised in interpreting the

absolute values of the J_P₋_S_econstants, the diﬀerence between

the most- and least-electron-donating JohnPhos analogues

Installation of an aryl group at phosphorus can be achieved

via Pd-catalyzed P−C cross-coupling of the phosphonium salts

(4l,o; ΔJ

= 37 Hz) is signiﬁcant and is the same as the

diﬀerence between triphenylphosphine and Buchwald’s

P−Se

(

Scheme 6). In this way, a library of novel (2-biphenyl)di-tert-

RuPhos. To obtain a measure of sterics, gold(I) chloride

complexes 5 were synthesized, and the buried volumes were

calculated from crystal structure data using the SambVca2

alkylphosphines 3 was prepared without the use of either PCl₃

or reactive tert-alkyllithium/Grignard reagents at any stage.

Although cross-coupling with the sterically demanding

o‑biphenyl (pseudo)halide proved successful for the majority

of phosphonium salts, those featuring especially large tert-alkyl

substituents (1e,j) could not be engaged eﬀectively. The

program (Scheme 6C). Again, a signiﬁcant diﬀerence is

observed across the ligand series, with a span between the

largest and the smallest ligands (5c,h; Δ%V (2 Å) = 9.3%)

that is comparable to the diﬀerence between triphenylphos-

bur

resulting phosphines are analogues of JohnPhos 3o a

phine and tri-tert-butylphosphine (Δ%V (2 Å) = 9.1%).

bur

7a−c

member of the privileged Buchwald ligand class and

constitute a standardized, catalysis-relevant platform with

which to investigate the stereoelectronic properties of the

tert-alkyl groups.

The tert-alkyl groups that can be installed using our

methodology therefore confer distinct physical and spectro-

scopic properties on the resulting phosphines and signiﬁcantly

extend the range of accessible ligand space beyond that

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Scheme 6. Synthesis and Characterization of JohnPhos Analogues, Their Selenides, and Their Gold(I) Chloride Complexes

P NMR spectroscopic data refer to dilute solutions in CDCl ; %V was determined using SambVca2. Abbreviations: Ar = o-biphenylyl; n.d. =

bur

not determined because single crystals of suﬃcient quality for X-ray diﬀraction could not be obtained. 3f: thermal ellipsoids at 30% probability. 5h:

thermal ellipsoids at 50% probability and a molecule of water omitted for clarity.

occupied by the commercially available 1-adamantyl and tert-

butyl substituents (Scheme 6B,C).

architecture by variation of its DTAP substructure can have

signiﬁcant consequences for its catalytic properties. By using

our methodology to vary ligands through this previously

inaccessible vector, it is thus now possible to access new

regions of ligand space and, ultimately, reaction space.

Finally, we sought to demonstrate that modiﬁcation of a

ligand through its DTAP substructure can have a direct and

meaningful eﬀect on catalysis. As one possible indicator of

catalyst performance, we investigated the chemoselectivity of

oxidative addition under Suzuki−Miyaura conditions. To this

end, the eﬀect of JohnPhos analogues 3 on product

distribution was measured by intermolecular competition

between regioisomeric aryl bromides (Scheme 7). Notably,

data concerning intermolecular competitions between un-

biased systems are absent from the literature, although the

chemoselectivity of oxidative addition has been studied and

CONCLUSIONS

■

−

We have developed an umpolung (P /C ) approach to P−C

bond formation that enables the scalable, redox-eﬃcient

synthesis of di-tert-alkylphosphines from readily available tert-

alkyl esters and bench-stable Zn P . In this way, the

conventional dependence on PCl₃is avoided and an

unprecedented variety of tert-alkyl substituents can be installed

at phosphorus. The resulting DTAP building blocks can be

used in the preparation of diverse new analogues of established

ligand classes, thereby providing facile access to uncharted

regions of ligand space. We show that even apparently minor

variations in the DTAP substructure can have a dramatic eﬀect

on the steric and electronic properties of a ligand and

ultimately on its performance in catalysis. This study therefore

demonstrates that the DTAP motif need no longer be

considered an immutable component of a ligand but should

now be treated as another vector for optimization in ligand

design. We are actively seeking to exploit the opportunities that

this methodology presents.

exploited in the context of intramolecular competitions. As

illustrated in Scheme 7, simply changing the tert-alkyl

substituents on a common JohnPhos core resulted in

chemoselectivities ranging from 2.0:1 to 5.5:1, which

corresponds to a 0.6 kcal mol⁻diﬀerence in relative activation

energies.

That the observed selectivity trend does not correlate to

simple ligand descriptors, such as J_P₋_S_eand %V , reinforces

bur

the fact that prediction of catalyst activity is nontrivial and

highlights the value of being able to access new ligand

structures for laboratory assessment. More importantly, we

have demonstrated that modiﬁcation of a pre-existing ligand

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Complete contact information is available at:

Research Article

Scheme 7. Application of JohnPhos Analogues to Suzuki−

Authors

Miyaura Cross-Coupling: Chemoselectivity of Oxidative

Thomas Barber − School of Chemistry and GSK Carbon

Neutral Laboratories for Sustainable Chemistry, University of

Nottingham, Nottingham NG7 2RD, U.K.

Addition Depends on Di-tert-alkylphosphino Substructure

Stephen P. Argent − School of Chemistry, University of

Nottingham, Nottingham NG7 2RD, U.K.

https://pubs.acs.org/10.1021/acscatal.0c01414

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

This work was supported by the Engineering and Physical

Sciences Research Council (EPSRC) Centre for Doctoral

Training in Sustainable Chemistry (grant number EP/

S022236/1) through a Ph.D. studentship to T.B.

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AUTHOR INFORMATION

Corresponding Author

Liam T. Ball − School of Chemistry and GSK Carbon Neutral

Laboratories for Sustainable Chemistry, University of

Nottingham, Nottingham NG7 2RD, U.K.; orcid.org/0000-

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