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. 2025 Apr 10;147(16):13120–13125. doi: 10.1021/jacs.5c02331

Rh-Catalyzed Enantioselective Aryl C–H Bond Cyclopropylation

Eric Palomo †,§, Anastasiya Krech †, Yu Jen Hsueh †, Zexian Li †, Marcos G Suero †,‡,*
PMCID: PMC12022978  PMID: 40210211

Abstract

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Herein, we disclose the discovery and development of a site-, regio-, diastereo-, and enantioselective aryl C–H bond cyclopropylation using diazomethyl hypervalent iodine reagents, styrenes, and paddlewheel dirhodium carboxylate catalysts. A key aspect of this work was the catalytic generation of a chiral Rh(II) carbene through an electrophilic aromatic substitution with chiral Rh(II) carbynoids. The strategy allows the construction of cyclopropane rings using aryl C–H bonds from aromatic feedstocks and drug molecules and promises to reach an unexplored “cyclopropanated” chemical space highly difficult to reach by current strategies.

The cyclopropane ring is a stalwart in drug design currently found in more than 60 marketed pharmaceutical agents and appeared in 642 patent applications during 2019 (Figure 1A).1 Often used as an isostere of alkyl substituents (iso-propyl, tert-butyl), phenyl, and morpholine rings as well as alkenes, the cyclopropane ring is well-known to increase potency, provide conformational stability, as well as improve pharmacokinetics and solubility of drug candidates (Figure 1A).1 There is a wealth of synthetic methodologies and strategies developed for the stereocontrolled synthesis of poly substituted cyclopropanes.2 Surprisingly, there has been a lack of methodologies amenable for the cyclopropylation of aryl C–H bonds.

Figure 1.

Figure 1

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Novel catalytic generation of donor/acceptor Rh(II)-carbenes from Rh-carbynoids enables an enantioselective aryl C–H bond cyclopropylation.

Related examples of such type of process were reported by the groups of DiRocco employing photoredox catalysis and cyclopropanecarboxylic peroxyanhydride as cyclopropyl radical precursor3 and Ackermann and Johansson using ruthenium catalysis and ethyl 1-bromocyclopropane-1-carboxylate.4 While both processes were applied to the late-stage functionalization of drug molecules, they were limited to a single simple cyclopropane reagent. Moreover, both strategies may have limitations to introduce more complex cyclopropane rings in a diastereo- and enantioselective fashion. In this sense, the discovery and development of a general strategy that constructs at will simple and complex cyclopropane rings using aryl C–H bonds in simple arenes and drug molecules promise to reach an unexplored “cyclopropanated” chemical space highly difficult to reach by current strategies and that could be of high utility in drug discovery.5

Recently, we hypothesized that a simple approach to the regio-, diastereo-, and enantioselective construction of cyclopropane rings using aryl C–H bonds could involve a novel electrophilic aromatic substitution of chiral Rh(II)-carbynoids to generate chiral Rh(II)-carbenes (Figure 1B). Such type of process is unprecedented, and that would represent a unique strategy to the catalytic generation of chiral Rh(II)-carbenes—chemical multitalents well-known for their excellent capabilities in cyclopropanation reactions and catalyst-controlled C–H bond functionalizations, among others.6 Herein, we disclose the successful development of this hypothesis for a new enantioselective synthesis of cyclopropanes using aromatic rings, styrenes, hypervalent iodine reagents, and arenes (Figure 1B).

Our group has established a catalytic carbyne transfer platform based on the generation of Rh(II)-carbynoids, a class of Rh(II)-carbenes substituted with a hypervalent iodine(III), which is capable of transferring its carbynoid ligand to alkenes7 or alkynes8 through [2 + 1] cyclizations. Recently, we also demonstrated that such type of processes could be done with excellent enantioinduction using chiral dirhodium carboxylate catalysts.9

Additionally, we observed that Rh(II)-carbynoids underwent nucleophilic attack by carboxylic acids and generated Fischer-type acyloxy Rh(II)-carbenes.10 DFT calculations unveiled (i) an initial attack of the carboxylic acid to the hypervalent iodine(III) and (ii) the departure of the iodine(III) leaving group may occur through the formation of a transient intermediate, where both an iodine(III) atom and a carbynoid carbon atom bind the carboxylic acid carbonyl.11 Based on this, we wondered whether aromatic rings could undergo electrophilic aromatic substitutions with chiral Rh(II)-carbynoids int-I and generate chiral donor/acceptor Rh(II)-carbenes int-II, a well-established class of metal carbenes12 capable of cyclopropanating styrenes with excellent diastereo- and enantioselectivity (Figure 2).13

Figure 2.

Figure 2

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Mechanistic hypothesis.

Our envisaged catalytic cyclopropane synthesis was initially tested with anisole (1a), pseudocyclic hypervalent iodine compound 2a as limiting reagent, and styrene (3a) using Du Bois catalyst14 Rh2(esp)2 in CH2Cl2 at −50 °C (Table 1). We were pleased to see the formation of cyclopropane 4a in 21% yield as a single diastereoisomer from a para-selective C–H bond functionalization of anisole (entry 1). However, we also observed the formation of product 5 that was generated from a para-selective C–H bond functionalization of anisole with int-II.

Table 1. Optimization Studiesa.

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entry 2 1a:2:3a Rh2 cat. Yield 4a (5)b e.r.
1 2a 5:1:2 Rh2(esp)2 21% (30%) -
2 2a 3:1:2 Rh2(esp)2 25% -
3 2a 3:1:2 Rh2(esp)2 31%c -
4 2a 3:1:1.1 Rh2(esp)2 60%c -
5 2b 3:1:1.1 Rh2(esp)2 57%c -
6 2c 3:1:1.1 Rh2(esp)2 70%c -
7 2c 3:1:1.1 Rh2(S-NTTL)4 33%c 80:20
8 2c 3:1:1.1 Rh2(S-PTTL)4 76%c 95:5
9 2c 3:1:1.1 Rh2(S-TCPTTL)4 31%c 78:22
10 2c 3:1:1.1 Rh2(S-TPPTTL)4 79%c 71:29
11 2c 3:1:1.1 Rh2(S-BPTTL)4 71%c 97:3
12 2c 3:1:1.1 Rh2(S-BPTTL)4 85%c,d 99:1
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a

Performed at 0.1 mmol scale by addition of 2a–c in CH2Cl2 over 1a, 3a, and 1 mol % of the corresponding dirhodium catalyst in CH2Cl2 at −50 °C during 30 min.

b

Yields are reported based on 1H NMR analysis using CH2Br2 as the internal standard; 4a was obtained as single regio- and diastereoisomer in each entry.

c

Performed at 0.1 mmol scale by addition of 2 and 3a over 1a and the Rh catalyst in CH2Cl2 at −50 °C during 30 min.

d

Reaction performed using 2 mol % of the Rh catalyst and CH2Cl2:PhCl (1:1) as solvent mixture. esp = α,α,α′,α′-tetramethyl-1,3-benzenedipropanoate. Enantiomeric ratios (e.r.) were determined by supercritical fluid chromatography mass spectrometry (SFC-MS) analysis on a chiral stationary phase of the isolated pure product 4a by using flash column chromatography.

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Formation of 5 was suppressed by reducing the equivalents of anisole (entry 2), while the yield could be slightly improved by adding a mixture of 2a and 3a over anisole and Rh2(esp)2 (entry 3). Considering that Rh-carbynoid int-I could react with 3a through a cyclopropanation reaction,7a,7b we decreased the equivalents of styrene and observed a dramatic improvement of yield (entry 4). Next, we evaluated alternative hypervalent iodine reagents 2 and found that while triflate pseudocyclic derivative 2b gave a similar yield (entry 5), linear reagent 2c provided a better efficiency (entry 6).

After this, we turned our attention to evaluating a range of chiral dirhodium catalysts. We previously observed that C4-symmetric dirhodium carboxylate complex Rh2(S-NTTL)4 (S-NTTL = N-naphthaloyl-(S)-tert-leucinate) performed well in the enantioselective single-carbon insertion of alkenes with pseudocyclic hypervalent iodine reagents.9 By using the reaction conditions from entry 6, we found that Rh2(S-NTTL)4 provided 4a in low yield and enantioinduction (entry 7, 33%, e.r. = 80:20). However, Rh2(S-PTTL)4 (S-PTTL = N-phthaloyl-(S)-tert-leucinate) led to a dramatic increase of yield and enantioselectivity (entry 8, 76%, e.r. = 95:5). Alternative phthaloyl-based catalysts substituted with chlorine (entry 9) or phenyl (entry 10) groups provided low enantiocontrol. In contrast, Rh2(S-BPTTL)4 (S-BPTTL = N-benzophthaloyl-(S)-tert-leucinate) led to slightly superior enantiocontrol in comparison with Rh2(S-PTTL)4 (entry 11). Finally, both an increment of catalyst loading to 2 mol % and the use of CH2Cl2 and PhCl (1:1) as solvents led to 4a in 85% yield and 99:1 of enantiomeric ratio (entry 12). The improved efficiency observed with the CH2Cl2/PhCl mixed solvent system is likely due to a better solubility of the dirhodium catalyst at low temperatures. A similar effect has been noted in our previous studies with an alternative catalyst.9

With the optimized conditions in hand, we investigated the scope of this novel C–H bond cyclopropylation with a range of substituted arenes 1, hypervalent iodine reagents 2, and styrenes 3 (Table 2). We were delighted to observe that para-, meta-, and ortho-substituted styrenes with halides (4b-d,j,m-o), alkyl (4e,f,k,p), phenyl (4g), boronic ester (4h), and trifluoromethyl (4i) groups generally provided good yields and enantioselectivities. However, we noticed a drop in enantiocontrol when bulky substituents were placed in para (4f, e.r. = 91:9) and ortho (4p,q, e.r. = 90:10–92:8) positions.

Table 2. Scope of the Enantioselective Catalytic C–H Bond Cyclopropylation with Chiral Rh-Carbynoidsa.

graphic file with name ja5c02331_0005.jpg

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a

Performed at 0.2 mmol scale by addition of 2c (1 equiv) and 3 (1.1 equiv) in CH2Cl2:PhCl (1:1) over 1 (2 equiv) and Rh2(S-BPTTL)4 (2 mol %) in CH2Cl2:PhCl (1:1) at −50 °C during 30 min.

b

Rh2(S-PTTL)4 (2 mol %) was used as catalyst.

c

Rh2(S-TFPTTL)4 (2 mol %) was used as catalyst.

d

Rh2(S-tBuPTTL)4 (2 mol %) was used as catalyst.

e

Rh2(R-p-Ph-TPCP)4 (2 mol %) was used as catalyst.

f

Reaction performed at −78 °C.

g

CH2Cl2 used as solvent. Enantiomeric ratios (e.r.) indicated in parentheses were determined by SFC-MS analysis on a chiral stationary. Diastereomeric ratios were determined to be >20:1 by 1H NMR analysis of the reaction crude mixture unless otherwise indicated in brackets. The absolute configuration of the cyclopropanes 4a-r and 6a-f was assigned by analogy to that of alcohol 4d–OH derived from the ester reduction of 4d with DIBAL-H, which was determined by single-crystal X-ray diffraction analysis (See Supporting Information for details).

Besides, we found that while α-substitution on the styrene was well-tolerated (4r,s), β-substitution did not yield the corresponding cyclopropane or any product resulting from allylic carbene C–H bond functionalization (4t) (Table 2B).15 Furthermore, cyclic styrene derivative indene was transformed into the desired cyclopropane 4u, albeit with poor enantioselectivity (e.r. = 73:27). In contrast, benzofuran underwent cyclopropanation with moderate yield and excellent enantioselectivity (4v, 50%, e.r. = 97:3).

Later, we explored the arene scope and observed that a broad range of phenyl ethers substituted with alkyl (4w-y), aryl (4z,aa), and vinyl (4ab) could be tolerated (Table 2B). We were pleased to find that the electrophilic aromatic substitution of the chiral Rh-carbynoid with ortho-substituted anisole derivatives proceeds with excellent regioselectivity in every single case (4ac-i, >20:1) and although enantiomeric ratios observed were good (e.r. ≥95:5), isolated yields were lower in comparison to anisole (38–71%). Moreover, cyclic derivatives 1,2-dihydrobenzofurane and 1,3-benzodioxole could undergo regio-, diastereo-, and enantioselective C–H bond cyclopropylation (4aj,ak). Unfortunately, meta- and para-substituted anisoles provided poor enantioselectivity (4al, 75%, e.r. 72:28) or no product (4am), respectively. Alternatively, arenes such as para-xylene or para-bromoanisole also did not lead to the desired compounds. Steric clashes between the chiral Rh-carbynoids and the para-substituted arene may prevent the electrophilic aromatic substitution to occur.

Alternative mono- and disubstituted benzene rings such as phenol, biphenyl, tert-butylbenzene, and ortho-xylene led to cyclopropanes 4an-aq with lower yields and enantioselectivities in comparison to substituted phenol derivatives (Table 2C). In addition, we observed that pyrrole or thiophene derivatives could be cyclopropylated with excellent regio- and enantioselectivity (Table 2D, 4ar,as). It is worth highlighting that while some thiophenyl diazo compounds have been synthesized using classic diazo transfer reactions,17 pyrrolyl derivatives are unknown.18 In specific arenes or styrenes, Rh2(S-BPTTL)4 was not a suitable catalyst since low yield and/or enantiomeric ratio were obtained. Upon a small screening, we were delighted to generally improve both yields and e.r. with Rh2(S-PTTL)4 (for 4i,p,r,s,an,ap), Rh2(S-TFPTTL)4 (S-TFTTL = N-tetrafluorophthaloyl-(S)-tert-leucinate) (for 4v), Rh2(S-tBuPTTL)4 (S-tBuPTTL = N-(4-tert-butylphthaloyl)-(S)-tert-leucinate) (for 4y), and Rh2(R-p-Ph-TPCP)4 (R-p-Ph-TPCP = (R)-1-(4-phenyl(phenyl))-2,2-diphenylcyclopropane carboxylate) (for 4z).19

The scope of hypervalent iodine reagents was explored using anisole and styrene. We found that various ester (6a-c), ketone (6d,e), and trifluoromethyl (6f) groups efficiently generated the corresponding cyclopropanes with good enantiomeric ratios. Moreover, we successfully applied our Rh-catalyzed enantioselective C–H bond cyclopropylation to a selection of drug molecules and insecticides (Figure 3A, 7-12), observing a remarkable site- and regio-selectivity. The latter examples clearly demonstrated the potential of our process as a tool for accessing a “cyclopropanated” chemical space that is difficult to reach using current late-stage functionalization platforms and for increasing the sp3 character of drug candidates or approved drugs.20

Figure 3.

Figure 3

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Late-stage C–H bond cyclopropylation and control experiments. aPerformed at 0.2 mmol scale by addition of 2c (1 equiv) and 3a/3e (1.1 equiv) in CH2Cl2:PhCl (1:1) over the drug molecule (2 equiv) and Rh2(S-BPTTL)4 (2 mol %) in CH2Cl2:PhCl (1:1) at −50 °C during 30 min. bRh2(R-p-Ph-TPCP)4 was used as catalyst. cCH2Cl2 used as solvent and Rh2(R-BPTTL)4 (2 mol %) as catalyst. dPerformed at 0.2 mmol scale by addition of 13 (1 equiv) and 3e (1.1 equiv) in CH2Cl2:PhCl (1:1) over Rh2(S-BPTTL)4 (2 mol %) in CH2Cl2:PhCl (1:1) at −50 °C during 30 min. Enantiomeric ratios (e.r.) indicated in parentheses were determined by SFC-MS analysis on a chiral stationary. Diastereomeric ratios were determined to be >20:1 by 1H NMR analysis of the reaction crude mixture unless otherwise indicated in brackets.

Control experiments were conducted to support the generation of a chiral Rh(II)-carbene from a Rh(II)-carbynoid via para-selective electrophilic C–H bond functionalization. First, we confirmed that diazo compound 13 can be used as chiral Rh-carbene precursors for the diastereo- and enantioselective cyclopropanation of styrene 3e under our optimized reaction conditions (Figure 3B).21 Then we wanted to discard the possibility that the reaction proceeds through a styrene cyclopropanation with Rh-carbynoid int-I forming int-IV that would undergo an electrophilic aromatic substitution to provide cyclopropane 4e (Figure 3C). The experiment was performed by adding 2c to a mixture of Rh2(S-BPTTL)4 and 3e followed by addition of anisole. In this case, we obtained alkene 14, which corresponds to the attack of anisole to an allylic cation produced from an electrocyclic ring-opening of int-IV.22

In conclusion, the first catalytic generation of chiral donor/acceptor Rh(II)-carbene from aryl C–H bonds and Rh(II)-carbynoids enabled a regio-, diastereo-, and enantioselective C–H bond cyclopropylation. The key to the process was an electrophilic aromatic substitution that occurred with excellent selectivity in electron-rich aromatic rings of simple arenes and complex bioactive molecules with chiral Rh(II)-carbynoids.

Acknowledgments

The European Research Council (ERC-CoG 2019, 865554), the Agencia Estatal de Investigación (AEI, 10.13039/501100011033) of the Ministerio de Ciencia, Innovación y Universidades and FEDER (PID2022-140286NB-I00, Severo Ochoa Excellence Accreditation 2020-2023-CEX2019-000925-S), the ICIQ Foundation, the ICREA Foundation, and the CERCA Programme are gratefully acknowledged for financial support. We thank the AEI and FSE for a FPI predoctoral fellowship (PRE2020-092989) (to E.P.) and AGAUR for a postdoctoral fellowship Beatriu de Pinos (2023 BP 00237) (to Z.L.).

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c02331.

  • Experimental procedures and spectral data (PDF)

Author Contributions

∥ Anastasiya Krech and Yu Jen Hsueh contributed equally to this work.

The authors declare no competing financial interest.

Supplementary Material

ja5c02331_si_001.pdf (18.3MB, pdf)

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  21. The exact pathway by which the electrophilic aromatic substitution occurs is not well-understood. We have never formed cyclopropane products in which the phenyl ring from the hypervalent iodine reagent was incorporated instead of the anisole. In this sense, a possibility could be based on the initial formation of [Rh]=C(E)–IPhAr from an electrophilic aromatic substitution with Ar–H at the I(III) center followed by a kinetic-controlled reductive elimination of the Ar group in [Rh]=C(E)–IPhAr to form [Rh]=C(E)–Ar.

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