Defluorodearomatization: A Photocatalytic Birch-Like Reduction That Enables C-C Bond Formation and Provides Access to Unnatural Cannabinoids

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Deﬂuorodearomatization: A Photocatalytic Birch-Like Reduction

That Enables C−C Bond Formation and Provides Access to

Unnatural Cannabinoids

Jon I. Day,^∇Sascha Grotjahn,^∇Sameera Senaweera, Burkhard Koenig, and Jimmie D. Weaver III*

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ABSTRACT: Within the framework of discovery chemistry,

polyﬂuorination remains a synthetic challenge despite its ability

to provide useful characteristics, such as a reduction in the number

of hydrogen bond donors and metabolic stability. Coupling a

reversal of this methodology with photocatalysis has been

demonstrated to allow the rapid synthesis of previously diﬃcult

or impossible targets by starting with ﬂuorines everywhere and

selectively removing or functionalizing them. Herein, we

demonstrate a novel method to synthesize 1,4-cyclohexadienes

through a dearomative photocatalytic C−C coupling reaction. This allows for access to materials that are orthogonal to the

selectivity of the Birch reaction and are more functional-group-tolerant. The reaction also allows the eﬃcient synthesis of

polyﬂuorinated cannabinoids. While the yields are modest, the access to the new chemical space provided by the reaction is

unprecedented by any means. The triﬂuorinated analog of THC, 1-deoxy-1,2,4-triﬂuoro-THC, is synthesized, demonstrating the

importance of discovery chemistry and the ability to explore otherwise unknown structure−activity relationships.

Table 1. Some Important Entries in the

Fluoropharmacopeia

INTRODUCTION

■

Fluorine has a greater ability than any other element to

dramatically alter, and often enhance, the properties of a

molecule without dramatically altering its shape or function.

Perhaps due to the fact that there are few natural products that

contain ﬂuorine,¹⁻⁵which are usually toxic derivatives of

ﬂuoroacetate,⁶ﬂuorination was historically overlooked as a

legitimate direction for investigation. In 1953,⁷however, a

ﬂuorinated analog to hydrocortisone, ﬂudrocortisone (1), was

introduced to the literature. It was found to have a 10-fold

increase in glucocorticoid activity compared to the non-

ﬂuorinated hormone cortisol and up to 800× the miner-

alocorticoid activity (Table 1).⁸As time has passed,

ﬂuorination has assumed a lead role in discovery chemistry

because of its ability to improve a host of properties in a

multitude of applications.⁹⁻¹³To further emphasize, an

appreciation for the importance of ﬂuorination in pharma-

ceuticals can be gained from an examination of the drugs

approved per annum by the U.S. FDA, 30% of which^14,15

typically contain a C−F bond. Of the small-molecule entities

that were approved by the U.S. FDA in 2018, 17 contained a

C−F bond, 12 were ﬂuoroarenes, and 3 were polyﬂuorinated

arenes¹⁶(baloxavir marboxil (2), larotrectinib (3), and

bictegravir (4)), indicating that arene polyﬂuorination

speciﬁcally is becoming an increasingly important synthetic

objective.

Received: January 21, 2021

Published: June 2, 2021

Despite the importance of ﬂuorinated molecules in the

pharmacopeia, linear syntheses to include ﬂuorine are diﬃcult.

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In contrast to more modern procedures, methods for

sequential ﬂuorine installation, such as the Balz−Schiemann

and halex reactions,¹⁷exist but are diﬃcult and are typically

not functional group tolerant. Recent developments have

increased the number of functional groups that can be

transformed into ﬂuorine.^17,18While useful for monoﬂuorina-

tion, these methods contribute little in the exploration of

multiﬂuorinated molecules because they would require a

library of multisite prefunctionalized nonﬂuorinated starting

materials to perform a comprehensive structure−activity

relationship (SAR) study, and these starting materials are

generally not available.

Scheme 1b. Reissig 1999

structurally related to the product of a Birch-type³⁴dissolving

metal reduction (Scheme 1a). However, it simultaneously

formed a new C−C bond in addition to the reduction. Another

key diﬀerence is the regioselectivity of the diene, which diﬀers

from those formed under Birch conditions for substrates

possessing an electron-withdrawing group (Scheme 1a).^34,35

The conditions used for the Birch reaction (alkali metals in

condensed liquid ammonia) are harsh and severely limit the

scope of the reaction, while the reactions presented here

proceed in much milder conditions and could be expected to

be signiﬁcantly more functional group tolerant. Work by

Reissig demonstrated the ability of a ketyl radical to undergo

dearomative cyclization using a stoichiometric amount of

Sm(II).³⁶It is important to note that during the exploration of

this methodology, a few photocatalytic dearomative methods

have surfaced in the literature (Scheme 1cc−1e);³⁷⁻³⁹

Some of us^19,20have approached the synthesis of organo-

ﬂuorines from the other way around. Rather than approaching

ﬂuorination through harsh, multistep, or low-yielding linear

syntheses, the desired organoﬂuorine can be realized, starting

with all of the ﬂuorines already in place with poly- or

perﬂuorinated core molecules and then either replacing the

unwanted ﬂuorines through hydrodeﬂuorination (HDF)²¹⁻²⁵

or turning them into a desirable substituent through direct

alkylation, alkenylation, arylation, and prenylation.^20,26−32

Visible-light photocatalysis with an iridium-based photocatalyst

has played a critical role in this area, and the interplay between

photocatalytic C−F functionalizations and other methods has

the potential to allow for sophisticated but as of yet largely

unrealized SARs with respect to ﬂuorine. Furthermore, the

mild nature of these reactions may lend itself to the formation

of unnatural products, i.e., ﬂuorinated natural products,¹⁷

which could create new opportunities to explore the eﬀect of

ﬂuorination on the function of natural productsa mostly

unexplored domain.

Scheme 1c. Stephenson 2020

Previously, we showed that it was possible to couple a

perﬂuoroarene directly with an arene partner via C−F and C−

H functionalization. During this investigation,²⁸a careful

assessment of some of the minor products in the crude

reaction NMR spectra revealed vinylic ¹H signals, and GC-MS

analyses showed the [M + 2] peak with respect to the expected

product, a highly unexpected result. We expected that a

cyclohexadienyl radical was a likely intermediate in the

mechanism for the ﬂuoroaryl arylation reaction and that the

majority of the materials would proceed through a mechanism

in which they rearomatized, formally losing a H atom in the

process. Under certain conditions, the reduction of that

intermediate had in fact gained an H atom, resulting in what

amounts to a formal hydrogenation of the intended products.

After careful isolation, we generated simulated NMR spectra

of all possible perturbations of the diene geometry to compare

them to the experimental spectra using the method of Bally

and Rablen.³³Of these, several contenders were similar to the

experimental spectrum of 8, although the 1,4-diene depicted in

Scheme 1b appeared to most accurately match the

experimental spectra (see the Supporting Information for

details). Seeking more concrete data, we grew a crystal and

submitted it for single-crystal X-ray diﬀraction analysis, which

conﬁrmed its structure (Table 3, structure 8). This product is

Scheme 1d. Jui 2020

Scheme 1e. Miyake 2020

however, the reaction discussed within (Scheme 1f) is unique

in that it forms a C−C bond but does not require the pieces to

be tethered together, it is not a spirocyclization, and it abstracts

hydrogen (formally) from water.⁴⁰The intermolecular nature

of the reaction may facilitate SAR studies in ways that

intramolecular reactions cannot. We reasoned that, because of

the structural complexity and functional richness of these

dienes, it would be a valuable asset to the chemical community

and thus set out to discover optimized conditions (Table 2)

that would favor the formation of the reduced 1,4-diene.

Scheme 1a. Birch Reduction

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lower loadings as the reaction simply required more time to

reach completion. Upon scaling the reaction up, the increased

path length proved to slow the reaction rate, although the

catalyst loading could be decreased to 0.01 mol % without

decreasing the yield. It was further found that the reaction

depends heavily on the reaction solvent, with poor or no

reactivity in all solvents we tried except acetonitrile (see the

Supporting Information for full optimization details). The

reaction temperature (−2 to 50 °C) was found to have little

impact on the yield (see the Supporting Information for full

optimization details), allowing subsequent reactions to be run

at convenient temperatures. The optimization experiments

provided insight into the inﬂuence of the various parameters;

however, the yields remained meager. Additionally, under no

conditions found could the minor side products, which were

signiﬁcant and ill-deﬁned, be completely diminished. However,

given the commercial availability of all the reagents, the

operational simplicity of the reaction, and the rapid enhance-

ment of the structural complexity of the reaction, we

investigated the scope.

The reaction operates in a number of diﬀerent ﬂuoroarenes

and coupling partners (Table 3). Reactions that varied the Ar−

H bond with benzoate esters (structures 5, 6, 9, 11, and 13−

20), ketones (8), benzonitriles (10), and amides (7 and 12)

progressed nicely, though in lower yields. In addition, the

separation of the material from the reaction mixture proved

diﬃcult, especially for those reactions in which the Ar−H bond

was not appreciably volatile, and thus could not be separated

via distillation, such as the benzamides. The variation of the

ﬂuoroarene revealed that a wide variety of ﬂuoroarenes

operated similarly, although the variation of the Ar−H bond

from 4-methyl (6) to 4-tert-butyl (5) benzoates resulted in

somewhat better yields or easier separations. Interestingly, the

reaction with a bromopentaﬂuorobenzene resulted in the

typical 1,4-diene product, which was connected at the position

formerly occupied by the bromine (19). This is interesting

because it serves as a mechanistic probe, suggesting the

involvement of an aryl radical (see the discussion below). The

reaction with 3-chloro-2,4,5,6-tetraﬂuoropyridine also under-

goes a chemoselective fragmentation of the chloride, super-

seding the regioselectivity of the 4-position to yield the dihydro

product (20) and revealing an interesting property of the

products. The bicyclic motif is rotationally locked into a

conformation, producing atropisomers that do not interconvert

at room temperature.⁴⁹While likely true for all substrates, it is

not evident with symmetrical ﬂuoroarenes. In this case, C−C

bond formation gives rise to both axial and point chirality, with

a slight preference for one diastereomer (2.4:1). These

diastereomers can be partially separated by recrystallization,

with the minor diastereomer becoming enriched (1:1.9; see the

characterization of 20 in the Supporting Information). Under

these conditions, the reaction operates with all the ﬂuoroarenes

shown here, and reactions attempted with a simple

perﬂuorobenzene did not react at all, indicating that the

ﬂuoroaryl reduction potential (−2.11 V in DMF vs SCE)^25,50

is outside that reachable by the photocatalyst. Additionally,

when 4-iodobenzonitrile, which is devoid of ﬂuorine, was

subjected to the reaction conditions with 4-methyl acetophe-

none, only trace amounts of the coupled products (both diene

and biaryl) were detected by GCMS; instead, hydrodeiodina-

tion was the major product. This suggests that the ﬂuorine

substituents, compared to the deﬂuoroarene, facilitate C−C

bond formation. While yields are generally modest, this

Scheme 1f. This Work

RESULTS AND DISCUSSION

■

Searching for optimal reaction conditions revealed that the

mass balance for the products of the reaction, apart from

several major products, consisted of a complex mixture of

oligomers. Upon screening the photocatalysts (Table 2, entries

1−9), it was discovered that bis-4-(tert-butyl)-2-(4-(tert-

butyl)phenyl)pyridine-4,4′-di-tert-butyl-2,2′-bipyridyl iridium-

(III) hexaﬂuorophosphate (Ir(dtbbpy)(dtbppy)2PF₆) (PC3),

a somewhat oxidizing^41,42and sterically bulky photocatalyst

that has thus far been relatively underrepresented in the

literature, was optimal, having a triplet-state emissive energy of

49.4 kcal/mol⁴³and energies of E⁰(Ir^II/Ir^III*) = −1.04 V and

E⁰(Ir^II/Ir^III)= +1.13 V⁴⁴. While PC5 had a similar outcome in

terms of the intended product, the reaction produced many

minor side products and was therefore rejected to the simplify

puriﬁcation.

Recently, Chaterjee and Koenig⁴⁵disclosed a dearomatiza-

tion reaction that was proposed to take place by triplet energy

transfer, followed by SET. However, because the molecular

radius of the photocatalyst has been shown to be critical for the

energy transfer to occur,²⁷the presence of large tert-butyl

groups on this photocatalyst makes the probability of the

necessary orbital overlap of the photocatalyst and the substrate

unlikely.⁴⁶Moreover, given the relatively low triplet-state

energy of (Ir(dtbbpy)(dtbppy)₂PF₆) (49.4 kcal/mol),^27,47the

energy transfer is unlikely to be operative.

It was discovered that the presence of water signiﬁcantly

enhances the reaction outcome (Table 2, entries 10−13).

Further, the addition of water causes the reaction mixture to

remain a pale yellow color, while in the absence of water it

darkens signiﬁcantly. It could be that the presence of water

further stabilizes a charged intermediate or transition state, or

water could serve to stabilize and solvate the fragmenting

ﬂuoride, a potentially very exothermic process (see a discussion

of the mechanism below). It could also serve a more abstruse

role, such as preventing the formation of light absorbing

compounds that could lead to photostarvation (Figure 1).⁴⁸

The screening for the identity of the terminal reductants

revealed that tributylamine and diisopropylethylamine (Table

2, entries 14−16 and the Supporting Information) were nearly

identical, while all the other reductants attempted gave poor

yields of or no product. We chose to utilize DIPEA due to its

comparatively higher vapor pressure and water solubility,

which we anticipated would facilitate product isolation. A

precipitous decline in the yield of the intended diene was

observed on either side of the optimized stoichiometry (1.0−

1.2 equiv) with respect to the amount of the terminal reductant

(Table 2, entries 17−22). Hydrocarbon arene coupling partner

(Ar−H) equivalents were found to be optimal at 3.0 equiv

(Table 2, entries 23−25). The photocatalyst loading (Table 2,

entries 26−28) was found to be optimal for an NMR tube at

0.25 mol %, but the product distribution was not aﬀected at

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b

Table 2. Optimization of the Reaction Conditions

a

b

Reactions were performed at rt. Conversions or yields determined against the internal standard. Conducted in a 1 ml solvent NMR tube.

reaction provides a rapid increase in complexity from

commercially available starting materials and scales well.

Compound 6 was run on a 10 mmol scale and produced

553 mg of ﬂuorinated diene. A 12.0 mmol scale batch reaction

produced 947 mg of diene 14 according to general procedure

B, which was suﬃcient for downstream synthetic manipu-

lations. Reactions could be scaled using either high intensity

LEDs and tubes with the addition of a stirbar or a ﬂow reactor

setup (see the Supporting Information for more details).

While phenols are largely incompatible with these

conditions, Boc-protected methyl paraben was investigated

and found to be a competent coupling partner. Upon cleavage

with TFA, this reaction provides a keto-cyclohex-enyl methyl

carboxylate. The two-step process formally provides access to

the product of Michael addition with the keto-tautomer of

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that when normal water was replaced with heavy water (15

equiv D₂O, Scheme 3a) the reaction resulted in 69%

deuterium incorporation into the diastereotopic methylene

signal. Resubjecting the isolated product (22 or 23) to the

reaction conditions with the inclusion of D₂O rather than H₂O

showed that the postreaction exchange was not operative (slow

HDF was observed). Furthermore, the deuterium incorpo-

ration occurred with a ca. 3:1 (75%) selectivity on the side

opposite the perﬂuoroaryl ring. These ﬁndings obviate the

possibility of the reaction proceeding solely through a

hydrogen atom transfer (HAT) process because the bond

dissociation energy of water at 117.9 kcal/mol⁵⁴is far from the

weakest bond (the BDE for cyclohexadiene is ca. 77 kcal/

mol,⁵⁵that for neutral DIPEA is ca. 90 kcal/mol, and that for

DIPEA as the amine radical cation is ca. 42 kcal/mol),^54,56

placing water well outside the realm of reasonable H atom

sources. It is more likely that the reaction proceeds through

either an anionic reaction mechanism similar to the traditional

Birch reaction or through a proton-coupled electron transfer

(PCET) event in which the cyclohexadienyl radical is reduced

to the carbanion and protonated. Because the deuteration is

incomplete, however, it is possible that the reaction proceeds

through both an anionic pathway and an HAT event.⁵⁷

Attempts to identify more acidic or nonaqueous additives

instead of water (isopropanol, ethanol, and triﬂuoroethanol)

that would favor the formation of the intended product proved

deleterious to the reaction.

Figure 1. Darkening of the reaction as a function of the equivalents of

water added.

methyl paraben (Scheme 2, right). With ﬁve sites of reactive

functional groups, it is both functional-group dense and

provides access to a complex molecule that can facilitate

further synthetic manipulations.

Upon further investigation, a kinetic isotope eﬀect (KIE)

was observed in parallel experiments where either H₂O or D₂O

were included in the reaction mixture, with a k_H/k_Dof 1.4

(Scheme 3b, eq 1) that is consistent with a secondary KIE or a

solvent KIE.⁵⁸This indicates that the rate-determining step

(RDS) is not the protonation of an anionic intermediate by

water nor a PCET event, steps for which a larger KIE could be

expected.⁵⁹One potential explanation could be that there is a

pre-rate-determining equilibrium and the protonation of the

carbanionic intermediate is near the rate-determining step.

Alternatively, it could also be explained by the fragmentation of

a ﬂuoride as the RDS. The observed KIE would result from the

solvation of the fragmenting ﬂuoride,⁶⁰a generally exothermic

step by ca. 104.4 kcal/mol that could be expected to aﬀect the

kinetics of this step.^61,62By comparison, the solvations of

chloride and bromide are generally less exothermic (74.5 and

68.3 kcal/mol respectively) and in general undergo faster

mesolytic fragmentation.⁶²Reactions with either bromopenta-

ﬂuorobenzene or 3-chloro-tetraﬂuoropyridine (Scheme 3b, eqs

2 and 3, respectively) lead to a 1,4-diene product by

fragmenting a nonﬂuorine halogen. Initial rate studies with

these substrates indicate a KIE of 1.1, which is much less than

those of analogous substrates in which a C−F bond is

functionalized. This suggests that the RDS is the mesolytic

fragmentation of the radical anion for the substrates from

which ﬂuoride is fragmented.

Mechanism. While the selectivity of the reaction involves

C−F fragmentation selectivity, C−C bond formation regiose-

lectivity, C−H bond formation regioselectivity, and in certain

case modest atropselectivity, it is remarkably predictable,

forming only a single dearomatized isomer. The halogen

selectivity follows trends we have previously observed in

photocatalytic C−F functionalization. The 4-position of any

monosubstituted perﬂuoroarene fragments preferentially⁵¹

and, when present, heavier halogens preferentially undergo

fragmentation (structure 19 and 20, Table 3).^21,26,28,32The

regioselectivity of C−C bond formation between the ﬂuoroaryl

fragment and the hydrocarbon aryl coupling partner appears to

be dictated by the LUMO of the Ar−H partner. The reaction

is selective for the carbon ortho to an electron-withdrawing

group and works best for substrates in which the predicted

LUMO is larger at the ortho-position and signiﬁcantly smaller

elsewhere (see the Supporting Information for details). Arenes

lacking electron-withdrawing groups fail to give any cyclo-

hexadiene product, suggesting that the electron-withdrawing

functional group may play other critical roles. At this time, the

driving forces that lead to the observed diene regioisomer are

unclear.

As mentioned above, water played a critical role in the

reaction. The darkening of the reaction mixture could be

avoided by adding water (Figure 1). This accompanied much-

welcomed improvements in the product distribution (Table 2)

and a reduction of the number of minor side products formed.

This might be explained by the formation of cyanine dyes that

arise from the oligomerization of DIPEA, as they are known to

form under similar conditions and participate in photocatalytic

reactions. The inclusion of water may either prevent their

formation or hydrolyze them if they do form.^52,53

Taking the above experiments and observations, we present

our working mechanistic understanding (Scheme 4). After that

absorption of a photon, an initial singlet photocatalyst rapidly

undergoes intersystem crossing to yield the triplet excited-state

photocatalyst.^63,64Based on redox potentials, the reaction is

expected to proceed through a reductive quenching cycle in

which the triplet photocatalyst (E⁰(Ir^II/Ir^III*) = −1.04 V⁴⁴) is

reduced by an amine (E_oxca. 0.5 V vs SCE⁶⁵). The reduced

photocatalyst then undergoes SET to the ﬂuoroarene (A) to

form the radical anion (B) and return the photocatalyst to the

We had presumed that the amine indirectly (as the radical

cation) served as both the terminal reductant and the source of

a H atom in the formation of the diene. However, we found

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e

Table 3. Scope

a

b

c

d

e

Batch reaction conditions. Flow reaction conditions. Produces atropisomers. NMR yield. Isolated yields.

Scheme 2. Cleavage of the Boc Protecting Group

ground state. In the RDS, this radical anion, aided by water,

fragments mesolytically to give the ﬂuoroaryl radical (C) and a

ﬂuoride anion.^21,26,28Based on BDEs, the ﬂuoroaryl radical is

expected to easily abstract a H atom from either DIPEA or its

corresponding radical cation to give the major byproduct, the

hydrodeﬂuorinated product (D).

One might expect that the ﬂuoroaryl radical anion (B,

Scheme 4) with its abundance of electron density could

potentially act nucleophilically,^66,67attacking the LUMO of the

Ar−H bond to produce an intermediate distonic radical anion.

While there are reports of nucleophilic attacks by related

radical anions,⁶⁷it seems unlikely in this reaction. This is due

to the observation that both chlorinated and brominated

ﬂuoroarenes lead to the same 1,4-diene product, the

observation of a rate enhancement upon an increase in the

amount of H₂O, and the observation that the KIE is

signiﬁcantly retarded in the presence of a fragmenting bromide

or chloride, all of which are consistent with the fragmentation

of the halogen being rate-determining. In other words, the rate

of halogen fragmentation increases as the size of the halogen

increases and the corresponding radical anions are less reliant

on solvation (compared to ﬂuoride) to facilitate fragmentation.

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Scheme 3a. Deuteration

Scheme 3b. KIE

Consequently, the k_H/k_Dvalue diminishes as the rate of

fragmentation increases, barring a mechanistic change between

these substrates. This rate could be expected to be much more

rapid upon the formation of an intermediate distonic radical

anion. A solvent KIE, if observed at all under such conditions,

would be the same for all substrates regardless of the identity

of the fragmenting halogen.

classical cannabinoids (Scheme 5a), the most prominent, and

also most notorious, of which is trans-Δ⁹-tetrahydrocannabinol

(THC),⁶⁹the molecule responsible for not only most of the

psychoactive eﬀects of cannabis but also many of its medicinal

properties. Despite the extensive and ongoing research on

classical cannabinoids, F₃-THC has, to the best of our

knowledge, not been reported before. Related compounds

with mono-⁷⁰or diﬂuorination⁷¹are known in the

literature^72,73and have been shown to have bioeﬃcacy

(Scheme 5b). This method allows access to a completely

unknown series of triﬂuoro analogs with substitution at either

the Ar−F or Ar−H bond for diversiﬁcation through a

straightforward series of reactions and, importantly, will allow

us to investigate the role of the hydroxyl group on THC.

For the synthesis of F₃-THC, we chose a diene (14, Scheme

5a) as the most suitable starting material because reactions

toward a more direct route with the simple pentyl alkyl

pentaﬂuoroarene produced none of the intended intermediate

materials, presumably because the reduction potential is too

high due to an electron-donating pentyl group. Following the

photo-Birch reaction, we began an investigation of methods for

the deoxygenation of the aromatic ketone. Following a clean

reduction of the ketone with NaCNBH₃, we obtained

compound 24 (Scheme 6) in a high yield. We found the

Barton−McCombie⁷⁴approach attractive and pursued the

elegant photochemical approach developed by Reiser et al.,⁷⁵

which provided the intended deoxygenated product in three

straightforward steps^75,76with a total yield of 76%.

Therefore, as with previous photocatalytic reactions we have

reported, we are proposing that the reaction occurs through

the mesolytic fragmentation of the radical anion (B, Scheme 4)

to form the ﬂuoroaryl radical (C), which then attacks the

LUMO of the Ar−H bond and leads directly to (E). The

partial incorporation of protium may be best explained by a

mechanistic bifurcation from intermediate E. Therefore, we

propose that the delocalized doubly allylic radical (E) is itself

either reduced by the photocatalyst to give an anionic

intermediate⁶⁸(G), which provides the observed 1,4-diene

(H) upon protonation, or oxidized to give the other observed

major byproduct, the rearomatized biaryl product (F). It is also

possible that the formation of the biaryl product and the

intended dienyl product originate from the disproportionation

reaction of the radical E in which the cyclohexadienyl radical

abstracts a H atom from another cyclohexadienyl radical E to

form both the observed reduced product (BDE ca. 77 kcal/mol

for the unsubstituted substrate)⁵⁵and the oxidized biaryl.

Although this pathway fails to account for the incorporation of

the deuterium from water, the deuteration is incomplete. The

amount of the biaryl side product is always less than the

amount of the 1,4-diene, which supports a mechanistic

bifurcation although it is hardly conclusive.

Following the successful formation of the desired

intermediate diene (26), the reduction of the Michael system

was addressed. This proved to be remarkably diﬃcult. This was

surprising given the expected electronic and steric diﬀerences

between the alkenes, and yet when using a number of the more

Application. Returning to our original goal of enabling the

synthesis of unnatural products, we were pleased to see that

this motif maps very nicely onto the structural skeleton of

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Scheme 4. Mechanistic Discussion

common methods we observed an unselective reaction,

unintended side products, or a poor conversion. The most

reliable method was found to be a derivative of the method by

Chandrasekhar et al.,⁷⁷i.e., hydrogenation via polymethylhy-

drosiloxane (PHMS) with the strong Lewis acid tris-

(pentaﬂuorophenyl)borane (Scheme 7), which ultimately

gave the hydrogenated product in modest yields and in a

diastereomeric ratio of around 5:1 (varying between 4:1 and

6:1) in favor of the cis-product (27) over the trans-product

(28). The desired epimer 28 could be achieved using a

stoichiometric amount of KHMDS in THF to yield a 1:44

diastereomeric ratio in favor of trans-28. The trans-diaster-

eomer was desirable in part as natural (trans) THC has a

higher aﬃnity for cannabinoid receptors than its cis-counter-

part. It could be reasonably expected that the ﬂuorinated

analogs would perform similarly.

Scheme 5a. THC Fluoroanalog Target

Scheme 5b. Known Cannabinoid Fluoroanalogs

Having determined a route to the trans-intermediate

cyclohexene (28), we then investigated the formation of the

bridging ring (Scheme 8). We initially hoped to be able to

form the third ring through the tandem nucleophilic addition

of the methyl groups, followed by the subsequent S_NAr

displacement of the ﬂuoride. Unfortunately, this did not prove

fruitful with either a methyl Grignard or lithiate reagent. Of

note, while the cis- and trans-cyclohexenyl methyl esters (27

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a

Scheme 6. Deoxygenation

a

Reagents and conditions are as follows: (a) Znl₂(1−5 equiv), NaBH₃CN (7.5 equiv), DCE, 80 °C, 97%; (b) bis(triﬂuoromethyl)benzoyl chloride

(1.1 equiv), 80 °C, 89%; and (c) DIPEA (2.0 equiv), [Ir(dtbbpy)(dtbppy)₂]PF₆(1.5 mol %), 45 °C, 455 nm irradiation, 86%.

Scheme 7. Reduction of the Michael System

Scheme 8. Intramolecular Cyclization

and 28) were challenging to separate, conversion to the

corresponding cis- and trans- alcohols (29) showed diﬀerent R_f

values, and the compounds could be more easily separated

chromatographically. However, treating alcohol (29) with

KHMDS caused cyclization, similar to the work by Westphal,

Trauner, Carreira, Frank, and co-workers,⁷¹and provided the

intended cannabinoid product (30) with a 93% yield over two

steps (Scheme 8). Ultimately, the reaction starts with two

commodity chemicals and takes place in eight succinct steps

with 6% overall yield. Furthermore, several points of

diversiﬁcation exist that could be used for further exploration

of the motif. Several ﬂuorinated cannabinoids are undergoing

bioassay analysis now. The results will be reported in due

course.

CONCLUSION

■

We have demonstrated a new reaction that provides a new and

expedient route to 1,4-dienes that, despite being produced in

modest yields, represent a rapid enhancement in chemical

complexity, which may prove useful in discovery chemistry.

Further, we have shown that the reaction likely proceeds

through an anionic intermediate, which opens the door for

potential further diversiﬁcation through a Birch-like alkylation.

These dienes map readily onto the carbon framework of

classical cannabinoids, which we have shown can be

synthesized in short order and would otherwise have been

prohibitively diﬃcult to reach. In addition, the synthetic steps

oﬀer a wealth of synthetic possibilities for diversiﬁcation.

Further, we expect that the synthesis laid out herein can

provide access to ﬂuorinated analogs of existing CB1/CB2

agonists, such as classical THC, related cannabinoids, or

perrottetinenes. In addition, one of the major byproducts, the

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General Procedure B (Batch) For the Formation of the 1,4-

Diene. Perﬂuoroarene (12 mmol), an aromatic trapping agent (31.2

mmol, 2.6 equiv), and [Ir(dtbbpy)(dtbppy)₂]PF₆(2 mg, 0.014 mol

%) were dissolved in 120 mL of acetonitrile inside a Tauchschacht

reactor (for more details, see the Supporting Information). DIPEA

(14.4 mmol, 2.52 mL, 1.2 equiv) was added, and the solution was

irradiated at 455 nm. After three days, the solvent was removed under

reduced pressure. The residue was dissolved in 100 mL of boiling

hexanes and ﬁltered to remove insoluble components. The solvent

was removed under reduced pressure, and most of the Ar−H coupling

partner was distilled oﬀ with Kugelrohr distillation (for methyl toluate

and methyl acetophenone; 95 °C, 1 mbar, 80−90% recovered). The

residue was puriﬁed analogously to that in general procedure A.

General Procedure C (Flow) For the Formation of the 1,4-

Diene. In a darkened labspace, the same as above, a 250 mL PFA

round-bottom ﬂask test tube ﬁtted with a stirbar was charged the

ﬂuoroarene and a stock solution consisting of the Ar−H (3.0 equiv),

DIPEA (1.1 equiv), Ir(dtbbpy)(dtbppy)₂PF₆(0.125 mol %), water

(15 equiv), and acetonitrile (0.1 M). The ﬂask was ﬁtted with a

rubber septum. The solution was attached to low and constant

positive argon pressure and circulated through PFA tubing via a

peristaltic pump at 70 rpm. the solution was irradiated and held at

room temperature until NMR spectroscopy indicated the of complete

consumption of SM through an analysis of the aliquot. The products

were isolated analogously to that in general procedure A.

rearomatized biaryl species, could lead to additional analogs of

the natural cannabinoid cannabinol (CBN). Coupled with

existing deﬂuorination techniques and the possibilities present

for downstream diversiﬁcation, the possibilities for a more

complete SAR with respect to ﬂuorination are possible. The

reactivity we have shown was previously unknown and is

orthogonal to other dearomative reactions.

EXPERIMENTAL PROCEDURES

■

General Comments. All reactions were conducted in dried and

deoxygenated solvents. Solvents for column chromatography were

used without further puriﬁcation. Commercially available starting

materials were used as received and included all Ar−F compounds

except the pentaﬂuorophenyl butyl ketone. Photocatalysts PC1,⁷⁸

PC4,⁷⁹PC5,⁷⁹PC7,⁷⁹PC8,⁸⁰and PC9⁸¹were synthesized according

1

to literature procedures, and structures were conﬁrmed by H NMR

spectroscopy. PC2, PC3, and PC6 were purchased and used as

received. Structural assignments were made with additional

information from gCOSY, gHSQC, and gHMBC experiments.

Melting Points. Melting points were determined on a Stuart

SMP10 melting point apparatus and are reported uncorrected.

NMR Analysis. NMR spectra were recorded using a Bruker

1

Avance 400 spectrometer (400 MHz for H, 101 MHz for ¹³C, and

376 MHz for ¹⁹F) or a Bruker Neo 600 spectrometer with a BBO

General Procedure D (NMR Scale). Same as general procedure

A except in a clean and dry NMR tube. A sealed melting point

capillary containing a deuterated solvent was included in the NMR

tube. The tube was then chilled to 0 °C and degassed by sparging with

argon through an 18 gauge stainless steel needle for 10 min. The

NMR tube was ﬁtted with a septum and sealed with paraﬁlm.

Synthesis of 1-(Perﬂuorophenyl)pentan-1-one. Literature-

known compound. A 1 M solution of bromopentaﬂuorobenzene (6.17

1

BBF-H-D-05 SmartProbe (599 MHz for H, 564 MHz for ¹⁹F, and

151 MHz for ¹³C) as noted. Chemical shifts are reported in parts per

million (ppm) on the δ scale using the residual solvent signal as an

internal standard. As abbreviations for the multiplicity were used as

follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet,

pt = pseudo triplet, and app = apparent.

The analysis of reaction mixtures was performed in undeuterated

solvents with either a DMSO-d₆or C₆D₆capillary as reference.

Spectra were analyzed using Topspin 4.0.6 or MestReNova 14.0.1-

23559 software.

Thin-Layer Chromatography. Thin-layer chromatography was

done on with silica gel-precoated aluminum sheets (Machery-Nagel,

silica gel 60 G/UV254, 0.2 mm), and UV light (254 nm) and a

potassium permanganate stain were used for visualization.

High-Resolution Mass Spectrometry. HRMS was performed

on a ThermoFisher LTQ OrbitrapXL or an Agilent Q-TOF 6540

UHD.

X-ray Analysis. X-ray analysis was performed by the crystallog-

raphy laboratory of the University of Regensburg. Structure solving

was done by Florian Meurer.

General Procedure A (Batch) For the Formation of the 1,4-

Diene. In a darkened lab space, a new 25 mL test tube ﬁtted with a

stirbar was charged the ﬂuoroarene (2.0 mmol) and a stock solution

consisting of the Ar−H (3.0 equiv), DIPEA (1.1 equiv), Ir(dtbbpy)-

(dtbppy)₂PF₆(0.125 mol %), water (15 equiv), a C₆F₆internal

standard (1/6 equiv, testing showed no diﬀerence between reactions

in which the standard was included and those in which it was not),

and acetonitrile (0.1 M). The test tube was ﬁtted with a rubber

septum. This solution was chilled to 0 °C and then sparged with

argon for 10 min at 0 °C. The solution was attached to low and

constant positive argon pressure, added to an irradiation bath at 460

nm, and held at 0 °C until NMR analysis indicated the complete

consumption of SM. The reaction was then concentrated and

extracted at least thrice with boiling hexanes or until no remaining

color was apparent in the hexanes extracts. The pooled hexanes

extracts were then concentrated, and the resultant mixture was heated

in a 10 mL round bottomed ﬂask at 90 °C under high vacuum for 1−

2 h. The resultant mixture was then dry-loaded onto silica and

subjected to ﬂash chromatography on a silica column with a hexanes/

ethyl acetate mobile phase. The fractions containing the product were

pooled and concentrated in a 20 mL scintillation vial. To the resultant

oil was added a minimal amount of methanol from which pure crystals

formed upon repeated freezing of the solution in liquid nitrogen,

followed by vigorous shaking as the solution warmed.

g, 25 mmol) was prepared and slowly added to activated magnesium

turnings (729 mg, 30 mmol, 1.2 equiv). First, enough of the solution

was added to cover the Mg. A grain of iodine was added, and the

solution was heated until the color of the iodine disappeared. The

remaining solution was added dropwise while stirring to keep the

reaction mixture reﬂuxing slightly. After all the bromopentaﬂuor-

obenzene was added, the mixture was stirred until it had cooled to

room temperature. A solution of pentanal (2.37 g, 27.5 mmol, 1.1

equiv based on bromopentaﬂuorobenzene) in 20 mL of THF was

added to the Grignard solution. The reaction mixture was stirred

overnight at rt, quenched with a saturated NH₄Cl solution, extracted

with ethyl acetate, and dried over MgSO₄. The solvent was evaporated

under reduced pressure. The crude alcohol was used for the Jones

oxidation without further puriﬁcation.

The crude secondary alcohol was dissolved in approximately 50×

its volume of acetone. The exact amount of solvent did not have any

observable eﬀect on the yield. A 2 M solution of CrO₃in a 5:1

mixture (volume) of water/sulfuric acid was added in small portions

while stirring until the complete consumption of starting material

occurred. The reaction progress was monitored via TLC. After the

completion of the reaction, isopropanol was added to decompose the

remaining Cr(VI). Small amounts of water and ethyl acetate were

added to the mixture, and the mixture extracted with ethyl acetate,

washed with water, and dried over MgSO₄. The solvent was removed

under reduced pressure. The crude product was puriﬁed by vacuum

distillation (100 °C, 1 mbar) to give the product as a slightly yellow

liquid. Isolated yield: 3.10 g, 11.9 mmol, 49% based on

bromopentaﬂuorobenzene. The spectra matched the literature

values.⁸²

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¹⁹F NMR (CDCl₃377 MHz): δ −141.42 to −141.67 (m, 2 F),

fractions, which provided a peak that contained the intended product

and the biaryl product. The material was found to crystallize only

from pentane. Colorless crystalline solid, mp 165−167 °C. ¹⁹F NMR

(CDCl₃, 376 MHz) δ −135.27 to −135.57 (m, 2F), −142.00 to

1

−150.06 to −150.35 (m, 1 F), −160.06 to −160.37 (m, 2 F). H

NMR (CDCl₃, 400 MHz): δ 2.88 (t, 2H, J = 7.48 Hz), 1.76−1.65 (m,

2 H), 1.46−1.34 (m, 2 H), 0.95 (t, 3H, J = 7.3 Hz). ¹³C{¹H} NMR

(CD₃CN, 101 MHz): δ 194.2, 144.0 (dm, J = 252.86 Hz), 142.5 (dm,

J = 258.11 Hz), 137.6 (dm, J = 255.97 Hz), 115.6−115.0 (m), 44.80,

25.55, 22.01, 13.50.

1

−142.19 (m, 2F). H NMR (CD₃CN, 400 MHz): δ 6.03−5.91 (m,

2H), 5.67 (ddt, 1H, J = 10.0, 3.9, 2.1 Hz), 4.90−4.80 (m, 1H), 3.75

(s, 3H), 3.04−2.74 (m, 2H), 1.21 (d, 6H, J = 6.7 Hz), 1.01 (s, 6H).

¹³C{¹H} NMR (CD₃CN, 101 MHz): δ 169.4, 147.6 (ddt, 4.0 Hz, J =

258.7, 16.9), 145.9 (app. dm, J = 248.4 Hz), 131.7, 130.7, 129.6, 128.7

(t, J = 15.0 Hz), 126.6, 125.1, 123.0, 108.3 (t, J = 3.8 Hz), 93.1 (tt, J =

17.6, 3.0 Hz), 33.6 (p, J = 1.5 Hz), 26.1, 20.5, 20.2. HRMS (ESI/ion

trap) m/z: [M − H⁺]⁻Calcd for C₂₀H₁₉F₄N₂O⁻379.1439, found

379.1458. NMR yield: 25.0%. Isolated yield: 19.7 mg, 2.6%.

(5) Methyl 5-(tert-Butyl)-4′-cyano-2′,3′,5′,6′-tetraﬂuoro-1,4-di-

hydro-[1,1′-biphenyl]-2-carboxylate. General procedure A was

(8) 1-(4-Methyl-6-(perﬂuoropyridin-4-yl)cyclohexa-1,4-dien-1-

yl)ethan-1-one. Synthesized according to general procedure C from

followed. Colorless crystalline solid, mp 108−110 °C. ¹⁹F NMR

(CD₃CN, 376 MHz,): δ −136.63 (td, 2F, J = 16.0, 7.1 Hz), −143.09

1

(td, 2F, J = 16.0, 7.1 Hz). H NMR (CD₃CN, 400 MHz): δ 7.28 (t,

1H, J = 3.9 Hz), 5.60−5.36 (m, 1H), 4.89 (q, 1H, J = 6.1 Hz), 3.62 (s,

3H), 3.17−3.00 (m, 2H), 1.08 (s, 9H). ¹³C{¹H} NMR (CD₃CN, 151

MHz): δ 165.6, 147.1 (ddt, J = 257.6, 17.2, 4.0 Hz), 145.3 (d, J =

248.2 Hz), 144.3, 140.6, 129.6 (t, J = 14.7 Hz), 125.8, 114.2, 107.9 (t,

J = 3.8 Hz), 91.8 (tt, J = 17.6, 3.1 Hz), 51.3, 34.7, 33.1 (t, J = 2.1 Hz),

28.0, 26.4. HRMS (ESI/ion trap) m/z: [M − H⁺]⁻Calcd for

pentaﬂuoropyridine and p-methyl acetophenone. Puriﬁcation via

column chromatography (5% EA in PE) yielded a mostly clean

product, which was contaminated with the rearomatized product as a

viscous yellow liquid that solidiﬁed within three days. Recrystallization

from either n-hexane or MeOH yielded the clean product. Colorless

crystalline solid, mp 57−58 °C. The structure of this compound could

be deﬁnitively determined by single crystal X-ray diﬀractometry. TLC:

R_f= 0.35 (hexanes/ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 377 MHz):

−

C₁₉H₁₆F₄NO₂366.1123, found 366.1137. NMR yield: 32.9%.

Isolated yield: 151.0 mg, 20.5%.

(6) Methyl 4′-cyano-2′,3′,5′,6′-tetraﬂuoro-5-methyl-1,4-dihydro-

1

[1,1′-biphenyl]-2-carboxylate. General procedure C was followed.

δ = −92.86 to −93.10 (m, 2F), −146.26 to −146.51 (m, 2F). H

NMR (CDCl₃, 400 MHz): δ 7.19−7.14 (m, 1H), 5.37−5.29 (m, 1H),

4.86−4.77 (m, 1H), 3.14−2.99 (m, 1H), 2.99−2.85 (m, 1H), 2.29 (s,

3H), 1.76 (s, 3H). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 197.1,

144.8−144.4 (m), 142.3−141.9 (m), 141.9−141.5 (m), 141.1,

139.4−138.9 (m), 136.7−136.2 (m), 135.7, 132.6, 117.6, 32.3, 32.2,

+

25.0, 22.4. HRMS (+APCI): Calcd for [C₁₄H₁₁F₄O + NH₄]⁺

303.1115, found: 303.1133. Isolated yield: 765 mg, 22%.

(9) Methyl 4′-Cyano-2′,3′,5′,6′-tetraﬂuoro-1,4-dihydro-[1,1′-bi-

phenyl]-2-carboxylate. General procedure A was followed using a 4 g

Colorless crystalline solid, mp 91−95 °C. ¹⁹F NMR (CDCl₃, 376

MHz): δ −133.47 (td, 2F, J = 16.6, 7.4 Hz), −141.19 (td, 2F, J =

1

15.9, 6.8 Hz). H NMR (CDCl₃, 400 MHz): δ 7.25 (t, 1H, J = 3.8

Hz), 5.39−5.22 (m, 1H), 4.83 (q, 1H, J = 5.6 Hz), 3.67 (s, 3H), 2.98

(dd, 1H, J = 23.8, 7.9 Hz), 2.85 (dt, 1H, J = 23.9, 5.5 Hz), 1.76 (s,

3H). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 166.0, 147.1 (ddt, J =

261.5, 16.6, 3.7 Hz), 145.2 (app-dm, J = 250.4 Hz), 140.3, 133.2,

129.5 (t, J = 14.3 Hz), 126.4, 117.5, 107.9 (t, J = 3.8 Hz), 92.3, 52.0,

33.2 (t, J = 2.1 Hz), 32.1, 22.7. HRMS (ESI/ion trap) m/z: [M −

silica column. Colorless crystalline solid, mp 147−149 °C. ¹⁹F NMR

(CD₃CN 376 MHz): δ −136.45 (td, J = 16.0, 7.0 Hz), −143.01 (app.

td, J = 16.1, 7.0 Hz). ¹H NMR (CD₃CN, 400 MHz): δ 7.25 (t, 1H, J

= 4.0 Hz), 6.18−5.86 (m, 1H), 5.76−5.52 (m, 1H), 5.03−4.73 (m,

1H), 3.63 (s, 3H), 3.17−2.90 (m, 2H). ¹³C{¹H} NMR (CD₃CN, 101

MHz): δ 166.6, 148.2 (ddt, J = 257.8, 17.1, 3.9 Hz), 146.2 (d, J =

247.6 Hz), 140.9 (t, J = 1.4 Hz), 130.1 (t, J = 14.7 Hz), 127.4, 126.3,

123.6, 108.9 (t, J = 3.8 Hz), 93.1 (tt, J = 17.5, 2.6 Hz), 52.4, 32.9 (p, J

= 2.1 Hz), 27.8. HRMS (ESI/ion trap) m/z: [M − H⁺]⁻Calcd for

C₁₅H₈F₄NO₂⁻310.0497, found 310.0509. NMR yield: 25.0%. Isolated

yield: 98.5 mg, 15.8%.

−

H⁺]⁻Calcd for C₁₆H₁₀F₄NO₂324.0653, found 324.0665. Isolated

yield: 552.9 mg, 17.0%.

(7) 4′-Cyano-2′,3′,5′,6′-tetraﬂuoro-N,N-diisopropyl-1,4-dihydro-

[1,1′-biphenyl]-2-carboxamide. General procedure A was followed,

(10) 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-1,4-dihydro-[1,1′-biphenyl]-

2,4′-dicarbonitrile. General procedure A was followed, except that

the material was repeatedly recrystallized from either hexanes or

methanol. Colorless crystalline solid, mp 117−120 °C. ¹⁹F NMR

(CDCl₃, 376 MHz): δ −131.79 (td, 2F, J = 16.8, 7.3 Hz), −140.34

except Ar−H was not removed by heating under high vacuum but

rather separated by column chromatography using a 40 g silica

column. The material was eluted with large amount of benzamide

Ar−H. A second 24 g silica column was run on these combined

1

(td, 2F, J = 16.6, 6.5 Hz). H NMR (CDCl₃, 400 MHz): δ 6.87 (td,

6H, J = 3.7, 1.6 Hz), 5.44−5.19 (m, 6H), 4.85−4.49 (m, 6H), 3.13−

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during column chromatography (0 → 5% EtOAc in hexanes) and a

better separation.

(13) Dimethyl 3-(Perﬂuoropyridin-4-yl)cyclohex-1-ene-1,4-dicar-

boxylate. General procedure B was followed. The Ar−H was not

2.73 (m, 12H), 1.78 (s, 20H), 1.25 (s, 1H). ¹³C{¹H} NMR (CDCl₃,

151 MHz): δ 147.4 (ddt, J = 259.1, 16.8, 3.9 Hz), 145.2 (ddt, J =

250.0, 11.7, 5.2 Hz), 145.0, 133.2, 131.8, 126.1 (t, J = 14.4 Hz), 115.4,

108.7, 107.7 (t, J = 3.9 Hz), 93.6 (tt, J = 17.4, 2.6 Hz), 34.2, 30.9,

−

21.7. HRMS (ESI/ion trap) m/z: [M − H⁺]⁻Calcd for C₁₅H₇F₄N₂

removed by heating under high vacuum but rather separated by

column chromatography, mp 93−94 °C. ¹⁹F NMR (CDCl₃, 376

MHz): δ −90.76 to −91.23 (m, 2F), −142.62 to −143.66 (m, 2F).

¹H NMR (CDCl₃, 400 MHz): δ 6.84−6.45 (m, 1H), 4.35 (d, 1H, J =

10.5 Hz), 3.74 (s, 3H), 3.63 (s, 3H), 2.95 (ddd, 1H, J = 12.5, 10.4, 2.8

Hz), 2.77−2.56 (m, 1H), 2.54−2.22 (m, 2H), 1.99−1.65 (m, 1H).

¹³C{¹H} NMR (CDCl₃, 101 MHz) δ 173.5, 166.6, 143.7 (dddd, J =

246.0, 16.5, 13.0, 3.1 Hz), 140.7 (d, J = 259.5), 134.8, 134.7 (tt, J =

14.3, 2.4 Hz), 132.1, 52.4, 52.1, 43.2 (t, J = 2.2 Hz), 35.8 (t, J = 2.0

Hz), 26.0, 23.9. HRMS (ESI/ion trap) m/z: [M + H]⁺Calcd for

291.0551, found 291.0552. NMR yield: 16.4%. Isolated yield: 30.0

mg, 9.1%.

(11) Methyl 5-((tert-Butoxycarbonyl)oxy)-4′-cyano-2′,3′,5′,6′-

tetraﬂuoro-1,4-dihydro-[1,1′-biphenyl]-2-carboxylate. General pro-

+

C₁₅H₁₄F₄NO₄348.0853, found 348.0856. Isolated yield, 200 mg,

575.93 umol, 4.8%.

Example of the Large-Scale Synthetic Method. (14) Methyl

2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-pentanoyl-1,4-dihydro-[1,1′-bi-

cedure A was followed but with only 1 equiv of water. The Ar−H was

not removed by heating under high vacuum but rather separated by

column chromatography using a 40 g silica column. Colorless

crystalline solid, mp 104−105 °C. ¹⁹F NMR (CDCl₃, 376 MHz): δ

−132.84 (td, 2F, J = 16.6, 7.3 Hz), −140.61 (td, 2F, J = 16.5, 15.8, 6.7

Hz). ¹H NMR (CDCl₃, 400 MHz): δ 7.13 (ddd, 1H, J = 4.4, 3.0, 1.0

Hz), 5.43 (dd, J = 4.3, 2.0 Hz, 1H), 4.98 (q, J = 6.1 Hz, 1H), 3.61 (s,

3H), 3.23 (ddt, 1H, J = 23.4, 7.5, 2.7 Hz), 3.06 (ddd, 1H, J = 23.4,

6.4, 4.6 Hz), 1.43 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ

165.7, 151.0, 147.5, 147.5 (ddt, J = 262.2, 16.6, 3.1 Hz), 145.6 (d, J =

250.0 Hz), 139.0, 128.3 (t, J = 14.0 Hz), 126.6, 110.3, 108.0 (t, J = 3.6

Hz), 84.3, 52.6, 33.5, 31.4, 29.2, 28.1. HRMS (ESI/ion trap) m/z: [M

phenyl]-2-carboxylate. General procedure B was followed from 1-

(perﬂuorophenyl)pentan-1-one and methyl p-toluate. Puriﬁcation via

column chromatography (5% EA in PE) yielded the product, which

was contaminated with variable amounts of the rearomatized product

as a viscous yellow liquid. Recrystallization from MeOH yielded the

product as colorless needles, mp 66.8 °C. TLC: R_f= 0.50 (hexanes/

ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 376 MHz): δ −143.85 to

−14.17 (m, 4F). ¹H NMR (CDCl₃, 400 MHz): δ 7.24−7.17 (m, 1H),

5.42−5.21 (m, 1H), 4.78 (q, 1H, J = 6.2, 5.8 Hz), 3.65 (s, 3H), 3.11−

2.70 (m, 4H), 1.73 (t, 3H, J = 1.4 Hz), 1.67 (p, J = 7.4 Hz, 2H), 1.36

(h, J = 7.4 Hz, 2H), 0.91 (t, J = 7.3 Hz, 3H). ¹³C{¹H} NMR (CDCl₃,

101 MHz): δ 195.8, 166.1, 145.2 (ddt, J = 253.8, 16.3, 5.4 Hz), 143.5

(dddd, J = 254.4, 17.6, 6.5, 5.0 Hz), 139.7, 132.2, 127.0, 124.6 (t, J =

14.0 Hz), 118.3, 118.1 (t, J = 17.8 Hz), 51.8, 44.8, 32.6 (p, J = 1.9

Hz), 32.0, 25.7, 22.6, 22.2, 13.8. HRMS (EI) m/z: [M]⁺exact mass

Calcd. for C₂₀H₂₀F₄O₃384.1349, found 384.1337. Isolated yield: 947

mg, 2.46 mmol, 21%.

−

− H]⁻Calcd for C₂₀H₁₆F₄NO₅426.0970, found 426.0995. Isolated

yield: 118.6 mg, 13.8%.

(12) (4-Methyl-6-(perﬂuoropyridin-4-yl)cyclohexa-1,4-dien-1-yl)-

(piperidin-1-yl)methanone. General procedure B was followed, at a

12 mmol scale, with 2.6 equiv of Ar−H and 10 equiv of water. The

Ar−H was not removed by heating under high vacuum but rather

separated by column chromatography. The product was recrystallized

from n-hexane. Colorless crystalline solid. ¹⁹F NMR (CDCl₃, 376

MHz): δ −92.00 to −92.38 (m, 2F), −145.53 to −145.89 (m, 2F).

¹H NMR (CDCl₃, 400 MHz): δ 6.08 (ddd, 1H, J = 4.2, 2.9, 1.7 Hz),

5.32 (td, 1H, J = 3.1, 1.6 Hz), 4.93 (q, 1H, J = 6.4 Hz), 3.65−3.22 (m,

3H), 2.89 (dd, 1H, J = 23.3, 6.8 Hz), 2.75 (ddd, 1H, J = 22.9, 7.3, 4.0

Hz), 1.75 (s, 3H), 1.59 (p, 2H, J = 5.8 Hz), 1.53−1.18 (m, 5H).

¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 168.6, 145.0−141.9 (m), 140.6

(dd, J = 260.6, 20.8 Hz), 135.4 (t, J = 13.3 Hz), 133.5, 129.0, 128.3,

117.0, 34.4, 31.6, 30.9, 26.2, 24.5, 22.7, 14.1. HRMS (+ESI) m/z: [M

+ H]⁺Calcd for C₁₈H₁₉F₄N₂O⁺355.1428, found 355.1423. Isolated

yield: 220.0 mg, 6.2%. The reaction was repeated at a later stage with

the organic photocatalyst 4CzIPN (PC9). Crude NMR spectra sowed

similar results. The isolated yield was 9.9% due to a slower gradient

(15) Dimethyl 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-1,4-dihydro-[1,1′-

biphenyl]-2,4′-dicarboxylate. General procedure A was followed.

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The product eluted at 5% EtOAc in hexanes after 38 CV in a 24 g

column as a colorless crystalline solid, mp 91−95 °C. ¹⁹F NMR

(CDCl₃, 564 MHz): δ −139.20 (dd, J = 22.2, 12.6 Hz, 2F (biaryl

impurity)), −139.46 (dd, J = 22.6, 13.0 Hz, 2F (biaryl impurity)),

−140.33 to −140.90 (m, 2F), −142.99 to −143.96 (m, 2F). ¹H NMR

(CDCl₃, 599 MHz) δ 7.25−7.16 (m, 1H), 5.39−5.25 (m, 1H), 4.81

(q, 1H, J = 5.5, 5.0 Hz), 3.95 (s, 3H), 3.66 (s, 2H), 2.97 (ddt, 1H, J =

24.8, 6.5, 2.4 Hz), 2.83 (dt, 1H, J = 23.8, 5.5 Hz), 1.74 (s, 3H).

¹³C{¹H} NMR (CDCl₃, 151 MHz): δ 166.2, 160.6, 145.3 (ddt, J =

249.6, 14.3, 4.7 Hz), 144.7 (ddt, J = 256.7, 15.9, 4.4 Hz), 139.8, 132.4,

126.9, 125.7 (t, J = 14.7 Hz), 118.2, 110.5 (t, J = 15.8 Hz), 53.3, 51.9,

32.7, 32.1, 22.6. HRMS (ESI/ion trap) m/z: [M + Na⁺]⁺Calcd for

C₁₇H₁₃F₄O₄Na 381.0726, found 381.0707. Isolated yield: 99.6 mg,

13.8%.

followed, except the product was recrystallized from isopropanol.

Colorless crystalline solid, mp 104−105 °C. ¹⁹F NMR (CD₃CN, 564

MHz): δ −57.07 (t, 3F, J = 21.3 Hz), −144.10 to −144.22 (m, 2F),

−144.22 to −144.46 (m, 2F). ¹H NMR (CD₃CN, 400 MHz): δ

7.24−7.17 (m, 1H), 5.41−5.34 (m, 1H), 4.83 (q, 1H, J = 5.5 Hz), 3.6

(s, 3H), 2.99 (ddt, 1H, J = 24.2, 6.6, 2.5 Hz), 2.88 (ddd, 1H, J = 24.1,

6.5, 4.6 Hz), 1.74 (s, 3H). ¹³C{¹H} NMR (CD₃CN, 151 MHz): δ

166.6, 146.5 (d, J = 246.3 Hz), 145.0 (d, J = 235.4 Hz), 140.7, 133.8,

128.2 (t, J = 14.7 Hz), 127.4, 122.2 (q, J = 273.3 Hz), 108.5−107.4

(m), 52.2, 33.6 (t, J = 2.1 Hz), 32.4, 22.5. HRMS (ESI/ion trap) m/z:

[M − H⁺]⁻Calcd for C₁₆H₁₀F₇O₂⁻367.0575, found 367.0587. NMR

yield: 29.3%. Isolated yield: 84.0 mg, 11.4%.

(19) Methyl 2′,3′,4′,5′,6′-Pentaﬂuoro-5-methyl-1,4-dihydro-

[1,1′-biphenyl]-2-carboxylate. General procedure A was followed

(16) Methyl 4-Methyl-6-(perﬂuoropyridin-4-yl)cyclohexa-1,4-

diene-1-carboxylate. General procedure A was followed. Separation

from bromopentaﬂuorobenzene. Colorless oily semisolid. Partial

isolation was achieved via silica gel chromatography using a 4 g

column with hexanes/ethyl acetate. ¹⁹F NMR (CD₃CN, 376 MHz): δ

−146.20 (dd, 2F, J = 21.2, 7.8 Hz), −160.17 (td, 1F, J = 20.2, 1.1 Hz),

−165.56 to −165.83 (m, 2F). ¹H NMR (CD₃CN, 400 MHz): δ

7.22−7.12 (m, 1H), 5.41−5.34 (m, 1H), 4.74 (q, 1H, J = 6.1 Hz),

3.03−2.90 (m, 1H), 2.92−2.79 (m, 1H), 1.73 (s, 3H). ¹³C{¹H} NMR

(CD₃CN, 151 MHz): δ 165.8, 145.4 (d, J = 245.3 Hz), 139.8 (d, J =

247.4 Hz), 139.3, 137.5 (d, J = 247.5 Hz), 132.2, 129.2, 127.0, 118.2,

51.2, 31.9, 31.4, 21.5. HRMS (ESI/ion trap) m/z: [M − H⁺]⁻Calcd

occurred via a 4 g chromatography column. Colorless crystalline solid,

mp 93−96 °C. ¹⁹F NMR (CD₃CN, 564 MHz) δ −94.96 to −95.25

(m, 2F), −146.97 to −147.15 (m, 2F). ¹H NMR (CD₃CN, 599

MHz): δ 7.38−7.13 (m, 1H), 5.45−5.34 (m, 1H), 4.93−4.82 (m,

1H), 3.63 (s, 3H), 3.02 (app. dd, 1H, J = 24.3, 7.2, Hz), 2.92 (dddt,

1H, J = 24.1, 6.5, 4.5, 0.9 Hz), 1.79−1.76 (m, 3H). ¹³C{¹H} NMR

(CD₃CN, 151 MHz): δ 166.6, 144.3 (apparent d, J = 241.7 Hz),

141.8 (apparent d, J = 256.9 Hz), 137.5 (tt, J = 13.3, 2.2 Hz), 134.3,

127.1, 117.7, 52.3, 34.1 (t, J = 1.9 Hz), 32.4, 30.9, 22.6. HRMS (ESI/

ion trap) m/z: [M − H⁺]⁻Calcd for C₁₄H₁₀F₄NO₂⁻300.0653, found

300.0658. NMR yield: 13.2%. Isolated yield: 69.1 mg, 11.4%.

−

for C₁₅H₁₀F₅O₂317.0606, found 317.0628. NMR yield: 18.1%

(corresponding to 115 mg).

(17) Methyl 4-(tert-Butyl)-6-(perﬂuoropyridin-4-yl)cyclohexa-1,4-

diene-1-carboxylate. General procedure A was followed. Colorless

(20) Methyl 4-Methyl-6-(perﬂuoropyridin-3-yl)cyclohexa-1,4-

diene-1-carboxylate. General procedure A was followed with 3-

crystalline solid, mp 59−60 °C. ¹⁹F NMR (CDCl₃, 376 MHz) δ

1

−91.85 to −92.17 (m, 2F), −145.34 to −145.88 (m, 2F). H NMR

chloroteteraﬂuoropyridine. Partial resolution of the atropisomers was

achieved through repeated recrystallizations. HRMS (ESI/ion trap)

m/z: [M − H⁺]⁻Calcd for C₁₄H₁₀F₄NO₂⁻300.0653, found 300.0668.

NMR yield: 21.3% (corresponding to 128 mg), 2.4:1 dr.

(CDCl₃, 400 MHz) δ 7.30 (td, 1H, J = 3.9, 1.1 Hz), 5.40 (dt, 1H, J =

4.3, 1.5 Hz), 4.89 (q, 1H, J = 5.9 Hz), 3.67 (s, 3H), 3.05 (ddd, J = 6.7,

4.0, 1.5 Hz, 2H), 1.07 (s, 9H). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ

165.9, 144.9, 143.6 (d, J = 248.4 Hz), 141.1, 140.8 (d, J = 273.3 Hz),

136.3 (t, J = 13.1 Hz), 125.8, 114.1, 52.0, 35.2, 33.5 (t, J = 1.8 Hz),

28.8, 26.9 (t, J = 1.6 Hz). HRMS (ESI/ion trap) m/z: [M − H⁺]⁻

Atropisomer 1 (Major). ¹⁹F NMR (CD₃CN, 376 MHz): δ −73.99,

−89.41 (ddd, J = 22.2, 18.8, 14.6 Hz, 1F), −118.89 (q, J = 17.2 Hz,

1

1F), −168.50 (ddd, J = 24.0, 21.8, 18.4 Hz, 1F). H NMR (CD₃CN,

−

Calcd for C₁₇H₁₆F₄NO₂342.1123, found 342.1143. NMR yield:

400 MHz): δ 6.77 (m, 1H), 5.75 (m, 1H), 4.47 (q, 1H, J = 6.5 Hz),

3.73 (s, 3H), 3.00 (ddp, 2H, J = 7.6, 3.9, 2.0 Hz), 1.67−1.56 (m, 3H).

¹³C{¹H} NMR (CD₃CN, 151 MHz): δ 167.6, 159.7 (d, J = 261.0

Hz), 154.1 (d, J = 242.3 Hz), 149.1 (d, J = 240.2 Hz), 134.4 (d, J =

256.4 Hz),134.5, 130.4, 129.1, 122.4, 112.2, 52.3, 37.1, 26.8, 20.8.

Atropisomer 2 (Minor). ¹⁹F NMR (CD₃CN, 376 MHz): δ −74.63

(dt, J = 21.0, 14.3 Hz), −90.73 (ddd, J = 21.9, 18.2, 14.8 Hz, 1F),

−119.82 (tdd, 1F, J = 18.2, 14.8, 1.2 Hz), −169.33 (ddd, 1F, J = 23.9,

22.0, 18.4 Hz). ¹H NMR (CD₃CN, 400 MHz): δ 7.22 (m, 1H), 5.40

(m, 1H), 4.74−4.60 (m, 1H), 3.62 (s, 3H), 3.07−2.94 (m, 1H),

2.94−2.79 (m, 1H), 1.77 (s, 3H). ¹³C{¹H} NMR (CD₃CN, 151

MHz): δ 166.7, 159.3 (d, J = 262.2 Hz), 153.8 (d, J = 237.5 Hz),

148.4 (d, J = 244.8 Hz), 134.0 (d, J = 267.7 Hz), 133.5, 127.5, 112.0,

118.6, 52.2, 140.5, 32.6, 32.3, 22.5.

16.7%. Isolated yield: 99.5 mg, 14.5%.

(18) Methyl 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-(triﬂuoromethyl)-

1,4-dihydro-[1,1′-biphenyl]-2-carboxylate. General procedure A was

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(21) Methyl 4′-Cyano-2′,3′,5′,6′-tetraﬂuoro-5-oxo-1,4,5,6-tetra-

hydro-[1,1′-biphenyl]-2-carboxylate. Methyl 5-((tert-

butoxycarbonyl)oxy)-4′-cyano-2′,3′,5′,6′-tetraﬂuoro-1,4-dihydro-

[1,1′-biphenyl]-2-carboxylate (11) (5.0 mg, 0.0117 mmol) was

dissolved in DCM (0.02 M) in an NMR tube. to the NMR tube

was added 10 equiv of triﬂuoroacetic acid (TFA), and the mixture was

sonicated for 2 h. An additional 50 equiv of TFA was added, and the

mixture sonicated 2 h. An additional 50 equiv of TFA was added, and

the mixture sonicated for 2 h, after which TLC indicated the complete

consumption of (11). ¹⁹F NMR (CDCl₃, 376 MHz): δ −131.70 to

pressure, and the product was puriﬁed via column chromatography

(0−10% EA in PE) to yield the product as a viscous colorless liquid as

a mixture of diastereomers. The diastereomers are not distinguishable

1

in the ¹⁹F and H NMR spectra, but most of the ¹³C resonances

1

appeared as slightly split signals.

−132.11 (m, 2F), −138.94 to −139.44 (m, 2F). H NMR (CDCl₃,

TLC. R_f= 0.70 (hexanes/ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 376

MHz): δ −63.62 (s, 6F), −144.34 to −144.57 (m, 2F), −145.02 (dd,

J = 21.3, 12.2 Hz, 2F). ¹H NMR (CDCl₃, 400 MHz): δ 8.49 (s, 2H),

8.07 (s, 1H), 7.22−7.18 (m, 1H), 6.31 (t, J = 7.43 Hz, 1H), 5.37−

5.31 (m, 1H), 4.83−4.74 (m, 1H), 3.67−3.63 (2s, overlapping, 3H),

3.04−2.90 (m, 1H), 2.81 (dt, 1H, J = 23.74, 5.26 Hz), 2.33−220 (m,

1H), 2.11−2.00 (m, 1H), 1.77−1.70 (m, 3H), 1.51−1.25 (m, 4H +

2H impurities), 0.92 (t, J = 7.09 Hz, 3H). ¹³C{¹H} NMR (CDCl₃,

101 MHz): δ 166.3 (d, J = 4.8 Hz), 163.3 (d, J = 3.5 Hz), 145.3 (d, J

= 246.5 Hz), 144.7 (d, J = 246.9 Hz), 139.6 (d, J = 8.2 Hz), 132.5 (q,

J = 34.0 Hz), 132.2 (d, J = 2.2 Hz), 130.0 (d, J = 3.9 Hz), 127.2,

127.0−126.4 (m), 123.0 (q, J = 273.1 Hz), 122.4 (td, J = 14.7, 3.0

Hz), 118.7 (d, J = 2.2 Hz), 115.9 (t, J = 14.7 Hz), 69.4, 51.8 (d, J =

2.6 Hz), 33.4, 32.5, 32.1, 27.8, 22.7, 22.6, 22.3, 13.9. Isolated yield:

1.30 g, 2.08 mmol, 89%.

400 MHz): δ 7.31 (dd, 1H, J = 4.4, 3.4 Hz), 4.88 (d, 1H, J = 8.5 Hz),

3.72 (s, 3H), 3.24 (s, 2H), 2.96 (dd, 1H, J = 15.7, 8.6 Hz), 2.63 (dd,

1H, J = 15.6, 3.1 Hz). HRMS (ESI/ion trap) m/z: [M − H+]- Calcd

−

for C₁₅H₈F₄NO₃326.0446, found 326.0453. NMR yield: 94%

(corresponding to 3.6 mg).

(24) Methyl 2′,3′,5′,6′-Tetraﬂuoro-4′-(1-hydroxypentyl)-5-meth-

yl-1,4-dihydro-[1,1′- biphenyl]-2-carboxylate. The reaction was

(26) Methyl 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-pentyl-1,4-dihy-

dro-[1,1′-biphenyl]-2-carboxylate. According to a procedure derived

derived from the literature procedure⁷⁶for the deoxygenation of

aromatic ketones. Compound 14 (77 mg, 200 μmol) was dissolved in

1 mL of DCE. Anhydrous ZnI₂(96 mg, 300 μmol, 1.5 equiv) and

NaBH₃CN (94 mg, 7.5 equiv) were added to the mixture, and the

dispersion was heated to 80 °C in an oil bath for 6 h. After cooling to

room temperature, 2 mL of 2 M HCl was added dropwise until the

excess NaBH₃CN was decomposed. The solution was extracted with

DCM, the organic layer was dried with Na₂SO₄, and the solvent was

removed under reduced pressure. Puriﬁcation via column chromatog-

raphy (10% EA in PE) yielded the product as a slightly yellow viscous

liquid, which solidiﬁed from CHCl₃as a white waxy solid.

from Reiser and co-workers,⁷⁵25 (376 mg, 600 μmol), 10 mg of

[Ir(dtbbpy)(dtbppy)₂]PF₆, and DIPEA (210 μL, 2 equiv) were

dissolved in a mixture of 15 mL of acetonitrile and 1 mL of water. The

solution was degassed and irradiated for 3 h at 455 nm while heating

to 45 °C in an oil bath. After cooling to room temperature, 20 mL of

petroleum ether was added. The solution washed with a concentrated

K₂CO₃solution and water and dried over Na₂SO₄.. The solvent was

removed under reduced pressure, and the residue was puriﬁed via

column chromatography (5% EA in PE) to yield the product, which

was contaminated with small amounts of the rearomatized product as

a slightly yellow viscous liquid. Recrystallization from MeOH yielded

the product as colorless needles, mp 54−55 °C. TLC: R_f= 0.70

(hexanes/ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 376 MHz): δ

−146.66 to −147.14 (m, 4F). ¹H NMR (CDCl₃, 400 MHz): δ

7.21−7.16 (m, 1H), 5.40−5.31 (m, 1H), 4.82−4.71 (m, 1H), 3.65 (s,

3H), 3.03−2.91 (m, 1H), 2.80 (dpt, 1H, J = 23.7, 5.4 Hz), 2.65 (t, J =

7.7, 2H), 1.74 (s, 3H), 1.62−1.52 (m, 2H), 1.26−1.28 (m, 4H), 0.89

(t, J = 6.9 Hz). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 166.2, 146.3−

145.8 (m), 143.9−143.3 (m), 139.0, 131.2, 127.5, 119.1, 119.02−

118.40 (m), 51.5, 32.1, 31.9, 31.3, 28.9, 22.6, 22.4, 22.3, 13.8. HRMS

(EI) m/z: [M]⁺exact mass Calcd for C₂₀H₂₂F₄O₂370.1556, found:

370.1545. Isolated yield: 193 mg, 521 μmol, 86%.

TLC. R_f= 0.30 (hexanes/ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 376

MHz): δ −145.70 (dd, 2F, J = 21.51, 12.24 Hz), −146.51 (dd, 2F, J =

1

21.50, 12.24 Hz). H NMR (CDCl₃, 400 MHz): δ 7.13 (d, J = 2.81

Hz, 1 H), 5.27 (s, 1 H), 5.00−4.89 (m, 1 H), 4.75−4.67 (m, 1 H),

3.58 (s, 3 H), 2.98−2.67 (m, 2 H), 2.20−2.07 (m, 1 H), 1.96−1.86

(m, 1 H), 1.80−1.70 (m, 1 H), 1.67 (s, 3 H), 1.44−1.11 (m, 5 H),

0.83 (t, 3 H). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 166.3, 145.1 (d, J

= 245.8 Hz), 144.4 (d, J = 245.0 Hz), 139.4, 131.6, 127.3, 120.9 (t, J =

14.7 Hz), 120.3 (t, J = 15.2 Hz), 118.8, 66.7, 51.7, 36.7, 32.3(t, J = 2.2

Hz), 32.0, 31.6, 28.0, 22.7, 22.5, 22.4, 14.1, 13.9. HRMS (EI) m/z:

[M]+ exact mass Calcd for C₂₀H₂₂F₄O₃386.1500, found 386.1498.

Isolated yield: 75 mg, 194 μmol, 97%.

(25) Methyl 4′-(1-((3,5-Bis(triﬂuoromethyl)benzoyl)oxy)pentyl)-

2′,3′,5′,6′-tetraﬂuoro-5- methyl-1,4-dihydro-[1,1′-biphenyl]-2-car-

boxylate. According to a procedure derived from Reiser and co-

workers,⁷⁵compound 24 (900 mg, 2.33 mmol) was dissolved in 24

mL of DCM and cooled in an ice bath. 3,5-Bis(triﬂuoromethyl)-

benzoyl chloride (460 μL, 1.1 equiv) was added dropwise. The

solution was warmed to room temperature, and the solvent was

removed under reduced pressure. The residue was extracted with hot

petroleum ether, most of the solvent was removed under reduced

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a saturated NH4Cl solution and extracted with ethyl acetate. Column

chromatography (20% EA in PE) yielded the tertiary alcohol. The

product was obtained as a viscous colorless liquid (19 mg, 51 μmol,

95%). The cis- and trans-isomers were separable by column

chromatography.

cis-(29). TLC: R_f= 0.35 (hexanes/ethyl acetate 9:1). ¹⁹F NMR

(CDCl₃, 376 MHz): δ −135.83 to −136.11 (m, 1F), 142.71 (dd, 1F, J

= 22.4, 11.6 Hz), 146.10 (dd, 1 F, J = 22.4, 12.2 Hz), −146.40 (dd,

1

1F, J = 21.8, 11.7 Hz). H NMR (CDCl₃, 400 MHz): δ 5.30−5.24

(m, 1H), 4.08−4.00 (m, 1H), 2.68 (t, 2H, J = 7.6 Hz), 2.19−2.13 (m,

1H), 2.06−1.97 (m, 1H), 1.94−1.76 (m, 2H), 1.70 (s, 3H), 1.63−

1.52 (m, 2H), 1.37−1.29 (4H), 1.07 (s, 3H), 1.00 (s, 3H), 0.89 (t,

3H, J = 6.9 Hz). ¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 135.7, 120.5,

119.3−118.7 (m), 72.7, 49.5, 32.0, 31.3, 30.8, 28.9, 28.3, 27.2, 23.4,

22.7, 22.3, 20.4, 20.3, 13.9. HRMS (EI) m/z: [M − H₂O]⁺exact mass

(27 and 28) Methyl 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-pentyl-

1,2,3,4-tetrahydro-[1,1′-biphenyl]- 2-carboxylate. Diene (26) (800

μmol) and PMHS (101 mg, 1.68 mmol, 2.1 equiv) were put into a

crimp vial under nitrogen. A solution of tris(pentaﬂuorophenyl)-

borane (4 mg, 8 μmol, 1 mol %) in 4 mL of DCM was added. The

solution was stirred overnight at room temperature and the stirred for

either another 24 h with a saturated NH₄F solution or another 2 h

with TBAF·3H₂O in DCM. Shorter quenching times led to the

incomplete cleavage of the silyl ethers formed and diminished the

yield. The solution was extracted with DCM, column chromatography

(5% EA in PE) yielded the product. The products were obtained as

mixtures of the cis- and trans-isomer, which were not separable by

means of column chromatography. Column chromatography (5% EA

in PE) yielded the product as a viscous colorless liquid. Diﬀerent

reactions gave the product in varying drs of 4−6 in favor of the cis-

diastereomer. Isolated yield: 26 mg, 70 μmol, 37%.

+

Calcd for C₂₁H₂₆F₄354.1965, found 354.1962.

trans-(29). TLC: R_f= 0.40 (hexanes/ethyl acetate 9:1). ¹⁹F NMR

(CDCl₃, 376 MHz): −144.51 to −144.94 (broad s, 2F), −146.84 (dd,

1

2F, J = 22.02, 12.18 Hz). H NMR (CDCl₃, 400 MHz): δ 5.05 (s,

1H), 3.82 (d, 1H, J = 9.3 Hz), 2.65 (t, 2H, J = 7.7 Hz), 2.25−2.10 (m,

2 H), 2.03−1.92 (m, 2H), 1.68 (s, 3H), 1.63−1.52 (m, 2H + 1H

impurities), 1.49−1.38 (m, 1H), 1.36−1.28 (m, 4 H), 1.20 (s, 3H),

1.12 (s, 3H), 0.93 (s, 1H), 0.89 (t, 3H, J = 7.0 Hz). ¹³C{¹H} NMR

(CDCl₃, 101 MHz): δ 146.3−145.5 (m), 143.9−143.1 (m), 135.2,

123.4 (t, J = 15.20 Hz), 117.8 (t, J = 18.9 Hz), 122.1, 73.7, 48.0, 34.1,

31.4, 30.2, 29.0, 28.9, 23.2, 22.6, 22.3.

(30) 1,2,4-Triﬂuoro-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahy-

dro-6H-benzo[c]chromene (1-Deoxy-1,2,4-triﬂuoro-THC). The pro-

(27) cis-Methyl 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-pentyl-

1,2,3,4-tetrahydro-[1,1′-biphenyl]- 2-carboxylate. NMR data were

derived from subtraction of the pure trans-diastereomer. TLC: R_f=

0.70 (hexanes/ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 376 MHz): δ

−142.16 (dd, J = 21.5, 12.2 Hz, 2F), −146.63 (dd, 2F, J = 21.9, 12.3

Hz). ¹H NMR (CDCl₃, 400 MHz): δ 5.40 (d, J = 3.1 Hz, 1H), 4.2 (s,

1H), 3.5 (s, 3H), 3.0−2.9 (m, 1H), 2.7 (t, 2H, J = 7.6 Hz), 2.25−2.14

(m, 1H), 2.14−1.99 (m, 2H), 1.94−1.83 (m, 1H), 1.73 (s, 3H),

1.62−1.52 (m, 2H), 1.38−1.27 (m, 4H), 0.89 (t, 3H, J = 6.7 Hz).

¹³C{¹H} NMR (CDCl₃, 101 MHz): δ 174.0, 146.6−154.8 (m),

144.2−143.5 (m), 136.2, 119.4 (t, J = 18.9), 117.0 (t, J = 14.8 Hz),

51.4, 43.7, 33.3, 31.3, 28.8, 28.7, 23.5, 22.7, 22.3, 21.4, 13.9. HRMS

(EI) m/z: [M]⁺exact mass Cacld for C₂₀H₂₄F₄O₂372.1707, found

372.1706.

(28) trans-Methyl 2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-pentyl-

1,2,3,4-tetrahydro-[1,1′-biphenyl]- 2-carboxylate. TLC: R_f= 0.70

(hexanes/ethyl acetate 9:1). ¹⁹F NMR (CDCl₃, 376 MHz): δ −144.6

(dd, 2F, J = 21.8, 12.5 Hz), to −146.3 (dd, 2F, J = −22.1, 12.5 Hz).

¹H NMR (CDCl₃, 400 MHz): δ 5.19 (s, 1H), 4.11 (d, 1H, J = 10.0

Hz), 3.58 (s, 3H), 2.94−2.86 (m, 1H), 2.67 (t, 2H, J = 7.6 Hz), 2.24−

2.11 (m, 2H), 2.10−2.00 (m, 1H), 1.92−1.79 (m, 1H), 1.70 (s, 3H),

1.63−1.52 (m, 2H + 2H impurities), 1.36−1.28 (m, 4H + 2H

impurities), 0.89 (t, 3H + 1H impurities, J = 6.87 Hz). ¹³C{¹H} NMR

(CDCl₃, 101 MHz): δ 175.0, 146.3−145.8 (m), 143.8−143.4 (m),

134.6, 120.7, 51.7, 119.4 (t, J = 15.7 Hz), 119.0 (t, J = 19.0 Hz), 44.2,

34.9, 31.3, 29.3, 28.9, 26.7, 23.2, 22.7, 22.3, 13.9. HRMS (EI) m/z:

[M]⁺exact mass Calcd for C₂₀H₂₄F₄O₂372.1707, found 372.1700.

(29) 2-(2′,3′,5′,6′-Tetraﬂuoro-5-methyl-4′-pentyl-1,2,3,4-tetrahy-

dro-[1,1′-biphenyl]-2-yl)propan-2-ol. A 3 M solution of MeMgBr in

cedure was derived from that of Carreira and co-workers.⁷¹Tertiary

alcohol 29 (14 mg, cis/trans 4:1) was dissolved in dry THF. A 1 M

solution of KHMDS in THF (1.5 equiv) was added. The solution was

heated to 40 °C in an oil bath for 15 min. The reaction is quenched

with a saturated NH₄Cl solution and extracted with ethyl acetate.

Column chromatography (2% EA in PE) yielded the target

compound as a viscous colorless liquid. Isolated yield: 13 mg, 37

μmol, cis/trans 4:1, 98%.

cis-(30). ¹⁹F NMR (CDCl₃, 376 MHz): δ −142.75 to −142.90 (m,

1

1F), −145.54 (d, 1F, J = 12 Hz), −153.50 (d, 1F, J = 22.41 Hz). H

NMR (CDCl₃, 400 MHz): δ 6.39−6.31 (m, 1H), 4.03−3.96 (m, 1H),

2.97 (t, J = 7.5 Hz, 2H), the alkyl region could not be analyzed due to

overlaps from both diastereomers. Colorless viscous liquid. HRMS

(EI)m/z: [M]⁺exact mass Calcd for C₂₁H₂₇F₃O⁺352.2009, found

352.1999.

trans-(30). ¹⁹F NMR (CDCl₃, 376 MHz): δ −145.04 to −145.17

(m, 1F), −145.40 (d, 1F, J = 14 Hz), −154.26 (d, 1F, J = 22.8 Hz).

¹H NMR (CDCl₃, 400 MHz): δ 6.41 (s, 1H), 3.69 (d, J = 11.4 Hz,

1H), alkyl region could not be analyzed due to overlaps from both

diastereomers. HRMS (EI) m/z: [M]⁺exact mass Calcd for

C₂₁H₂₇F₃O⁺352.2009, found 352.2004.

ASSOCIATED CONTENT

* Supporting Information

■

sı

The Supporting Information is available free of charge at

https://pubs.acs.org/doi/10.1021/acs.joc.1c00169.

Et₂O (7 equiv) was added to a 2 M solution of ester (20 mg, 54

μmol) in dry THF while cooling in an ice bath. The solution was

warmed to rt and stirred for 30 min. The reaction was quenched with

Experimental details, additional experiments, spectra,

and X-ray diﬀraction analysis(PDF)

7942

https://doi.org/10.1021/acs.joc.1c00169

J. Org. Chem. 2021, 86, 7928−7945

The Journal of Organic Chemistry

pubs.acs.org/joc

Article

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P. Correction to Natural Occurrence of Organofluorine and Other

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products: the biosynthesis of fluoroacetate and 4-fluorothreonine in

Streptomyces cattleya. Chemosphere 2003, 52, 455.

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Accession Codes

CCDC 2060753 contains the supplementary crystallographic

data for this paper. These data can be obtained free of charge

via www.ccdc.cam.ac.uk/data_request/cif, or by emailing

data_request@ccdc.cam.ac.uk, or by contacting The Cam-

bridge Crystallographic Data Centre, 12 Union Road,

Cambridge CB2 1EZ, UK; fax: +44 1223 336033.

AUTHOR INFORMATION

■

Corresponding Author

Jimmie D. Weaver III − Department of Chemistry, Oklahoma

State University, 74078 Stillwater, Oklahoma, United States;

orcid.org/0000-0003-4427-2799;

Email: jimmie.weaver@okstate.edu

(9) Böhm, H. J.; Banner, D.; Bendels, S.; Kansy, M.; Kuhn, B.;

Muller, K.; Obst-Sander, U.; Stahl, M. Fluorine in Medicinal

̈

Authors

Chemistry. ChemBioChem 2004, 5, 637.

Jon I. Day − Department of Chemistry, Oklahoma State

University, 74078 Stillwater, Oklahoma, United States;

orcid.org/0000-0002-0632-1812

(10) Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.;

Meanwell, N. A. Applications of Fluorine in Medicinal Chemistry. J.

Med. Chem. 2015, 58, 8315.

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introduction to the C-F bond. Chem. Soc. Rev. 2008, 37, 308.

(12) O’Hagan, D. Fluorine in health care: Organofluorine containing

blockbuster drugs. J. Fluorine Chem. 2010, 131, 1071.

(13) Zhan, C.-G.; Landry, D. W. Theoretical Studies of Competing

Reaction Pathways and Energy Barriers for Alkaline Ester Hydrolysis

of Cocaine. J. Phys. Chem. A 2001, 105, 1296.

Sascha Grotjahn − Institut fur Organische Chemie, Universität

̈

Regensburg, 93053 Regensburg, Germany

Sameera Senaweera − Center for Drug Design, College of

Pharmacy, University of Minnesota, Minneapolis, Minnesota

55455, United States

Burkhard Koenig − Institut fur Organische Chemie,

̈

Universität Regensburg, 93053 Regensburg, Germany;

(14) Wang, J.; Sanchez-Rosello, M.; Acena, J. L.; del Pozo, C.;

Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.; Liu, H. Fluorine in

pharmaceutical industry: fluorine-containing drugs introduced to the

market in the last decade (2001 −2011). Chem. Rev. 2014, 114, 2432.

orcid.org/0000-0002-6131-4850

Complete contact information is available at:

https://pubs.acs.org/10.1021/acs.joc.1c00169

(15) Zhou, Y.; Wang, J.; Gu, Z.; Wang, S.; Zhu, W.; Acena, J. L.;

̃

Author Contributions

Soloshonok, V. A.; Izawa, K.; Liu, H. Next Generation of Fluorine-

Containing Pharmaceuticals, Compounds Currently in Phase II-III

Clinical Trials of Major Pharmaceutical Companies: New Structural

Trends and Therapeutic Areas. Chem. Rev. 2016, 116, 422.

(16) Mei, H.; Han, J.; Fustero, S.; Medio-Simon, M.; Sedgwick, D.

M.; Santi, C.; Ruzziconi, R.; Soloshonok, V. A. Fluorine-Containing

Drugs Approved by the FDA in 2018. Chem. - Eur. J. 2019, 25, 11797.

(17) Furuya, T.; Klein, J. E. M. N.; Ritter, T. Carbon-Fluorine Bond

Formation for the Synthesis of Aryl Fluorides. Synthesis 2010, 2010,

1804.

(18) Sun, A. D.; Love, J. A. Nickel-Catalyzed Selective

Defluorination to Generate Partially Fluorinated Biaryls. Org. Lett.

2011, 13, 2750.

(19) Capdevila, L.; Meyer, T. H.; Roldán-Gómez, S.; Luis, J. M.;

Ackermann, L.; Ribas, X. Chemodivergent Nickel(0)-Catalyzed Arene

C-F Activation with Alkynes: Unprecedented C-F/C-H Double

Insertion. ACS Catal. 2019, 9, 11074.

^∇Authors contributed equally to this publication.

Notes

The authors declare no competing ﬁnancial interest.

ACKNOWLEDGMENTS

■

S.S. discovered the vinyl signals during his doctoral studies.

The authors would like to thank the National Institutes of

Health for ﬁnancial support under NIH NIGMS

(5R01GM115697) for of this work. This work was supported

by the German Science Foundation (DFG, KO 1537/18-1).

This project has received funding from the European Research

Council (ERC) under the European Union’s Horizon 2020

Research and Innovation Programme (Grant agreement

741623). S.G. thanks the elite network of Bavaria (ENB,

SynCat program) for ﬁnancial support. The computing for this

project was performed at the OSU High Performance

Computing Center at Oklahoma State University, which is

supported in part through the National Science Foundation

Grants OAC−1126330 and OAC−1531128.

(20) Luo, Z.-J.; Zhao, H.-Y.; Zhang, X. Highly Selective Pd-

Catalyzed Direct C-F Bond Arylation of Polyfluoroarenes. Org. Lett.

2018, 20, 2543.

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Hydrodefluorination: Facile Access to Partially Fluorinated Aro-

matics. J. Am. Chem. Soc. 2014, 136, 3002.

(22) Chen, K.; Berg, N.; Gschwind, R.; König, B. Selective Single

C(sp3)-F Bond Cleavage in Trifluoromethylarenes: Merging Visible-

Light Catalysis with Lewis Acid Activation. J. Am. Chem. Soc. 2017,

139, 18444.

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Functionalization of Unactivated Trifluoromethylarenes. J. Am. Chem.

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https://doi.org/10.1021/acs.joc.1c00169

J. Org. Chem. 2021, 86, 7928−7945

Article Doi

Defluorodearomatization: A Photocatalytic Birch-Like Reduction That Enables C-C Bond Formation and Provides Access to Unnatural Cannabinoids

DOI: 10.1021/acs.joc.1c00169

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Article abstract of DOI:10.1021/acs.joc.1c00169

Full text of DOI:10.1021/acs.joc.1c00169

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