Mechanistic Study of a Re-Catalyzed Monoalkylation of Phenols

Article

pubs.acs.org/Organometallics

Cite This: Organometallics XXXX, XXX, XXX −XXX

Mechanistic Study of a Re-Catalyzed Monoalkylation of Phenols

Dan Lehnherr,* Xiao Wang,* Feng Peng, Mikhail Reibarkh, Mark Weisel, and Kevin M. Maloney

Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, United States

S

* Supporting Information

ABSTRACT: A mechanistic study of a rhenium catalyzed monoalkylation of phenols is described. Reaction kinetics reveals a

zero-order dependence on both alkene and phenol and a half order dependence on catalyst. Isotopic labeling studies,

competition experiments, kinetic isotope eﬀects, and Hammett analysis together aﬀord experimental data consistent with a

reversible C−H activation step and an irreversible hydrometalation process. The turnover-limiting step is identiﬁed as catalyst

deaggregation. NMR studies of binary mixtures of catalyst and a single substrate (alkene or phenol) as well as those of reaction

mixtures identify potential intermediates and oﬀ-cycle species. Despite the numerous Re complexes formed in these mixtures,

the overall reaction is both high yielding and highly selective for monoalkylation of phenols.

converts commodity feedstocks to pharmaceutically relevant

intermediates.

INTRODUCTION

■

Eﬃcient introduction of a single alkyl group onto an arene

remains a challenging transformation. For example, Friedel−

Crafts alkylations generally provide regioisomeric mixtures in

addition to overalkylated products.¹Oleﬁn hydroarylation

reactions can eﬀectively control the regioisomeric site of

alkylation on arenes, although controlling for branched versus

linear products (Markovnikov versus anti-Markovnikov

addition) is challenging and can require impractical directing

groups.²Methods to obtain the linear hydroarylation product

are well-documented;³however, the identiﬁcation of branch

selective methods remain signiﬁcantly more elusive.⁴

POTENTIAL REACTION MECHANISMS

■

Several potential reaction mechanisms were initially considered

for this transformation, and our experiments were designed to

probe for evidence that would either support or refute these

postulated mechanisms. Alkylation of electron rich arenes

immediately draws attention to the possibility of a Friedel−

Crafts type mechanism (electrophilic aromatic substitution)

whereby a cationic intermediate derived from the alkene is

trapped by the electron-rich arene (Scheme 2A). Alternatively,

a Re-catalyzed C−H activation processes may be operational

and such reactions have been previously reported.^8,9The

hydroxyl group could act as a directing group for metalation of

the arene via a C−H activation-type mechanism, with an

alkene hydrometalation process occurring either after or prior

to the C−H activation step (Scheme 2B,C, respectively) and in

either case followed by a reductive coupling step. The

hydrometalation event could be a concerted 1,2-metal hydride

insertion into the alkene or alternatively proceed via a 2-step

process in which hydrogen atom transfer (HAT) to the oleﬁn

provides a radical pair that subsequently recombines to aﬀord a

net hydrometalation;¹⁰a subsequent reductive coupling could

aﬀord product. Scheme 2D illustrates an alternative cyclo-

metalation pathway in which a phenol bound to the Re catalyst

could serve as a template for the alkene to annulate the arene

via a dearomatization-rearomatization pathway, followed by

either reductive elimination or protodemetalation. This

A rhenium-catalyzed alkylation of phenols with terminal

alkenes was initially reported by Takai and co-workers

(Scheme 1).^5,6This reaction provides exclusively the

Scheme 1. Re-Catalyzed Regioselective Markovnikov

Monoalkylation of Mequinol

monoalkylation product, is highly regioselective, and results

in sole observation of the branched product. This result is in

contrast to other methods of functionalizing phenols that

aﬀord mixtures of mono- and bis-alkylated products.⁷As part

of our eﬀorts to obtain an eﬃcient synthesis of ortho-

monoalkylated phenols for the development of active

pharmaceutical ingredients, we sought to leverage this Re-

catalyzed reaction as well as to gain understanding of the

underlying reaction mechanism. Herein we report a detailed

mechanistic investigation of this reaction that successfully

Special Issue: The Roles of Organometallic Chemistry in Pharma-

ceutical Research and Development

Received: July 31, 2018

A

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Scheme 2. Selected Potential Mechanisms Prior to Mechanistic Study

cyclometalation pathway would bear a resemblance to

literature-proposed two-π-component cyclization processes

involving rhenium carbonyl catalysts.^6,11

Scheme 3. Competition Reaction Under Re-Catalyzed

Alkylation Conditions

ELECTRONIC EFFECTS

■

While a variety of phenols and alkenes are competent

substrates in the reaction shown in Scheme 1,^5,6we chose to

use mequinol (1) and 1-octene (2) as model substrates to

study the generation of monoalkylated phenol 3. Due to both

the solvent and the alkene having boiling points below the

reaction temperature of 140 °C, some of the mechanistic

studies focused on the closely related system that employs

mesitylene and 1-dodecene (4), both of which have higher

boiling points, to generate phenol 5.¹²

mechanism, these competitive alkylation reactions did not

aﬀord any bis-alkylated products.

Furthermore, if the reaction involves a Friedel−Crafts type

mechanism, then the rate of alkylation should be proportional

to the electron density of the arene across a substrate series.

The relative initial rate of product formation was measured for

para-substituted phenols (R = F, MeO, Me) in order to probe

this hypothesis (Figure 1). Alkylation of ﬂuorophenol (8) was

observed to be the fastest, followed by methoxyphenol (1), and

ﬁnally methylphenol (6). Attempts to correlate these rates with

Hammett parameters are shown in Figure 1. While no

correlation is observed with the σ_paraparameters (Figure 1,

right) that would reﬂect correlation with regards to the general

electron density of the ring, the σ_metavalues do correlate with

the rates of alkylation (Figure 1, left). The σ_metacorrelation

illustrates that the rate increases with more electron with-

drawing groups related to the site of alkylation, with ﬂuoro

being the most electron withdrawing in this series, followed by

methoxy then methyl. This trend is inconsistent with a

Friedel−Crafts type mechanism that would show increasing

rates as the electron density increase on the carbon meta to the

substituent being varied.

If a Friedel−Crafts-type mechanism were operational

(Scheme 2A), then the electrophilic cation intermediate

derived from the alkene should be trapped by arenes, such

as 1,4-dimethoxybenzene, with comparable sterics and

electronics to that of mequinol. In a competitive alkylation

reaction using a 1:1 molar mixture of mequinol (1) and 1,4-

dimethoxybenzene (6) subjected to the typical Re-catalysis

conditions in Scheme 1 but with 3 equiv of 1-octene, we failed

to observe any alkylation of dimethoxybenzene; instead, only

alkylation of mequinol was observed, along with recovery of

1,4-dimethoxybenzene (Scheme 3). This result was incon-

sistent with a Friedel−Crafts-type mechanism and also

highlights that even if the phenol were required to generate

the active catalyst and necessary intermediates a hydroxyl

group must be attached to the arene in order for that arene to

undergo alkylation. Consistent with preserving the operating

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Re−π-allyl complex)¹³or the vinyl C−D bonds.¹⁴The

observations shown in Scheme 4 are consistent with an

irreversible hydrometalation process.

If the mechanism involves C−H activation of the arene, then

the C−H cleavage can be in one of three categories: (1)

reversible, thus not turnover-limiting, (2) irreversible and

turnover-limiting, or (3) irreversible but not turnover-limiting.

This aspect was probed using deuterated-mequinol in the Re-

catalyzed alkylation (Scheme 5). To assess the former scenario,

Scheme 5. Experiments Illustrating Reversibility of C−H

Activation and Lack of a Large (≥3) Primary Kinetic

Isotope Eﬀect

Figure 1. Relative initial rate of product formation measured after the

induction period plotted versus: (left) σ_metavalue with R²= 0.93

(correlation), and (right) σ_parawith R²= 0.26 (lack of correlation).

KINETIC ISOTOPE EFFECT AND DEUTERIUM

LABELLING STUDIES

We utilized a series of deuterium-labeled substrates in the Re-

catalyzed alkylation of mequinol in order to gain insight into

the C−H bond-breaking events, including potential reversi-

bility (Scheme 4). Using 1-octene labeled with deuterium(s) at

■

Scheme 4. Deuterium-Labelling Experiments Using Various

Alkene Substrates

either the terminal (C1) or internal (C2) alkene position, or

even at the allylic position (C3), all resulted in exclusive

transfer of deuterium(s) to the product without scrambling or

depletion of the deuterium content. Speciﬁcally, using 1,1-d₂-

oct-1-ene (1,1-d₂-2) with two deuteriums at the terminal

alkene position provided product 1,1-d₂-3, while products

associated with loss of one or both deuteriums (i.e., 1-d₁-3 or

1,1-d₀-3) were not observed. Similarly, subjecting 2-d₁-oct-1-

ene (2-d₁-2) to the reaction conditions in the presence of

mequinol provided product (2-d₁-3) exclusively, without

observing products associated with scrambling or loss of

deuterium content (e.g., 2-d₀-3). Using 3,3-d₂-oct-1-ene (3,3-

d₂-2) in the reaction provided exclusively 3,3-d₂-3. All of these

observations are consistent with a reaction pathway that does

not involve reversible cleavage of the allylic C−D bonds (e.g.,

we utilized 2,3,5,6-d₄-1 and terminated the reaction at partial

conversion (ca. 50% conversion) to recover the unreacted

starting material and measure its deuterium content by NMR

spectroscopy (Scheme 5A). If C−D cleavage is reversible, we

expect depleted deuterium content in the recovered starting

material relative to its original content, particularly at the site

of alkylation (ortho to the hydroxyl group), for which the

hydroxyl group from mequinol may serve as a potential proton

source (vide infra). Indeed, the recovered mequinol was

observed to have signiﬁcant loss in deuterium content ortho to

the hydroxyl group (ca. 26% H incorporation) relative to the

loss observed at the meta positions (ca. 7% H incorporation),

consistent with reversible C−H activation prior to the

turnover-limiting step. The product isolated from that reaction

mixture clearly illustrates similar levels of depletion at the

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remaining ortho position (ca. 23% H incorporation), while the

sites meta to the hydroxyl group reveal clear diﬀerences. The

position ortho to the site of alkylation shows 10% H

incorporation, comparable to levels observed in the recovered

starting material. In contrast, the other site meta to the OH

(para to the site of alkylation) reveals 23% H incorporation,

signiﬁcantly greater than the 7% observed in the recovered

starting material. This observation is consistent with a process

involving reversible C−H activation para to the site of

alkylation; however, the catalyst appears to be unable to

promote subsequent alkylation to the bis-alkylated product,

which results in the selectivity for the monoalkylation product.

Summarizing, reversible C−H activation occurs preferen-

tially at the position ortho to the OH on the arene (Scheme

5A) where the depletion of deuterium is signiﬁcantly greater at

the ortho-position versus the meta-position on the recovered

mequinol. The observation that the alkylation product

obtained in the Scheme 5A has a higher degree of deuterium

depletion at the sites meta to OH relative to those found in the

recovered mequinol implies that the (undesired) C−H

cleavage at the meta-site occurs preferentially on the

monoalkylation product than on the starting material

(mequinol). While C−H cleavage does occur to a small

degree at the sites meta to the OH (Scheme 5A), alkylation is

not observed meta on the OH on either the starting material or

the monoalkylated product, suggesting that the alkylation

regioselectivity is not arising solely from the C−H activation

step but mostly due to the subsequent step(s).

When reacting 2,3,5,6-d₄-mequinol with 1-octene as shown

in Scheme 5A,B, the newly formed methyl group in the

product is a mixture of CH₂D and CH₃groups as observed by

quantitative ¹³C NMR, consistent with phenol OH and the

arene C−H taking part in a reversible exchange process. This

hypothesis is solidiﬁed when using OD-d₁-mequinol with 1-

octene and observing deuterium incorporation in the newly

formed methyl group in the product (Scheme 5C). We

emphasize that the methyl group obtained in these experiment

are exclusively CH₃or CH₂D groups, and no evidence of

generating a CD₂H group was observed; these results are

consistent with an irreversible hydrometalation process.

The reversibility of the arene C−H cleavage event implies it

is not the turnover-limiting step, and we solidiﬁed this

conclusion using proof by contradiction logic. If C−H cleavage

were turnover-limiting, then a large primary kinetic isotope

eﬀect (KIE) should be observed (typically greater than 3) in

alkylation rates for protio vs deutero arene analogs when

carried out in parallel experiments (Scheme 5D). Initial rates

reveal a KIE of 1.39, which is inconsistent with C−H cleavage

being turnover-limiting. A value slightly greater than one could

be due to an equilibrium isotope eﬀect, in which there is a

preference of the resting state of the catalyst to be bound to

mequinol over the d₄-mequinol.

°C for 24 h (Scheme 6). The recovered dimethoxybenzene was

analyzed by NMR spectroscopy and revealed partial depletion

Scheme 6. Probing Necessity of a Hydroxyl Group for C−H

Activation into the Arene

of its deuterium content, namely, ca. 10% H incorporation.

This observation is consistent with reversible C−H activation

into the arene and the alkylation selectivity arising from a

subsequent step in the catalytic cycle. It should be emphasized

that the deuterium depletion could be proceeding via a

diﬀerent mechanism or catalytic intermediate than that

necessary for productive alkylation of the phenol.

To provide further mechanistic insight, we performed

several additional experiments with deuterated substrates

(Scheme 7). KIE experiments using alkenes with one or

more deuterium(s) at the C1-, C2-, or C3-position of 1-octene

support the mechanism shown in Scheme 2B and disprove the

one in Scheme 2C. Using 3,3-d₂-oct-1-ene (3,3-d₂-2) in a

competition experiment with unlabeled oct-1-ene (2, 5 equiv

of each alkene) did not aﬀord an appreciable KIE (KIE = 1.18)

as determined by quantitative ¹³C NMR analysis of the

product mixture at full conversion (Scheme 7C). This result

invalidates mechanisms proceeding via Re−π-allyl intermedi-

ates.¹³A similar experiment using 2-d₁-oct-1-ene (2-d₁-2) once

again results in the absence of a KIE (KIE = 1.01, Scheme 7B).

The use of 1,1-d₂-oct-1-ene (1,1-d₂-2) in a one-pot

intermolecular competition experiments aﬀorded a small

normal KIE of 1.50, as measured via NMR product ratios;

this KIE was determined to be even smaller in independent

parallel rate experiments (KIE = 1.22, Scheme 7A). These data

are inconsistent with hydrometalation being turnover-limiting,

as the rehybridization from sp²to sp³should aﬀord an inverse

secondary KIE (KIE < 1) and this was not observed.

The lack of an inverse secondary KIE when using either 2-

d₁-2 or 2,3,5,6-d₄-1 indicates that C−C bond formation is not

turnover-limiting. One should expect an inverse secondary KIE

with H versus D isotopologues that have the isotope directly

attached to the carbon undergoing rehybridization from sp²to

sp³, namely, the arene C−H ortho to the hydroxyl (Scheme

5D) and for alkenes with deuterium atom at C2 (Scheme 7B).

Experimentally, neither of these two experiments revealed an

inverse secondary KIE: the former gave a KIE of 1.39 and the

later experiment gave KIE of 1.01. While rhenium carbonyl

complexes are known to be able to cleave vinyl C−H bonds,¹⁴

the lack of a large primary KIE (>3) in any of the reactions in

Scheme 6 with deuterated analogs of 1-octene rule out any C−

H bond breaking events occurring on the alkene at C1-, C2-,

and C3-positions in the turnover-limiting step; these results are

consistent with mechanisms shown in Scheme 2B.

Returning to the question of why 1,4-dimethoxybenzene

does not get alkylated by 1-octene under typical reaction

conditions (Scheme 2), we considered two potential reasons.

Either the C−H activation necessitates an OH to be present on

the arene. Alternatively, the C−H activation occurs, but one of

the subsequent steps has an energy barrier too high to allow

alkylation to occur. Toward discerning between the two

scenarios, we carried out an analogous competitive alkylation

process as shown in Scheme 2 but using a 1:1 mixture of

mequinol and d₄-1,4,-dimethoxybenzene in the presence of

excess 1-octene with 3 mol % of Re₂(CO)₁₀in toluene at 140

KINETICS

■

In order to gain further insight into the mechanism and its

turnover-limiting step, we obtained kinetic data for the

alkylation reaction in Scheme 1. We sought to use NMR

spectroscopy to monitor the reaction as it would simulta-

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Scheme 7. Determination of KIEs Using Various Deuterium-Labelled Alkenes

neously provide an opportunity to gain structural information

into potential intermediates, the catalyst resting state, and oﬀ-

cycle species. The high temperature of this reaction together

with the temperature limitation of NMR probes precluded us

from carrying reactions at the typical 140−150 °C range. We

were however able to use ¹H NMR spectroscopy to monitor a

representative reaction mixture at 130 °C containing mequinol

(1 equiv), 1-octene (1.5 equiv), and Re₂(CO)₁₀(2.5 mol %) in

d₈-toluene in a ﬂame-sealed NMR tube. We observed an

overall zero-order reaction proﬁle as the concentration of

product increased linearly. Consumption of each substrate

(mequinol and 1-octene) revealed a linear decrease in their

temporal concentration proﬁles, consistent with zero-order

dependency. These observations imply one of two scenarios:

(scenario 1) Both substrates are bound to the catalyst in its

resting state prior to the turnover-limiting step. (scenario 2)

One substrate is bound to the catalyst in its resting state, and

the interaction with the second substrate does not occur until

after the turnover-limiting transition state. In scenario 2, the

turnover-limiting step could include ligand dissociation or

catalyst reorganization (e.g., deaggregation of the catalyst or

oxidative addition/reductive elimination events). One addi-

tional observation from Figure 2 is the non-zero x-intercept in

the product formation linear ﬁt which suggests an induction

period, consistent with precatalyst Re₂(CO)₁₀losing one or

more CO ligands to coordinate substrate(s).

If CO dissociation is required for precatalyst Re₂(CO)₁₀to

achieve the active catalyst, then CO would act as an inhibitor

in the reaction, which should result in an inverse rate

dependency in CO concentration. Indeed, upon comparing

reactions with a ﬁnite headspace volume (closed vessel system)

versus pseudoinﬁnite headspace (open vessel system), two

clear observations were made. The closed reaction system,

having higher CO concentration, had a slower rate of product

formation and a longer induction period compared to the open

reaction systems, which should have lower concentrations of

CO. This comparison is illustrated in the time course data

shown in the Supporting Information for reactions carried out

at 140 °C using 1-dodecene (bp 214 °C) in mesitylene (bp

163 °C) instead of 1-octene (bp 122 °C) in toluene (bp 110

Figure 2. Temporal concentration proﬁles of 1-octene (2), mequinol

(1), and alkylated product (3) monitored by H NMR recorded at

130 °C in the presence of 2.5 mol % Re₂(CO)₁₀in d₈-toluene.

1

°C) in which 5 mol % Re₂(CO)₁₀was used to amplify the

eﬀect of CO on reaction rate.

Initial rate kinetic data measured after the induction period

were obtained at 150 °C to examine the rate of product

formation as a function of catalyst loading. Varying the total

catalyst loading (0.625 mol %, 1.25 mol % and 2.50 mol %)

revealed a half order dependence (Figure 3). This fractional

order dependency is consistent with the catalyst resting state

having to deaggregate prior to the turnover-limiting transition

state. Several likely scenarios exist, particularly since dinuclear

(Re₂L_n) and tetranuclear (Re₄L_n) rhenium carbonyl complexes

have been reported.^15,16The resting state catalyst could be

dinuclear (ReL_n)₂implying that the turnover-limiting step

would feature a mononuclear form (ReL_n). In an alternate

scenario, the catalyst resting state could be tetranuclear

(ReL_n)₄implying that the turnover-limiting step would feature

a dinuclear form (ReL_n)₂. Given that cleavage of Re−Re bonds

has been reported to be mediated both by thermal and

photochemical methods,¹⁷it is not unreasonable to propose

deaggregation via cleavage of a Re−Re bond under the

reaction conditions presented herein. In fact, heating a 1:1

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were detected as well as other internal alkene isomers (cis-

and/or trans-2c and 2d) with a ratio of 1/2a/2b/(2c + 2d) =

1:0.37:0.28:0.52 (Scheme 8). Cleavage of the terminal vinyl

C−H bond in terminal alkenes has previously been reported

under photolysis conditions via the formation of complex 10,

(R = Bu, δ_Hof −14.7 ppm).^14aAnalysis of the hydridic H

1

NMR region (ca. −5 to −20 ppm) reveals signals at δ_Hof

−14.4 and −17.31 ppm, each corresponding to less than 1% of

the reaction mixture (relative to 1-octene). DOSY character-

ization reveals both hydrides correspond to diﬀusion

coeﬃcients D = 8.0 × 10⁻¹⁰m²/s compared to 17.9 × 10⁻¹⁰

m²/s for the oleﬁns, consistent with the hydride complexes

being larger than 1-octene. The signal at δ_H−14.4 ppm is

consistent with formation of bridging hydride complex 11,

analogous to complex 10,^14awhich may be associated with the

alkene isomerization described above. The signal at δ_H−17.3

ppm is characteristic of bridging hydrides in cyclic Re clusters,

most likely that of cyclic trimer [Re(μ₂-H)(CO)₄]₃(12).¹⁸

Figure 3. Eﬀect of total catalyst concentration on the initial rate of

product formation in the alkylation of mequinol using 1-octene at 150

°C in toluene.

mixture of isotopically labeled ¹⁸⁵Re₂(CO)₁₀and ¹⁸⁷Re₂(CO)₁₀

in octane for 16 h at 150 °C provides nearly complete

conversion to the crossover product ¹⁸⁵Re¹⁸⁷Re(CO)₁₀which

is consistent with cleavage of the Re−Re bond.^17a

1

Interestingly, H NMR spectra of reaction mixtures do not

contain a signal at −14.4 ppm associated with bridging hydride

complex 11, and alkene isomerization of 1-octene is minimal.

Since we did not observe scrambling or depletion of deuterium

content in products obtained when using deuterium-labeled

alkenes at the C1-, C2-, or C3-position in Scheme 4, we

propose the isomerization processes in Scheme 8 are not

relevant to the on-cycle behavior for the alkylation of mequinol

(vide infra). Toward gaining insight into the mass balance of

the alkene isomerization process in Scheme 8, we carried out

prolonged heating of a binary mixture of 1-octene and

Re₂(CO)₁₀for 24 h at 150 °C and used an external standard

(1,2,4-trichlorobenzene) to determine the sum of octene

isomers both at T = 0 and 24 h. The sum of all octene isomers

at 24 h accounts for quantitative recovery relative to the initial

1-octene content, allowing us to rule out an alkene polymer-

ization process as a signiﬁcant decomposition pathway.

Next we shifted our attention toward understanding how

mequinol interacts with Re₂(CO)₁₀. Independent reaction of

either methanol or phenol with Re₂(CO)₁₀in the presence of

trimethylamine-N-oxide, an oxidant used to remove CO

ligands from metal carbonyls,¹⁹provides bridged oxide

(CO)_nRe−(μ₂-OR)(μ₂-H)−Re(CO)_nor their related dehy-

drogenated forms (CO)_nRe−(μ₂-OR)_m−Re(CO)_n(m = 2 or

3, R = Ph, Me, H).¹⁵Tetrameric Re clusters as well as linear

oligomers have been characterized in the literature by both

NMR spectroscopy and X-ray crystallography.¹⁶It is also

known that photolysis of ethereal solutions of Re₂(CO)₁₀in

the presence of H₂O results in quantitative formation of

tetrameric Re₄(CO)₁₂(OH)₄via a H₃Re₃(CO)₁₂intermediate

(12).^16q−s,17cBy analogy, we wondered if the phenol in our

reaction could participate in a similar process to generate either

dimeric (CO)₄Re(μ₂-OAr)₂Re(CO)₄or tetrameric

Re₄(CO)₁₂(OAr)₄.

NMR STUDY OF BINARY MIXTURES

■

We were interested in gaining further insight into potential

intermediates and the resting state of the catalyst; however,

due to experimental limitations in obtaining detailed 2D NMR

at 130 °C, as well as signal broadening in the ¹H NMR data at

those temperatures, we relied on data acquisition at (or

around) room temperature on reaction mixtures as well as

binary mixtures. We prepared binary mixtures of Re₂(CO)₁₀(1

equiv) with either 1-octene (4 equiv) or mequinol (4 equiv) in

d₈-toluene solutions and heated those samples to 150 °C for 2

h, followed by cooling to 25 °C for analysis via NMR

spectroscopy (Scheme 8 and Scheme 9). The binary mixture of

Scheme 8. Experiment Probing Binary Reactivity of 1-

Octene and Re₂(CO)₁₀

Using a combination of 1D and 2D NMR spectroscopy

including DOSY NMR, we observed ﬁve diﬀerent compounds

were formed when characterizing a 4:1 mixture of mequinol

1-octene and Re₂(CO)₁₀revealed that oleﬁn isomerization

occurs; both cis- and trans-2-octene (2a and 2b, respectively)

Scheme 9. Experiments Probing Binary Reactivity of Mequinol and Re₂(CO)₁₀

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1

Figure 4. H NMR of 4:1 mequinol/Re₂(CO)₁₀mixture in d₈-toluene at 25 °C after heating for 2 h at 150 °C.

1

Table 1. H and ¹³C NMR Chemical Shift (ppm) of the Mequinol Ligands of Complexes 14−16 and Mequinol (1) in d₈-

Toluene along with the Diﬀusion Coeﬃcient Obtained from DOSY Spectrum at 25 °C

c

assignment

complex 14 (2:1 ligand ratio)

complex 15

154.6

114.5

118.3

161.7

54.7

complex 16

mequinol (1)

149.9

114.7

115.9

153.7

54.8

C-1

C-2

C-3

C-4

C-5

154.0; 134.1

114.5; 85.6

119.5; 85.0

159.3; 149.4

54.9; 56.9

159.7

85.6

83.0

159.8

54.7

6.77 (d, 9.0 Hz)

4.28 (d, 7.7 Hz)

7.47 (d, 9.0 Hz)

5.97 (d, 7.7 Hz)

3.36 (s); 2.58 (s)

a

H-2

6.65

4.13 (dd, 4.9, 3.2 Hz)

6.64 (d, 9.0 Hz)

H-3

H-5

6.97 (d, 9.0 Hz)

3.31 (s)

5.07 (dd, 4.9, 3.2 Hz)

3.31 (s)

6.56 (d, 9.0 Hz)

3.35 (s)

b

hydride

−10.7 (s)

D (× 10⁻¹⁰m²/s)

4.80

5.98

6.92

11.5

a

COSY NMR experiments reveal this signal is coupled to the doublet at δ_H6.97 but due to being obstructed by signals associated with mequinol,

the coupling constant could not be measured. While the signal at δ_H−17.3 ppm has a comparable diﬀusion coeﬃcient (D) as the signals assigned

to complex 16 according to the DOSY spectrum, this signal was assigned to complex 12. See Scheme 9 for the atom numbering deﬁnition.

b

c

and Re₂(CO)₁₀in d₈-toluene that had been heated to 150 °C

prior to its characterization at, or near, 25 °C (Scheme 9 and

Figure 4) due to instrumental limitations precluding character-

ization at 150 °C. While the equilibrium distribution and

composition observed at 25 °C may diﬀer signiﬁcantly from

those present under elevated reaction temperature, these

experiments nonetheless provided valuable structural informa-

tion. We observed two metal hydrides complexes devoid of

mequinol ligands (12 and 13), as well as three Re complexes

containing mequinol ligands (14−16) based on NMR analysis

(Table 1), in addition to the majority of the mequinol

remaining nonligated to Re.

(13);²⁰additionally, a signal characteristic of a bridging

hydride from a cyclic Re clusters was observed at δ_H−17.3

ppm, likely that of cyclic trimer 12, [Re(μ₂-H)(CO)₄]₃, also

observed in the binary mixture experiment with 1-octene and

Re₂(CO)₁₀.¹⁸DOSY NMR experiments are in agreement with

the signal at δ_H−17.3 ppm being associated with a structure of

signiﬁcantly larger size than that of the complex associated with

the signal at −5.6 ppm (HRe(CO)₅, 13). HMBC NMR

analysis reveals H−C coupling between each of the above Re-

hydride signals to a set of CO ligands. Speciﬁcally, the signal at

δ_Hof −5.6 ppm is correlated to two ¹³C signals, δ_C182.3 (²J_CH

= 7.4 Hz) and 182.7 (²J_CH= 7.5 Hz) ppm, consistent with the

two inequivalent CO ligands in HRe(CO)₅. The signal at δ_Hof

−17.3 ppm is correlated to two ¹³C signals, δ_C179.3 (²J_CH< 2

¹H NMR revealed a signal at δ_H−5.61 ppm, characteristic of

a terminal rhenium hydride complex, speciﬁcally HRe(CO)₅

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Hz) and 181.2 (²J_CH< 2 Hz), consistent with the two

inequivalent CO ligands in cyclic trimer 12, [Re(μ₂−

H)(CO)₄]₃.

the largest molecular weight, followed by 15 and then 16

which should have a molecular weight similar to that of 12

(898 g/mol) since they have comparable diﬀusion coeﬃcients,

and ﬁnally HRe(CO)₅(13, 327 g/mol, D = 13.4 × 10⁻¹⁰m²/

s).

The three complexes that contain mequinol as a ligand,

tentatively assigned as 14−16 (see Supporting Information).

Complexes 14 and 15 are not associated with hydridic signals

based on DOSY NMR, whereas complex 16 has the same

diﬀusion coeﬃcient as hydridic signals at δ_H−10.7 ppm and

−17.3 ppm (either by coincidence or due to the complex truly

having a hydride). Since the signal at δ_H−17.3 ppm was also

observed in mixtures not containing mequinol, namely, the

mixture of 1-octene and Re₂(CO)₁₀described above and

assigned to trimeric [HRe(CO)₄]₃(12), we do not believe this

signal is associated with a mequinol derived complex. Complex

16 is associated with a bridging rhenium hydride signal appears

(δ_H−10.72 ppm) which is correlated to four ¹³C signals, δ_C

Since no alkylation of mequinol occurs when reactions are

carried out at 115 °C, we compared spectral data of 4:1

mixtures of mequinol and Re₂(CO)₁₀that were obtained via

either heating to 115 or 150 °C, and the only diﬀerence was

that complex 16 was not observed in the 115 °C treated

sample. This observation could suggest that compound 16 is

derived from a catalytically relevant intermediate. When a

reaction mixture (1 equiv of mequinol, 1.5 equiv of 1-octene,

and 30 mol % of Re₂(CO)₁₀in d₈-toluene) was heated to

partial conversion at 130 °C and subsequently analyzed at 25

°C by NMR spectroscopy, we observed complexes that were

previously identiﬁed in binary mixtures. Speciﬁcally, the

reaction mixture contained HRe(CO)₅(13), complexes 14

and 15, and [HRe(CO)₄]₃(12), while no signals associated

with complex 11 were observed. Only the hydride at −10.7

ppm associated with complex 16 was observed, while the

remaining expected signals for 16 were obscured by other

resonances from 1-octene. No evidence of alkene coordination

to the Re was observed, consistent with no complexation

occurring before the turnover-limiting step. Analysis of the

NMR data of a reaction mixture at 130 °C did reveal the

presence of HRe(CO)₅(13) and [HRe(CO)₄]₃(12) as well as

signals associated with mequinol ligands diﬀerent than

unligated mequinol (1); unfortunately, due to signal broad-

ening, limited sensitivity, and lack of 2D NMR data we were

not able to identify their structure.

At this point all the data is consistent with a mechanism

outlined in Scheme 2B; while we already discussed reasons for

ruling out Scheme 2A,C above, we turn the discussion as to

why many variations based on Scheme 2D can be ruled out. If

the mechanism in Scheme 2D was operational, then the lack of

a primary KIE when using d₄-1 versus 1 implies that the third

step could not be turnover-limiting; similarly, the lack of an

inverse KIE when using either d₄-1 or 1,1,-d₂-2 versus 2 rule

out the second step as the turnover-limiting (consistent with

the lack of evidence for a Re complex containing an alkene

when analyzing reaction mixtures by NMR). If the fourth step

in Scheme 2D was turnover-limiting, then reaction mixtures

would contain a buildup of an intermediate that has the new

C−C bond between the octyl side chain and the arene carbon

ortho to the OH, which we did not observe. While a positive

order in 1-octene would be expected if the ﬁrst step Scheme

2D was turnover-limiting (unless the turnover-limiting step

requires ligand dissociation from the Re complex prior to

alkene coordination). While we cannot completely rule out all

variations of Scheme 2D from operating, we do have evidence

for speciﬁc steps of the catalytic cycle associated with Scheme

2B (e.g., reversibility in the C−H activation), unlike that for

Scheme 2D. Additionally, speciﬁc examples from the substrate

scope (vide infra) showcase examples for which alkylation can

occur para instead of ortho to the OH when using gem-

disubstituted alkenes for the alkylation of phenol,^5aruling out

the possibility of a cyclometalation pathway illustrated in

Scheme 2D.

2

187.4, 184.5, 184.0, 180.6 ppm (all with J_CH< 2 Hz), which

are presumably CO ligands bound to Re.

While the structures of 14−16 could not be conclusively

determined, tentative proposals are shown in the Supporting

Information along with a more detailed discussion. Complex

15 is the second most abundant of these complexes and

features one type of mequinol ligand whose NMR signals are

minimally perturbed compared to nonligated mequinol (1).

We propose the mequinol is oxygen bound to the Re instead of

C-bound which would strongly perturb the ¹H and ¹³C

chemical shifts and coupling constants associated with

mequinol.^15,21In contrast, the most abundant complex (14)

features two types of chemically inequivalent mequinol ligands

with a 2:1 ligand stoichiometry, implying a total of at least

three mequinol ligands on the complex. The major set of

mequinol ligand signals in complex 14 are quite similar to that

found in complex 15, suggesting similar oxygen-bound

coordination,¹⁵while the minor set of mequinol ligand signals

of 14 diﬀer signiﬁcantly as evidenced by the dramatic upﬁeld

shift in the ¹³C signals signal for C2 and C3 of the arene ring

(see Scheme 9 for the atom numbering deﬁnition), namely ca.

δ_C84 ppm in 15 versus δ_C115 ppm in mequinol, 1. The

chemical shift of these types of mequinol ligands is suggestive

of a cationic Re complexed with the arene via the π-system in a

symmetrical fashion (e.g., η₅- or η₆-binding, or rapidly

equilibrating η₂-binding relative to the NMR time scale).

This type of Re-arene interaction provides increased electron

density, which not only results in the dramatic upﬁeld shift in

the ¹³C signals signal for C2 and C3, but also in a decreased

magnitude of the ³J_HHcoupling for the hydrogens at those ring

4

positions, while increasing magnitude of the J_HHmeta

coupling through Re. The minor ligand in complex 14 displays

chemical shift and coupling constant eﬀects (ca. δ_C2/C385

3

ppm, J_H2H3= 7.7 Hz) resembling those found in complex 16

(ca. δ_C2/C384 ppm, ³J_H2H3= 4.9 Hz) that features similar Re−

arene π-system interaction, in contrast to the unligated

mequinol (ca. δ_C2/C3115 ppm, J_H2H3= 9.0 Hz).²¹Rhenium

3

complexes featuring an η₅- and/or η₆-bound phenolate or

phenol have been characterized in the literature both by NMR

spectroscopy and X-ray crystallography, and display related

chemical shift eﬀects (see the Supporting Information for

complexes displaying similar chemical shift and coupling

constant eﬀects to those observed with 14 and 16 upon η₅-

and/or η₆-binding to Re).²¹On the basis of the diﬀusion

coeﬃcient of each Re complex in the mixture from Scheme 8

and that smaller diﬀusion coeﬃcients are associated with larger

molecular weight compounds, we propose that complex 14 has

PROPOSED REACTION MECHANISM

Arriving at a detailed catalytic cycle with structures for each

intermediate is rendered diﬃcult due to the fact that (1)

■

H

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numerous Re complexes were observed both in mixtures

derived from the reaction and those from binary component

experiments; (2) not all Re complexes could be structurally

determined (e.g., complexes 14−16), and (3) signal broad-

ening and limited sensitivity in the spectral data collected on

reaction mixtures at 130 °C made structural assignment and

correlation to the signals observed at 25 °C challenging.

Nonetheless, we propose a catalytic cycle shown in Scheme

10 consistent with the collection of experimental evidence

Subsequent reductive coupling from 23 generates product 3.

The fact that alkylated product 3 was not observed when

radical inhibitors such as TEMPO or ABNO were present (10

mol %) when attempting the Re-catalyzed alkylation of

mequinol with 1-octene at 140 °C in toluene for 24 h is

consistent with the proposed hydrometalation proceeding via a

radical pathway.²³

This net hydroarylation reaction features catalyst deaggrea-

tion as the turnover-limiting step which is in contrast with Rh-

catalyzed hydroarylation reactions in which the reductive

elimination is turnover-limiting and C−H activation is

reversible,²⁴also in contrast to numerous Pd and Rh C−H

activation functionalization methods that feature C−H

cleavage as the turnover-limiting step.²⁵Finally we note the

induction period observed in this Re-catalysis is associated

with CO dissociation from precatalyst Re₂(CO)₁₀to open one

or more coordination sites in order to bind mequinol (18) and

generate the resting state of the catalyst. Several subtle details

of this Re-catalysis require elaboration, speciﬁcally aspects of

potential alkene isomerization and the role of the OH on the

arene, both of which are discussed below.

Scheme 10. Proposed Catalytic Cycle for the Re-Catalyzed

Alkylation of Phenols

Scheme 11 illustrates how alkene isomerization and

migration may occur in reactions where mequinol is absent,

Scheme 11. Rationalization for Alkene Isomerization in the

Absence of Mequinol

presented herein. From the isotopic labeling experiments, it is

clear that C−H activation is reversible, and the net

hydrometalation process on the alkene is irreversible.²²The

NMR spectroscopic characterization of binary mixtures as well

as a reaction mixture highlight that complexation of mequinol

to Re is feasible before the turnover-limiting step. On the basis

of the zero-order overall kinetics of the reaction and the

fractional order in catalyst, we suggest that C−H activation of

mequinol occurs ﬁrst, directed by the OH group preferentially

to the ortho-position, followed by the turnover-limiting step of

deaggregating catalyst resting state 19. Subsequent to the

turnover-limiting step, a net hydrometalation process occurs. If

hydrometalation was proceeding via direct insertion into the

alkene, then sterics would predict formation of the linear

alkylation product, which is not observed. In contrast, the

observed branched selectivity in the net hydroarylation process

is consistent a radical rebound mechanism proceeding via a

radical pair (Scheme 2B, bottom pathway) in which generation

of a 2° akyl radical is preferred over a 1° one. Net

hydrometalation of alkenes via a radical pair mechanism is

known for HMn(CO)₅,^10b,cas well as other metal carbonyl

hydride complexes.^10dHydrogen atom transfer to the C1-

position of the terminal alkene aﬀords a radical pair consisting

of 21 and 22. Subsequent geminate recombination of the

radical pair provides the net hydroarylation product 23, a Re

complex with both an octyl and an arene as ligands (23).

that is, the binary mixture of 1-octene and Re₂(CO)₁₀shown in

Scheme 8. In the absence of mequniol to act as a ligand on Re,

thermal homolysis of Re₂(CO)₁₀generates Re(CO)₅(24)

•

which could promote isomerization via intermediate 25 via a

hydrogen atom transfer mechanism (Scheme 11A). Repeating

the process starting from 2-octene 2a or 2b could lead to 3-

octene 2c. In contrast, when mequinol is present, minimal

Re₂(CO)₁₀is present since the catalyst resting state features

mequinol ligated to Re, thus attenuating isomerization pathway

shown in Scheme 11A. Instead, mequinol-ligated rhenium

hydride (26) can be added to 1-octene to provide a radical pair

consisting of 27 and 28 (Scheme 11B) that can either undergo

subsequent radical recombination to the hydrometalated

intermediate (29) or subsequent hydrogen atom abstraction

to regenerate an alkene, such as 1-octene or isomeric 2-octene

with either trans- or cis-geometry (2a or 2b, respectively).

Since no evidence of reversible hydrometalation was observed

in Scheme 4, we conclude that the ligand(s) attached to the Re

(either CO and/or mequinol depending on the reaction

condition), may inﬂuence the reversibility or selectivity of

either reaching hydrometalated intermediate 29 or regener-

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ation of an alkene. While β-hydride elimination is known occur

with many transition metals (e.g., Pd, Rh, etc.), we note that

this process is known to be disfavored for Re.²⁶Additionally, if

the reductive coupling from intermediate 29 to generate

product 3 is fast relative to β-hydride elimination back to

octene derivatives, then we do not expect to observe evidence

of reversibility in the hydrometalation (including alkene

isomerization).

consistent with HAT to the alkene aﬀording an alkyl radical

that if stabilized has a lifetime long enough to allow for the

rhenium in intermediate 22 to migrate to the sterically favored

para-position on the arene prior to radical recombination

(intermediate 23) and subsequent reductive coupling to the

alkylated product (e.g., 34 and 37). Finally, since C−H

activation occurs preferentially but not exclusively at the

position ortho to the OH (see Scheme 5A); thus the exclusive

ortho-regioselectivity for alkylation when using 1-octene must

arise from a step subsequent to the C−H activation, likely

related to the catalyst deaggreation step in which the barrier for

meta-rhenated-arene is energetically destabilized relative to its

ortho-isomer.

Finally, we turned our attention to several interesting

examples from the substrate scope initially reported by Takai^5a

and rationalize the unexpected product outcome. Scheme 12

Scheme 12. Rationalizing the Alkylation Products Observed

when Using Gem-Disubstituted Alkenes

CONCLUSIONS

■

The mechanism of a rhenium-catalyzed monoalkylation of

phenols using terminal alkenes was studied. The results suggest

that the reaction does not proceed via a Friedel−Crafts type

pathway but instead proceeds via a reversible C−H activation,

then a net hydroarylation process. The branched hydro-

arylation product is accounted by the hydrometalation process

proceeding via a radical rebound mechanism of hydrogen atom

transfer to the alkene, followed by geminate recombination of

the radical pair. The turnover-limiting step is proposed to be

catalyst deaggregation of the resting state dimer that contains

mequinol ligands followed by the irreversible hydrometalation

2-step process and subsequent reductive coupling aﬀords

selectively the mono-ortho-alkylated product. We propose the

resting state of the catalyst contains mequinol ligands as

supported by the kinetics and various NMR experiments.

Interestingly, the kinetic dependence on catalyst was found to

be half-order, indicating that the resting state of the catalysts is

a dimeric form of that found in the turnover-limiting transition

state; presumably, cleavage of this dimer necessitates the high

temperatures required for the transformation. This require-

ment for high temperature is the major drawback of this highly

selective and high yielding reaction. The mechanistic insight

obtained from this study suggests designing catalysts able to

undergo deaggregation at lower temperatures could improve

catalysis. Figure 1 illustrates that the rate of alkylation is

dependent on the substituent on the phenol. This is

rationalized due to the phenol derivative being a ligand on

the Re complex undergoing the turnover-limiting deaggrega-

tion step; thus, the electronics of the phenol could inﬂuence

the energy barrier of this process. The data supporting that

phenol is a ligand on the Re complex in the turnover-limiting is

based on the kinetics displaying zero-order in phenol and the

observation that the arene C−H activation is reversible

(Scheme 5A). Deaggregation of the active catalyst may be

inﬂuenced through innovative ligand design or heterobimetal-

lic systems to modulate the strength of the bond associated

with deaggreation process.²⁷We hope this work will inspire

and provide direction for future research to address current

limitations of this remarkably selective and convergent catalytic

method to access ortho-monoalkylated phenols.

illustrates how the use of phenol with diﬀerent alkenes can

generate either ortho- or para-functionalization depending on

the alkene. While the use of 1-octene provides ortho-

functionalization of phenol to generate 33 in 76% yield,

para-alkylation product 34 (and 4% of the ortho-product, not

shown) is obtained when using closely related 2,2-disubsutited

alkene 35. We rationalize this explanation based on our

mechanistic proposal that HAT to the alkene generates an

alkyl radical intermediate, the latter example generates a radical

(3° radical) that is signiﬁcantly more stabilized compared to

the former example (2° radical). The more stable the radical,

the less reactive it should be; therefore, providing more time

for intermediate Ar−[Re]^•(22) to undergo potential

rearrangement (Re-migration from the ortho to the para-site

relative to the OH), in turn allowing the formation of the

sterically favored para-product instead of the ortho-product.

Similarly, HAT to diene 36 would produce a stabilized allylic

radical that can react via the sterically more accessible C4-

carbon instead of the C2-carbon to generate product 37. The

formation of para-substituted products 34 and 37 clearly

enable us to rule out Scheme 2D since cyclometalation process

would proceed via a closed transition state only able to

generate ortho-susbstitution products, decisively placing the

proposed mechanism in Scheme 10 as the operating

mechanism.

EXPERIMENTAL SECTION

■

The role of the OH on the arene clearly facilitates the C−H

activation at the ortho-position (see recovered mequinol in

Scheme 5A), yet the examples from Scheme 12 clearly

highlight that alkylation is not solely directed to the ortho-

position, since para-alkylation products can be obtained when

using gem-disubstituted alkenes. These observations are

General Experimental Details. Unless otherwise noted, all

reactions were performed in an N₂-ﬁlled glovebox using 10 mL

microwave vials (Biotage Microwave Reaction Vials, part number

351521) or 30 mL microwave vials (Biotage Microwave Reaction

Vials, part number 354833) equipped with a magnetic stir bar

(Biotage Stirbars, part number 355543) and sealed using a Biotage

J

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Microwave Cap with Septum (part number 352298) with the aid of a

Biotage microwave vial crimper (part number 353671). Reaction vials

were heated by being placed inside a heated metal block (IKA Dry

Block Heater DB 4.5, part number 0004469000, for round-bottom

tubes (15/16 mm), pore size: Ø 17.5 mm, no. of holes: 12, hole

depth: 48.4 mm, block dimensions (width × depth × height): 95 × 76

× 51 mm). Heating of reaction mixtures was performed using a

temperature-controlled hot plate equipped with stirring and a

thermocouple. Evaporation and concentration in vacuo was done using

variable vacuum via a vacuum controller (ca. 400−40 mmHg).

Column chromatography was done using a Teledyne ISCO

CombiFlash Rf+ chromatography system using prepacked single-use

silica packed cartridges (RediSep Rf Gold Normal-Phase Silica, 20−

40 μm average particle size, 60 Å average pore size).

Materials. Reagents were purchased (reagent-grade) from

commercial suppliers and used without further puriﬁcation, unless

otherwise described. Anhydrous solvents (toluene and mesitylene)

were obtained from Sigma-Aldrich as part of their Sure/Seal bottles

product line. 1-Octene (98%) was purchased from Acros; 1-dodecene

(≥99.0%, GC) was purchased from Sigma-Aldrich, Re₂(CO)₁₀

(sublimed) was purchased from Acros. 1,1-d₂-Oct-1-ene (98% purity,

> 99% d₂-content) was purchased from Cambridge Isotope

Laboratories. 3,3-d₃-Oct-1-ene (98% purity) and 2,3-d₂-4-methox-

yphenol (≥98.0% purity) were purchased from ALSACHIM. 2-d₁-

Oct-1-ene (>97% purity, 99.5% d₁-content) was purchased from

CDN Isotopes. 2,3,5,6-d₄-4-Methoxyphenol was purchased from

CDN Isotopes (98% purity, >99% d₄-content) as light beige solid

and repuriﬁed by column chromatography (silica gel, gradient 0−20%

EtOAc in hexanes to aﬀord a white solid, ≥99% purity by NMR,

>99% d₄-content by NMR) prior to using.

prior to being cooled to room temperature. Column chromatography

(silica gel, gradient 0−20% EtOAc in hexanes) aﬀorded 3 (0.285 g,

97%). ¹H NMR (600 MHz, CD₂Cl₂) δ 6.72 (d, J = 3.0 Hz, 1H), 6.68

(d, J = 8.6 Hz, 1H), 6.59 (dd, J = 8.6, 3.0 Hz, 1H), 4.62 (s, 1H), 3.02

(hept, J = 7.0 Hz, 1H), 1.62 (dddd, J = 13.2, 9.9, 7.5, 5.1 Hz, 1H),

1.57−1.50 (m, 1H), 1.34−1.22 (m, 8H), 1.20 (d, J = 6.9 Hz, 3H),

0.87 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CD₂Cl₂) δ 154.5,

147.6, 135.5, 116.3, 113.7, 111.5, 56.1, 37.7, 33.1, 32.4, 30.0, 28.2,

23.2, 21.3, 14.4. Spectral characterization is consistent with that

reported in ref 5a.

Typical Procedure for the Synthesis of 5.^5bIn an N₂-ﬁlled

glovebox, a 10 mL microwave vial was equipped with a magnetic stir

bar and charged with Re₂(CO)₁₀(0.020 g, 0.031 mmol), followed by

4-methoxyphenol (0.155 g, 1.25 mmol), followed by addition of

toluene (0.625 mL), and ﬁnally 1-dodecene (0.416 mL, 0.315 g, 1.87

mmol) was added to the mixture. The vial was sealed using a

microwave cap with the aid of a microwave vial crimper. The sealed

microwave vial was placed into a 140 °C preheated metal block. The

reaction mixture was aged for 24 h accompanied by rotary stirring

prior to being cooled to room temperature. Column chromatography

(silica gel, gradient 0−20% EtOAc in hexanes) aﬀorded 5 (0.330 g,

1

90%). δ H NMR (600 MHz, CD₂Cl₂) δ 6.71 (d, J = 3.0 Hz, 1H),

6.68 (d, J = 8.6 Hz, 1H), 6.59 (dd, J = 8.6, 3.0 Hz, 1H), 4.56 (s, 1H),

3.73 (s, 3H), 3.01 (hept, J = 7.0 Hz, 1H), 1.65−1.57 (m, 1H), 1.57−

1.49 (m, 1H), 1.33−1.22 (m, 16H), 1.20 (d, J = 6.9 Hz, 3H), 0.88 (t,

J = 7.0 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CD₂Cl₂) δ 154.5, 147.6,

135.5, 116.3, 113.6, 111.4, 56.1, 37.7, 33.1, 32.5, 30.4, 30.2, 30.2, 30.2,

29.9, 28.3, 23.3, 21.3, 14.5.

Spectral Data of Deuterated Starting Materials. Spectra

1

Data for 1,1-d₂-2. H NMR (500 MHz, CD₂Cl₂) δ 5.85−5.80 (m,

Instrumentation. Proton nuclear magnetic resonance (¹H NMR)

spectra and carbon nuclear magnetic resonance (¹³C NMR) spectra

were recorded at 25 °C (unless stated otherwise). The NMR

spectrometer used for the KIE measurements was a Bruker AVANCE

III HD 600 MHz NMR spectrometer equipped with a 5 mm BBO

CryoProbe Prodigy. The NMR spectrometers used for the character-

ization of the Re complexes and binary mixtures were a Bruker

AVANCE III HD 600 MHz NMR spectrometer and Bruker

AVANCE III HD 500 MHz equipped with a 5 mm BBO SmartProbe.

The NMR spectrometer for reaction time course data at 130 °C was

the Varian VNMRS 600 MHz NMR spectrometer equipped with a 5

mm OneProbe. All other NMR characterization performed on a

Bruker AVANCE III HD 500 MHz equipped with a 5 mm BBO

probe. Chemical shifts for protons are reported in parts per million

downﬁeld from tetramethylsilane and are referenced to residual

proton of the NMR solvent according to values reported in the

literature.²⁸Chemical shifts for carbon are reported in parts per

million downﬁeld from tetramethylsilane and are referenced to the

carbon resonances of the NMR solvent. The solvent peak was for

1H), 2.06 (q, J = 7.1 Hz, 2H), 1.44−1.36 (m, 2H), 1.35−1.25 (m,

6H), 0.90 (t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (126 MHz, CD₂Cl₂) δ

139.7, 113.9 (p, J = 23.7 Hz), 34.4, 32.429.7, 29.5, 23.3, 14.5.

Spectral Data for 2-d₁-2. ¹H NMR (500 MHz, CD₂Cl₂): δ 5.01−

4.98 (m, 1H), 4.94−4.92 (m, 1H), 2.05 (t, J = 7.2 Hz, 2H), 1.44−

1.24 (m, 8H), 0.90 (t, J = Hz, 3H). ¹³C{¹H} NMR (125 MHz,

CD₂Cl₂): δ 139.61 (t, J = 23.1 Hz), 114.31, 34.38, 32.43, 29.63, 29.53,

23.32, 14.51.

Spectral Data for 3,3-d₂-2. ¹H NMR (500 MHz, CD₂Cl₂): δ 5.83

(dd, J = 10.2, 17.2 Hz, 1H), 5.00 (d, J = 17.2 Hz, 1H), 4.93 (d, J =

10.2, Hz, 1H), 1.41−1.24 (m, 8H), 0.90 (t, J = 6.1 Hz, 3H). ¹³C{¹H}

NMR (126 MHz, CD₂Cl₂): δ 139.88, 114.51, 33.75 (p, J = 19.2 Hz),

29.50, 29.47, 23.32, 14.51.

1

Spectral Data for 2,3,5,6-d₄-1. H NMR (500 MHz, CD₂Cl₂): δ

5.48 (br s, 1H), 3.76 (s, 3H). ¹³C{¹H} NMR (126 MHz, CD₂Cl₂): δ

154.12, 150.10, 116.23 (t, J = 24.2 Hz), 115.07 (t, J = 24.3 Hz), 56.32.

Synthesis of OD-d₁-Mequinol (OD-d₁-1). To a vial containing

mequinol (1, 2.10 g, 16.9 mmol) was added d₄-methanol (>99.8% d₄-

content, 15 mL) at 25 °C, and the mixture was attached to a rotary

evaporator and the vial partially submerged in a 40 °C water bath.

The mixture was mixed for 5 min via spinning the sample with the aid

of the rotary evaporator without applying vacuum, followed by

removal of the solvent in vacuo. This H−D exchange cycle was

repeated a total of ﬁve times to obtain OD-d₁-1 (2.1 g, quantitative)

as a white solid. ¹H NMR (500 MHz, CD₂Cl₂): δ 6.84−6.77 (m, 4H),

3.77 (s, 3H). ¹³C{¹H} NMR (126 MHz, CD₂Cl₂): δ 154.14, 150.16,

116.53, 115.49.

1

samples in CDCl₃was referenced to 7.26 ppm for H and 77.0 ppm

for ¹³C, while for samples in CD₂Cl₂, it was referenced to 5.32 ppm

for ¹H and 54.0 ppm for ¹³C. Analysis of reaction mixtures and

quantiﬁcation of starting material and product was done using HPLC

or NMR analysis.

NMR KIE Measurements. The ratio of protonated versus

deuterated carbon was determined by quantitative ¹³C NMR by

using inverse gated decoupling with calibrated 90 deg pulse, and d1

was set to 120 s (d1 > 10 T₁, where d1 is the total recycling delay

and T₁is the longitudinal (or spin−lattice) relaxation time decay

constant), and the transmitter frequency was place at the middle of

the protonated and deuterated carbon.

Synthesis of 2,3,5,6-d₄-6. To a 30 mL microwave vial containing

a PTFE stirbar was added 2,3,5,6-d₄-mequinol (2.40 g, 18.7 mmol)

followed by MeCN (20 mL), Cs₂CO₃(6.10 g, 18.7 mmol), and ﬁnally

MeI (5.83 mL, 13.3 g, 13.3 mmol) at 25 °C. The vial was sealed using

a microwave cap with the aid of a microwave vial crimper. The sealed

microwave vial was placed into a metal block and heated to 55 °C for

30 h accompanied by rotary stirring. The mixture was cooled to rt and

diluted with CH₂Cl₂, the organic phase washed with H₂O (2×), dried

over Na₂SO₄, ﬁltered, and the solvent removed in vacuo. Column

chromatography (silica gel, gradient 0−30% EtOAc in hexanes)

aﬀorded 2,3,5,6-d₄-6 (2.11 g, 79%). ¹H NMR (500 MHz, CD₂Cl₂): δ

3.75 (s, 6H). ¹³C{¹H} NMR (126 MHz, CD₂Cl₂): δ 154.32, 114.76

(t, J = 24.3 Hz), 56.16.

Typical Procedure for the Synthesis of 3.^5aIn an N₂-ﬁlled

glovebox, a 10 mL microwave vial was equipped with a magnetic stir

bar and charged with Re₂(CO)₁₀(0.020 g, 0.031 mmol), followed by

4-methoxphenol (0.155 g, 1.25 mmol), followed by addition of

toluene (0.625 mL), and ﬁnally 1-octene (0.297 mL, 0.212 g, 1.87

mmol) was added to the mixture. The vial was sealed using a

microwave cap with the aid of a microwave vial crimper. The sealed

microwave vial was placed into a 140 °C preheated metal block. The

reaction mixture was aged for 24 h accompanied by rotary stirring

K

DOI: 10.1021/acs.organomet.8b00543

Organometallics XXXX, XXX, XXX−XXX

Organometallics

Article

Reaction of Mequinol with 1,1-d₂-Oct-1-ene. In an N₂-ﬁlled

glovebox, a 10 mL microwave vial was equipped with a magnetic stir

bar and charged with Re₂(CO)₁₀(0.020 g, 0.031 mmol), followed by

4-methoxyphenol (0.155 g, 1.25 mmol) and then toluene (0.625 mL);

ﬁnally, 1,1-d₂-oct-1-ene (0.297 mL, 0.212 g, 1.87 mmol) was added to

the mixture. The vial was sealed using a microwave cap with the aid of

a microwave vial crimper. The sealed microwave vial was placed into a

140 °C preheated metal block. The reaction mixture was aged for 24 h

accompanied by rotary stirring prior to being cooled to room

temperature. Column chromatography (silica gel, gradient 0−20%

integration of the CH and CD signals at δ 32.4 (1.00C) and 32.0

(0.99C), respectively.

KIE Using 3,3-d₂-Oct-1-ene. The ratio of 3 to 3,3-d₂-3 was

determined to be 1.18 via quantitative ¹³C{¹H} NMR (151 MHz,

CD₂Cl₂) via integration of the CH₂and CD₂signals at δ 37.7 (1.00C)

and 36.8 (0.85C), respectively.

Reaction of OD-d₁-1 with 1-Octene. In an N₂-ﬁlled glovebox, a

10 mL microwave vial was equipped with a magnetic stir bar and

charged with Re₂(CO)₁₀(0.023 g, 0.035 mmol), followed by OD-d₁-1

(0.157 g, 1.26 mmol) and toluene (0.628 mL); ﬁnally, 1-octene

(0.295 mL, 0.211 g, 1.88 mmol) was added to the mixture. The vial

was sealed using a microwave cap with the aid of a microwave vial

crimper. The sealed microwave vial was placed into a 140 °C

preheated metal block. The reaction mixture was aged for 24 h

accompanied by rotary stirring prior to being cooled to room

temperature. Column chromatography (silica gel, gradient 0−20%

EtOAc in hexanes) aﬀorded d_n-3 (mixture of deuterium label content,

see Scheme 5C). The mixture was characterized by quantitative

¹³C{¹H} NMR (151 MHz, CD₂Cl₂) via integration of the CH₂and

CD₂signals at δ 20.8 (s, 1.00C) and 20.5 (t, J = 19.2 Hz, 0.19C),

respectively; additionally, we did not observe evidence for a CD₂H

group (lack of pentet around 20 ppm).

1

EtOAc in hexanes) aﬀorded 1,1-d₂-3 (0.280 g, 94%). H NMR (600

MHz, CD₂Cl₂) δ 6.81 (d, J = 2.9 Hz, 1H), 6.73 (d, J = 8.6 Hz, 1H),

6.65 (dd, J = 8.6, 2.9 Hz, 1H), 3.80 (s, 3H), 3.11 (q, J = 7.2 Hz, 1H),

1.74−1.63 (m, 1H), 1.63−1.55 (m, 1H), 1.42−1.24 (m, 8H), 1.22 (d,

J = 7.2 Hz, 1H), 0.98−0.91 (m, 3H). ¹³C{¹H} NMR (151 MHz,

CD₂Cl₂) δ 154.4, 148.0, 136.0, 116.6, 114.0, 111.7, 56.4, 37.8, 33.0,

32.6, 30.2, 28.4, 23.4, 20.9 (p, J = 29.2 Hz), 14.6.

Reaction of Mequinol with 2-d₂-Oct-1-ene. In an N₂-ﬁlled

glovebox, a 10 mL microwave vial was equipped with a magnetic stir

bar and charged with Re₂(CO)₁₀(0.020 g, 0.031 mmol), followed by

4-methoxyphenol (0.155 g, 1.25 mmol) and toluene (0.625 mL);

ﬁnally, 2-d₁-oct-1-ene (0.297 mL, 0.212 g, 1.87 mmol) was added to

the mixture. The vial was sealed using a microwave cap with the aid of

a microwave vial crimper. The sealed microwave vial was placed into a

140 °C preheated metal block. The reaction mixture was aged for 24 h

accompanied by rotary stirring prior to being cooled to room

temperature. Column chromatography (silica gel, gradient 0−20%

ASSOCIATED CONTENT

* Supporting Information

The Supporting Information is available free of charge on the

ACS Publications website at DOI: 10.1021/acs.organo-

met.8b00543.

■

S

1

EtOAc in hexanes) aﬀorded 2-d₁-3 (0.281 g, 95%). H NMR (600

MHz, CD₂Cl₂): δ 6.72 (d, J = 3.0 Hz, 1H), 6.68 (d, J = 8.6 Hz, 1H),

6.59 (dd, J = 8.6, 3.0 Hz, 1H), 4.68 (br, 1H), 3.74 (s, 3H), 1.64−1.57

(m, 1H), 1.56−1.50 (m, 1H), 1.34−1.20 (m, 8H), 1.19 (s, 3H), 0.87

(t, J = 7.0 Hz, 3H). ¹³C{¹H} NMR (151 MHz, CD₂Cl₂) δ 154.5,

147.6, 135.5, 116.3, 113.7, 111.5, 56.1, 37.6, 32.4, 30.0, 28.2, 23.2,

21.2, 14.4.

Additional experimental details and NMR spectra

(PDF)

AUTHOR INFORMATION

Corresponding Authors

*E-mail: dan.lehnherr@merck.com (D.L.).

*E-mail: xiao.wang1@merck.com (X.W.).

■

Reaction of Mequinol with 3,3-d₂-Oct-1-ene. In an N₂-ﬁlled

glovebox, a 10 mL microwave vial was equipped with a magnetic stir

bar and charged with Re₂(CO)₁₀(0.020 g, 0.031 mmol), followed by

4-methoxyphenol (0.155 g, 1.25 mmol) and toluene (0.625 mL);

ﬁnally, 3,3-d₂-oct-1-ene (0.297 mL, 0.212 g, 1.87 mmol) was added to

the mixture. The vial was sealed using a microwave cap with the aid of

a microwave vial crimper. The sealed microwave vial was placed into a

140 °C preheated metal block. The reaction mixture was aged for 24 h

accompanied by rotary stirring prior to being cooled to room

temperature. Column chromatography (silica gel, gradient 0−20%

ORCID

Dan Lehnherr: 0000-0001-8392-1208

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

1

■

EtOAc in hexanes) aﬀorded 3,3-d₂-3 (0.278 g, 94%). H NMR (600

We are grateful to David Hesk for coordinating procurement of

various isotopically labelled alkenes used in this manuscript.

We thank Huaming Sheng, Ryan Cohen, Yu-hong Lam,

Karthik Narsimhan, and Alexei Buevich (all at Merck & Co.,

Inc.) for their contributions to this project. We acknowledge

Louis-Charles Campeau, Rebecca Ruck, Artis Klapars, Jennifer

Obligacion, Patrick Fier, and Heather Johnson (all at Merck &

Co., Inc.) for useful feedback.

MHz, CD₂Cl₂) δ 6.62 (d, J = 3.1 Hz, 1H), 6.59 (d, J = 8.6 Hz, 1H),

6.50 (dd, J = 8.6, 3.1 Hz, 1H), 3.65 (s, 3H), 2.92 (q, J = 6.9 Hz, 1H),

1.24−1.12 (m, 8H), 1.11 (d, J = 6.9 Hz, 3H), 0.78 (t, J = 7.0 Hz, 3H).

¹³C{¹H} NMR (151 MHz, CD₂Cl₂) δ 154.5, 147.7, 135.6, 116.3,

113.7, 111.4, 56.1, 36.8 (p, J = 19.1 Hz), 32.9, 32.4, 30.0, 28.0, 23.2,

21.3, 14.4.

General Procedure for Determining the KIE for 1-Octene

versus d_n-Oct-1-ene (Competition Setting). In an N₂-ﬁlled

glovebox, a 10 mL microwave vial was equipped with a magnetic

stir bar and charged with Re₂(CO)₁₀(0.020 g, 0.031 mmol), followed

by 4-methoxyphenol (0.155 g, 1.25 mmol) and toluene (1.25 mL);

ﬁnally, 1-octene (0.701 g, 6.24 mmol) and d_n-oct-1-ene (6.24 mmol,

either 1,1-d₂-oct-1-ene, 2-d₁-oct-1-ene, or 3,3-d₃-oct-1-ene) were

added to the mixture. The vial was sealed using a microwave cap

with the aid of a microwave vial crimper. The sealed microwave vial

was placed into a 140 °C preheated metal block. The reaction mixture

was aged for 24 h accompanied by rotary stirring prior to being cooled

to room temperature. Column chromatography (silica gel, gradient

0−20% EtOAc in hexanes) aﬀorded a mixture of 3 and d_n-3.

KIE Using 1,1-d₂-Oct-1-ene. The ratio of 3 to 1,1-d₂-3 was

determined to be 1.50 via quantitative ¹³C{¹H} NMR (151 MHz,

CD₂Cl₂) via integration of the CH₂and CD₂signals at δ 21.3 (1.00C)

and 20.9 (0.66C), respectively.

ABBREVIATIONS

■

ABNO = 9-azabicyclo[3.3.1]nonane N-oxyl; EtOAc = ethyl

acetate; HPLC = high-pressure liquid chromatography; LC =

liquid chromatography; NA = not available; ND = not

detected; PTFE = polytetraﬂuoroethylene; rt = room temper-

ature (ca. 25 °C); TEMPO = 2,2,6,6-tetramethylpiperidine 1-

oxyl; v/v = volume per volume percent

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Article abstract of DOI:10.1021/acs.organomet.8b00543

Full text of DOI:10.1021/acs.organomet.8b00543

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