A general strategy for C(sp3)–H functionalization with nucleophiles using 1 methyl radical as a hydrogen atom abstractor 2
3 Isabelle Nathalie-Marie Leibler,‡ Makeda A. Tekle-Smith,‡ and Abigail G. Doyle 4
5 Department of Chemistry, Princeton University, Princeton, New Jersey 08544, United States 6
7
The development of general strategies for C(sp3)–H functionalization is critical to the 8
advancement of modern methods for molecular diversification. In recent years, photoredox 9
catalysis has provided many approaches to C(sp3)–H functionalization that enable selective 10
oxidation and C(sp3)–C bond formation via the intermediacy of a carbon-centered radical. 11
While highly enabling, functionalization of the carbon-centered radical is largely mediated 12
by electrophilic reagents, many of which require multi-step preparation and feature low 13
functional group tolerance. By contrast, nucleophilic reagents represent an abundant and 14
practical reagent class. However, few strategies for nucleophilic C(sp3)–H functionalization 15
from carbon-centered radicals have been identified and existing methodologies either 16
require strong stoichiometric oxidants or are not general for diverse nucleophile 17
incorporation. Here we describe a strategy that transforms C(sp3)–H bonds into 18
carbocations via sequential hydrogen atom transfer (HAT) and oxidative radical-polar 19
crossover, effecting formal hydride abstraction in the absence of a strong Lewis acid or 20
strong oxidant. The resulting carbocation can be functionalized by a variety of 21
nucleophiles—including halides, water, alcohols, thiols, an electron-rich arene, and an 22
azide—to affect diverse bond formations. Reaction development is demonstrated in the 23
context of nucleophilic fluorination of secondary and tertiary benzylic and allylic C(sp3)–H 24
bonds and is applicable to late-stage diversification of bioactive molecules. Mechanistic 25
studies indicate that HAT is mediated by methyl radical, a previously unexplored HAT agent 26
with complementary polarity to those used in photoredox catalysis. Accordingly, this 27
method can deliver unique site-selectivity for late-stage C(sp3)–H functionalization, as 28
illustrated for the fluorination of ibuprofen ethyl ester. 29
Catalytic methods for C(sp3)–H functionalization are of broad value for the construction of 30
synthetic building blocks from feedstock chemicals and for the late-stage derivatization of complex 31
molecules.1,2 While significant progress has been made in this area, interfacing the cleavage of 32
strong bonds with diverse and useful functionalization remains an outstanding challenge. Chemists 33
have identified multiple strategies for C(sp3)–H bond cleavage: oxidative addition with a transition 34
metal, concerted C(sp3)–H insertion, heterolytic cleavage via deprotonation or hydride abstraction, 35
and homolytic cleavage via hydrogen atom transfer (HAT) (Figure 1A).3–9 Among these tactics, 36
hydride abstraction has seen limited development as a result of the requirement for exceptionally 37
strong Lewis acids, which are often incompatible with desirable substrates and functionalization 38
reagents.6 Nevertheless, access to a carbocation from a C(sp3)–H bond represents a valuable 39
disconnection due to the versatility of the functionalization step, which can be general for a variety 40
of heteroatom and carbon-centered nucleophiles in their native state. 41
In contrast to hydride abstraction, HAT can offer a mild and versatile approach to C(sp3)–H 42
cleavage through the conversion of C(sp3)–H bonds to radical intermediates.8,10 While strategies 43
for the homolytic cleavage of C(sp3)–H bonds have been highly enabling, radical functionalization 44
in these methodologies is primarily restricted to electrophilic reagents (e.g., Selectfluor for 45
fluorination, peroxides for alkoxylation, azodicarboxylates for amination, and electron-deficient 46
arenes for C–C bond formation) (Figure 1B).11–15 Electrophilic reagents are often strong oxidants, 47
expensive to purchase, or require multi-step synthesis, posing significant limitations to their 48
use.16,17 Whereas nucleophilic reagents represent an abundant and practical reagent class, few 49
strategies have been reported for radical-based C(sp3)–H functionalization with nucleophiles.4,7,18–50
20 This deficit likely reflects the challenge of productively engaging a nucleophilic carbon-centered 51
radical with a nucleophilic functionalizing reagent.21 52
53 Figure 1. (A) Current mechanisms employed for C(sp3)–H activation and subsequent 54 functionalization. (B) Array of common electrophilic and nucleophilic functionalizing reagents. 55 (C) Recent examples of nucleophilic C(sp3)–H functionalization.22–28 (D) This work. HAT = 56 hydrogen atom transfer. 57
Recent contributions have centered on the use of a transition-metal catalyst to mediate radical 58
capture and bond formation, rendering the nucleophile an electrophilic ligand in the presence of a 59
stoichiometric oxidant. For example, Stahl and coworkers have demonstrated the utility of copper-60
catalysis for several nucleophilic C(sp3)–H functionalization methods, including C(sp3)–H 61
etherification, cyanation, and azidation (Figure 1C).22–24 Additionally, seminal work from Groves 62
and coworkers has provided strategies for nucleophilic C(sp3)–H halogenation and azidation using 63
a bioinspired Mn porphyrin catalyst (Figure 1C).25–28 Zhang and coworkers have also developed 64
a fluorination of C(sp3)–H bonds using a CuIII fluoride complex generated in situ from fluoride.29 65
While highly enabling, the requirement for strong or super-stoichiometric oxidants in these 66
methods limits their application in synthesis and generality across diverse nucleophile coupling 67
D. This work: Radical-polar crossover for nucleophilic C(sp3)–H functionalization
mild conditions modular strategy complementary site-selectivity
C. Prior art: Radical relay for nucleophilic C(sp3)–H functionalization
GrovesH Nu
LMn, PhIO
nucleophile
Stahl
H NuLCu, NFSI
nucleophileLCu
N N
NN
Ar
Ar
Ar
Ar
MnIII
Cl
Nu: F, Cl, N3
MeAr MeAr
Nu: ROH, CN, N3
N
O X
N
O
R RCu
LMn
B. C(sp3)–H diversification reagents
Electrophile Pool Nucleophile Pool
multi-step preparationoften strong oxidants
inexpensive, native functionalityfunctional group tolerant
H2O
Bu4N X
R2NH
NaN3
EDG
RSH
MX
[18F]KFOR
OSiR3
X2
NN
Cl
F2X N
X
O O
Me
ON
NRO2CCO2R
A. C(sp3)–H bond-breaking strategies
SSR
R
H
R R
R R
FG
R RHAT
hydride abstraction
R R+
electrophiles
Radical-Polar Crossover
R3R2
R1
Nu: F, Cl, ROH, RSH, ArH, N3
NuR1
R3
R2R1
R3
R2
HAT Nu
nucleophiles
R1 R2R3
HMe
partners.19 Thus, the identification of mechanistically distinct strategies for the application of 68
nucleophilic coupling partners could advance the scope and practicality of C(sp3)–H 69
functionalization methods in chemical synthesis. 70
Recently, we disclosed a photocatalytic strategy for the decarboxylative nucleophilic 71
fluorination of redox-active esters.30 This methodology leveraged N-acyloxyphthalimides as alkyl 72
radical precursors and an oxidative radical-polar crossover (ORPC) mechanism for the generation 73
of a carbocation poised for nucleophilic addition.31 Seeking to develop a modular nucleophilic 74
C(sp3)–H functionalization without the requirement for strong oxidants, we questioned whether 75
photocatalytic ORPC could be combined with principles of HAT to achieve formal hydride 76
abstraction from C(sp3)–H bonds. Given the versatility of carbocation intermediates, such a 77
reaction platform could provide a general route to numerous desirable transformations such as 78
C(sp3)–H halogenation, hydroxylation, and C–C bond formation by combining two abundant and 79
structurally diverse feedstocks. While access to carbocation intermediates may be accomplished 80
electrochemically, contemporary methodologies are largely limited by the high overpotential 81
required for reactivity, thereby restricting the scope of amenable C(sp3)–H and nucleophile 82
coupling partners.32,33 Whereas C(sp3)–H functionalization via HAT-ORPC has been proposed in 83
a recent study from Liu and Chen, the method uses a strong, stoichiometric oxidant and solvent 84
quantities of nucleophile.7 Here we report a HAT-ORPC platform for C(sp3)–H functionalization 85
using a mild, commercially available N-acyloxyphthalimide as HAT precursor. The platform 86
enables C(sp3)–H fluorination of secondary and tertiary benzylic and allylic substrates using 87
Et3N•3HF. Additionally, we demonstrate the versatility of the reaction platform to achieve C(sp3)–88
H chlorination, hydroxylation, etherification, thioetherification, azidation, and carbon–carbon 89
bond formation. 90
Our initial investigations focused on C(sp3)–H fluorination, a valuable transformation in 91
organic synthesis due to the unique chemical properties conferred by fluorine substitution.34,35 Few 92
reports detailing C(sp3)–H fluorination with fluoride have been disclosed, due not only to the broad 93
challenges posed by C(sp3)–H activation, but also the attenuated nucleophilicity of 94
fluoride.18,25,29,36–38 Despite these challenges, the development of nucleophilic C(sp3)–H 95
fluorination methods is desirable given the low cost of fluoride sources and their application to 96
radiofluorination for positron emission tomography (PET) imaging.35 97
To evaluate the feasibility of the HAT-ORPC strategy for C(sp3)–H fluorination, we 98
investigated the conversion of diphenylmethane to fluorodiphenylmethane 2 using a variety of 99
phthalimide-derived HAT precursors (Table 1). We focused on N-acyloxyphthalimides and N-100
alkoxyphthalimides, as these redox-active species deliver a radical HAT agent via reductive 101
fragmentation, leaving an oxidized photocatalyst available to execute ORPC; furthermore, these 102
reagents are easy to prepare and tune, and are less oxidizing than the stoichiometric oxidants used 103
in radical relay strategies.39 Optimization of the HAT precursor focused on three design elements: 104
1) redox compatibility, 2) bond dissociation energy (BDE) of the radical generated upon 105
fragmentation (favorable thermodynamics), and 3) nucleophilicity of the HAT byproduct 106
(competitive carbocation functionalization). We were pleased to find that using Ir(p-F-ppy)3 as a 107
photocatalyst, Et3N•3HF as a fluoride source, and HAT abstractor 3 (MeO–H BDE = 105 108
kcal/mol) in pivalonitrile afforded alkyl fluoride 2 in 45% yield (Table 1, entry 1).40,41 In addition 109
to desired fluoride 2, we observed generation of the corresponding benzhydryl methyl ether in 7% 110
yield, resulting from competitive trapping of 111
the carbocation with methanol. Moreover, 112
analysis of the reaction mixture indicated 113
poor conversion of 3, possibly arising from 114
inefficient single-electron reduction and 115
fragmentation of the N-alkoxyphthalimide 116
(E1/2red ∼ −1.42 V vs. SCE).42 117
These observations prompted us to 118
evaluate N-acyloxyphthalimide 4 (E1/2red ∼ 119
−1.2-1.3 V vs. SCE), a benzoyloxy radical 120
precursor.42 Upon HAT, this radical generates 121
benzoic acid, a less nucleophilic byproduct 122
than methanol. However, 4 did not improve 123
the reaction yield (Table 1, entry 2), likely 124
due to competitive generation of the 125
insufficiently reactive phthalimide radical 126
upon SET and fragmentation (phthalimide 127
N–H BDE = 89.1 kcal/mol vs. benzoic acid 128
O–H BDE = 111 kcal/mol).43 Instead, we 129
found that N-acyloxyphthalimide 1 —a methyl radical precursor— was the most effective HAT 130
reagent, delivering the desired fluoride 2 in 88% yield (Table 1, entry 3). Abstractor 1 is likely 131
effective because there is a strong thermodynamic and entropic driving force associated with 132
formation of methane (BDE = 105 kcal/mol), an inert, non-nucleophilic byproduct.40 Notably, 1 is 133
Table 1. Reactions performed on 0.15 mmol scale with 1-fluoronaphthalene added as an external standard (19F NMR yield). t-BuCN = pivalonitrile. All potentials given are versus a saturated calomel electrode (SCE) and taken from ref. 46. aParentheses indicate yield of the benzhydryl methyl ether product (1H NMR yield). bEach control reaction was completed independently in the absence of key reaction components.
N
O
O
O
O
4-F-C6H4
4
Deviation % Yield 2
none
CH2Cl2 instead of t-BuCN
1 equiv. diphenylmethane
abstractor 4
abstractor 3
20
abstractor 5 3
Entry
3
5
6
8
2
1a
4
2
45 (7)
88
Ir(p-F-ppy)3 (1 mol%)Et3N•3HF (6 equiv.)
t-BuCN (0.6 M)
34W blue LEDs, 6 h
Ph Ph Ph Ph
F
ON
O
OH
[Ir(dF-CF3-ppy)2(dtbpy)]PF6 instead of Ir(p-F-ppy)3
Ir(ppy)3 instead of Ir(p-F-ppy)3
without abstractor, without photocatalyst, without light
3 equiv. diphenylmethane9
10
11b
7 MeCN instead of t-BuCN
N
O
O
O
ON
O
O
MeOCl
Cl
ClCl
5
Me
3
Ir(p-F-ppy)3
21
43
25
44
53
17
0
N
FN
F
N
F
Ir
Ir(ppy)3
N
N NIr
[Ir(dF-CF3-ppy)2(dtbpy)]PF6
N
F
N
N
N
F3C
Ir
t-Bu
t-Bu
F3CF
F
F
PF6
6 equiv.Me
O
1
IrIV/*IrIII = -1.9 VIrIV/IrIII = 0.96 V
IrIV/*IrIII = -1.73 VIrIV/IrIII = 0.78 V
IrIV/*IrIII = -0.89 VIrIV/IrIII = 1.7 V
commercially available and can also be prepared on multi-decagram scale in one step from low-134
cost, readily available materials.44 Tetrachlorophthalimide analogue 5 was also investigated, but 135
the poor solubility of 5 led to trace conversion (Table 1, entry 4).45 With 1, Ir(p-F-ppy)3 was the 136
optimal photocatalyst for this transformation, presumably because Ir(p-F-ppy)3 allows for both the 137
reductive generation of methyl radical (*IrIII/IrIV E1/2 = -1.9 V vs. SCE for Ir(p-F-ppy)3 and E1/2red 138
= -1.24 V vs. SCE for 1) and the oxidation of diphenylmethyl radical (IrIV/IrIII E1/2 = 0.96 V vs. 139
SCE and E1/2ox = 0.35 V vs. SCE for 2° benzylic).42,46,47 Use of either less reducing or less oxidizing 140
photocatalysts resulted in diminished yields (Table 1, entries 5-6). While highest yields were 141
observed with 6 equivalents of the C(sp3)–H partner, 3 equivalents and 1 equivalent of the substrate 142
could also be used, albeit with diminished reactivity (53% and 17% yield respectively) (Table 1, 143
entry 9 and 10). Finally, control reactions indicate that HAT reagent 1, photocatalyst, and light 144
are all necessary for reactivity (Table 1, entry 11). 145
With optimized conditions established, we set out to examine the scope of C(sp3)–H 146
fluorination (Figure 2). Notably, benzhydryl C(sp3)–H partners supplied fluorinated products in 147
good to excellent yield (2, 6-10). ortho-Substitution was also tolerated (9). For substrates 148
possessing both primary and secondary benzylic C(sp3)–H bonds (8-10), excellent regioselectivity 149
was observed for secondary benzylic fluorination (e.g., 10:1 2°:1° for 8, >20:1 2°:1° for 9 and 10). 150
Next, a series of electronically diverse ethylbenzene derivatives were examined. A broad range of 151
functional group handles, including halogen (16-18), ether (11 and 12), carbonyl (19 and 20), 152
nitrile (22), and trifluoromethyl (21) substituents, afforded the corresponding fluorinated products. 153
Electron-rich functionality, traditionally vulnerable to electrophilic reagents or stoichiometric 154
oxidants, was well tolerated (11 and 12).48,49 In general, electron-rich ethylbenzenes displayed 155
higher reactivity (11-13 and 15) than more electron-deficient analogues (19-22). This trend is 156
consistent with electron donating substituents conferring higher carbocation stability than electron 157
withdrawing analogues. For substrates possessing multiple secondary benzylic C(sp3)–H bonds, 158
selective monofluorination was observed (23-25). The geometric constraints inherent to the 159
frameworks of acenaphthene and 9H-fluorene resulted in diminished yields, suggesting that 160
carbocation planarity and stabilizing hyperconjugation effects are advantageous structural 161
characteristics (25 and 26).50 162
163 Figure 2. Scope of C(sp3)–H fluorination (0.25 mmol scale, 6.0 equiv. C(sp3)–H coupling partner, 164 6.0 equiv. Et3N•3HF, 19F NMR yields). a 3.0 equiv. C(sp3)–H coupling partner. b Reaction 165 performed with 20 mol % n-Bu4NPF6. c Reaction performed using Ir(p-CF3-ppy)3 as photocatalyst, 166 1,2-difluorobenzene as solvent, and abstractor 3. 167
Tertiary benzylic C(sp3)–H partners underwent functionalization to generate fluorinated 168
products often inaccessible via nucleophilic fluorination due to slow substitution and competitive 169
elimination (28, 29, and 35).51 Fluorination of benzal chloride yielded a tetra-substituted center 170
with mixed multi-halogenation (27). Moreover, fluorination of triphenylmethane proceeded in 171
Ir(p-F-ppy)3 (1 mol%) 1 (1 equiv.)
t-BuCN (0.6 M)
34W blue LEDs, 6 h
R
H
RR
F
R
benzylic fluorination
26 29% yielda
FF
23 68% yield 24 41% yield
FF
25 29% yielda
allylic fluorination
31 63% yield
N
F
PhPh Me
S
F
32 47% yield
Br
Me
S
33 20% yield
F
Me
F
R11-22
111213
52% yield36% yield44% yieldMe
OPhOMe
65% yield1516 38% yieldF
Cl
Ph
17 35% yield14 38% yieldH Br18 31% yield
21% yield1920 14% yieldCOMe
CF3
CO2Me
21 11% yieldCN22 11% yield
28 58% yield
Me
F
Me
30 95% yielda
Ph
F
PhF
MeMei-Pr
i-Pr
F
39 55% yield
F
42 15% yielda,b
HO
OMe
Me F
40 14% yield
celestolide
t-Bu
OMe
Me Me
F
36 68% yieldbisacodyl
MeCO2 O2CMe
N
F
37 49% yielda
F
43 15% yieldc, 14:1 rr
34 71% yield
29 55% yield
Me
FO
MeMe
Me
HO
O
N
SF
35 43% yielda
febuxostat derivative
aliphatic fluorination
rotenone
OO
MeO
H
H
O
OMe
OMe
ibuprofen ethyl ester38 34% yield, 2.4:1 rr
Me
Me
Me
O
OEtF
41 33% yielda, 4.5:1 dr
F
Et3N•3HF
9 ortho 43% yield10 para 61% yield
F
MeF
R R
80% yield26 77% yieldF
Cl
H
7 50% yield
Me8 58% yield1,6-8
27 27% yield
Cl
F
Cl
95% yield from only 3 equiv. of the C(sp3)–H coupling partner (30). Notably, 4-pyridyl 172
diphenylmethane underwent fluorination in 63% yield, demonstrating tolerance to a valuable N-173
heterocycle scaffold (31).52 Other heterocycles such as thiophenes, furans, and thiazoles were also 174
tolerated under the reaction conditions (32-35). Since many bioactive compounds contain 175
heterocyclic fragments, this observation prompted us to evaluate the method for the late-stage 176
derivatization of various pharmaceuticals and complex molecules. Gratifyingly, commercially 177
available bioactive molecules such as a febuxostat derivative, celestolide, bisacodyl, and ibuprofen 178
ethyl ester gave the corresponding fluorinated products in 43%, 68%, 49%, and 34% yield, 179
respectively (35-38). 180
Nucleophilic fluorination could also be extended to allylic C(sp3)–H coupling partners. Allylic 181
fluorides are valuable motifs in medicinal chemistry and are useful building blocks in synthesis.53 182
The development of allylic C(sp3)–H fluorination methods has proven challenging, as most 183
electrophilic reagents and stoichiometric oxidants utilized in fluorination methodologies favor 184
olefin oxidation over C(sp3)–H functionalization; alternatively most sources of fluoride facilitate 185
competitive elimination.29,37,54,55 As an illustration of the mildness of a HAT-ORPC strategy, the 186
fluorination of cyclohexene proceeded in 55% yield (39), a significant improvement to our prior 187
efforts in the allylic C(sp3)–H fluorination of this substrate using a Pd/Cr cocatalyst system.37 188
Furthermore, the fluorination of 4-methyl-2-pentenoic acid and the pesticide rotenone occurred in 189
14% and 33% yield, respectively (40 and 41). Finally, as a proof of concept, the unactivated 190
C(sp3)–H scaffolds of cyclooctane and adamantane underwent fluorination to deliver 42 and 43 in 191
low yield. 192
Difluoromethylene units have emerged as 193
important lipophilic bioisosteres of hydroxyl 194
and thiol functional groups in drug design.56 195
Deoxyfluorination with (diethylamino)sulfur 196
trifluoride (DAST) and pre-oxidized ketones is 197
typically used to install this group.57 198
However, given the handling difficulties 199
associated with DAST and its tendency to promote elimination, novel strategies for 200
difluoromethylation are in high demand. We envisioned that benzylic fluorides generated in situ 201
from their monochlorinated precursors could deliver difluorinated products under optimized 202
C(sp3)–H fluorination conditions. To our delight, difluorinated products 44 and 45 were obtained 203
in 63% and 29% yield from the corresponding benzyl chloride (Figure 3). To our knowledge, this 204
represents the first nucleophilic C(sp3)–H fluorination to achieve difluorinated motifs. Notably, 205
difunctionalization is not observed to an appreciable extent in the fluorination of ArCH2R 206
precursors, even though HAT with the mono-fluorinated product is favorable on account of weaker 207
BDFEs and polarity matching (methyl radical is mildly nucleophilic).58 We hypothesize that 208
monofluorination selectivity results from the relative stoichiometry of starting material and 209
abstractor, which likely serves to mitigate unproductive side-reactivity involving methyl radical.59 210
Next, we evaluated whether this strategy could serve as a platform for C(sp3)–H 211
functionalization with other nucleophiles (Figure 4). Indeed, we were pleased to find that only 212
minor adjustments to the standard fluorination conditions were needed to accommodate 213
nucleophiles other than Et3N•3HF. Irradiation of 4,4′-difluorodiphenylmethane with 1 mol % Ir(p-214
F-ppy)3, 15 mol % Et3N•3HF, HAT precursor 1, and 6 equiv. of water in pivalonitrile afforded 215
Figure 3. Scope of C(sp3)–H difluorination (0.25 mmol scale, 19F NMR yield). See SI for reaction details.
Ir(p-F-ppy)31, Et3N•3HF
t-BuCN
34W blue LEDs, 6 h
H
R
Cl F
R
FH
R
FEt3N•3HF
44 63% yield
F F
45 29% yield
F
Me
F
t-Bu
benzhydryl alcohol 46 in 36% yield (vide infra). Hydroxylation took place with no evidence of 216
overoxidation to the ketone in the synthesis of both 46 and 47, a common limitation of many 217
C(sp3)–H oxidation methods.60 These conditions were also amenable to the hydroxylation of a 218
tertiary C(sp3)–H substrate (57). Furthermore, nucleophiles such as methanol and methanol-d4 219
afforded methyl ether products 48 and 49 in 40% and 42% yield, respectively. More complex 220
oxygen-centered nucleophiles, including a 1,3-diol and dec-9-en-1-ol, were also compatible (52 221
and 53). Furthermore, we were pleased to accomplish the installation of a C(sp3)–Cl bond using 222
HCl•Et2O as a nucleophile61 (50), and to discover that C(sp3)–N bond formation could be achieved 223
through cross coupling with azidotrimethylsilane (51). The construction of medicinally valuable 224
thioethers was also possible, using cyclohexanethiol (54) and methylthioglycolate (55) as sulfur-225
based nucleophiles. In particular, the implementation of sulfur nucleophiles highlights the 226
mildness of reaction conditions, as thiol oxidation could otherwise interfere with C(sp3)–S bond 227
formation under alternative C(sp3)–H functionalization approaches. Finally, carbon–carbon bond 228
formation via a mild, direct Friedel-Crafts alkylation was accomplished in 41% yield from the 229
coupling of 1,3,5-trimethoxybenzene and 4,4′-difluorodiphenylmethane (56). Friedel-Crafts 230
reactions typically require pre-oxidized substrates—such as alkyl halides—and Lewis or Brønsted 231
acid conditions that are often incompatible with the desired nucleophiles.62,63 232
233 Figure 4. Scope of general nucleophilic C(sp3)–H functionalization (0.25 mmol, 6.0 equiv. C(sp3)–234 H coupling partner, 6.0 equiv. nucleophile, isolated yields). a 3.0 equiv. nucleophile. b 19F NMR 235 yield. c 6 hour reaction. d Reaction was performed without Et3N•3HF. e Reaction was performed 236 without Et3N•3HF and with 0.15 equiv. H2O. 237
Having evaluated the scope of this transformation, we set out to interrogate its mechanism 238
(Figure 5). According to our prior studies30 and literature precedent64, we propose that visible light 239
irradiation of the photocatalyst Ir(p-F-ppy)3 generates a long-lived excited state that serves as a 240
single-electron reductant of 1. Fragmentation of the resulting radical anion followed by extrusion 241
of CO2 forms phthalimide anion and methyl radical. Since methyl radical is thermodynamically 242
disfavored to undergo oxidation by IrIV, it is instead available to facilitate HAT with the C(sp3)−H 243
coupling partner to deliver a carbon-centered radical and methane as a byproduct (E1/2ox ~2.5 V 244
vs. SCE for methyl radical). Oxidative radical-polar crossover between IrIV and the substrate 245
radical generates a carbocation and turns over the photocatalyst. Subsequent nucleophilic trapping 246
of the carbocation intermediate furnishes the desired product (Figure 5A). 247
Ir(p-F-ppy)3 (1 mol%) Et3N•3HF (0.15 equiv.)
1 (1 equiv.)
t-BuCN (0.6 M)34W blue LEDs, 24 h
H Nu
46 36% yieldb
56 41% yielda
48 40% yieldb,c
OH
49 42% yieldb,c 50 25% yieldd
57 41% yield
Me
OH
Me
54 31% yieldc 53 33% yielda 55 30% yieldc 52 42% yielda
47 40% yieldb 51 17% yieldb,e
18OH OMe OCD3 Cl N3
O Ph
HO
O 7 S S OMeO
OMe
MeOOMe
F F F F
tertiary hydroxylation
nucleophile
248 Figure 5. (A) Proposed catalytic cycle. (B) Radical trapping experiments. (C) Investigation of 249 regioselectivity via competition experiments among 3°, 2° and 1° C(sp3)–H coupling partners. (D) 250 Investigation of kinetic isotope effect via parallel initial rates experiment with ethylbenzene and 251 ethylbenzene-d10. (E) Hammett analysis and correlation of selectivity with computed BDFE for a 252 series of ethylbenzene derivatives (See SI). a For reaction conditions see Figure 2 (19F NMR 253 yields). b Reaction performed with 1.5 equiv. TEMPO (1H NMR yield). 254
Consistent with the proposed first step of this mechanism, emission quenching experiments 255
demonstrated that 1 is the only reaction component that quenches the excited state of the 256
photocatalyst (See SI). Our analysis also indicates that the rate of quenching is moderately 257
enhanced in the presence of Et3N•3HF. This observation is consistent with the higher yields 258
observed when Et3N•3HF is employed as a catalytic additive for the construction of C(sp3)–O, 259
C(sp3)–S, and C(sp3)–C bonds. The presence of an acidic additive could aid reduction of 1 via 260
proton-coupled electron transfer, as reported for related systems in the literature.65 In addition, the 261
additive could prevent back-electron transfer and aid fragmentation of the reduced N-262
acyloxyphthalimide 1. 263
A. Catalytic Cycle
B. Radical Trapping
Ph
Phreaction conditionsa
ONPhth
O
Me MePh
F Ph
59 98% yield
Ph
H TEMPOb
reactionconditionsa
58 32% yield
PhNO
Me
MeMe
MeMe
Ph
F
Ph
2 4% yield
ONPhth
O
Me
C. Selectivity Competition Experiments
E. Linear Free-Energy Relationships
D. Intermolecular KIE Experiment
photocatalytic cycle
*IrIII
reductant
IrIV
oxidant
IrIII
RR'
R''
RR'
R'' Nu
ON
O
O
O
Me
SET
N
O
O
CO2
HAT
HR'R''
R
Me MeH
RR'R''
Nu
SET
hυvisible light nucleophile
trapping
H
MePh MePh
F
MePh MePhMe
F
5 equiv. 5 equiv.
65% 35%
MeH
:
H
Ph Ph
F
Ph Ph
F
5 equiv. 5 equiv.
95% 5%
H
:
reaction conditionsa
reaction conditionsa
Me Me
1
1
1
1428
6014
-0.5 0.0 0.5 1.0-0.6
-0.4
-0.2
0.0
0.2
0.4
σp
log
Rat
io R
/H
OPh
MeOMe
H
FCl
CN
CF3y = -0.64x + 0.03R2 = 0.92
77.0 77.5 78.0 78.5 79.0-0.6
-0.4
-0.2
0.0
0.2
0.4
BDFE (kcal/mol)
log
Rat
io R
/H
CN
CF3
Cl
OMe Me
HF
OPh
y = 0.21x – 16.45R2 = 0.19
reaction conditionsa
kH/kD = 12.1
D5C6 CD3
D D
6 equiv.
D5C6 CD3
F D
Ph Me
H
6 equiv.
Ph Me
Freaction conditionsa
14
61
Next, radical trapping experiments were conducted to evaluate the identity of key radical 264
intermediates in the proposed mechanism. When the fluorination of diphenylmethane was 265
conducted under standard conditions in the presence of 1.5 equiv. of TEMPO, we observed the 266
methyl radical–TEMPO adduct (58) in 32% yield, accompanied by nearly complete suppression 267
of fluorination (Figure 5B). Additionally, when 1,1-diphenylethylene was employed as a substrate 268
under standard conditions, nearly quantitative carbofluorination was observed, wherein methyl 269
radical addition into the olefin followed by radical oxidation and nucleophilic fluorination 270
delivered product 59. (Figure 5B). This example of carbofluorination not only provides clear 271
evidence for methyl radical formation, but also serves as a useful framework for sequential C(sp3)–272
C(sp3) and C(sp3)–F alkene difunctionalization. As further evidence, in situ NMR studies revealed 273
evolution of methane gas as the reaction proceeded, supporting the involvement of methyl radical 274
in HAT (Figure S25). 275
To our knowledge, methyl radical guided HAT has not been previously explored for 276
photocatalytic C(sp3)–H functionalization. As such, we set out to understand the reactivity and 277
selectivity effects inherent to the system. We conducted a series of competition experiments with 278
cumene, ethylbenzene, and toluene under standard C(sp3)–H fluorination conditions (Figure 5C). 279
We found that HAT mediated by methyl radical and subsequent ORPC is preferential for 3°>2°>1° 280
benzylic C(sp3)–H bonds. The data suggest that steric or polarity effects associated with HAT from 281
a mildly nucleophilic methyl radical are minimal in these systems. Instead, the observed site-282
selectivity is consistent with the relative BDFEs and radical oxidation potential of the tertiary, 283
secondary, and primary substrates. 284
To probe the independent roles of HAT and radical oxidation, we first conducted a kinetic 285
isotope effect (KIE) study with ethylbenzene. A KIE of 12.1 was measured via parallel initial rate 286
experiments using ethylbenzene and ethylbenzene-d10 (Figure 5D). The magnitude of the KIE is 287
consistent with prior studies of HAT involving methyl radical and suggests that HAT is the 288
turnover-limiting step.66,67 To probe the effect of electronics on a HAT-ORPC mechanism, a 289
Hammett analysis of the relative rate of benzylic fluorination across a series of para-substituted 290
ethylbenzenes (determined by competition experiments, see SI) was performed (Figure 5E). 291
Given the mild nucleophilicity of methyl radical, we might expect electron-deficient ethylbenzenes 292
to undergo fluorination at a faster rate than electron-rich ethylbenzenes. However, the measured r 293
value of -0.64 ± 0.07 (R2 = 0.92) indicates that electron-rich ethylbenzenes undergo C(sp3)–H 294
fluorination more favorably than electron-deficient derivatives. We interpret this result to suggest 295
that radical oxidation—wherein electronic effects should contribute significantly to carbocation 296
stabilization—is irreversible and governs product distribution. Additionally, analysis of selectivity 297
outcomes with respect to computed C(sp3)–H BDFEs across the ethylbenzene series indicates no 298
significant correlation between product selectivity and BDFE (Figure 5E).68 These findings are 299
most consistent with turnover-limiting HAT followed by an irreversible, product-determining 300
radical oxidation. Further studies are ongoing to probe additional mechanistic details. 301
Altogether, this work suggests that a HAT-ORPC strategy can provide a site-selective platform 302
for C(sp3)–H functionalization. An advantage to this method is the utilization of phthalimide-303
derived species as redox-active HAT reagents; these reagents are not only readily available, but 304
also are highly tunable. In this context, we questioned whether site-selectivity in the fluorination 305
of ibuprofen ethyl ester—a complex substrate possessing various C(sp3)–H bonds—could be tuned 306
on the basis of the radical species used in HAT (Figure 6A). Under standard conditions with the 307
methyl radical precursor 1, the fluorination of ibuprofen ethyl ester favored C(sp3)–H 308
functionalization at the tertiary benzylic site over the secondary benzylic site (38, 2.4:1 rr) (Figure 309
6A). This site-selectivity is orthogonal to previously reported HAT-guided strategies (Figure 310
6B)7,22,38 but consistent with our mechanistic studies that indicate a preference for tertiary C(sp3)–311
H functionalization according to BDFE and radical oxidation potential considerations (Figure 312
5C). Furthermore, methyl radical is polarity matched to abstract a hydrogen atom proximal to an 313
electron withdrawing group. By contrast, the prior art relies on electrophilic HAT mediators that 314
are polarity mismatched to abstract a hydrogen atom proximal to an electron withdrawing group. 315
As such, we hypothesized that employment of 3, a precursor to the electrophilic methoxy radical, 316
would afford distinct site-selectivity, favoring more electron-rich C(sp3)–H sites. Indeed, we 317
observed a reversal of site-selectivity in this case, wherein ibuprofen ethyl ester was fluorinated in 318
31% yield with a 5.3:1.5:1 rr favoring the secondary benzylic site (62). This example demonstrates 319
the potential for this platform to engage readily available small molecule HAT reagents for tunable 320
and predictable site-selective C(sp3)–H functionalization. 321
322 Figure 6. (A) Tunable selectivity for the C(sp3)–H functionalization of ibuprofen demonstrating 323 favorable secondary benzylic fluorination with methoxy radical (left) and favorable tertiary 324 benzylic fluorination with methyl radical (right). (B) Previous examples of site-selectivity in the 325 C(sp3)–H functionalization of ibuprofen. a Reaction performed using abstractor 3 and standard 326 reaction conditions described in Figure 2. b Reaction performed using abstractor 1 and standard 327 reaction conditions described in Figure 2. 328
In conclusion, we have developed a photocatalytic method that employs widely available, low-329
cost nucleophiles and a readily accessible HAT precursor for C(sp3)–H fluorination, chlorination, 330
etherification, thioetherification, azidation, and carbon–carbon bond formation. Mechanistic 331
B. Prior ibuprofen site selectivityA. Tunable regioselectivity guided by HAT reagent identity
Me
Me
Me
O
O MeH
H
38 34% yieldb
Me
Me
Me
O
OEtF
47 31% yielda
Me
Me
Me
O
OEt
F
MeMeOibuprofen ethyl ester
N N
NN
Ar
Ar
Ar
Ar
MnIII
Cl
N
O
N
O
R RCu
Groves StahlChen
Me
Me
Me
O
OMe
FMe
Me
Me
O
OMe
NHAcMe
Me
Me
O
OMe
OMe
O I OH
O
precedent affords C(sp3)–H functionalization exclusively at secondary benzylic siteregioselectivity: 5.3 : 1.5 : 1 regioselectivity: 2.4:1
studies are consistent with methyl radical-mediated HAT and linear free-energy relationships 332
suggest that radical oxidation influences site-selectivity. Furthermore, this approach was highly 333
effective for the construction of multi-halogenated scaffolds and the late-stage functionalization 334
of several bioactive molecules and pharmaceuticals with tunable regioselectivity. 335
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64. Huihui, K. M. M., Caputo, J. A., Melchor, Z., Olivares, A. M., Spiewak, A. M., Johnson, K. 493 A., DiBenedetto, T. A., Kim, S., Ackerman, L. K. G. & Weix, D. J. Decarboxylative Cross-494 Electrophile Coupling of N-Hydroxyphthalimide Esters with Aryl Iodides. J. Am. Chem. Soc. 138, 495 5016–5019 (2016). 496
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66. Salomon, M. Isotope Effects in Methyl Radical Abstraction Reactions. Can. J. Chem. 42, 610–501 613 (1964). Large KIEs observed in this study are in accordance with KIEs observed in previous 502 experimental and theoretical studies for methyl radical HAT. 503
67. Baik, M.-H., Newcomb, M., Friesner, R. A. & Lippard, S. J. Mechanistic Studies on the 504 Hydroxylation of Methane by Methane Monooxygenase. Chem. Rev. 103, 2385–2420 (2003). 505
68. BDFEs were computed according to: John, P. C. St., Guan, Y., Kim, Y., Kim, S. & Paton, R. 506 S. Prediction of organic homolytic bond dissociation enthalpies at near chemical accuracy with 507 sub-second computational cost. Nat. Commun. 11, 2328 (2020). In our experience, different levels 508 of theory give slightly different ordering of the compounds by BDFE. This is due to energetic 509 differences that are small relative to the error associated with DFT. However, all levels of theory 510 evaluated gave similarly poor correlations and do not affect the conclusions drawn. 511
512
513
Data Availability 514
Materials and methods, experimental procedures, mechanistic studies, characterization data, 515 spectral data, and xyz files (in accompanying zip drive) associated with computational data are 516 available in the Supplementary Information. 517
Acknowledgements. Financial support was generously provided by NSF (CHE-1565983). M. A. 518 T.-S. wishes to thank Princeton’s Presidential Postdoctoral Fellowship for funding. István Pelzer, 519 Kenneth Conover, and John Eng are acknowledged for analytical aid. We thank Dr. Eric W. 520 Webb for early intellectual and experimental contributions to the project. 521 522 Author Contributions. Authors I. N.-M. L. and M. A. T.-S. contributed equally. 523 524 Competing Interests. The authors declare no competing interests. 525 526 Additional information 527 Supplementary information is available in the online version of the paper. 528 Correspondence and requests for materials should be addressed to A. G. D. 529