Mechanism-Driven Development of Group 10 Metal-Catalyzed Decarbonylative Coupling Reactions

CONSPECTUS.

Transition metal-catalyzed cross-coupling reactions are widely used in both academia and industry for the construction of carbon–carbon and carbon–heteroatom bonds. The vast majority of cross-coupling reactions utilize aryl (pseudo)halides as the electrophilic coupling partner. Carboxylic acid derivatives (RC(O)X) represent a complementary class of electrophiles that can engage in decarbonylative couplings to produce analogous products. This decarbonylative approach offers the advantage that RC(O)X are abundant and inexpensive. In addition, decarbonylative coupling enables both intramolecular (between R and X of the carboxylic acid derivative) as well as intermolecular bond-forming reactions (in which an exogeneous nucleophile is coupled with the R group derived from RC(O)X). In these intermolecular reactions, the X-substituent on the carboxylic acid can be tuned to facilitate both oxidative addition and transmetalation, thus eliminating the need for an exogeneous base. This Account details our group’s development of a diverse variety of base-free decarbonylative coupling reactions catalyzed by group 10 metals. Furthermore, it highlights how catalyst design can be guided by stoichiometric organometallic studies of these systems.

Our early studies focused on intramolecular decarbonylative couplings that transform RC(O)X to the corresponding R–X with extrusion of CO. We first identified Pd and Ni monodentate phosphine catalysts that convert aryl thioesters (ArC(O)SR) to the corresponding thioethers (ArSR). We next expanded this reactivity to fluoroalkyl thioesters, using readily available fluoroalkyl carboxylic acids as the fluoroalkyl (R_F) source. A Ni-phosphinoferrocene catalyst proved optimal, and the large bite angle bidentate ligand was necessary to promote the challenging R_F–S bond-forming reductive elimination step.

We next pursued intramolecular decarbonylative couplings of aroyl halides. Palladium-based catalysts bearing dialkylbiaryl ligands (e.g., BrettPhos) were identified as optimal for converting aroyl chlorides (ArC(O)Cl) to aryl chlorides (ArCl). These ligands were selected based on their ability to facilitate the key C–Cl bond-forming reductive elimination step of the catalytic cycle. In contrast, all attempts to convert aroyl fluorides [ArC(O)F)] to aryl fluorides (ArF) were unsuccessful with either Pd or Ni-based catalysts. Organometallic studies of the Ni-system show that C(O)–F oxidative addition and CO de-insertion proceed smoothly, but the resulting nickel (II) aryl fluoride intermediate fails to undergo C–F bond-forming reductive elimination.

In contrast to its inertness to reductive elimination, this nickel(II) aryl fluoride proved highly reactive towards transmetalation. The fluoride ligand serves as an internal base, such that no additional base is required. We leveraged this ‘transmetalation active’ intermediate to achieve base-free Ni-catalyzed intermolecular decarbonylative coupling reactions between aroyl fluorides and boron reagents to access both biaryl and aryl-boronate ester products. By tuning the electrophile, transmetalating reagent, and catalyst, this same approach also proved applicable to base-free intermolecular decarbonylative fluoroalkylation (between difluoromethylacetyl fluoride and arylboronate esters) and aryl amination (between phenol esters and silyl amines).

Moving forward, a key goal is to identify catalyst systems that enable more challenging bond constructions via this manifold. In addition, CO inhibition remains a major issue leading to the requirement for high temperatures and high catalyst loadings. Identifying catalysts that are resistant to CO binding and/or approaches to remove CO under mild conditions will be critical for making these reactions more practical and scalable.

Graphical Abstract

1. INTRODUCTION

Transition metal-catalyzed decarbonylative coupling reactions between carboxylic acid-derived electrophiles and various nucleophiles have emerged as an attractive approach to C–C and C–heteroatom bond formation (Scheme 1A).⁴ In comparison to more widely studied cross-couplings of aryl halides, these decarbonylative reactions offers several key advantages. First, carboxylic acids are abundant and inexpensive starting materials relative to their aryl halide counterparts.^4,5 Second, carboxylic acids can be transformed into a wide variety of derivatives (RC(O)X, including amides, acid halides, esters, and anhydrides) in a single step.⁴ The X group becomes one of the ligands at the metal center during coupling, and thus can dramatically influence the barriers for different elementary steps of the catalytic cycle.^4,6,7 Finally, decarbonylative coupling reactions can be tuned by modifying the metal, ligand, and coupling partners to achieve a broad range of bond-forming reactions via a common mechanistic manifold (Scheme 1B).^6,7

Scheme 1.

(A) Intra- and intermolecular decarbonylative coupling. (B) Catalytic cycle.

2. CATALYTIC CYCLE

Scheme 1B shows a general catalytic cycle for coupling reactions of RC(O)X electrophiles via group 10 metal catalysts. Step i involves oxidative addition of the C(O)–X bond at the M⁰ catalyst to generate M^II(acyl)(X) intermediate I. Carbonyl de-insertion then releases CO along with M^II(R)(X) (II, step ii). Complex II is analogous to intermediates generated in cross-coupling reactions of organohalides, which undergo salt metathesis followed by transmetalation and subsequent reductive elimination to release coupled products. However, decarbonylative reactions enable a much wider diversity of X, including fluoride, alkoxides/phenoxides, thiolates/thiophenolates, and amines. As such, following CO de-insertion, II can directly participate in either intra- or intermolecular couplings. For instance, reductive elimination from II (step iii-a) affords RX as a product of intramolecular decarbonylative coupling. Alternatively, directly intercepting II with a nucleophile (R¹–M’) followed by subsequent reductive elimination (steps iii and iv) releases R–R¹, the product of intermolecular decarbonylative coupling. As detailed below, the reactivity of intermediate II (in which both ligands R and X are dictated by the choice of RC(O)X precursor) is central to controlling selectivity between the intra- and intermolecular manifolds.

In 1980, Yamamoto and co-workers demonstrated that the combination of Ni(cod)₂ and PPh₃ reacts with phenolate esters like phenyl propionate, via oxidative addition into the C(O)–OPh bond and subsequent CO de-insertion.^8a The resulting Ni^II(Et)(OPh) complex (analogue of II) rapidly decomposed to ethylene, phenol, and a mixture of nickel(0) carbonyl complexes (Scheme 2A). This transformation implicated the feasibility of decarbonylative coupling reactions at group 10 metal centers. Over the ensuing four decades, this reactivity was leveraged by numerous researchers to develop Ni and/or Pd-catalyzed decarbonylative couplings of aryl carboxylic acid derivatives (ArC(O)X) that form Ar–C, Ar–B, Ar–N, Ar–O, Ar–S, Ar–R_F (R_F = fluoroalkyl), and Ar–Si bonds. This prior art [through 2017, when the work in this Account began] includes seminal contributions from Chatani, Garg, Gooßen, Itami, Love, Rueping, Shi, Stephan, Szostak, de Vries, Wang, Yamaguchi, Yu, and others.⁹ The pre-2017 work has been extensively reviewed; as such, this section focuses on summarizing general features of and challenges associated with these studies. Literature precedent that is more recent or that is directly relevant to our group’s work is discussed in more detail throughout this Account.

Scheme 2.

(A) Early example of Ni/PPh₃-mediated decarbonylation of esters. (B) State-of-the-art for decarbonylative cross-coupling in 2017.

In 2017, when we initiated our efforts in this area, the vast majority of literature examples involved Ni- or Pd-catalyzed intermolecular cross-coupling reactions of either ester or twisted amide substrates (X = OR or NR₂; Scheme 2B).⁹ In these systems, the choice of X was largely driven by the feasibility and rate of oxidative addition. Following oxidative addition, the X-ligand was treated as a sacrificial placeholder rather than as a useful handle for further steps of the catalytic cycle. As such, it was rapidly exchanged with an exogenous base (M’Y) to generate the ‘transmetalation-active’ intermediate II-Y, which then engaged in cross-coupling (Scheme 2B). The bases used in these systems (MO^tBu, MF, M₃PO₄, M₂CO₃, MOAc, where M = Li, Na, K, Cs) mirror those employed in cross-couplings of aryl halides. Thus, these early decarbonylative reactions retained many of the limitations of traditional cross-couplings, including modest compatibility with base-sensitive functional groups and sub-optimal atom economy due to the formation of salt by-products. In addition, these studies largely ignored the potential of the X ligand as a productive coupling partner. As such, there were few reports of intramolecular decarbonylative coupling.^8b–e

At the outset of our studies, we hypothesized that the X group of RC(O)X coupling partners could be exploited as a versatile and flexible handle for tuning multiple steps of the catalytic cycle. We reasoned that appropriate selection of X would open up a wide range of intramolecular decarbonylative coupling processes. Furthermore, we sought to leverage variation of the X-group in intermolecular couplings to tune the rates of both oxidative addition at M⁰ and of transmetalation at subsequent M^II intermediates. This latter feature should preclude the requirement for an exogeneous base, while providing a handle to control selectivity between decarbonylated versus ketone products.

The first section of this Account describes our group’s studies of intramolecular decarbonylative coupling reactions. Building on the work from these reports, we develop general methods for the intramolecular conversion of aryl¹ and (fluoro)alkyl thioesters^6d to (fluoroalkyl)thioethers, as well as acid chlorides to aryl chlorides.^6a We then leverage knowledge gained from the intramolecular systems to design base-free intermolecular decarbonylative C–C,^2,3 C–B,^6b and C–N^6c cross-coupling reactions. Throughout this Account, our selection of specific metal catalysts, ligands, electrophiles, and nucleophiles is described in detail. We show how stoichiometric organometallic experiments can provide an understanding of the relative rates of the elementary catalytic steps and how to tune reaction component to achieve the desired reactivity. Ultimately this discussion should inspire new developments and mechanistic understanding of decarbonylative coupling processes.

3. GENERAL CONSIDERATIONS

The development of decarbonylative coupling reactions requires the optimization of metal precatalyst, L- and X-type ligands, the RC(O)X electrophile, and the nucleophile with respect to the hypothesized rate- and/or selectivity limiting step(s) of the target transformation. Below, we present a brief summary of general considerations in the selection of metal, ligands, and electrophile in these transformations.

Selection of metal.

Our studies have focused on palladium and nickel-based catalysts cycling between the 0 and +2 oxidation states. In these oxidation states, both Pd and Ni are known to effect each of the individual steps of the catalytic cycle in Scheme 1: oxidative addition (at M⁰),^4,10 CO de-insertion (at M^II),^4,10 transmetalation (at M^II),^4,5,10 and reductive elimination (at M^II).^4,10 Furthermore, as discussed above, both Ni- and Pd-catalyzed base-promoted decarbonylative cross-couplings of esters and twisted amides were well-precedented when we initiated the work described herein.⁹ Overall, our selection of Pd versus Ni for a given transformation is dictated by which of the individual steps is most challenging with respect to reaction kinetics, selectivity or both. For instance, Pd is generally the optimal choice when the reductive elimination step is slow (e.g., in reactions involving the formation of fluoroalkyl–carbon bonds).¹¹ In contrast, Ni is typically preferred in systems where oxidative addition is challenging (e.g., in reactions of acid fluoride and ester electrophiles).^4,9,10 Finally, Ni is often superior when fast CO de-insertion is required for selectivity.¹⁰ This latter issue is particularly salient in intermolecular reactions, as fast CO de-insertion is required to limit the formation of acylation side-products [RC(O)R¹] via premature transmetalation/reductive elimination at metal acyl intermediate I (Scheme 1B).

Selection of L-type ligand.

Phosphines have been widely explored as supporting ligands in traditional as well as decarbonylative cross-coupling processes,^12,13 and diverse mono- and bidentate derivatives are readily available and can be tuned to vary steric and electronic properties.^12,13 In addition, there is an extensive organometallic literature on the impact of phosphine ligand structure on the rates of oxidative addition, CO de-insertion, transmetalation, and reductive elimination at group 10 metals.^12,13 This enables selection of a phosphine ligand to optimize the most challenging elementary step of the catalytic cycle. In general, that no single phosphine ligand is universally effective for Ni and/or Pd-decarbonylative couplings, as the relative barriers for each step vary as a function of the RC(O)X and M’–R¹ coupling partners. Thus, diverse phosphine ligands, including monodentate (PMePh₂, PCy₃, PAd₂Bn), dialkylbiaryl (BrettPhos, RuPhos), and bidentate (dppf, dcype) derivatives have proven optimal for the different transformations presented in this Account.

Selection of RC(O)X electrophile.

In traditional cross-coupling reactions of aryl halides (ArX) as well as early work on decarbonylative cross-couplings of ArC(O)X, the X group was selected to enable the oxidative addition step of the catalytic cycle. Following oxidative addition, this substituent is typically subjected to salt metathesis with an exogeneous base to generate a ‘transmetalation-active’ intermediate for subsequent coupling (II-Y in Scheme 2B). We envisioned an alternative paradigm in which the X group is designed to play a central role throughout the catalytic cycle rather than being sacrificed after oxidative addition. We hypothesized that this would enable diverse intramolecular decarbonylative couplings as well as exogeneous base-free intermolecular coupling reactions.

For intramolecular decarbonylative processes (Scheme 1B, left), the choice of R and X will be dictated by the target product (RX). Thus, X cannot be varied to modulate the reactivity of the electrophilic coupling partner and/or transition metal intermediates. As such, these transformations will only be feasible where X renders RC(O)X sufficiently electrophilic to undergo oxidative addition at M⁰ but also maintains sufficient nucleophilicity to participate in R–X bond-forming reductive elimination.

In contrast, the X group of RC(O)X is a key variable in the design of intermolecular decarbonylative couplings (Scheme 1B, right). To access the intermolecular manifold, it is crucial to minimize intramolecular coupling processes. As such, X as either fluoride or phenoxide has been a common choice in our systems, since these undergo slow reductive elimination at Pd^II and Ni^II centers.¹⁴ Additionally, the ideal X group should render RC(O)X reactive towards oxidative addition at [M⁰], while enabling facile transmetalation with M’–R¹. Acid fluorides and esters are electrophilic carboxylic acid derivatives, while F and O form strong bonds with boron and silicon, thus providing a driving force for the transmetalation step of the catalytic cycle.

4. INTRAMOLECULAR DECARBONYLATIVE COUPLING OF ACYL ELECTROPHILES

Arylthioesters to thioethers.

Our first studies focused on the intramolecular decarbonylative conversion of aryl thioesters (ArC(O)SR) to thioethers (ArSR, Scheme 3A, b). This transformation would serve as an alternative to well-precedented cross-couplings of aryl halides with thiols in the presence of base (Scheme 3A, a).¹⁵ The latter reaction has been established using both Pd^15b and Ni^15a,c catalysts, supporting the feasibility of the C–S bond-forming reductive elimination step of the catalytic cycle (Scheme 3B, step iii).

Scheme 3.

(A) (a) Cross-coupling route to thioethers (known); (b) Proposed intramolecular decarbonylative route to thioethers. (B) Catalytic cycle.

At the outset of these studies, we noted sporadic literature examples of decarbonylative thioetherification.^8c–e A seminal example was a 1987 report by Yamamoto showing that Pd(PCy₃)₂ catalyzes the conversion of a small set of aryl thioesters to the corresponding thioethers (Scheme 4A).^8c A few years later, Wenkert and co-workers used stoichiometric NiCl₂•6H₂O in the presence of Zn dust and PPh₃ for the decarbonylative synthesis of aryl and alkenyl thioethers from thioesters (Scheme 4B).^8d However, these and other early examples^8e were limited by application to a very small range of unfunctionalized substrates and/or by the requirement for stoichiometric metals.

Scheme 4.

(A) Yamamoto’s Pd(PCy₃)₂-catalyzed intramolecular decarbonylative thioetherification (1987). (B) Wenkert’s stoichiometric synthesis of thioethers using stoichiometric Ni (1991).

We first revisited Yamamoto’s Pd⁰-catalyzed transformation (Scheme 4A), evaluating modern palladium(0) precatalysts and phosphine ligands. Initial studies focused on the decarbonylative conversion of S-phenyl 4-(trifluoromethyl)benzothioate to phenyl(4-(trifluoromethyl)phenyl)sulfide. Using [Pd(P-o-tol₃)₂] as a catalyst, this reaction proceeded in 48% yield after 20 h at 150 °C (Scheme 5). Consistent with Yamamoto’s observations,^8c the use of PCy₃ as a ligand led to an enhancement in yield (in this case to 61%). Screening a variety of more recently developed sterically bulky and electron-rich dialkylbiaryl and trialkyl phosphine ligands revealed that PAd₂Bu afforded the highest yield at 88%.

Scheme 5.

Selected examples from ligand screen of Pd-catalyzed decarbonylative thioetherification.

This [Pd(P-o-tol₃)₂]/PAd₂Bn-catalyzed decarbonylative thioetherification proved quite general, proceeding in good to excellent yield for twenty different thioester substrates, including aryl, heteroaryl, alkenyl, and benzyl derivatives and those bearing ester, boronate ester, and sulfonamide substituents (see Scheme 6 for examples). A noteworthy limitation of the Pd-catalyzed method is modest conversions and yields with aryl thioesters bearing electron donating substituents. For instance, S-phenyl 4-methoxybenzothioate afforded just 27% yield of the thioether product. This is consistent with oxidative addition being the challenging step of the catalytic cycle.

Scheme 6.

(A) Optimized conditions for Pd and Ni-catalyzed decarbonylative thioetherification. (B) Representative substrate scope.

We hypothesized that this limitation could be addressed by developing a nickel-catalyzed version of this transformation, since oxidative addition is typically much more facile at Ni⁰ versus Pd⁰ centers.¹⁰ Ligand screening uncovered the combination of Ni(cod)₂ and PCy₃ as an efficient catalyst system that is particularly effective for electron rich thioester substrates (Scheme 6). For instance, S-phenyl 4-methoxybenzothioate reacts to afford the corresponding thioether in 72% yield (compared to just 27% under Pd catalysis). Electron rich and sterically encumbered phenyl(o-tolyl)sulfide also afforded higher yield with Ni (99% compared to only 79% with Pd). In contrast, Ni catalysis proved completely ineffective for the conversion of S-benzyl benzothioate to benzyl(phenyl)sulfide, while the same reaction proceeded in 82% yield with the Pd catalyst. These results highlight the complementarities between the two metals.

Concurrent and subsequent¹⁶ reports by other groups demonstrated analogous intramolecular decarbonylative routes to (thio)ethers (Scheme 7). These employ various phosphines, including PⁿBu₃^16a and diphenylphosphinopropane^16b (dppp) for Ni, as well as diphenylphosphinobutane (dppb) for Pd^16c. In some cases, a carbonate base is required, which may serve to activate the Ni^II pre-catalysts. Notably, Yamaguchi reported a related Ni-catalyzed K₃PO₄-promoted decarbonylative etherification of pyridine-derived aryl esters using phosphinothiophene-based catalysts (Scheme 7B).¹⁷

Scheme 7.

Concurrent and subsequent reports of decarbonylative (thio)etherification.

Fluoroalkylthioesters to fluoroalkylthioethers.

We next targeted the conversion of fluoroalkylthioesters to fluoroalkyl thioethers (Scheme 8A, b)^6d. An attractive feature of this approach is that the fluoroalkyl (R_F) group is derived from readily available and inexpensive fluoroalkyl carboxylic acids.¹⁸ While methods have been developed for coupling CHF₂ and CF₃ carbene precursors or radical generators with thiols,¹⁹ the metal-catalyzed cross-coupling of R_FX with thiols remains challenging (Scheme 8A, a). The proposed catalytic cycle closely resembles that in Scheme 2B. The key difference is that there is not literature precedent for R_F–SR bond-forming reductive elimination (Scheme 8B, step iii), and we anticipated that this was likely to be the most challenging step of the cycle.

Scheme 8.

(A) (a) Metal-catalyzed cross-coupling of R_FX with HSR to form fluoroalkylthioethers (unknown); (b) Proposed intramolecular decarbonylative route to fluoroalkylthioethers. (B) Catalytic cycle.

Reductive elimination reactions involving fluoroalkyl groups have significantly more precedent at Pd than Ni.^7c,20 As such, we first evaluated Pd-based catalysts for the conversion of S-phenyl 2,2-difluoroethanethioate to (difluoromethyl)(phenyl)sulfide (Scheme 9A, a). However, a variety of Pd precatalysts and phosphine ligands (including PAd₂Bn, which was optimal for the reactions in Scheme 4) afforded minimal (~10%) consumption of the thioester and only traces (<1%) of the product (Scheme 9A, b). We next evaluated the Ni/PR₃ (PR₃ = PCy₃, PⁿBu₃) catalysts that were effective for the reactions in Schemes 6 and 7. Again these afforded <10% conversion and <1% yield of the difluoromethyl thioether (Scheme 9A, b).

Scheme 9.

(A) (a) Pd and (b) Ni catalysts with monodentate phosphine ligands are ineffective for decarbonylative fluoroalkylation of thioesters. (B) Stoichiometric reaction of S-phenyl 2,2-difluoroethanethioate with Ni(cod)₂/PⁿBu₃ and Ni(cod)₂/dppf.

To gain insight into where the Ni catalysis was failing, we examined the stoichiometric reaction of Ni(cod)₂/PⁿBu₃ with S-phenyl 2,2-difluoroethanethioate (Scheme 9B, a). Oxidative addition and CO de-insertion proceeded within 1 h at 25 °C to afford trans-(PⁿBu₃)₂Ni^II (CHF₂)(SPh). However, no PhSCHF₂ was observed upon heating this Ni^II intermediate for 16 h at 130 °C. This observation is consistent with reductive elimination being challenging. We reasoned that bidentate phosphinoferrocene ligands could lower the barrier for reductive elimination, based on literature reports using these ligands in other Ni-catalyzed coupling reactions involving CF₂H groups.^20b The stoichiometric reaction between S-phenyl 2,2-difluoroethanethioate and Ni(cod)₂/1,1’-bis-(diphenylphosphino)ferrocene (dppf) resulted in rapid consumption of the thioester starting material within at 25 °C (Scheme 9B,b). Broad signals were observed by NMR spectroscopy, consistent with a fluxional Ni^II intermediate that we propose to be (dppf)Ni^II(CHF₂)(SPh).^20c Heating to 130 °C²¹ resulted in PhS–CF₂H coupling to afford (difluoromethyl)(phenyl)sulfide in 90% yield. Overall, this sequence demonstrates the feasibility of all three steps of the catalytic cycle using a dppf-ligated Ni complex.

Ni(cod)₂/dppf was next tested as a catalyst for converting difluoromethyl thioesters to the corresponding thioethers. As shown in Scheme 10, electronically diverse aryl and alkyl difluoromethyl thioether products were formed in high yields. Thioethers bearing other fluoroalkyl (R_F) groups, including monofluoromethyl, 3,3,3-trifluoroethyl, and difluorobenzyl, were formed under analogous conditions. In all cases the substrates were accessed directly from the commercial starting materials R_FCO₂H and RSH. A limitation of this method is that perfluoroalkyl (CF₃, CF₃CF₂) derivatives afford <1% yield. In these systems, reductive elimination remains prohibitively slow at all Ni catalysts that we have examined to date.

Scheme 10.

Representative scope of [Ni⁰]/dppf-catalyzed decarbonylative fluoroalkylation.

Aroyl halides to aryl halides.

We next targeted intramolecular decarbonylative reactions of aroyl halides (ArC(O)X) to form aryl halides (ArX; X = chloride, fluoride; Scheme 11A, b). This transformation would complement traditional cross-couplings between aryl halides and MX salts (Scheme 11A, a).²² A proposed catalytic cycle would involve oxidative addition into the C(O)–X bond, carbonyl de-insertion, and carbon-halogen bond-forming reductive elimination to release the product (Scheme 11B). Similar to the fluoroalkyl thioether synthesis in Schemes 8–10, we anticipated that reductive elimination would be a particularly challenging step in this sequence.²³

Scheme 11.

(A) (a) Cross-coupling approach to aryl halides (known); (b) Proposed decarbonylative route to aryl halides. (B) Catalytic cycle.

We initiated these studies by studying the conversion of methyl 4-(chlorocarbonyl)benzoate to methyl 4-chlorobenzoate (Scheme 12). To select an appropriate catalyst, the literature precedent for each elementary step of the catalytic cycle was considered. The oxidative addition of aroyl halides is known at both Ni⁰ and Pd⁰ centers.^24–26 Carbonyl de-insertion at M^II(acyl) intermediates has also been demonstrated for both metals.^6–9 In contrast, examples of carbon–halogen bond-forming reductive elimination remain relatively rare, and the majority involve Pd complexes bearing sterically large and electron-rich mono-phosphine ligands.^13,22,23 These considerations led us to initially evaluate Pd⁰ catalysts bearing P^tBu₃ and dialkylbiaryl phosphines (Scheme 12). Gratifyingly, the combination of Pd[P(o-tol)₃]₂ and BrettPhos proved highly effective for this transformation, affording methyl 4-chlorobenzoate in 84% yield.

Scheme 12.

Ligand screen for Pd⁰-catalyzed decarbonylative chlorination.

This Pd⁰/BrettPhos-catalyzed decarbonylative chlorination was applied to the synthesis of various (hetero)aryl and benzyl chlorides (Scheme 13A). The transformation was also leveraged to achieve a one-pot, two-step method for decarbonylative chlorination followed by cross-coupling of the product with the same Pd catalyst (Scheme 13B).²¹ This enabled the formation of C(sp²)–C(sp²), C(sp²)–C(sp³), C(sp²)–B, C(sp²)–O, C(sp²)–S, and C(sp²)–N bonds.

Scheme 13.

(A) Representative scope of [Pd⁰]/BrettPhos-catalyzed decarbonylative chlorination. (B) One-pot decarbonylative chlorination/cross-coupling.

We next pursued the analogous decarbonylative conversion of benzoyl fluoride to fluorobenzene. However, the use of Pd[P(o-tol)₃]₂/BrettPhos (or other Pd⁰/phosphine combinations) failed to afford even traces of the aryl fluoride (Scheme 14A). To gain further insights, we monitored the stoichiometric reaction between Pd[P(o-tol)₃]₂/BrettPhos and benzoyl fluoride via NMR spectroscopy. At both room temperature and 130 °C, there was minimal conversion of the acid fluoride, and no new Pd–F resonances were detected (Scheme 14B). Palladium black was observed at elevated temperatures. This suggests that oxidative addition and CO de-insertion are either kinetically and/or thermodynamically inaccessible under these conditions. Notably, Grushin demonstrated the microscopic reverse of these two steps in the reaction of trans-(PPh₃)₂Pd(Ar)(F) with CO to form benzoyl fluoride.²⁷ In addition, a 2018 report by Schoenebeck showed that CO de-insertion at (XantPhos)Pd^II(acyl)(F) has a high barrier, and that the F must be replaced with an alternative X-type ligand to achieve reactivity.²⁶

Scheme 14.

(A) Unsuccessful decarbonylative fluorination of benzoyl fluoride; (B) Stoichiometric reaction of benzoyl fluoride with Pd⁰/BrettPhos; (C) Stoichiometric reaction of benzoyl fluoride with Ni⁰/PCy₃.

We reasoned that the oxidative addition of aroyl fluorides and subsequent CO de-insertion should be more facile at Ni versus Pd.^10,28 As such, we next examined the reaction of benzoyl fluoride with Ni(cod)₂/PCy₃ (Scheme 14C). In contrast to the Pd⁰/BrettPhos system, the Ni reaction resulted in a rapid oxidative addition to form Ni^II(benzoyl)(F) intermediate C in 95% yield. CO de-insertion then proceeded at 25 °C to afford Ni^II(phenyl)(F) D in 90% yield. This sequence demonstrates the feasibility of steps i and ii. The challenge with Ni is achieving C(sp²)–F bond-forming reductive elimination.^10,28 Heating D up to 130 °C did not lead to even traces of the aryl fluoride product. Similar results were observed with numerous other phosphine ligands. To date we have been unable to achieve Ar–F coupling with Ni centers.

Intramolecular decarbonylative fluorination remains a key target of our ongoing research efforts. Achieving this transformation requires developing Pd catalysts that undergo fast oxidative addition/CO de-insertion with aroyl fluorides or Ni-based catalysts that engage in C(sp²)–F coupling. However, in the meantime, we hypothesized that the inertness of D towards reductive elimination could be exploited to achieve intermolecular decarbonylative coupling reactions.

5. INTERMOLECULAR DECARBONYLATIVE CROSS-COUPLING OF ACYL ELECTROPHILES

Decarbonylative Suzuki-Miyaura cross-coupling reaction of aroyl fluorides.

Informed by reports from Hartwig^29a and Denmark,^29b we hypothesized that trans-(PCy₃)₂Ni(Ph)(fluoride) D would be highly reactive towards transmetalation with organoboron nucleophiles without the need for exogenous base. Indeed, the treatment of complex D with para-fluorophenylboronic acid led to the formation of 4-fluoro-1,1’-biphenyl in 90% yield at 25 °C (Scheme 15). This reaction is proposed to proceed via transmetalation to form E followed by C(sp²)–C(sp²) bond-forming reductive elimination. Notably no exogeneous base is required, as fluoride (originally derived from the acid fluoride electrophile) is already present as a ligand at Ni^II.

Scheme 15.

Transmetalation between D and aryl boronic acids.

We sought to leverage this reactivity to develop a decarbonylative cross-coupling reaction between acid fluorides and organoboronic acids (Scheme 16A, b). This transformation complements traditional Suzuki couplings³⁰ of aryl (pseudo)halides with organoboron reagents (Scheme 16A, a) for two reasons: (1) it involves carboxylic acid derivatives as electrophiles, and (2) it precludes the requirement for an exogenous base. The proposed catalytic cycle (Scheme 16B) involves a sequence of steps that have been demonstrated stoichiometrically in Schemes 14 and 15: oxidative addition of an aroyl fluoride at Ni⁰, CO de-insertion, transmetalation with ArB(OH)₂, and C–C bond-forming reductive elimination. A key challenge for achieving productive catalysis is ensuring that CO de-insertion is faster than transmetalation. This is essential to minimize the formation of the ketone by-product via premature transmetalation at the Ni^II(acyl)(F) intermediate and subsequent reductive elimination (Scheme 16, v).

Scheme 16.

(A) (a) Coupling of aryl halides with aryl boronic acids (known; requires base); (b) Proposed base-free decarbonylative Suzuki reaction. (B) Catalytic cycle and key challenge

We initiated these investigations by studying the Ni-catalyzed cross-coupling of benzoyl fluoride with phenylboronic acid using three ligands: PEt₃, PCy₃, and PPh₂Me. The reactions afford mixtures of 1,1-biphenyl and the ketone by-product benzophenone (Scheme 17). The choice of phosphine ligand has a dramatic impact on selectivity. PEt₃ affords a 30:70 mixture of 1,1-biphenyl to benzophenone, while PCy₃ and PPh₂Me favor the biaryl with 85:15 and 99:1 selectivity, respectively. These ligand effects mirror the rates of CO de-insertion at trans-(PR₃)₂Ni(acyl)(F), where de-insertion is slowest with PEt₃ and fastest with PPh₂Me. A longer-lived Ni^II(acyl)(F) intermediate enables premature transmetalation/reductive elimination (Scheme 16B, step v) to yield the ketone product.

Scheme 17.

Ligand effects on selectivity

This Ni⁰/PPh₂Me catalyst proved effective for the base-free decarbonylative coupling of various aroyl fluoride and boronic acid partners (Scheme 18). This method proved compatible with base-sensitive boronic acids, including polyfluorinated and alpha-heteroaryl derivatives. The aroyl fluorides can be generated in situ via reaction of carboxylic acids with TFFH (tetramethylfluoroaminidium hexafluorophosphate) and Proton Sponge^®. This enables one-pot decarbonylative Suzuki reactions of various bioactive carboxylic acids, including flavone, tambibarotene, and a variety of probenecid derivatives.²¹

Scheme 18.

Optimized conditions, in situ acid fluoride generation, and representative scope.

A near simultaneous and conceptually related report by Nishihara^31a demonstrated the base-free Ni-catalyzed decarbonylative coupling of aroyl fluorides with trialkylboranes (Scheme 19). Similar to our observations, the use of PCy3 as a ligand led to mixtures of Ar–R and ketone products due to slow CO de-insertion. Diphenylphosphinoethane (dppe) proved to be the optimal ligand for this transformation. The reaction was applied to a small scope of (heteroaryl)acid fluorides.

Scheme 19.

Nishihara’s base-free decarbonylative alkylation of aroyl fluorides.

Additionally, while our work on acid fluoride/organoboron decarbonylative coupling was underway, Schoenebeck²⁶ reported a Pd⁰/Xantphos-catalyzed decarbonylative coupling of acid fluorides with TESCF3. The authors propose a similar mechanism to that in Scheme 16B, with transmetalation occurring directly between TESCF3 and a Pd^II(Ar)(F) intermediate (Scheme 20). Notably, the optimal reaction conditions for this method use 0.2 equiv of an exogeneous base (K3PO4). In the absence of base, the chemoselectivity shifted to favor the trifluoromethyl ketone product, suggesting that it may play a role in promoting CO de-insertion.

Scheme 20.

Schoenebeck’s Pd-catalyzed decarbonylative aryl trifluoromethylation of aroyl fluorides with TESCF3 and base.

Decarbonylative borylation of aroyl fluorides.

We envisioned that an analogous decarbonylative borylation could be achieved by intercepting Ni^II(Ar)(F) intermediates with diboron reagents (Scheme 21A, b). This route would constitute the base-free conversion of aroyl fluorides to the corresponding aryl boronate esters, a transformation that would complement traditional Miyaura borylations of aryl halides in the presence of base (Scheme 21A, a). The proposed catalytic cycle (Scheme 21B) involves oxidative addition of an acid fluoride at Ni⁰, CO de-insertion, transmetalation with a diboron reagent, and C(sp²)–B bond-forming reductive elimination. Promising precedent by Nishihara (published as our work was underway) demonstrated the feasibility of this transformation with a Ni⁰/PPh₃-based catalyst.^31b However, this system required exogenous KF (<1% yield without this additive), suggesting a potentially more complex mechanistic manifold than the base-free sequence proposed in Scheme 21B. A key challenge for achieving selective catalysis is limiting re-entry of the aryl boron product into the catalytic cycle via transmetalation with the Ni^II(Ar)(F) intermediate. This consumes ArB(OR)₂ to generate Ar–Ar coupled side products.

Scheme 21.

(A) (a) Borylation of aryl halides with B₂(OR)₂ (known; requires base); (b) Proposed base-free decarbonylative borylation. (B) Catalytic cycle and key challenge

We hypothesized that re-entry of the aryl boron product into the cycle could be slowed by careful selection of the boronate ester substituents (OR). To identify the optimal OR groups, we studied the stoichiometric reaction between trans-(PCy₃)₂Ni^II (Ph)(F) and different aryl boronate esters. These reactions were monitored by NMR spectroscopy based on the appearance of the biaryl product. As shown in Scheme 22A, aryl boronic acids [ArB(OH)₂] were the most reactive, followed by aryl boronate catechol esters (ArBcat), aryl boronate neopentyl glycol esters (ArBneo), and lastly, aryl boronate pinacol esters (ArBpin).

Scheme 22.

(A) Comparing transmetalation of ArB(OH)₂, ArBcat, ArBneo, and ArBpin with D; (B) Comparing transmetalation of B₂cat₂, B₂neo₂, and B₂pin₂ with D.

An analogous study was next performed using the diboron reagents B₂cat₂, B₂neo₂, and B₂pin₂ (Scheme 22B). All three underwent transmetalation with D at room temperature. This represents strikingly higher reactivity than the arylboronate ester derivatives in Scheme 22A (which require 60–100 °C to react with D). The order of reactivity as a function of OR parallels that observed with ArB(OR)₂, with B₂cat₂ > B₂neo₂ >> B₂pin₂. Notably, the Ni^II product of transmetalation, trans-(PCy₃)₂Ni(Ph)(B(OR)₂) (E), is not detected. Instead, only starting material and the aryl boronate ester are observed, indicating that C(sp²)–B coupling is fast relative to transmetalation. Overall, these studies show a large rate difference between the transmetalation of diboron versus aryl boron reagents, particularly the Bneo and Bpin derivatives. Thus, we selected these boronate ester classes as optimal targets for selective catalysis.

To translate these stoichiometric studies to catalysis, we surveyed phosphine ligands and Ni sources. PPh₂Me (the optimal ligand for the decarbonylative Suzuki reactions) afforded some of the target product, but PCy₃ was identified as the best ligand for borylation. Ni(cod)₂ was an effective Ni⁰ source, but its air sensitivity led us to pursue Ni^II pre-catalysts. Ultimately, air-stable complex D was selected as an easy-to-handle catalyst for decarbonylative borylation. The D-catalyzed decarbonylative coupling of 4-(trifluoromethyl)benzoyl fluoride with different B₂(OR)₂ was explored (Scheme 23). Catalysis was observed at 115 °C in toluene for all three diboron reagents, but the selectivity for the aryl boronate ester versus biaryl product was highly dependent OR. B₂pin₂ afforded >40: 1 selectivity for the arylboronate ester. Selectivity decreased but remained high (18: 1) for B₂neo₂. In contrast B₂cat₂ afforded a 4.2: 1 mixture of boronate ester to biaryl. These results are consistent with the observations made during the stoichiometric studies (Scheme 22).

Scheme 23.

Ni catalyzed decarbonylative borylation: Selectivity as a function of B₂OR₂

Decreasing the temperature to 90 °C led to some improvement in the selectivity for ArB(OR)₂, particularly with B₂cat₂. However, the reaction was significantly slower; furthermore, minimal conversion was observed at lower temperatures. Stoichiometric studies show that each step of the catalytic cycle is feasible at 25 °C. However, under catalytic conditions the Ni⁰ catalyst is sequestered by CO that builds up during the reaction. Elevated temperatures are then required to release CO from (PCy₃)₂Ni(CO)₂, allowing active Ni⁰ to re-enter the catalytic cycle. This inhibition by CO is a general challenge for decarbonylative reactions and will need to be addressed in order to achieve milder conditions and lower catalyst loadings in these transformations.

Catalyst D was applied to the decarbonylative borylation of a series of aroyl fluoride substrates (Scheme 24). Again, the aroyl fluorides could be generated in situ from ArCO2H via deoxyfluorination with TFFH and Proton Sponge^®. Bpin and Bneo products derived from bioactive carboxylic acid starting materials, including bexarotene, tamibarotene, probenecid, and aspirin, were accessed in high yield and high selectivity.²¹ Following our report, several other groups^32,33 demonstrated related decarbonylative routes to aryl stannanes and silanes.

Scheme 24.

Optimized conditions, in situ acid fluoride generation, and representative scope.

Decarbonylative fluoroalkylation using difluoroacetyl fluoride.

We next targeted the decarbonylative coupling of fluoroalkyl acid fluorides [R_FC(O)F] with aryl organometallics to access fluoroalkylated arenes (Ar–R_F; Scheme 25A, c). Traditional cross-coupling approaches to Ar–R_F involve the reaction of aryl halides or pseudohalides with fluoroalkyl nucleophiles (Scheme 25A, a).^34,35 More recently, decarbonylative methods using aroyl halide electrophiles in combination with fluoroalkyl nucleophiles have been demonstrated (Scheme 25A, b and Scheme 20).^7c,26 While these latter approaches offer some key advantages (for instance, the reaction with aroyl chlorides proceeds at room temperature), they require the use of fluoroalkyl nucleophiles (e.g., R₃SiR_F), which have limited availability with diverse R_F groups and can be unstable under basic cross-coupling conditions.³⁶ In contrast, the proposed decarbonylative approach³⁷ would, in principle, enable coupling the dozens of commercially available and inexpensive fluoroalkyl carboxylic acid derivatives with aryl organometallics under base-free conditions (Scheme 25A, c).

Scheme 25.

(A) (a) Cross-coupling of aryl halides with fluoroalkyl organometallics (known, requires base); (b) Decarbonylative coupling of aroyl halides with fluoroalkyl organometallics (known, uses base); (c) Proposed decarbonylative coupling of R_FC(O)F with aryl organometallics. (B) Catalytic cycle and key challenge

The proposed catalytic cycle (Scheme 25B) involves oxidative addition of R_FC(O)F at M⁰, CO de-insertion, transmetalation with an aryl nucleophile, and Ar–R_F bond-forming reductive elimination. A key challenge for achieving productive catalysis is the high electrophilicity of R_FC(O)F, which renders these reagents susceptible to hydrolysis to the corresponding carboxylic acids or uncatalyzed addition of organometallic nucleophiles to form fluoroalkyl ketones (Scheme 25B).

Initial studies focused on identifying an organometallic reagent that minimizes uncatalyzed side reactions with fluoroalkyl acid fluorides. Difluoroacetyl fluoride (DFAF) was selected as the electrophile, and a series of aryl organometallics were explored (Scheme 26). Strongly nucleophilic diaryl zinc reagents react rapidly with DFAF to form ketones. Boronic acids react under analogous conditions to generate difluoroacetic acid. However, neopentylboronate esters (ArBneo), which are less reactive^6b than Ar₂Zn or ArB(OH)₂ and do not contain OH groups, show minimal background reaction with DFAF at 25 or 60 °C.

Scheme 26.

Identifying an aryl organometallic reagent compatible with DFAF

With ArBneo derivatives identified as compatible nucleophiles, we interrogated Ni-based catalysts for the decarbonylative coupling of DFAF with 4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)benzonitrile (Scheme 27). None of the target product, 4-(difluoromethyl)benzonitrile, was formed using PPh₂Me and PCy₃, monodentate ligands that were optimal for the decarbonylative Suzuki and borylation reactions. Based on our investigations of S–CF₂H couplings (Scheme 9B),^6d we hypothesized that reductive elimination would be challenging in this system. As such, we next moved to bidentate phosphinoferrocene ligands, which were effective in these earlier studies.^6d,20 Gratifyingly, dppf and t-Buppf afforded 14% and 18% of the target product, respectively. However, all attempts at further optimization to increase the yield proved unsuccessful.

Scheme 27.

Ligand screen for Ni-catalyzed decarbonylative difluoromethylation.

We hypothesized that the challenges associated with reductive elimination could be addressed by moving to Pd-based catalysts.¹⁰ While our previous studies (Scheme 14) showed that oxidative addition and CO de-insertion with aroyl fluorides are challenging at Pd centers, we noted that DFAF is significantly more electrophilic, which should lead to enhanced reactivity. Indeed, a screen of dialkylbiaryl phosphine ligands revealed that SPhos is effective for the catalytic decarbonylative coupling of DFAF with neopenylboronate esters. A representative scope of this transformation is shown in Scheme 28. Notably, it is currently significantly more limited²¹ than many of the other transformations in Scheme 25A. For instance, electron-deficient boronate esters are effective substrates, but minimal reactivity is observed with electron-neutral and -rich derivatives. The origin of this effect is under active investigation. In addition, we are working to expand this method to other fluoroalkyl (R_F) carboxylic acid derivatives, so as to fully exploit this readily available and inexpensive pool of reactants.

Scheme 28.

Selected scope for decarbonylative difluoromethylation of aryl boronate esters with DFAF

Decarbonylative amination of aryl esters.

A final study targeted decarbonylative amination to convert carboxylic acid derivatives to the corresponding amines (Scheme 29A, b). These transformations complement the Buchwald-Hartwig cross-coupling of aryl (pseudo)halides with amines in the presence of base (Scheme 29A, a).³⁸ Advantages of the decarbonylative approach include the use of readily available carboxylic acid starting materials and the ability to perform C(sp²)–N coupling in the absence of exogeneous base. The proposed mechanism (Scheme 29B) involves oxidative addition of ArC(O)X at M⁰, carbonyl de-insertion, transmetalation of a nitrogen-containing organometallic reagent, and C(sp²)–N bond-forming reductive elimination. The key challenge is identifying the optimal pairing of carboxylic acid derivative and nitrogen-organometallic to minimize acyl transfer reactions (Scheme 29B). As detailed below, most reagent combinations, particularly those involving nucleophilic 1° and 2° alkylamines, result in rapid uncatalyzed acyl transfer to generate amides.

Scheme 29.

(A) (a) Buchwald-Hartwig coupling of aryl halides with amines (known, requires base); (b) Proposed decarbonylative amination. (B) Catalytic cycle and key challenge

This challenge was highlighted in a 2017 paper³⁹ that demonstrated the Ni/dcype (dicyclohexylphosphinoethane)-catalyzed decarbonylative amination of phenolate esters with benzophenone imine in the presence of excess K₃PO₄ (Scheme 30, a). Benzophenone imine was an effective coupling partner due to its low nucleophilicity, which limited background amidation. However, attempts to use basic amines such as morpholine resulted in quantitative formation of the corresponding amide (Scheme 30, b).

Scheme 30.

(a) Rueping’s decarbonylative amination with benzophenone imine/base; (b) Background amidation with morpholine.

We hypothesized that amidation could be minimized by two key modifications: (1) using silylamines (R’₃SiNR₂) as weakly nucleophilic N-sources and (2) conducting the reactions under base-free conditions, wherein selective transmetalation between R’₃SiNR₂ and Ni would be selectively enabled by an appropriate X-ligand [derived from ArC(O)X]. To test this proposal, we first investigated the background reaction of trimethylsilylmorpholine with an aroyl chloride, fluoride, and phenolate ester, at 100 °C (Scheme 31A). Minimal amide formation was observed with the phenolate ester (versus ≥75% with the other two partners), indicating that the phenolate ester is a good choice to minimize background reactivity.

Scheme 31.

(A) Background acyl transfer between carboxylic acid derivatives and TMS-morpholine. (B) Transmetalation between E and TMS–indole.

We next examined whether a phenoxide ligand can promote transmetalation of a silylamine at Ni^II by evaluating the stoichiometric reaction of (dcype)Ni^II(Ph)(OPh), E, with TMS-indole (Scheme 31B). Transmetalation occurred within 1 h at 25 °C to afford Ni^II(aryl)(amine) intermediate, F. Heating F to 120 °C then resulted in C(sp²)–N coupling to afford 1-phenylindole.

These stoichiometric studies results support the feasibility of base-free decarbonylative coupling between aryl phenolate esters and TMS-amines. As such, we explored the target transformation using Ni/dcype-based catalysts (Scheme 32). Dcype was selected as the ligand based on Rueping’s work demonstrating that this ligand is effective for promoting C–N bond-forming reductive elimination at Ni^II.³⁹ At 150 °C, the Ni-catalyzed reaction of phenyl 4-(trifluoromethyl)benzoate with TMS-morpholine yielded the aryl amine product 4-(4-(trifluoromethyl)phenyl)morpholine in 90% yield and with >20:1 selectivity over the amide.

Scheme 32.

Ni/dcype-catalyzed decarbonylative amination

This Ni/dcype-catalyzed decarbonylative amination proved applicable to various amine and phenolate ester coupling partners (Scheme 33). The TMS-amines could be generated in situ by prestirring a solution of amine and N-methyl-N-(trimethylsilyl)trifluoroacetamide (MSTFA) and then adding the remaining reagents. A wide scope of 1° and 2° alkyl and aromatic amine coupling partners were effective, including base-sensitive amines such as 2,2-difluoroethan-1-amine and 2,2,2-trifluoroethan-1-amine.

Scheme 33.

Selected scope for Ni/dcype catalyzed decarbonylative amination with probenecid phenyl ester.

6. SUMMARY AND CONCLUSIONS

This Account demonstrates the diversity of intra- and intermolecular decarbonylative coupling reactions that have been developed in our lab. We highlight how the interrogation of catalytic intermediates provides key information about the impact of metal and ligand on the relative rates of oxidative addition, carbonyl de-insertion, transmetalation, and reductive elimination in these systems. These insights can then be applied to address reactivity and selectivity challenges in catalysis. We also show how the interrogation of unsuccessful reactions (for instance, the attempted conversion of aroyl fluorides to aryl fluorides) can lead to new chemistry (repurposing Ni^II(Ar)(F) intermediates for base-free intermolecular couplings).

Despite significant progress, there are still major challenges in this area. For instance, moving forward it will be critical to identify more effective catalyst systems for challenging bond formations, including carbon–fluorine, carbon–fluoroalkyl, and carbon–oxygen coupling reactions. Furthermore, decarbonylative reactions that engage C(sp³)-hybridized coupling partners remain rare, largely due to competing beta-hydride elimination from intermediate II. General solutions to this problem will provide access to a more diverse array of products.

Another ongoing challenge is identifying general strategies for achieving decarbonylative couplings under milder conditions (<100 °C) and with lower catalyst loadings (<5 mol %). These limitations stem from inhibition by the CO by-product, which binds strongly to M⁰ intermediates. Identifying M⁰ catalysts that are resistant to CO binding and/or approaches to efficiently remove CO will be essential for rendering these reactions more practical and scalable. Current work in our lab aims to address these challenges and thus provide the community with new, broadly applicable transition-metal catalyzed decarbonylative coupling reactions.

Biographies

Naish Lalloo grew up in Waxhaw, NC. He received his undergraduate degree in the Chemistry Honors program from North Carolina State University (NCSU) in 2017 and PhD from the University of Michigan (in 2022). Naish recently returned to NCSU to begin his career as an Assistant Teaching Professor of Chemistry.

Conor Brigham grew up in Sandwich, MA. He received his Bachelor’s degree in Biochemistry from Loyola University Chicago (in 2017) and PhD in Chemistry from the University of Michigan (in 2022). His current role is as a medicinal chemist at Roivant Sciences in Boston, MA.

Melanie S. Sanford grew up in Providence, RI. She received her undergraduate degree in chemistry from Yale (in 1996) and PhD from Caltech (in 2001). She was an NIH NRSA post-doctoral fellow at Princeton University (2001–3). She started her independent career at the University of Michigan in 2003 and is currently the Moses Gomberg Distinguished University Professor of Chemistry and Arthur F. Thurnau Professor of Chemistry.