1 A general strategy for C(sp3)–H functionalization with nucleophiles using 2 methyl radical as a hydrogen atom abstractor 3 4 Isabelle Nathalie-Marie Leibler,‡ Makeda A. Tekle-Smith,‡ and Abigail G. Doyle 5 6 Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States 7
8 The development of general strategies for C(sp3)–H functionalization is critical to the
9 advancement of modern methods for molecular diversification. In recent years, photoredox
10 catalysis has provided many approaches to C(sp3)–H functionalization that enable selective
11 oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical.
12 While highly enabling, functionalization of the carbon-centered radical is largely mediated
13 by electrophilic reagents, many of which require multi-step preparation and feature low
14 functional group tolerance. By contrast, nucleophilic reagents represent an abundant and
15 practical reagent class. However, few strategies for nucleophilic C(sp3)–H functionalization
16 from carbon-centered radicals have been identified and existing methodologies either
17 require strong stoichiometric oxidants or are not general for diverse nucleophile
18 incorporation. Here we describe a strategy that transforms C(sp3)–H bonds into
19 carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar
20 crossover, effecting formal hydride abstraction in the absence of a strong Lewis acid or
21 strong oxidant. The resulting carbocation can be functionalized by a variety of
22 nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an
23 azide—to affect diverse bond formations. Reaction development is demonstrated in the
24 context of nucleophilic fluorination of secondary and tertiary benzylic and allylic C(sp3)–H
25 bonds and is applicable to late-stage diversification of bioactive molecules. Mechanistic
26 studies indicate that HAT is mediated by methyl radical, a previously unexplored HAT agent 27 with complementary polarity to those used in photoredox catalysis. Accordingly, this
28 method can deliver unique site-selectivity for late-stage C(sp3)–H functionalization, as
29 illustrated for the fluorination of ibuprofen ethyl ester.
30 Catalytic methods for C(sp3)–H functionalization are of broad value for the construction of
31 synthetic building blocks from feedstock chemicals and for the late-stage derivatization of complex
32 molecules.1,2 While significant progress has been made in this area, interfacing the cleavage of
33 strong bonds with diverse and useful functionalization remains an outstanding challenge. Chemists
34 have identified multiple strategies for C(sp3)–H bond cleavage: oxidative addition with a transition
35 metal, concerted C(sp3)–H insertion, heterolytic cleavage via deprotonation or hydride abstraction,
36 and homolytic cleavage via hydrogen atom transfer (HAT) (Figure 1A).3–9 Among these tactics,
37 hydride abstraction has seen limited development as a result of the requirement for exceptionally
38 strong Lewis acids, which are often incompatible with desirable substrates and functionalization
39 reagents.6 Nevertheless, access to a carbocation from a C(sp3)–H bond represents a valuable
40 disconnection due to the versatility of the functionalization step, which can be general for a variety
41 of heteroatom and carbon-centered nucleophiles in their native state.
42 In contrast to hydride abstraction, HAT can offer a mild and versatile approach to C(sp3)–H
43 cleavage through the conversion of C(sp3)–H bonds to radical intermediates.8,10 While strategies
44 for the homolytic cleavage of C(sp3)–H bonds have been highly enabling, radical functionalization
45 in these methodologies is primarily restricted to electrophilic reagents (e.g., Selectfluor for
46 fluorination, peroxides for alkoxylation, azodicarboxylates for amination, and electron-deficient
47 arenes for C–C bond formation) (Figure 1B).11–15 Electrophilic reagents are often strong oxidants,
48 expensive to purchase, or require multi-step synthesis, posing significant limitations to their
49 use.16,17 Whereas nucleophilic reagents represent an abundant and practical reagent class, few 50 strategies have been reported for radical-based C(sp3)–H functionalization with nucleophiles.4,7,18–
51 20 This deficit likely reflects the challenge of productively engaging a nucleophilic carbon-centered
52 radical with a nucleophilic functionalizing reagent.21
A. C(sp3)–H bond-breaking strategies C. Prior art: Radical relay for nucleophilic C(sp3)–H functionalization Groves Cl Ar + H Nu N R R LMn, PhIO Ar N hydride nucleophiles MnIII N H abstraction FG N Ar nucleophile R R R R Ar HAT electrophiles Nu: F, Cl, N3 LMn R R Stahl O X O H LCu, NFSI Nu B. C(sp3)–H diversification reagents N N Cu Ar Me nucleophile Ar Me R R Electrophile Pool Nucleophile Pool Nu: ROH, CN, N3 LCu O MX H O R NH X RO2C N 2 2 2 N CO R 3 2 Me D. This work: Radical-polar crossover for nucleophilic C(sp )–H functionalization Bu4N X NaN3 RSH Cl Radical-Polar Crossover N Me H Nu O O R S OSiR3 R R3 N S R 18 HAT 3 Nu N 2X [ F]KF EDG R1 R1 R3 R3 X OR R1 R2 R2 R1 F R2 R2
Nu: F, Cl, ROH, RSH, ArH, N multi-step preparation inexpensive, native functionality 3 often strong oxidants functional group tolerant mild conditions modular strategy complementary site-selectivity 53 54 Figure 1. (A) Current mechanisms employed for C(sp3)–H activation and subsequent 55 functionalization. (B) Array of common electrophilic and nucleophilic functionalizing reagents. 56 (C) Recent examples of nucleophilic C(sp3)–H functionalization.22–28 (D) This work. HAT = 57 hydrogen atom transfer.
58 Recent contributions have centered on the use of a transition-metal catalyst to mediate radical
59 capture and bond formation, rendering the nucleophile an electrophilic ligand in the presence of a
60 stoichiometric oxidant. For example, Stahl and coworkers have demonstrated the utility of copper-
61 catalysis for several nucleophilic C(sp3)–H functionalization methods, including C(sp3)–H
62 etherification, cyanation, and azidation (Figure 1C).22–24 Additionally, seminal work from Groves
63 and coworkers has provided strategies for nucleophilic C(sp3)–H halogenation and azidation using
64 a bioinspired Mn porphyrin catalyst (Figure 1C).25–28 Zhang and coworkers have also developed
65 a fluorination of C(sp3)–H bonds using a CuIII fluoride complex generated in situ from fluoride.29
66 While highly enabling, the requirement for strong or super-stoichiometric oxidants in these
67 methods limits their application in synthesis and generality across diverse nucleophile coupling 68 partners.19 Thus, the identification of mechanistically distinct strategies for the application of
69 nucleophilic coupling partners could advance the scope and practicality of C(sp3)–H
70 functionalization methods in chemical synthesis.
71 Recently, we disclosed a photocatalytic strategy for the decarboxylative nucleophilic
72 fluorination of redox-active esters.30 This methodology leveraged N-acyloxyphthalimides as alkyl
73 radical precursors and an oxidative radical-polar crossover (ORPC) mechanism for the generation
74 of a carbocation poised for nucleophilic addition.31 Seeking to develop a modular nucleophilic
75 C(sp3)–H functionalization without the requirement for strong oxidants, we questioned whether
76 photocatalytic ORPC could be combined with principles of HAT to achieve formal hydride
77 abstraction from C(sp3)–H bonds. Given the versatility of carbocation intermediates, such a
78 reaction platform could provide a general route to numerous desirable transformations such as
79 C(sp3)–H halogenation, hydroxylation, and C–C bond formation by combining two abundant and
80 structurally diverse feedstocks. While access to carbocation intermediates may be accomplished
81 electrochemically, contemporary methodologies are largely limited by the high overpotential
82 required for reactivity, thereby restricting the scope of amenable C(sp3)–H and nucleophile
83 coupling partners.32,33 Whereas C(sp3)–H functionalization via HAT-ORPC has been proposed in
84 a recent study from Liu and Chen, the method uses a strong, stoichiometric oxidant and solvent
85 quantities of nucleophile.7 Here we report a HAT-ORPC platform for C(sp3)–H functionalization
86 using a mild, commercially available N-acyloxyphthalimide as HAT precursor. The platform
87 enables C(sp3)–H fluorination of secondary and tertiary benzylic and allylic substrates using
3 88 Et3N•3HF. Additionally, we demonstrate the versatility of the reaction platform to achieve C(sp )–
89 H chlorination, hydroxylation, etherification, thioetherification, azidation, and carbon–carbon
90 bond formation. 91 Our initial investigations focused on C(sp3)–H fluorination, a valuable transformation in
92 organic synthesis due to the unique chemical properties conferred by fluorine substitution.34,35 Few
93 reports detailing C(sp3)–H fluorination with fluoride have been disclosed, due not only to the broad
94 challenges posed by C(sp3)–H activation, but also the attenuated nucleophilicity of
95 fluoride.18,25,29,36–38 Despite these challenges, the development of nucleophilic C(sp3)–H
96 fluorination methods is desirable given the low cost of fluoride sources and their application to
97 radiofluorination for positron emission tomography (PET) imaging.35
98 To evaluate the feasibility of the HAT-ORPC strategy for C(sp3)–H fluorination, we
99 investigated the conversion of diphenylmethane to fluorodiphenylmethane 2 using a variety of
100 phthalimide-derived HAT precursors (Table 1). We focused on N-acyloxyphthalimides and N-
101 alkoxyphthalimides, as these redox-active species deliver a radical HAT agent via reductive
102 fragmentation, leaving an oxidized photocatalyst available to execute ORPC; furthermore, these
103 reagents are easy to prepare and tune, and are less oxidizing than the stoichiometric oxidants used
104 in radical relay strategies.39 Optimization of the HAT precursor focused on three design elements:
105 1) redox compatibility, 2) bond dissociation energy (BDE) of the radical generated upon
106 fragmentation (favorable thermodynamics), and 3) nucleophilicity of the HAT byproduct
107 (competitive carbocation functionalization). We were pleased to find that using Ir(p-F-ppy)3 as a
108 photocatalyst, Et3N•3HF as a fluoride source, and HAT abstractor 3 (MeO–H BDE = 105
109 kcal/mol) in pivalonitrile afforded alkyl fluoride 2 in 45% yield (Table 1, entry 1).40,41 In addition
110 to desired fluoride 2, we observed generation of the corresponding benzhydryl methyl ether in 7% 111 yield, resulting from competitive trapping of O Ir(p-F-ppy)3 (1 mol%) H F O Et3N•3HF (6 equiv.)
Ph Ph N Ph Ph 112 the carbocation with methanol. Moreover, Me O t-BuCN (0.6 M) 6 equiv. 1 O 34W blue LEDs, 6 h 2 113 analysis of the reaction mixture indicated Entry Deviation % Yield 2
1a abstractor 3 45 (7) 114 poor conversion of 3, possibly arising from 2 abstractor 4 20 3 none 88 115 inefficient single-electron reduction and 4 abstractor 5 3 5 [Ir(dF-CF3-ppy)2(dtbpy)]PF6 instead of Ir(p-F-ppy)3 21 116 fragmentation of the N-alkoxyphthalimide 6 Ir(ppy)3 instead of Ir(p-F-ppy)3 43 7 MeCN instead of t-BuCN 25
8 CH2Cl2 instead of t-BuCN 44 red 42 117 (E1/2 ∼ −1.42 V vs. SCE). 9 3 equiv. diphenylmethane 53 10 1 equiv. diphenylmethane 17 11b without abstractor, without photocatalyst, without light 0 118 These observations prompted us to Cl Cl O O O O red O Cl 119 evaluate N-acyloxyphthalimide 4 (E1/2 ∼ N N MeO 4-F-C6H4 O N O O Me O Cl O 120 −1.2-1.3 V vs. SCE), a benzoyloxy radical 3 4 5
F3C PF6 F 42 F 121 precursor. Upon HAT, this radical generates N t-Bu N N
F N F Ir Ir Ir N F N N N N 122 benzoic acid, a less nucleophilic byproduct N t-Bu F F 123 than methanol. However, 4 did not improve F3C Ir(p-F-ppy)3 [Ir(dF-CF3-ppy)2(dtbpy)]PF6 Ir(ppy)3 IrIV/*IrIII = -1.9 V IrIV/*IrIII = -0.89 V IrIV/*IrIII = -1.73 V IV III IV III IV III 124 the reaction yield (Table 1, entry 2), likely Ir /Ir = 0.96 V Ir /Ir = 1.7 V Ir /Ir = 0.78 V Table 1. Reactions performed on 0.15 mmol 125 due to competitive generation of the scale with 1-fluoronaphthalene added as an external standard (19F NMR yield). t-BuCN = 126 insufficiently reactive phthalimide radical pivalonitrile. All potentials given are versus a saturated calomel electrode (SCE) and taken 127 upon SET and fragmentation (phthalimide from ref. 46. aParentheses indicate yield of the benzhydryl methyl ether product (1H NMR 128 N–H BDE = 89.1 kcal/mol vs. benzoic acid yield). bEach control reaction was completed independently in the absence of key reaction 129 O–H BDE = 111 kcal/mol).43 Instead, we components.
130 found that N-acyloxyphthalimide 1 —a methyl radical precursor— was the most effective HAT
131 reagent, delivering the desired fluoride 2 in 88% yield (Table 1, entry 3). Abstractor 1 is likely
132 effective because there is a strong thermodynamic and entropic driving force associated with
133 formation of methane (BDE = 105 kcal/mol), an inert, non-nucleophilic byproduct.40 Notably, 1 is 134 commercially available and can also be prepared on multi-decagram scale in one step from low-
135 cost, readily available materials.44 Tetrachlorophthalimide analogue 5 was also investigated, but
45 136 the poor solubility of 5 led to trace conversion (Table 1, entry 4). With 1, Ir(p-F-ppy)3 was the
137 optimal photocatalyst for this transformation, presumably because Ir(p-F-ppy)3 allows for both the
III IV red 138 reductive generation of methyl radical (*Ir /Ir E1/2 = -1.9 V vs. SCE for Ir(p-F-ppy)3 and E1/2
IV III 139 = -1.24 V vs. SCE for 1) and the oxidation of diphenylmethyl radical (Ir /Ir E1/2 = 0.96 V vs.
ox 42,46,47 140 SCE and E1/2 = 0.35 V vs. SCE for 2° benzylic). Use of either less reducing or less oxidizing
141 photocatalysts resulted in diminished yields (Table 1, entries 5-6). While highest yields were
142 observed with 6 equivalents of the C(sp3)–H partner, 3 equivalents and 1 equivalent of the substrate
143 could also be used, albeit with diminished reactivity (53% and 17% yield respectively) (Table 1,
144 entry 9 and 10). Finally, control reactions indicate that HAT reagent 1, photocatalyst, and light
145 are all necessary for reactivity (Table 1, entry 11).
146 With optimized conditions established, we set out to examine the scope of C(sp3)–H
147 fluorination (Figure 2). Notably, benzhydryl C(sp3)–H partners supplied fluorinated products in
148 good to excellent yield (2, 6-10). ortho-Substitution was also tolerated (9). For substrates
149 possessing both primary and secondary benzylic C(sp3)–H bonds (8-10), excellent regioselectivity
150 was observed for secondary benzylic fluorination (e.g., 10:1 2°:1° for 8, >20:1 2°:1° for 9 and 10).
151 Next, a series of electronically diverse ethylbenzene derivatives were examined. A broad range of
152 functional group handles, including halogen (16-18), ether (11 and 12), carbonyl (19 and 20),
153 nitrile (22), and trifluoromethyl (21) substituents, afforded the corresponding fluorinated products.
154 Electron-rich functionality, traditionally vulnerable to electrophilic reagents or stoichiometric
155 oxidants, was well tolerated (11 and 12).48,49 In general, electron-rich ethylbenzenes displayed
156 higher reactivity (11-13 and 15) than more electron-deficient analogues (19-22). This trend is 157 consistent with electron donating substituents conferring higher carbocation stability than electron
158 withdrawing analogues. For substrates possessing multiple secondary benzylic C(sp3)–H bonds,
159 selective monofluorination was observed (23-25). The geometric constraints inherent to the
160 frameworks of acenaphthene and 9H-fluorene resulted in diminished yields, suggesting that
161 carbocation planarity and stabilizing hyperconjugation effects are advantageous structural
162 characteristics (25 and 26).50
Ir(p-F-ppy) (1 mol%) H 3 F 1 (1 equiv.)
R Et3N•3HF R R t-BuCN (0.6 M) R 34W blue LEDs, 6 h
benzylic fluorination F
F 2 H 80% yield F 11 OPh 52% yield 15 Ph 65% yield 19 CO2Me 21% yield Me 6 F 77% yield Me 12 OMe 36% yield 16 F 38% yield 20 COMe 14% yield
7 Cl 50% yield 13 Me 44% yield 17 Cl 35% yield 21 CF3 11% yield R R 9 ortho 43% yield R 1,6-8 8 Me 58% yield 10 para 61% yield 11-22 14 H 38% yield 18 Br 31% yield 22 CN 11% yield
F i-Pr F F F F F F F Cl Me Ph Me Ph Cl Me Me i-Pr
23 68% yield 24 41% yield 25 29% yielda 26 29% yielda 27 27% yield 28 58% yield 29 55% yield 30 95% yielda
Me F F F Me F F O t-Bu N O S Me Me Ph Me Me Me Ph HO N N S S F Br Me F Me O MeCO2 O2CMe 31 63% yield 32 47% yield 33 20% yield 34 71% yield 35 43% yielda 36 68% yield 37 49% yielda febuxostat derivative celestolide bisacodyl
allylic fluorination aliphatic fluorination
H O Me F O F F F O O Me Me Me HO OMe OEt O H Me F Me F O OMe 38 34% yield, 2.4:1 rr 39 55% yield 40 14% yield 41 33% yielda, 4.5:1 dr 42 15% yielda,b 43 15% yieldc, 14:1 rr ibuprofen ethyl ester rotenone 163 164 Figure 2. Scope of C(sp3)–H fluorination (0.25 mmol scale, 6.0 equiv. C(sp3)–H coupling partner, 19 a 3 b 165 6.0 equiv. Et3N•3HF, F NMR yields). 3.0 equiv. C(sp )–H coupling partner. Reaction c 166 performed with 20 mol % n-Bu4NPF6. Reaction performed using Ir(p-CF3-ppy)3 as photocatalyst, 167 1,2-difluorobenzene as solvent, and abstractor 3. 168 Tertiary benzylic C(sp3)–H partners underwent functionalization to generate fluorinated
169 products often inaccessible via nucleophilic fluorination due to slow substitution and competitive
170 elimination (28, 29, and 35).51 Fluorination of benzal chloride yielded a tetra-substituted center
171 with mixed multi-halogenation (27). Moreover, fluorination of triphenylmethane proceeded in 172 95% yield from only 3 equiv. of the C(sp3)–H coupling partner (30). Notably, 4-pyridyl
173 diphenylmethane underwent fluorination in 63% yield, demonstrating tolerance to a valuable N-
174 heterocycle scaffold (31).52 Other heterocycles such as thiophenes, furans, and thiazoles were also
175 tolerated under the reaction conditions (32-35). Since many bioactive compounds contain
176 heterocyclic fragments, this observation prompted us to evaluate the method for the late-stage
177 derivatization of various pharmaceuticals and complex molecules. Gratifyingly, commercially
178 available bioactive molecules such as a febuxostat derivative, celestolide, bisacodyl, and ibuprofen
179 ethyl ester gave the corresponding fluorinated products in 43%, 68%, 49%, and 34% yield,
180 respectively (35-38).
181 Nucleophilic fluorination could also be extended to allylic C(sp3)–H coupling partners. Allylic
182 fluorides are valuable motifs in medicinal chemistry and are useful building blocks in synthesis.53
183 The development of allylic C(sp3)–H fluorination methods has proven challenging, as most
184 electrophilic reagents and stoichiometric oxidants utilized in fluorination methodologies favor
185 olefin oxidation over C(sp3)–H functionalization; alternatively most sources of fluoride facilitate
186 competitive elimination.29,37,54,55 As an illustration of the mildness of a HAT-ORPC strategy, the
187 fluorination of cyclohexene proceeded in 55% yield (39), a significant improvement to our prior
188 efforts in the allylic C(sp3)–H fluorination of this substrate using a Pd/Cr cocatalyst system.37
189 Furthermore, the fluorination of 4-methyl-2-pentenoic acid and the pesticide rotenone occurred in
190 14% and 33% yield, respectively (40 and 41). Finally, as a proof of concept, the unactivated
191 C(sp3)–H scaffolds of cyclooctane and adamantane underwent fluorination to deliver 42 and 43 in
192 low yield. 193 Difluoromethylene units have emerged as
Ir(p-F-ppy)3 H Cl H F F F Et3N•3HF 1, Et3N•3HF 194 important lipophilic bioisosteres of hydroxyl R R R t-BuCN 34W blue LEDs, 6 h 195 and thiol functional groups in drug design.56
F F F F 196 Deoxyfluorination with (diethylamino)sulfur Me t-Bu 197 trifluoride (DAST) and pre-oxidized ketones is 44 63% yield 45 29% yield Figure 3. Scope of C(sp3)–H difluorination (0.25 198 typically used to install this group.57 mmol scale, 19F NMR yield). See SI for reaction 199 However, given the handling difficulties details.
200 associated with DAST and its tendency to promote elimination, novel strategies for
201 difluoromethylation are in high demand. We envisioned that benzylic fluorides generated in situ
202 from their monochlorinated precursors could deliver difluorinated products under optimized
203 C(sp3)–H fluorination conditions. To our delight, difluorinated products 44 and 45 were obtained
204 in 63% and 29% yield from the corresponding benzyl chloride (Figure 3). To our knowledge, this
205 represents the first nucleophilic C(sp3)–H fluorination to achieve difluorinated motifs. Notably,
206 difunctionalization is not observed to an appreciable extent in the fluorination of ArCH2R
207 precursors, even though HAT with the mono-fluorinated product is favorable on account of weaker
208 BDFEs and polarity matching (methyl radical is mildly nucleophilic).58 We hypothesize that
209 monofluorination selectivity results from the relative stoichiometry of starting material and
210 abstractor, which likely serves to mitigate unproductive side-reactivity involving methyl radical.59
211 Next, we evaluated whether this strategy could serve as a platform for C(sp3)–H
212 functionalization with other nucleophiles (Figure 4). Indeed, we were pleased to find that only
213 minor adjustments to the standard fluorination conditions were needed to accommodate
214 nucleophiles other than Et3N•3HF. Irradiation of 4,4′-difluorodiphenylmethane with 1 mol % Ir(p-
215 F-ppy)3, 15 mol % Et3N•3HF, HAT precursor 1, and 6 equiv. of water in pivalonitrile afforded 216 benzhydryl alcohol 46 in 36% yield (vide infra). Hydroxylation took place with no evidence of
217 overoxidation to the ketone in the synthesis of both 46 and 47, a common limitation of many
218 C(sp3)–H oxidation methods.60 These conditions were also amenable to the hydroxylation of a
3 219 tertiary C(sp )–H substrate (57). Furthermore, nucleophiles such as methanol and methanol-d4
220 afforded methyl ether products 48 and 49 in 40% and 42% yield, respectively. More complex
221 oxygen-centered nucleophiles, including a 1,3-diol and dec-9-en-1-ol, were also compatible (52
222 and 53). Furthermore, we were pleased to accomplish the installation of a C(sp3)–Cl bond using
61 3 223 HCl•Et2O as a nucleophile (50), and to discover that C(sp )–N bond formation could be achieved
224 through cross coupling with azidotrimethylsilane (51). The construction of medicinally valuable
225 thioethers was also possible, using cyclohexanethiol (54) and methylthioglycolate (55) as sulfur-
226 based nucleophiles. In particular, the implementation of sulfur nucleophiles highlights the
227 mildness of reaction conditions, as thiol oxidation could otherwise interfere with C(sp3)–S bond
228 formation under alternative C(sp3)–H functionalization approaches. Finally, carbon–carbon bond
229 formation via a mild, direct Friedel-Crafts alkylation was accomplished in 41% yield from the
230 coupling of 1,3,5-trimethoxybenzene and 4,4′-difluorodiphenylmethane (56). Friedel-Crafts
231 reactions typically require pre-oxidized substrates—such as alkyl halides—and Lewis or Brønsted
232 acid conditions that are often incompatible with the desired nucleophiles.62,63 Ir(p-F-ppy)3 (1 mol%) Et N•3HF (0.15 equiv.) H 3 Nu 1 (1 equiv.) nucleophile t-BuCN (0.6 M) F F 34W blue LEDs, 24 h F F
18 OH OH OMe OCD3 Cl N3
46 36% yieldb 47 40% yieldb 48 40% yieldb,c 49 42% yieldb,c 50 25% yieldd 51 17% yieldb,e
tertiary hydroxylation OMe OH O O S Ph 7 S O Me Me HO MeO MeO OMe
52 42% yielda 53 33% yielda 54 31% yieldc 55 30% yieldc 56 41% yielda 57 41% yield 233 234 Figure 4. Scope of general nucleophilic C(sp3)–H functionalization (0.25 mmol, 6.0 equiv. C(sp3)– 235 H coupling partner, 6.0 equiv. nucleophile, isolated yields). a 3.0 equiv. nucleophile. b 19F NMR c d e 236 yield. 6 hour reaction. Reaction was performed without Et3N•3HF. Reaction was performed 237 without Et3N•3HF and with 0.15 equiv. H2O. 238 Having evaluated the scope of this transformation, we set out to interrogate its mechanism
239 (Figure 5). According to our prior studies30 and literature precedent64, we propose that visible light
240 irradiation of the photocatalyst Ir(p-F-ppy)3 generates a long-lived excited state that serves as a
241 single-electron reductant of 1. Fragmentation of the resulting radical anion followed by extrusion
242 of CO2 forms phthalimide anion and methyl radical. Since methyl radical is thermodynamically
243 disfavored to undergo oxidation by IrIV, it is instead available to facilitate HAT with the C(sp3)−H
ox 244 coupling partner to deliver a carbon-centered radical and methane as a byproduct (E1/2 ~2.5 V
245 vs. SCE for methyl radical). Oxidative radical-polar crossover between IrIV and the substrate
246 radical generates a carbocation and turns over the photocatalyst. Subsequent nucleophilic trapping
247 of the carbocation intermediate furnishes the desired product (Figure 5A). A. Catalytic Cycle C. Selectivity Competition Experiments
H H F F reaction conditionsa Nu Nu Me Me R'' Ph Ph Me Ph Ph Me III R Me Me hυ Ir R' R R'' nucleophile R' 5 equiv. 5 equiv. 28 14 visible light trapping 65% : 35% SET
H H F F R reaction conditionsa R'' photocatalytic cycle R H Ph Me Ph Ph Me Ph R'' R' R' 5 equiv. 5 equiv. 14 60 *IrIII IrIV 95% : 5% reductant oxidant D. Intermolecular KIE Experiment HAT H F reaction conditionsa SET Ph Me Ph Me O O 6 equiv. 14 CO2 Me MeH k /k = 12.1 O O H D N N D D F D Me reaction conditionsa O O 1 D5C6 CD3 D5C6 CD3 6 equiv. 61
B. Radical Trapping E. Linear Free-Energy Relationships
0.4 0.4 TEMPOb H O Me Me F OPh OPh NPhth reaction Me N Me 0.2 Me 0.2 Me a OMe Ph Ph Me O conditions O Ph Ph OMe Me F R/H 0.0 R/H 0.0 H 1 58 32% yield 2 4% yield H Cl Cl F
-0.2 -0.2 log Ratio log Ratio CN CN Ph O F Ph -0.4 -0.4 a CF CF reaction conditions y = -0.64x + 0.03 3 y = 0.21x – 16.45 3 NPhth Me R2 = 0.92 2 Ph Me O Ph R = 0.19 -0.6 -0.6 -0.5 0.0 0.5 1.0 77.0 77.5 78.0 78.5 79.0 1 59 98% yield σ 248 p BDFE (kcal/mol) 249 Figure 5. (A) Proposed catalytic cycle. (B) Radical trapping experiments. (C) Investigation of 250 regioselectivity via competition experiments among 3°, 2° and 1° C(sp3)–H coupling partners. (D) 251 Investigation of kinetic isotope effect via parallel initial rates experiment with ethylbenzene and
252 ethylbenzene-d10. (E) Hammett analysis and correlation of selectivity with computed BDFE for a 253 series of ethylbenzene derivatives (See SI). a For reaction conditions see Figure 2 (19F NMR 254 yields). b Reaction performed with 1.5 equiv. TEMPO (1H NMR yield). 255 Consistent with the proposed first step of this mechanism, emission quenching experiments
256 demonstrated that 1 is the only reaction component that quenches the excited state of the
257 photocatalyst (See SI). Our analysis also indicates that the rate of quenching is moderately
258 enhanced in the presence of Et3N•3HF. This observation is consistent with the higher yields
3 259 observed when Et3N•3HF is employed as a catalytic additive for the construction of C(sp )–O,
260 C(sp3)–S, and C(sp3)–C bonds. The presence of an acidic additive could aid reduction of 1 via
261 proton-coupled electron transfer, as reported for related systems in the literature.65 In addition, the
262 additive could prevent back-electron transfer and aid fragmentation of the reduced N-
263 acyloxyphthalimide 1. 264 Next, radical trapping experiments were conducted to evaluate the identity of key radical
265 intermediates in the proposed mechanism. When the fluorination of diphenylmethane was
266 conducted under standard conditions in the presence of 1.5 equiv. of TEMPO, we observed the
267 methyl radical–TEMPO adduct (58) in 32% yield, accompanied by nearly complete suppression
268 of fluorination (Figure 5B). Additionally, when 1,1-diphenylethylene was employed as a substrate
269 under standard conditions, nearly quantitative carbofluorination was observed, wherein methyl
270 radical addition into the olefin followed by radical oxidation and nucleophilic fluorination
271 delivered product 59. (Figure 5B). This example of carbofluorination not only provides clear
272 evidence for methyl radical formation, but also serves as a useful framework for sequential C(sp3)–
273 C(sp3) and C(sp3)–F alkene difunctionalization. As further evidence, in situ NMR studies revealed
274 evolution of methane gas as the reaction proceeded, supporting the involvement of methyl radical
275 in HAT (Figure S25).
276 To our knowledge, methyl radical guided HAT has not been previously explored for
277 photocatalytic C(sp3)–H functionalization. As such, we set out to understand the reactivity and
278 selectivity effects inherent to the system. We conducted a series of competition experiments with
279 cumene, ethylbenzene, and toluene under standard C(sp3)–H fluorination conditions (Figure 5C).
280 We found that HAT mediated by methyl radical and subsequent ORPC is preferential for 3°>2°>1°
281 benzylic C(sp3)–H bonds. The data suggest that steric or polarity effects associated with HAT from
282 a mildly nucleophilic methyl radical are minimal in these systems. Instead, the observed site-
283 selectivity is consistent with the relative BDFEs and radical oxidation potential of the tertiary,
284 secondary, and primary substrates.
285 To probe the independent roles of HAT and radical oxidation, we first conducted a kinetic
286 isotope effect (KIE) study with ethylbenzene. A KIE of 12.1 was measured via parallel initial rate 287 experiments using ethylbenzene and ethylbenzene-d10 (Figure 5D). The magnitude of the KIE is
288 consistent with prior studies of HAT involving methyl radical and suggests that HAT is the
289 turnover-limiting step.66,67 To probe the effect of electronics on a HAT-ORPC mechanism, a
290 Hammett analysis of the relative rate of benzylic fluorination across a series of para-substituted
291 ethylbenzenes (determined by competition experiments, see SI) was performed (Figure 5E).
292 Given the mild nucleophilicity of methyl radical, we might expect electron-deficient ethylbenzenes
293 to undergo fluorination at a faster rate than electron-rich ethylbenzenes. However, the measured r
294 value of -0.64 ± 0.07 (R2 = 0.92) indicates that electron-rich ethylbenzenes undergo C(sp3)–H
295 fluorination more favorably than electron-deficient derivatives. We interpret this result to suggest
296 that radical oxidation—wherein electronic effects should contribute significantly to carbocation
297 stabilization—is irreversible and governs product distribution. Additionally, analysis of selectivity
298 outcomes with respect to computed C(sp3)–H BDFEs across the ethylbenzene series indicates no
299 significant correlation between product selectivity and BDFE (Figure 5E).68 These findings are
300 most consistent with turnover-limiting HAT followed by an irreversible, product-determining
301 radical oxidation. Further studies are ongoing to probe additional mechanistic details.
302 Altogether, this work suggests that a HAT-ORPC strategy can provide a site-selective platform
303 for C(sp3)–H functionalization. An advantage to this method is the utilization of phthalimide-
304 derived species as redox-active HAT reagents; these reagents are not only readily available, but
305 also are highly tunable. In this context, we questioned whether site-selectivity in the fluorination
306 of ibuprofen ethyl ester—a complex substrate possessing various C(sp3)–H bonds—could be tuned
307 on the basis of the radical species used in HAT (Figure 6A). Under standard conditions with the
308 methyl radical precursor 1, the fluorination of ibuprofen ethyl ester favored C(sp3)–H
309 functionalization at the tertiary benzylic site over the secondary benzylic site (38, 2.4:1 rr) (Figure 310 6A). This site-selectivity is orthogonal to previously reported HAT-guided strategies (Figure
311 6B)7,22,38 but consistent with our mechanistic studies that indicate a preference for tertiary C(sp3)–
312 H functionalization according to BDFE and radical oxidation potential considerations (Figure
313 5C). Furthermore, methyl radical is polarity matched to abstract a hydrogen atom proximal to an
314 electron withdrawing group. By contrast, the prior art relies on electrophilic HAT mediators that
315 are polarity mismatched to abstract a hydrogen atom proximal to an electron withdrawing group.
316 As such, we hypothesized that employment of 3, a precursor to the electrophilic methoxy radical,
317 would afford distinct site-selectivity, favoring more electron-rich C(sp3)–H sites. Indeed, we
318 observed a reversal of site-selectivity in this case, wherein ibuprofen ethyl ester was fluorinated in
319 31% yield with a 5.3:1.5:1 rr favoring the secondary benzylic site (62). This example demonstrates
320 the potential for this platform to engage readily available small molecule HAT reagents for tunable
321 and predictable site-selective C(sp3)–H functionalization.
A. Tunable regioselectivity guided by HAT reagent identity B. Prior ibuprofen site selectivity
H Cl Ar O I OH O O Me Ar N O IIIN O Mn N N N Ar Me N Cu O Me R R MeO Me H Me Ar ibuprofen ethyl ester Chen Groves Stahl
F NHAc F OMe Me Me O Me Me Me O O O O Me Me OEt Me Me Me OEt OMe OMe OMe Me F Me Me Me Me 47 31% yielda 38 34% yieldb regioselectivity: 5.3 : 1.5 : 1 regioselectivity: 2.4:1 precedent affords C(sp3)–H functionalization exclusively at secondary benzylic site 322 323 Figure 6. (A) Tunable selectivity for the C(sp3)–H functionalization of ibuprofen demonstrating 324 favorable secondary benzylic fluorination with methoxy radical (left) and favorable tertiary 325 benzylic fluorination with methyl radical (right). (B) Previous examples of site-selectivity in the 326 C(sp3)–H functionalization of ibuprofen. a Reaction performed using abstractor 3 and standard 327 reaction conditions described in Figure 2. b Reaction performed using abstractor 1 and standard 328 reaction conditions described in Figure 2. 329 In conclusion, we have developed a photocatalytic method that employs widely available, low-
330 cost nucleophiles and a readily accessible HAT precursor for C(sp3)–H fluorination, chlorination,
331 etherification, thioetherification, azidation, and carbon–carbon bond formation. Mechanistic 332 studies are consistent with methyl radical-mediated HAT and linear free-energy relationships
333 suggest that radical oxidation influences site-selectivity. Furthermore, this approach was highly
334 effective for the construction of multi-halogenated scaffolds and the late-stage functionalization
335 of several bioactive molecules and pharmaceuticals with tunable regioselectivity.
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506 68. BDFEs were computed according to: John, P. C. St., Guan, Y., Kim, Y., Kim, S. & Paton, R. 507 S. Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with 508 sub-second computational cost. Nat. Commun. 11, 2328 (2020). In our experience, different levels 509 of theory give slightly different ordering of the compounds by BDFE. This is due to energetic 510 differences that are small relative to the error associated with DFT. However, all levels of theory 511 evaluated gave similarly poor correlations and do not affect the conclusions drawn.
512
513
514 Data Availability
515 Materials and methods, experimental procedures, mechanistic studies, characterization data, 516 spectral data, and xyz files (in accompanying zip drive) associated with computational data are 517 available in the Supplementary Information.
518 Acknowledgements. Financial support was generously provided by NSF (CHE-1565983). M. A. 519 T.-S. wishes to thank Princeton’s Presidential Postdoctoral Fellowship for funding. István Pelzer, 520 Kenneth Conover, and John Eng are acknowledged for analytical aid. We thank Dr. Eric W. 521 Webb for early intellectual and experimental contributions to the project. 522 523 Author Contributions. Authors I. N.-M. L. and M. A. T.-S. contributed equally. 524 525 Competing Interests. The authors declare no competing interests. 526 527 Additional information 528 Supplementary information is available in the online version of the paper. 529 Correspondence and requests for materials should be addressed to A. G. D. 530 531