Regio- and Stereoselective Rhodium(II)-Catalyzed C–H Functionalization of Cyclobutanes

Article abstract of DOI:10.1016/j.chempr.2019.12.014

Recent developments in controlled C–H functionalization transformations continue to inspire new retrosynthetic disconnections. One tactic in C–H functionalization is the intermolecular C–H insertion reaction of rhodium-bound carbenes. These intermediates can undergo highly selective transformations through the modulation of the ligand framework of the rhodium catalyst. This work describes our continued efforts toward differentiating C–H bonds in the same molecule by judicious catalyst choice. Substituted cyclobutanes that exist as a mixture of interconverting conformers and possess neighboring C–H bonds within a highly strained framework are the targets herein for challenging the current suite of catalysts. Although most C–H functionalization tactics focus on generating 1,2-disubstituted cyclobutanes via substrate-controlled directing-group methods, the regiodivergent methods discussed in this paper provide access to chiral 1,1-disubstituted and cis-1,3-disubstituted cyclobutanes simply by changing the catalyst identity, thus permitting entry to novel chemical space. This study shows how to control site selectivity in C–H functionalization by simply using the correct catalyst. Cyclobutanes were used as the scaffold to illustrate the impact of catalyst control because the core unit is incorporated into various structures of biomedical interest. The catalysts control whether the chemistry occurs at C1 or C3 of the cyclobutane. Traditional synthetic strategies have viewed most C–H bonds as chemically inert and utilize functional groups for transformations. C–H functionalization is an attractive alternative strategy for the synthesis of complex organic molecules because it leads to the possibility of rapidly accessing novel chemical space. To fully develop this alternative approach, it is necessary to identify ways for reacting at specific C–H bonds even when a number of similar C–H bonds may exist in a substrate molecule. It would be particularly beneficial if a collection of catalysts were available, each with a preference for reaction at a specific C–H bond. Over the past few years, we have developed such a collection of catalysts for C–H functionalization chemistry of rhodium-bound carbenes. In this paper, we illustrate how these catalysts can be applied to the selective functionalization of cyclobutanes, leading to the formation of pharmaceutically relevant chiral building blocks.

Full text of DOI:10.1016/j.chempr.2019.12.014

Article
Regio- and Stereoselective Rhodium(II)-
Catalyzed C–H Functionalization of
Cyclobutanes
Zachary J. Garlets, Benjamin D.
Wertz, Wenbin Liu, Eric A.
Voight, Huw M.L. Davies
hmdavie@emory.edu
HIGHLIGHTS
Catalyst-controlled C–H
functionalization
Synthesis of chiral cyclobutane
derivatives
New strategy for the synthesis of
pharmaceutically relevant
compounds
This study shows how to control site selectivity in C–H functionalization by simply
using the correct catalyst. Cyclobutanes were used as the scaffold to illustrate the
impact of catalyst control because the core unit is incorporated into various
structures of biomedical interest. The catalysts control whether the chemistry
occurs at C1 or C3 of the cyclobutane.
Garlets et al., Chem 6, 304–313
January 9, 2020 ª 2019 Elsevier Inc.
https://doi.org/10.1016/j.chempr.2019.12.014

Article
Regio- and Stereoselective
Rhodium(II)-Catalyzed C–H
Functionalization of Cyclobutanes
Zachary J. Garlets,1 Benjamin D. Wertz,1 Wenbin Liu,1 Eric A. Voight,2 and Huw M.L. Davies1,3,
*
SUMMARY
The Bigger Picture
Traditional synthetic strategies
have viewed most C–H bonds as
chemically inert and utilize
Recent developments in controlled C–H functionalization transformations
continue to inspire new retrosynthetic disconnections. One tactic in C–H func-
tionalization is the intermolecular C–H insertion reaction of rhodium-bound
carbenes. These intermediates can undergo highly selective transformations
through the modulation of the ligand framework of the rhodium catalyst.
This work describes our continued efforts toward differentiating C–H bonds
in the same molecule by judicious catalyst choice. Substituted cyclobutanes
that exist as a mixture of interconverting conformers and possess neighboring
C–H bonds within a highly strained framework are the targets herein for chal-
lenging the current suite of catalysts. Although most C–H functionalization
tactics focus on generating 1,2-disubstituted cyclobutanes via substrate-
controlled directing-group methods, the regiodivergent methods discussed
in this paper provide access to chiral 1,1-disubstituted and cis-1,3-disubsti-
tuted cyclobutanes simply by changing the catalyst identity, thus permitting
entry to novel chemical space.
functional groups for
transformations. C–H
functionalization is an attractive
alternative strategy for the
synthesis of complex organic
molecules because it leads to the
possibility of rapidly accessing
novel chemical space. To fully
develop this alternative approach,
it is necessary to identify ways for
reacting at specific C–H bonds
even when a number of similar
C–H bonds may exist in a
substrate molecule. It would be
particularly beneficial if a
INTRODUCTION
collection of catalysts were
available, each with a preference
for reaction at a specific C–H
bond. Over the past few years, we
have developed such a collection
of catalysts for C–H
Catalyst-controlled C–H functionalization is of considerable current interest.1,2 The
ability to control which C–H bond in a particular compound is functionalized simply
by selecting the right catalyst offers exciting opportunities in organic synthesis.
Considerable effort has been directed toward developing small catalysts3–5 and
evolved enzymes6–8 that can achieve such selectivity without resorting to well-
defined functional groups on substrates. We have been developing the
dirhodium-catalyzed reactions of donor and acceptor carbenes as a robust system
for site-selective C–H functionalization reactions.9 The combination of both a
donor and an acceptor group on the carbene leads to an intermediate that is still
sufficiently reactive to functionalize C–H bonds, and because of the modulating
effect of the donor group, the system is prone to subtle catalyst control effects.
In recent years, we have prepared a series of catalysts that are capable of site-se-
lective functionalization of unactivated C–H bonds (Figure 1A).10 The catalysts
adopt unique geometries that dictate the substrate trajectory toward the
rhodium-bound carbene, thus enabling single C–H bonds to be transformed.
So far, catalysts have been designed to selectively functionalize primary,11 second-
ary,12 or tertiary13 C–H bonds (Figure 1B). Further ligand development has resulted
in catalysts that distinguish between benzylic and unactivated methylene C–H
functionalization chemistry of
rhodium-bound carbenes. In this
paper, we illustrate how these
catalysts can be applied to the
selective functionalization of
cyclobutanes, leading to the
formation of pharmaceutically
relevant chiral building blocks.
bonds,14 and most recently, we have introduced
desymmetrizing substituted cyclohexane rings.15
a catalyst capable of
304 Chem 6, 304–313, January 9, 2020 ª 2019 Elsevier Inc.

Figure 1. Site-Selective C–H Functionalization by Carbenoid Insertion Reactions
(A) Dirhodium tetracarboxylate catalysts possess structural diversity that enables functionalization
of specific C–H bonds.
(B) Primary, secondary, and tertiary C–H bonds can be selectively functionalized by judicious
catalyst choice.
(C) The work outlined herein showcases a regioselective C–H insertion reaction that permits access
to new chemical space.
1Department of Chemistry, Emory University,
1515 Dickey Drive, Atlanta, GA 30322, USA
The work described in this manuscript details our efforts toward applying this
growing suite of catalysts and our understanding of the behavior of C–H bonds for
the selective functionalization of arylcyclobutanes, either at C1 or C3, depending
on which catalyst is used (Figure 1C). Arylated cyclobutane rings occur frequently
in both natural products and pharmaceuticals. Many of the natural products arise
2Research & Development, AbbVie, 1 North
Waukegan Road, North Chicago, IL 60064, USA
3Lead Contact
*Correspondence: hmdavie@emory.edu
https://doi.org/10.1016/j.chempr.2019.12.014
Chem 6, 304–313, January 9, 2020 305

Figure 2. Analysis of Cyclobutane C–H Functionalization
Selective intermolecular C–H functionalization of cyclobutanes poses significant challenges.
Potential functionalization can occur at three carbon sites. On the basis of our understanding of
donor- and acceptor-carbene-induced C–H functionalization, we would expect the equatorial C–H
bonds at C1 and C3 to be preferred and distinguished by the appropriate choice of catalyst.
directly from photochemical [2 + 2] dimerization processes of simpler alkene build-
ing blocks, as in the truxillic and truxinic acids (from cinnamic acid)16 and sceptrin
(from hymenidin).17 Beyond these dimeric compounds, arylcyclobutane scaffolds
are also observed in monoterpenoids such as cannabicyclol,18 murrayamine M,19
rhodonoids A and B,20 and cochlearol B.21 Arylcyclobutanes are considered
intriguing systems for drug discovery because they place functionality in a defined
spatial orientation.22 These compounds can exhibit wide-ranging bioactivity, as
exemplified by the anti-clotting agent piperaborenine D,23 the glucocortecoid
receptor binding (À)-endiandrin A,24 and the CYP3 inhibitor dipiperamide A.25
1,3-cis-Disubstituted arylcyclobutanes are represented in a number of modern
drug candidates. Recently, researchers at AbbVie described a potent and selective
TRPV3 antagonist that is a 1,1-difunctionalized arylcyclobutane.26,27 In this study,
the stereochemistry at the cyclobutane ring was shown to have a significant effect
on the bioactivity of the analogs. In light of the significance of these substances, a
novel method for preparing chiral 1,1-difunctionalized arylcyclobutanes and 1,3-
cis-disubstituted arylcyclobutanes could be of significant value to the scientific
community.
Considerable effort has been expended in generating elaborate cyclobutanes by
means of C–H functionalization tactics that rely on the use of directing groups on
the substrate to control regiochemistry.28–34 Although these methods have pro-
vided elegant entries into complex natural products and access to enantioenriched
cyclobutane scaffolds, they are restricted to, and primarily successful with, the for-
mation of sp3–sp2 C–C bonds. Additionally, we are aware of only one example of
a carbene-induced C–H functionalization of a cyclobutane in which a sp3–sp3 C–C
bond is formed, but this was an intramolecular example.35
Even though phenylcyclobutane is a small molecule, it represents an interesting
challenge for C–H functionalization (Figure 2). The compound would be expected
to exist as two interconverting conformers (A and B), and conformer A is favored
where the substituent occupies an equatorial position (when R = Br the equatorial
isomer is favored by 1 kcal/mol36). From previous studies with donor and acceptor
carbenes conducted on alkylcyclohexane15 and acyclic alkanes,11–13 we would not
expect the methylene sites adjacent to the substituent to be sterically accessible.
Therefore, we would expect carbene insertion to be a competition between C1
(substituted carbon) and C3 (distal) functionalization. We also know from studies
on the C–H functionalization of cyclohexane that equatorial sites react about
306 Chem 6, 304–313, January 9, 2020

Figure 3. Optimization of C–H Functionalization of Substituted Cyclobutanes
The reaction conditions were as follows: the diazo compound 6 (0.25 mmol) in 1.5 mL solvent was
added over 3 h to a solution of the cyclobutane substrate 7 (0.75 mmol, 3.0 equiv) and catalyst
(1.0 mol %) in 3.0 mL dichloromethane at room temperature. The reaction was stirred for an
additional 2 h. All yields are isolated yields (98% of unreacted 6 was recovered). The enantiomeric
excess (ee) was determined by chiral HPLC analysis of the isolated product.
140 times faster than reactions at axial sites.15 Hence, we would expect that reaction
at C3 would occur at the equatorial site. If the reaction occurs at the major conformer
A, the resulting cyclobutane would be cis disubstituted, whereas reaction of the
minor conformer would give a trans-disubstituted product. Reaction at C1 is elec-
tronically preferred because of the influence of the aryl ring but is sterically encum-
bered as a tertiary site. The minor conformer B would be expected to be the most
reactive because the tertiary C–H bond is equatorial. However, it will not be possible
to distinguish whether the tertiary C–H bond functionalization is occurring through A
or B because each will generate the same C1 functionalized product. In order to
achieve insertion at the C3 position, a sterically bulky catalyst such as 2 or 3 would
be expected to be required, whereas attack at C1 would be expected to occur
with a less bulky catalyst such as 4 or 5.
RESULTS
This study began by surveying dirhodium tetracarboxylate catalysts for functionaliz-
ing readily available cyclobutane 6 (Figure 3).37 The reactions were conducted in
refluxing methylene chloride with 2,2,2-trichloroethyl 2-(4-bromophenyl)-2-diazoa-
cetate (7)38 as the carbene precursor. The use of 2,2,2-trihaloethyl ester groups is
often advantageous in the dirhodium-catalyzed reactions of donor and acceptor
carbenes because they can enhance enantioselectivity.39 Our analysis of the current
catalyst toolbox and our understanding of selective C–H bond transformations
informed which catalysts were selected for the initial reaction screen. The original
prolinate catalyst, Rh2(S-DOSP)4,40 is considered to be a relatively uncrowded
catalyst and gave a clean reaction at C1 to form 8 with no indication of the C3 prod-
uct 9. However, it is well established that this catalyst does not give high levels of
enantioselectvity in dichloromethane,41 and this behavior was confirmed in this
Chem 6, 304–313, January 9, 2020 307

case, such that 8 was formed in only 32% enantiomeric excess (ee). Similarly, high
site selectivities were observed with the phathlimido catalysts 4 and 5, but now
the enantioselectivity was also very high, reaching 98% ee with 4. The bulky catalysts
2 and 3, designed for functionalization of primary or secondary C–H bonds,12,14
caused a dramatic change in selectivity, favoring the C3 product 8 (2:1 for 2 and
5:1 for 3). Catalyst 1, designed for primary C–H functionalization,11 also preferred
attack at C3 (3:1) but did not outperform the site selectivity exhibited by catalyst 3
and also generated a further undefined isomer of the C–H functionalization prod-
ucts. On the basis of these studies, Rh2(S-TCPTAD)4 (3) was selected as the optimum
catalyst for C1 functionalization, and Rh2(S-2-Cl-5-BrTPCP)4 (3) was selected for C3
functionalization.
With these regiodivergent methods in place, the substrate scope was evaluated
(Figures 4 and 5). The cyclobutane substrates were readily accessed by a two-step
protocol (Grignard addition to cyclobutanone followed by reduction). The function-
alization of the benzylic site was first examined using Rh2(S-TCPTAD)4 (4) as a catalyst
(Figure 4). A variety of different arylcyclobutanes were used in this reaction along
with a number of aryldiazoacetates to generate the C1-functionalized products
10–21. Because the cyclobutane derivatives are the most valuable of the two re-
agents, these reactions were conducted with 2 equiv of the diazo compound.
Notable examples include the use of heteroaromatic groups in the formation of
18–21. Also notable is the functionalization of the cyclobutane ring in preference
to the primary benzylic site as shown for 15; in this instance, Rh2(S-TCPTAD)4 exhibits
complete selectivity for the more substituted benzylic site even though it is more ste-
rically crowded. The absolute configuration of the tertiary substitution was verified
by X-ray crystallographic analysis of 8, and the other examples were tentatively as-
signed by analogy.
We next investigated the selective functionalization of the distal site, C3, by using
Rh2(S-2-Cl-5-BrTPCP)4 as a catalyst (Figure 5). Despite our initial success, the devel-
opment of the cis-1,3-disubstituted cyclobutane scope would be more challenging
because the C1 position is electronically activated. In addition, the conformational
interconversion of different substituted cyclobutanes may lead to varying levels of
diastereoselectivity. In fact, a variety of different aryl substituted cyclobutanes and
aryldiazoacetates were competent to form the C3-functionalized products 22–32,
and the diastereoselectivity for distal functionalization was good for all the exam-
ples. Perhaps unsurprisingly, electron-deficient aryl rings on the cyclobutanes
lowered the production of the tertiary side-product as seen for 23 versus 22, but
importantly, Rh2(S-2-Cl-5-BrTPCP)4 was able to generate the desired cis-1,3-disub-
stituted cyclobutanes as the major product in all instances. The X-ray crystallo-
graphic analysis of 27 enabled the unambiguous assignment of the major stereoiso-
mer as cis, and this was further verified by nuclear Overhauser effect (nOe) analysis
wherein the hydrogens on the same face of the cyclobutane were coupled. This vali-
dated the hypothesis that the equatorial C–H bonds in conformer A would be most
susceptible to functionalization. This reaction was also amenable to heteroaryldia-
zoacetates and heteroarylcyclobutanes as illustrated in the formation of 29–32.
The successful C–H functionalization of the cyclobutanes is unexpected because the
C–H bonds in a cyclobutane ring have greater s character and are stronger than C–H
bonds contained in an unstrained system. Therefore, we conducted competition
experiments of 4-tert-butylphenylcyclobutane with substrates containing unstrained
primary, secondary, and tertiary benzylic C–H bonds (Figure 6; see Supplemental
Information for details). The competition reactions with Rh2(S-TCPTAD)4 revealed
308 Chem 6, 304–313, January 9, 2020

Figure 4. Reaction Scope for C–H Functionalization of Arylcyclobutanes at C1
The Rh2(S-TCPTAD)4 (4)-catalyzed reactions of aryldiazoacetates result in the selective C–H
functionalization of the tertiary benzylic site of the arylcyclobutane. The catalyst is relatively
uncrowded and reacts at the electronically preferred site. ee, enantiomeric excess.
that the tertiary benzylic C–H bond on the bicyclobutane is more reactive that the
tertiary site in isopropyl benzene. In the reaction with the sterically crowded cata-
lyst Rh2(S-2-Cl-5-BrTPCP)4, the electronically unactivated secondary site of the
cyclobutane is more reactive than the secondary benzylic site in ethyl benzene.
These results indicate that the cyclobutane C–H bonds are more reactive than their
unstrained counterparts, presumably because the C–H bonds would be more
sterically exposed or possibly because of hyperconjugative effects in the strained
ring.
Chem 6, 304–313, January 9, 2020 309

Figure 5. Reaction Scope for C–H Functionalization of Arylcyclobutanes at C3
The Rh2(S-2-Cl-5-BrTPCP)4 (3)-catalyzed reactions of aryldiazoacetates result in the selective C–H
functionalization of the C3 secondary site of the arylcyclobutanes. The catalyst is sterically
demanding and reacts at the sterically most accessible secondary site. ee, enantiomeric excess.
1The tertiary substituted product was obtained in 84% ee.
2The tertiary substituted product was obtained in 90% ee.
DISCUSSION
C–H functionalization tactics for generating substituted cyclobutanes are dominated
by the use of substrate control and directing groups, which limits the accessibility of
a variety of desirable substituted cyclobutanes. This report details an intermolecular
C–H insertion approach to chiral substituted cyclobutanes, which can generate both
1,1-disubstituted and 1,3-disubstituted cyclobutanes. The lessons we learned about
specific substrate interactions with our growing catalyst toolbox assisted the rapid
discovery of reaction conditions that were suitable for generating each set of
310 Chem 6, 304–313, January 9, 2020

Figure 6. Competition Studies for Site-Selective C–H Functionalization
The relative rates of functionalization of the cyclobutane C–H bonds versus the unstrained benzylic
C–H bonds in isopropyl-, ethyl-, and methylbenzene. The tertiary benzylic site of cyclobutane
(marked in red) is more reactive than the tertiary benzylic site in an unstrained system for both the
Rh2(S-TCPTAD)4- and Rh2(S-2-Cl-5-BrTPCP)4-catalyzed reactions (1.7 times and >15 times more
reactive, respectively). The electronically unactivated secondary site of the cyclobutane (marked in
blue) is 2.8 times more reactive in the Rh2(S-2-Cl-5-BrTPCP)4-catalyzed reaction and >10 times
more reactive in the Rh2(S-TCPTAD)4-catalyzed reaction.
substituted cyclobutanes. A less bulky dirhodium catalyst favors attack at the
tertiary benzylic site, whereas a bulky catalyst favors attack at the sterically most
accessible secondary site. These studies illustrate the potential of C–H functionaliza-
tion strategies to rapidly access novel chiral scaffolds of potential pharmaceutical
relevance.
EXPERIMENTAL PROCEDURES
General Procedure for the C–H Functionalization of Cyclobutanes
An oven-dried vial was equipped with a magnetic stir bar and sealed with a septa and
a cap. This was cooled under a vacuum; thereafter, it was flame dried once. After the
vial cooled to room temperature, it was loaded with rhodium catalyst (0.5–1 mol %),
the cyclobutane substrate (1 equiv), and anhydrous dichloromethane (2 mL dichloro-
methane and 1 mmol cyclobutane). The mixture was allowed to stir under argon (the
mixture was heated if heat was applied) while the diazo compound was prepared. A
solution of the diazo compound (2 equiv) was prepared by dissolving in the dichloro-
methane (3 mL dichloromethane and 0.25 mmol diazo compound), and then this
mixture was added dropwise with a syringe pump over 3 h. Upon completion of
the addition, the reaction was stirred for an additional 2–4 h. Residual solvent was
removed under reduced pressure (if the reaction was heated, it was allowed to
cool to room temperature before residual solvent was removed), and the crude
product was purified by silica gel chromatography. The regioisomeric ratio (rr) and
the diastereomeric ratio (dr) were determined by NMR analysis of the crude reaction
mixture. The enantioselectivity (ee) was determined by high-pressure liquid chroma-
tography analysis of the material after flash chromatography. Images of the key
spectral and analytical data of the compounds generated in this study are included
in Figures S1–S138.
DATA AND CODE AVAILABILITY
Crystallographic data for compounds 8 and 25 have been submitted to the
Cambridge Crystallographic Database under accession numbers CCDC: 1921680
and CCDC: 1921681, respectively.
Chem 6, 304–313, January 9, 2020 311

SUPPLEMENTAL INFORMATION
Supplemental Information can be found online at https://doi.org/10.1016/j.chempr.
2019.12.014.
ACKNOWLEDGMENTS
This work was supported by the NSF Center for Selective C–H Functionalization
(CHE 1700982) and NIGMS of the NIH under award number F32GM130020
(Z.J.G.). Additional financial support was provided by AbbVie. Instrumentation
used in this work was supported by the National Science Foundation
(CHE1531620 and CHE1626172). We wish to thank the members of the NSF Center
for C–H Functionalization (CHE 1700982) for helpful discussions regarding this work.
We thank Dr. John Bacsa and Mr. Thomas Pickel at the Emory X-ray Crystallography
Facility for the X-ray structural analysis.
AUTHOR CONTRIBUTIONS
Z.J.G., B.D.W., and W.L. performed the synthetic experiments; Z.J.G., B.D.W.,
H.M.L.D., and E.A.V. designed the experiments; and Z.J.G., B.D.W., and H.M.L.D.
wrote the manuscript.
DECLARATION OF INTERESTS
H.M.L.D. is a named inventor on a patent entitled ‘‘Dirhodium catalyst compositions
and synthetic processes related thereto’’ (US patent 8,974,428, issued March 10,
2015). The other authors declare no competing interests.
Received: September 8, 2019
Revised: December 2, 2019
Accepted: December 12, 2019
Published: January 9, 2020
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