Z-Selective Dienylation Enables Stereodivergent Construction of Dienes and Unravels a Ligand-Driven Mechanistic Dichotomy

Dienes and Unravels a Ligand-Driven Mechanistic Dichotomy

Research Article

Z‑Selective Dienylation Enables Stereodivergent Construction of

†

Hang T. Dang, Viet D. Nguyen, Graham C. Haug, Ngan T. H. Vuong, Hadi D. Arman,

and Oleg V. Larionov*

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sı Supporting Information

ABSTRACT: The development of stereoselective and eﬃcient

reactions for the construction of conjugated dienes and polyenes

has remained at the forefront of organic chemistry, due to their key

roles in medicinal chemistry, organic synthesis, and material

science. The synthesis of conjugated dienes and polyenes is

typically accomplished in a multistep manner by the sequential

installation of individual CC bonds because it allows for control

of stereoselectivity and eﬃciency of formation of each double

bond. A conceptually distinct dienylation approach entails a

stereoselective appendage of a four-carbon unit, shortcutting diene

synthesis. Dienylation with sulfolene provided a direct route to E-

dienes, but the synthesis of substantially more challenging Z-dienes remained elusive. Here, we report that a highly Z-selective

dienylation can now be achieved by a simple adjustment of a ligand, enabling stereodivergent synthesis of E- and Z-dienes from one

reagent and in one step. A detailed mechanistic investigation of the E- and Z-selective dienylation provided insight into the divergent

behavior of the two catalytic systems and revealed that diﬀerences in relative stabilities of catalytically active palladium phosphine

complexes have a major impact on the stereochemical outcomes of the dienylation.

KEYWORDS: conjugated dienes, cross-coupling, diastereoselectivity, palladium, phosphine

INTRODUCTION

and the lack of dienylation reagents that are stable and readily

available in a variety of substitution patterns.

■

Conjugated unsaturated motifs are abundant among natural

Existing methods, for example, Pd-catalyzed arylation

reactions of conjugated dienes, produce mixtures of regio-

and stereoisomers and suﬀer from low yields and narrow

products and drugs. They are crucial for the activity of these

compounds, and the conﬁguration of each CC bond is

important for the molecule to attain the required shape.

scope. Although dienylboronic acids have been explored for

Conjugated dienes are also key synthetic precursors to a variety

of functionalized intermediates because the reactive C(sp )

dienylation, they are unstable and diﬃcult to prepare.

Additionally, because of the stereospeciﬁcity of the cross-

coupling reactions, E- and Z-CC bonds have to be installed

using independently prepared E- and Z-vinylation reagents. A

conceptually distinct but hitherto unrealized approach that

would obviate the necessity to synthesize separate reagents to

install E- and Z-CC bonds in a dienyl group would require

the development of a stereodivergent cross-coupling with only

one coupling partner. Such a stereodivergent reaction would

produce either diastereomer on-demand in a highly stereo-

selective manner, e.g., by dialing in an appropriate ligand.

dienyl group can be transformed to a C unit with up to four

stereocenters and four functional groups in a stepwise fashion

by a variety of cycloaddition and functionalization reactions.

The regio- and stereochemistry of conjugated repeating CC

units are important not only for their biological activity but

also for synthetic applications, since only one diastereomer is

typically required to access a speciﬁc target molecule.

To control the regio- and stereoselectivity of the dienyl

group installation, a number of catalytic cross-coupling

methods have been developed that install the dienyl side

chain in a sequence of several steps, for example, by a

sequential appendage of two CC units (Figure 1). To

Received: December 19, 2020

Revised: December 25, 2020

Published: January 7, 2021

achieve a more convergent and eﬃcient synthesis of

conjugated dienes and polyenes, a reaction is required that

enables direct installation of a C unit. However, this synthetic

platform remained elusive due to the lack of reactions that

produce the dienyl unit in a regio- and stereoselective manner,

2021 American Chemical Society

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We recently described the E-selective dienylation with bulk

commodity chemical sulfolene 1 that eﬃciently produces E-

dienes with high stereoselectivity, typically with >30:1 E/Z

ratio. We found that the use of 1,2-(diphenylphosphino)-

benzene (dppbz) as a ligand was key for achieving high E-

selectivity, although the origin of the high E-selectivity

remained unknown. We now show that Z-dienes can be

synthesized in a stereoselective manner by a Pd/Xantphos-

catalyzed dienylation with sulfolene 1 that is stereocomple-

mentary to the previously developed Pd/dppbz-catalyzed E-

dienylation, thus demonstrating the feasibility of a one-step,

one reagent-either diastereomer approach to conjugated

dienes. We also provide a mechanistic rationale for the

ligand-driven stereodisparity.

Mechanistically, the reaction is initiated by a base-induced

ring-opening of sulfolene 1, producing Z-dienylsulﬁnate Z-2.

Given the overall E-selectivity of the Pd/dppbz-catalyzed

cross-coupling, it was initially hypothesized that the E-

selectivity is due to Z → E isomerization of sulﬁnate 2;

however, it was noted that the isomerization of salt Z-2 was not

fast enough to account for the high E-selectivity of the

dienylation, e.g., only 7:1 Z/E ratio was observed for sulﬁnate 2

after 1 h at 110 °C in tetrahydrofuran (THF). Although the

dienylation reaction was highly E-selective, initial formation of

Z-dienylsulﬁnate Z-2 suggested that the dienylation could be

rendered Z-selective, e.g., by an appropriate modiﬁcation of the

ligand. Successful execution of the strategy would result in a

stereodivergent dienylation that could produce either diene

diastereomer simply by switching the ligand. However, it

would require the development of a catalytic system that could

eﬃciently shuttle the Z-dienyl moiety through the catalytic

cycle via sulﬁnate complex A with subsequent extrusion of

sulfur dioxide en route to complex B and ensuing reductive

elimination to the Z-diene product, all of the while suppressing

deleterious side reactions, typically plaguing syntheses of Z-

dienes. Conjugated Z-dienes are particularly challenging to

synthesize, due to competing polymerization and Z → E

isomerization facilitated by thermodynamic instability of Z-

Figure 1. Stereodivergent dienylation.

Table 1. Reaction Conditions for the Z-Selective Dienylation

entry

Pd/L

base

additive

Z/E ratio

yield (%)

Pd(OAc) /dppe

KOMe/K CO₃

3:1

Pd(OAc) /DPEphos

KOMe/K CO₃

Pd(OAc) /TolBINAP

KOMe/K CO₃

2:1

Pd(OAc) /Xantphos

KOMe/K CO₃

10:1

11:1

17:1

18:1

>30:1

7:1

Pd(OAc) /Xantphos

KOMe/K CO₃

Pd(A) Cl /Xantphos

KOMe/K CO₃

Pd(A) Cl /Xantphos

KOMe/KHCO₃

KOtBu/KHCO₃

KOtBu

Pd(A) Cl /Xantphos

TEMPO

Pd(A) Cl /Xantphos

KHCO₃

>30:1

Reaction conditions: 4-bromobenzonitrile (4) (1 mmol), sulfolene 1 (2 mmol), Pd complex (5 mol %), ligand (11 mol %), base (1.6 mmol),

KHCO (2 mmol), additive (6.5 mol %), THF (9 mL), 110 °C, and 14 h. Determined by H NMR with 1,4-dimethoxybenzene as an internal

standard. 8 mol % diphosphine. The reaction was carried out in the atmosphere of air. Sulﬁnate Z-2 was used instead of sulfolene 1 and KOtBu.

A = MeCN.

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Table 2. Scope of the Z-Selective Dienylation

Reaction conditions: (hetero)aryl bromide or triﬂate (1 mmol), sulfolene 1 (2 mmol), Pd(MeCN) Cl (5 mol %), Xantphos (11 mol %), KOtBu

(

1.6 mmol), KHCO (2 mmol), TEMPO (6.5 mol %), THF (9 mL), 110 °C (100 °C for sulfonate substrates), and 12−16 h.

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dienes (e.g., density-functional theory, DFT-derived ΔG =

medicinally relevant sulfone, triﬂuoromethyl, and triﬂuorome-

thoxy groups (14−20). Z-Dienes were also readily synthesized

from substrates bearing alkyl, methoxy, and methylthio groups

(21−24). The Z-diene moiety can also be appended to

−

3.9 kcal/mol for the Z → E isomerization of diene 3, i.e.,

690:1 in favor of E-3 at equilibrium) and numerous

kinetically accessible isomerization pathways. However, even

in the context of the E-isomer synthesis and despite the high

thermodynamic driving force, most Z → E isomerizations do

not produce synthetically useful E/Z ratios, due to catalyst

,10

substituted naphthalenes (25, 26) and to the electron-rich

CC bond of phenanthrene (27). Nitrogen heterocycles are

centrally important medicinal motifs; however, their installa-

tion by means of Pd-catalyzed cross-couplings may be

deactivation or slow rates of isomerization.

problematic, due to catalyst inhibition. Gratifyingly, the Z-

selective dienylation performed equally well with a range of N-

heterocyclic substrates (28−45). Z-Dienylated pyridines

bearing methyl, methoxy, halogen, triﬂuoromethyl, and ester

groups were synthesized with high stereoselectivity (29−36).

Interestingly, two Z-dienyl moieties can be appended

simultaneously, aﬀording polyconjugated pyridine 37. Z-

Dienylpyrimidine 38 was also readily accessed. Furthermore,

heterocyclic substrates of benzazine and benzazole series,

including quinolines, isoquinolines, quinazolines, and benzo-

thiazole can be converted to the corresponding products 39−

RESULTS AND DISCUSSION

■

We began our studies adapting the reaction conditions

developed for the E-selective Pd/dppbz-catalyzed dienylation

with potassium carbonate as sulfur dioxide-sequestering

reagent and several diphosphines (8 mol %) as ligands that

are capable of diverting the reaction in favor of the Z-isomer

entries 1−3); however, the Z/E ratio and yield remained low

Table 1). Encouraging results were obtained with Xantphos

(

that provided promising Z-selectivity and yield (entry 4).

Increasing the ligand loading to 11 mol % led to a moderate

improvement of the Z-selectivity and eﬃciency. By contrast, a

signiﬁcant improvement of the Z-selectivity was achieved with

Pd(MeCN) Cl , although the yield remained modest (entry

5 bearing the Z-dienyl group in the proximal and distal

positions. The Z-dienylation also proceeded eﬃciently with

thiophene- and dibenzothiophene-derived bromides (46, 47).

Although aryl and heteroaryl bromides were used as the most

common and synthetically useful cross-coupling precursors, the

Z-dienylation was equally eﬃcient and highly stereoselective

with triﬂates and nonaﬂates (3, 5, 8, 11, 12, 14, 16, 23, 39),

allowing for facile conversion of phenols to Z-dienes.

). Switching to potassium bicarbonate brought the diene yield

in the synthetically useful range, while replacement of

methoxide with tert-butoxide drastically improved the Z-

selectivity (entries 7 and 8). Additional experiments indicated

that the formation of dienylsulﬁnate Z-2 from sulfolene 1 with

tert-butoxide is completed within 1 min at room temperature,

while the reaction with methoxide is substantially slower,

suggesting that the fast and irreversible deprotonation of

sulfolene 1 with tert-butoxide has a beneﬁcial eﬀect on the Z-

dienylation (see p. S11 in the Supporting Information, SI).

Further experimentation suggested that the propensity of Z-

dienes to undergo polymerization and other side reactions may

be aﬀecting the reaction performance. Several polymerization

inhibitors were tested, with TEMPO emerging as the optimal

additive, furnishing Z-diene 3 with high Z-selectivity and yield

The reaction was further tested with several heterocyclic

natural product and active pharmaceutical ingredient (API)

scaﬀolds. The naturally occurring umbelliferone (48) and the

skeletal muscle growth regulator urolithin B (49) were readily

converted to the corresponding Z-dienes. The Z-diene

derivative of the anticancer drug irosustat (50) was also

prepared. The Z-dienyl derivatives of other API were also

accessed with high stereoselectivity, including hypertriglycer-

idemia drug etoﬁbrate (51), antibiotic sulfadimethoxine (52),

Duchenne muscular dystrophy drug ataluren (53), and the

polyneuropathy and cardiomyopathy drug tafamidis (54).

Moreover, the dienylation can be carried out on a gram scale

(e.g., 3, 18, 20, 48), indicating that the reaction can be useful

for preparative applications. The stereochemical assignment of

the Z-dienes was unequivocally conﬁrmed by X-ray analysis of

(

entry 9). Of importance to further mechanistic discussion, the

reaction could be carried out in the atmosphere of air without

signiﬁcant detriment to the selectivity and eﬃciency (entry

0). The omission of the bicarbonate resulted in signiﬁcant

erosion of the stereoselectivity, suggesting that the additive

plays an important role in maintaining the stereochemical

products 3, 26, 43, and 48. In general, electron-withdrawing

groups improve the stability of Z-diene products that are more

readily isolated, due to the diminished eﬀects of polymer-

ization and isomerization. Similarly, vinyl-derived products

proved to be prone to polymerization and could not be

isolated.

integrity of the process. Additionally, consistent with the

prior observations made with the Pd/dppbz-catalyzed process,

no reaction was observed when butadiene was used instead of

sulfolene. Finally, replacement of sulfolene 1 and KOtBu with

sulﬁnate Z-2 aﬀorded product Z-3 in a comparable yield and

selectivity (entry 12), supporting the conclusion that the

dienylation proceeds via desulﬁtative coupling of Z-2.

Desulﬁtative cross-coupling reactions of (hetero)arylsulﬁnates

have recently attracted attention as eﬃcient alternatives to the

Mechanistic Studies of Stereoselectivity. To show that

complete stereodivergence can be achieved for the dienylation

reaction by a simple switch of the phosphine ligand, the

dienylation reaction was carried out with dppbz and Xantphos

boronate-based Suzuki coupling. However, stereoselective

desulﬁtative cross-couplings of vinylsulﬁnates have remained

unexplored, and the dienylation reaction sets an important

precedent for the feasibility of such highly stereoselective

couplings.

under otherwise identical conditions (Scheme 1A).

The Pd/dppbz-catalyzed reaction produced E-3 (85%, >30:1

E/Z), while the Pd/Xantphos reaction produced Z-3 (81%,

>30:1 Z/E). It is remarkable that the stereoselectivity of the

dienylation can be completely inverted from >30:1 in favor of

the E-isomer to >30:1 of the Z-isomer by a simple change of a

phosphine ligand. The stereodivergent process has a clear

synthetic advantage, as it requires only one reagent to access

either diene diastereomer. More importantly, it provides a

proof of principle for further development of stereodivergent

dienylation reactions. In this context, elucidation of the

The scope of the Z-selective dienylation was explored next

Table 2, 5−54). Various substitution patterns were well

tolerated (5−7). Substrates bearing nitrile, halogen, aldehyde,

ketone, and ester groups produced the corresponding Z-dienes

in good yields and with high stereoselectivity (5−13).

Similarly, the Z-dienylation can readily accommodate the

(

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stereoselectivity occurred relatively late (i.e., at ∼50%

Research Article

Scheme 1. Ligand-Enabled Stereodivergent Dienylation (A)

and Isomerization of Diene Z-18 under the Conditions of

the Pd/dppbz-Catalyzed Dienylation (B)

conversion), the high stereoselectivity of the Pd/dppbz process

could not be explained by either Z → E isomerization of

dienylsulﬁnate salt 2 or a faster dienylation with E-sulﬁnate E-

, as both scenarios would result in a much lower E-selectivity.

Rather, it points to the isomerization of the less stable Z-diene

to the E-product. To support this conclusion, the Pd/dppbz-

catalyzed dienylation was carried out in the presence of Z-

diene Z-18, and complete isomerization to E-18 was observed

(

Scheme 1B). Interestingly, the lower Z-selectivity of the Pd/

Xantphos-catalyzed dienylation under unoptimized conditions

Table 1, entry 5) was also found to be due to Z → E

(

isomerization, albeit at a substantially slower rate than in the

Pd/dppbz system.

These results suggest that Xantphos suppresses the Z → E

isomerization more eﬃciently than dppbz. To gain insight into

the mechanistic aspects of the stereodivergent dienylation, a

series of kinetic experiments were carried out. The study was

guided by the observation that the Pd/Xantphos-catalyzed

reaction proceeds at a higher rate (Figure 2), indicating that

the turnover-limiting step occurs at the transmetalation, sulfur

dioxide extrusion, or reductive elimination steps. The trans-

metalation may be accelerated by the participation of the

Xantphos oxygen atom in the displacement of bromide in

ArPd(diphosphine)Br, while the reductive elimination

underlying causes for the drastic ligand-driven stereodiver-

gence is key to the future successful development of other

catalytic transformations based on this approach. At this

juncture, we set out to investigate the kinetics of the

dienylation with the two ligands. As expected, the Pd/

Xantphos-catalyzed dienylation proceeded with high Z-

selectivity that remained unchanged throughout the reaction

beneﬁts from the substantially larger bite angle (111° for

Xantphos, 83° for dppbz).

P NMR Studies. Monitoring the reaction by ³¹P NMR

spectroscopy revealed that ArPd(Xantphos)Br was the only

Pd-bound phosphine species present in the solution (Figure

), consistent with the hypothesis that transmetalation is the

turnover-limiting step in the Pd/Xantphos-catalyzed dienyla-

tion. Additionally, the absence of phosphine monoxide

suggests that other reducing species, e.g., sulﬁnate Z-2 mediate

(Figure 2A). Surprisingly, the Pd/dppbz-catalyzed dienylation

exhibited an entirely diﬀerent kinetic behavior (Figure 2B).

The Pd/dppbz-catalyzed reaction was also Z-selective at low

conversions, with the Z/E ratio eroding from 4.5:1 to 1:1 in

the course of the ﬁrst 4.5 h. Thereafter, the stereoselectivity

reversed in favor of the E-isomer, and the E/Z ratio continued

to grow gradually until the E/Z ratio exceeded 30:1 by the time

the reaction was complete. Given that the switch in the

the reduction of the Pd precursor to the active Pd catalyst,

reﬂecting the increased steric hindrance within the larger bite

angle ligand. In a remarkable contrast, both Pd(dppbz) and

ArPd(dppbz)Br were present in the reaction mixture in the

case of the Pd/dppbz-catalyzed dienylation, with Pd(dppbz)₂

being the predominant species.

Figure 2. Time course graphs for the dienylation reaction with the diene 3 yield (●, left axis) and the percentage of the E-diene in the

diastereomeric mixture of product 3 (▲, right axis). Green and purple parts of the E-diene percentage line denote Z- and E-selective periods of the

reaction. The dotted bisecting line separates the top half with E-3 as the major diastereomer (E-selective) and the bottom half with Z-3 as the major

diastereomer (Z-selective). (A) Pd/Xantphos-catalyzed dienylation is consistently Z-selective. (B) Pd/dppbz-catalyzed dienylation starts as a Z-

selective process but reverses to E-selective and achieves high E-selectivity by the time of completion.

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Figure 3. ³¹P NMR study of the Pd/Xantphos- (A ) and Pd/dppbz- (B ) catalyzed dienylation reactions, after 1 h at 110 °C, Ar = p-NCC H .

Figure 4. Kinetic study of the key steps in the Pd/Xantphos- and Pd/dppbz-catalyzed dienylation at 110 °C in THF, Ar = p-NCC H . Yield on the

y-axis is for the product of each reaction as speciﬁed below. (A) Pd/Xantphos. (B) Pd/dppbz. PdL + ArBr (2 equiv), THF, 110 °C; reaction

product: ArPd(L)Br (●). ArPd(L)Br + Z-2 (4 equiv) + L (1.5 equiv), THF, 110 °C; reaction product: diene 3 (▲). ArPd(L)(Z-2) + L (1.5

equiv), THF, 110 °C; and reaction product: diene 3 (■). c = 0.038 M. Loadings of ArBr and Z-2 were one-tenth of the ones used in the

dienylation reaction. Ligand was added to the reaction of ArPd(L)(Z-2) to stabilize the Pd byproduct.

Kinetic Studies. To further clarify the role of individual

steps, kinetic studies of the Z- and E-dienylation reactions were

carried out. First order in the catalyst, aryl bromide, and

sulﬁnate Z-2 was observed for the Pd/Xantphos-catalyzed Z-

selective reaction, consistent with the transmetalation as the

The diﬀerence in the oxidation behavior of Pd(Xantphos)

and Pd(dppbz) is remarkable and consistent with P NMR

studies that showed the presence of Pd(dppbz) but not

Pd(Xantphos) in the reaction mixture. Notably, the reaction

of ArPd(L)Br with sulﬁnate Z-2 was slower for dppbz than for

Xantphos, reﬂecting, as discussed above, the beneﬁcial eﬀects

of Xantphos on the transmetalation and sulfur dioxide

extrusion/reductive elimination steps. The study also allowed

for direct observation of the stereoselectivity of the diene

formation from ArPd(dppbz)(Z-2) complex. The reaction

proceeded with high Z-selectivity (Z/E > 30:1), indicating that

the Pd/dppbz-catalyzed dienylation is intrinsically highly Z-

selective, and the E-selectivity is caused by the Z → E

isomerization of the diene product. To further probe the

turnover-limiting step. To directly test this conclusion, the

bromide was exchanged with the triﬂate to give [Pd-

(

Xantphos)]OTf, featuring Xantphos as a tridentate P,O,P-

ligand. The triﬂate intermediate was converted to the

corresponding Pd sulﬁnate complex ArPd(Xantphos)(Z-2).

The rates of the oxidative addition, sulfur dioxide extrusion/

reductive elimination from ArPd(Xantphos)(Z-2), and the

reaction of ArPd(Xantphos)Br with sulﬁnate Z-2 were then

compared, revealing a substantially slower reaction of ArPd-

(

Xantphos)Br with Z-2 and supporting the conclusion that the

distinctive roles of PdL and ArPd(L)Br in the Pd/Xantphos

transmetalation is the turnover-limiting step (Figure 4A).

Remarkably, the Pd/dppbz system exhibited a distinctly

diﬀerent kinetic behavior (Figure 4B). While the reaction of

ArPd(dppbz)Br with Z-2 was again slower than the sulfur

dioxide extrusion/reductive elimination from ArPd(dppbz)(Z-

and Pd/dppbz dienylation processes, the dienylation reactions

were conducted with PdL and ArPd(L)Br as catalysts (Figure

5). As expected from the spectroscopic and kinetic studies,

both Pd(Xantphos) and ArPd(Xantphos)Br were competent

catalysts with regard to selectivity and eﬃciency. In contrast,

), no oxidative addition was observed with Pd(dppbz) even

divergent catalytic behavior was observed for Pd(dppbz) and

after prolonged heating.

ArPd(dppbz)Br. While ArPd(dppbz)Br exhibited high catalytic

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Figure 5. (A) Catalytic activity of PdL and ArPd(L)Br in the dienylation reaction (Ar = p-NCC H ). (B) Inﬂuence of the dppbz/Pd ratio on the

dienylation eﬃciency. (C) X-ray structure of Pd(dppbz)₂.

activity, resulting in a highly E-selective dienylation, Pd-

(

dppbz) was essentially catalytically inactive, indicating that it

is an oﬀ-cycle reservoir of Pd. Additionally, the 1:1 E/Z ratio of

product 3 indicates that Pd(dppbz)₂is not substantially

involved in the Z → E isomerization. These results suggest that

Pd(dppbz) is the actual on-cycle catalyst, which may explain

the reduced dppbz loading (8 mol %) under the optimal

conditions. Indeed, an increase in the dppbz loading resulted in

a complete shutdown of the dienylation (Figure 5).

Furthermore, no Z → E isomerization of diene 3 was observed

in the presence of Pd(dppbz) (5 mol %), at 110 °C in THF

after 16 h, ruling out its involvement in the isomerization

process. Taken together, the spectroscopic and kinetic studies

indicate that the E-selective dienylation is catalyzed by

Pd(dppbz) with ArPd(dppbz)Br as an on-cycle resting species.

The reaction is intrinsically Z-selective, with the eﬃcient Z →

E isomerization eﬀected by a side process that originates from

the Pd(dppbz)/ArPd(dppbz)Br cycle, while Pd(dppbz) is not

signiﬁcantly involved in the reaction.

Involvement of Heterogeneous Catalytic Channels.

Although cross-coupling reactions are typically assumed to

proceed by homogenous pathways via well-deﬁned molecular

catalysts, the involvement of catalytically active colloidal metal

particles was shown to be central to observed net catalytic

reactivities or side reactions in many metal-catalyzed

Figure 6. Hot ﬁltration test of the Pd/Xantphos- and Pd/dppbz-

catalyzed dienylation of bromide 4 to diene 3.

processes. In this context, colloidal palladium was implicated

isomerization was substantially slower after the hot ﬁltration

for the Pd/dppbz-catalyzed process. Importantly, and in

contrast to the Pd/Xantphos system, the solid residue that

was ﬁltered from the reaction mixture eﬃciently catalyzed the

Z → E isomerization of diene Z-3. This result supports the

involvement of colloidal palladium in the Z → E isomerization

as the underlying mechanism for the observed net E-selectivity

and suggests that the catalytic colloids are formed in the early

stages of the reaction.

in alkene isomerizations proceeding via a reversible Pd−H

b,20

addition to double C−C bonds.

To test the involvement of

a heterogenous Pd-catalyzed Z → E isomerization in the Pd/

dppbz-catalyzed dienylation, hot ﬁ ltration

19,21

experiments

were carried out (Figure 6, see also Figures S4 and S5 in the

SI), wherein the reaction was interrupted and ﬁltered hot to

remove all insoluble material including metal catalyst

particulate if formed, and then allowed to continue with a

fresh batch of KHCO and Z-2. The hot ﬁltration test can be

The reversible addition of palladium hydride species that is

followed by β-hydride elimination is a common mechanism

implicated in alkene isomerizations and chain-walking

used to distinguish heterogeneous and homogenous catalysis.

For comparison, the experiment was ﬁrst carried out with the

Pd/Xantphos-catalyzed reaction, and no negative eﬀects on the

Z-selectivity were observed. In contrast, the Z → E

processes. We thus hypothesized that Pd particles implicated

in the E-selective Pd/dppbz-catalyzed dienylation may carry

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catalytically active Pd−H sites eﬀecting the isomerization or

act as catalytic reservoirs releasing and recapturing soluble Pd−

Scheme 3. Computed Gibbs Free Energies for the Stepwise

Dissociation of Pd(Xantphos) and Pd(dppbz) and the

Mechanism of Colloidal Pd Formation, Directly and with a

Labile Transient Ligand (L = Phosphine, L′ = Diene or

Sulﬁnate)

9,22

H species.

To test the involvement of the Pd−H-mediated isomer-

ization in the Pd/dppbz-catalyzed dienylation, the reaction was

carried out in the presence of palladium hydride traps

(

TEMPO, galvinoxyl, and air). Signiﬁcantly, the dienylation

proceeded with substantially reduced E-selectivity (TEMPO)

or became Z-selective (galvinoxyl, air), pointing to the

involvement of the Pd−H-mediated pathway (Scheme 2).

Scheme 2. Inﬂuence of Palladium Hydride Traps on the Pd/

dppbz-Catalyzed Dienylation of Bromide 4 to Diene 3

This result stands in stark contrast to the Z-selective Pd/

Xantphos dienylation that can be performed under air without

signiﬁcant deterioration of the stereoselectivity and eﬃciency

that led to complete isomerization of diene Z-3. Furthermore,

substitution in dienylsulﬁnate salts and diene products can

inﬂuence the reactivity, stability, size, and rates of formation of

colloidal palladium (and active Pd−H species) via ligation, as

shown in Scheme 3, providing additional elements of control

of the stereoselectivity.

(

Table 1, entry 10). Taken together, the studies indicate that

the Z → E isomerization observed in the Pd/dppbz-catalyzed

dienylation is eﬀected by Pd particles that may carry

catalytically active Pd−H sites or serve as reservoirs that

release and recapture soluble Pd−H species. To test this

mechanism, diene Z-3 was subjected to palladium on charcoal

that was previously shown to eﬀect Z → E isomerization of

20a

alkenes via palladium colloids,

and complete Z → E

isomerization was observed. Other sources of colloidal Pd were

also tested with similar results. Importantly, in all cases, the Z

→

traps.

E isomerization was suppressed by the palladium hydride

Collectively, the combined evidence from spectroscopic,

kinetic, and computational studies suggest that both Pd/

Xantphos and Pd/dppbz-catalyzed dienylations are intrinsically

Z-selective (Figure 7). The E-selectivity of the Pd/dppbz-

catalyzed reaction is explained by the eﬃcient Z → E

isomerization caused by palladium colloids that may be

formed from the catalytically competent Pd(dppbz) due its

Stability of Palladium(0)−Phosphine Complexes. The

experimental evidence indicates that palladium colloids are

readily formed in the Pd/dppbz system, in contrast to Pd/

Xantphos, suggesting that Pd /dppbz complexes may be less

stable and more prone to ligand dissociation that results in Pd

aggregation. Indeed, the computed Gibbs free energy of

dissociation for Pd(dppbz) is substantially lower than for

Pd(Xantphos) in the PdL series (Scheme 3), supporting the

conclusion that the dissociation is more facile in the Pd/dppbz

system and may be additionally facilitated by sulﬁnate Z-2 or

the diene product acting as transient labile ligands that may

promote the departure of the phosphine and the growth of Pd

lower stability, while Pd(dppbz)

participate in the reaction because of the lower propensity to

shed the ﬁrst phosphine ligand. In contrast, Pd(Xantphos)

does not signiﬁcantly

dissociates more readily, providing a pathway for eﬃcient

dienylation, while the increased stability of Pd(Xantphos)

precludes the formation of Pd colloids, thus suppressing the Z

→ E isomerization and ensuring the high Z-selectivity.

colloids. In contrast, in the PdL series, the departure of the

ﬁrst ligand is more thermodynamically favorable for Pd-

CONCLUSIONS

(

Xantphos) . The disparity in the dissociation energies of PdL

■

and PdL highlights the more favorable proﬁle of Xantphos,

since more readily formed and more stable PdL species is

beneﬁcial for the overall reaction performance and selectivity.

Substituted dienes are expected to have diﬀerent reactivities

toward Pd−H that may aﬀect their stability under the Pd/

dppbz conditions. Indeed, when 1Z-diene 55 that is formed

under the Pd/dppbz conditions from the corresponding

disubstituted sulfolene was subjected to palladium on charcoal,

no Z → E isomerization was observed under the conditions

In conclusion, we developed a Pd/Xantphos-catalyzed, highly

Z-selective dienylation that together with the Pd/dppbz-

catalyzed E-selective dienylation enables the synthesis of either

diastereomer of conjugated dienes in one step and using the

same dienylation reagentbulk commodity chemical sulfolene

1. We further show that the stereodivergent behavior of the

Xantphos- and dppbz-based reactions is due to high Z-

selectivity and suppression of the Z → E isomerization in the

Pd/Xantphos-catalyzed reaction. In contrast, the Pd/dppbz-

049

ACS Catal. 2021, 11, 1042−1052

Complete contact information is available at:

Research Article

Figure 7. Summary of the mechanistic and computational studies of the Pd/Xantphos (X)- and Pd/dppbz (D)-catalyzed dienylation.

catalyzed dienylation is in fact intrinsically highly Z-selective

but is subject to eﬃcient Z → E isomerization that results in

the overall highly E-selective process. The underlying cause of

the disparate catalytic behavior of Pd/Xantphos and Pd/dppbz

systems is the more facile ﬁrst ligand dissociation for Xantphos

Graham C. Haug − Department of Chemistry, The University

of Texas at San Antonio, San Antonio, Texas 78249, United

States

Ngan T. H. Vuong − Department of Chemistry, The

University of Texas at San Antonio, San Antonio, Texas

78249, United States

in the PdL series, and the lower stability for dppbz in the PdL

series, leading to the formation of palladium colloids and the Z

Hadi D. Arman − Department of Chemistry, The University of

Texas at San Antonio, San Antonio, Texas 78249, United

States

→

E isomerization. The stereodivergent dienylation with

sulfolene 1 provides a blueprint for further development of

diene and polyene syntheses with other sulfolenes and

electrophilic coupling partners based on the one reagent-either

diastereomer concept.

https://pubs.acs.org/10.1021/acscatal.0c05574

Author Contributions

H.T.D. and V.D.N. contributed equally to this work.

Notes

ASSOCIATED CONTENT

sı Supporting Information

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acscatal.0c05574.

†

■

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

Experimental, spectral, and X-ray crystallographic details

for all new compounds and all reactions reported (PDF)

■

Financial support by NIGMS (GM134371) and the Welch

Foundation (AX-1788) is gratefully acknowledged. The UTSA

NMR and X-ray crystallography facilities were supported by

the NSF (CHE-1625963 and CHE-1920057). The authors

acknowledge the Texas Advanced Computing Center (TACC)

at UT Austin for providing computational resources.

Crystallographic data (CIF)

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AUTHOR INFORMATION

Corresponding Author

Oleg V. Larionov − Department of Chemistry, The University

of Texas at San Antonio, San Antonio, Texas 78249, United

States; orcid.org/0000-0002-3026-1135;

Email: oleg.larionov@utsa.edu

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052