Native functionality in triple catalytic cross-coupling: sp3 C-H bonds as latent nucleophiles

Article abstract of DOI:10.1126/science.aaf6635

The use of sp³ C-H bonds - which are ubiquitous in organic molecules - as latent nucleophile equivalents for transition metal - catalyzed cross-coupling reactions has the potential to substantially streamline synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have developed a highly selective and general C-H arylation protocol that activates a wide array of C-H bonds as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations to selectively functionalize α-amino and α-oxy sp³ C-H bonds in both cyclic and acyclic systems.

Full text of DOI:10.1126/science.aaf6635

REPORTS
Cite as: M. H. Shaw et al., Science
10.1126/science.aaf6635 (2016).
Native functionality in triple catalytic cross-coupling:
sp3 C–H bonds as latent nucleophiles
Megan H. Shaw,* Valerie W. Shurtleff,* Jack A. Terrett,* James D. Cuthbertson, David W. C. MacMillan†
Merck Center for Catalysis at Princeton University, Princeton, NJ 08544, USA.
*These authors contributed equally to this work.
†Corresponding author. Email: dmacmill@princeton.edu
The use of sp3 C–H bonds—which are ubiquitous in organic molecules—as latent nucleophile equivalents
for transition metal-catalyzed cross-coupling reactions has the potential to dramatically streamline
synthetic efforts in organic chemistry while bypassing substrate activation steps. Through the
combination of photoredox-mediated hydrogen atom transfer (HAT) and nickel catalysis, we have
developed a highly selective and general C–H arylation protocol that activates a wide array of C–H bonds
as native functional handles for cross-coupling. This mild approach takes advantage of a tunable HAT
catalyst that exhibits predictable reactivity patterns based on enthalpic and bond polarity considerations
to selectively functionalize α-amino and α-oxy sp3 C–H bonds in both cyclic and acyclic systems.
Over the past fifty years, transition metal-catalyzed cross- directing groups to accomplish selective sp3 C–H bond func-
coupling reactions have transformed the field of synthetic tionalization (9–13), or more recently by focusing upon the
organic chemistry via the evolution of a wide variety of C–C use of inductive effects to deactivate C–H bonds (14). En-
and C–heteroatom bond-forming reactions (1, 2). During zymes accomplish selective sp3 C–H bond functionalization
this time, the seminal studies of Negishi, Suzuki, Miyaura, by taking advantage of the diverse electronic and enthalpic
Stille, Kumada, and Hiyama have inspired numerous proto- characteristics of carbon–hydrogen bonds found within
cols to construct carbon–carbon bonds using palladium, complex organic molecules (15). Inspired by this biochemi-
nickel, or iron catalysis. These strategies enable highly effi- cal blueprint, we speculated that a small-molecule catalyst
cient and regiospecific fragment couplings with high func- platform could be developed that would differentiate be-
tional group tolerance, facilitating the application of tween a diverse range of C–H groups using a combination of
modular building blocks in early- or late-stage synthetic ef- bond energies and polarization, thereby enabling a unique
forts. Traditionally, cross-coupling methods have relied up- pathway toward native arylation or vinylation.
on the use of organometallic nucleophiles such as aryl or
A fundamental mechanistic step in organic synthesis is
vinyl boronic acids, zinc halides, stannanes, or Grignard the simultaneous movement of a proton and an electron—a
reagents that undergo addition to a corresponding metal- process termed hydrogen atom transfer (HAT) (16, 17). HAT
activated aryl or vinyl halide.
has long served as an effective way to access radical inter-
An emerging strategy for C–C bond formation has been mediates in organic chemistry; however, the capacity to re-
the application of native organic functionality as latent nu- gioselectively abstract hydrogens among a multitude of
cleophilic handles for transition metal-mediated cross- diverse C–H locations has been notoriously difficult to con-
couplings. In this context, the use of olefin, methoxy, ace- trol. Recently, driven by developments in small-molecule
toxy, and carboxylic acid moieties as organometallic re- catalyst design, general methods for C–H bond functionali-
placements has enabled a variety of carbon–carbon bond zation via HAT have begun to achieve levels of selectivity
formation protocols using feedstock materials (3–8). How- that were previously restricted to enzymatic systems (18, 19).
ever, without question the most common approach for tran- In this context, our laboratory has demonstrated that pho-
sition metal-mediated native functionalization has been the toredox-mediated HAT catalysis can exploit native sp3 C–H
use of C–H bonds—the most ubiquitous chemical bonds bonds for a range of C–C bond constructions, such as Minis-
found in nature—as nucleophilic coupling partners. Among ci reactions, conjugate additions, and radical–radical cou-
the well-established challenges with sp3 C–H bond function- plings (20–23). Nevertheless,
a
general strategy for
alization, regioselectivity is perhaps preeminent, given that functionalization of C–H bonds via HAT–transition metal
organic molecules incorporate a diverse combination of me- cross-coupling has yet to be achieved (24, 25).
thyl, methylene, and/or methine groups. Several elegant
We recently questioned whether it would be possible to
methodologies have navigated this question via the use of utilize a tertiary amine radical cation—generated via a pho-
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release) 1

toredox-mediated single electron transfer (SET) event (23, dox-mediated HAT nickel cross-coupling by evaluating a
26–28)—to accomplish H-atom abstraction from a diverse broad range of photoredox catalysts, nickel–ligand systems,
range of substrates (Fig. 1). Given the electrophilic nature of and quinuclidine analogs. Upon exposing N-Boc pyrrolidine
amine radical cations, we proposed that such a catalytic and methyl 4-bromobenzoate to visible light (34 W blue
strategy might allow the selective abstraction of hydridic, LEDs) in the presence of iridium photocatalyst
electron-rich C–H bonds in the presence of electron- Ir[dF(CF3)ppy]2-(dtbbpy)PF6, NiBr2•3H2O, 4,7-dimethoxy-
deficient and neutral C–H bonds, which are abundant 1,10-phenanthroline, and 3-acetoxyquinuclidine, we were
throughout organic molecules. We envisioned that the ex- pleased to observe 81% yield of the desired α-amino C–C
ploitation of polarity effects in the abstraction event would coupled product. More importantly, this product was the
impart a high degree of kinetic selectivity into an otherwise only detectable regioisomer formed, indicating that quinu-
unselective HAT process (29). Thereafter, we assumed the clidine HAT catalyst 3 was selective for the most hydridic
resulting radical intermediate might readily intersect with a C–H bond available. Notably, employing quinuclidine in lieu
Ni-catalyzed coupling cycle, thereby enabling C–C bond of 3-acetoxyquinuclidine resulted in diminished reactivity,
formation with a range of aryl electrophiles.
indicating the necessity for an electron-withdrawing sub-
A detailed description of our proposed mechanistic cycle stituent. This substantial difference in reaction efficiency
for the sp3 C–H cross-coupling via photoredox HAT–nickel illustrates the capacity to tune the reactivity of the HAT cat-
catalysis is outlined in Fig. 2. Initial excitation of the iridi- alyst via electronic modification of the substituent at the 3-
um(III)
photocatalyst
Ir[dF(CF3)ppy]2(dtbbpy)PF6 position. It is important to note that under these reaction
[dF(CF3)ppy
=
2-(2,4-difluorophenyl)-5-(trifluorometh- conditions, amine 3 serves as both the HAT catalyst and the
yl)pyridine, dtbbpy = 4,4'-di-tert-butyl-2,2'-bipyridine] (1) base (34)
would produce the long-lived photoexcited state 2 (τ = 2.3
With the optimal conditions in hand, we next sought to
μs) (30). The *Ir(III) catalyst 2 is sufficiently oxidizing to examine the generality of this transformation by exploring
undergo SET with a tertiary amine HAT catalyst (such as 3), the scope of the electrophilic aryl halide coupling partner.
red
to generate Ir(II) 4 and amine radical cation 5 (E1/2
As outlined in Fig. 3, a wide variety of bromoarenes function
[*IrIII/IrII] = +1.21 V vs. saturated calomel electrode (SCE) in efficiently in this HAT cross-coupling protocol. For example,
CH3CN, Ep [3-acetoxyquinuclidine] = +1.22 V vs. SCE in electron-deficient aryl bromides containing ketones, trifluo-
CH3CN) (30). As a central design element, we postulated romethyl groups, fluorines, sulfones, and esters were all ef-
that amine radical cation 5 would be sufficiently electron- fective arylating agents (15–18, 71–84% yield). Notably, 4-
deficient to engender a kinetically selective HAT event at chlorobromobenzene gave chlorophenyl amine product 19
the most electron-rich site of C–H nucleophile substrate 6, as the only observable arylation product in 70% yield,
thereby exclusively delivering radical intermediate 7. At the demonstrating that a high degree of chemoselectivity can be
same time, we hypothesized that this abstraction event achieved in the oxidative addition step. The HAT arylation
should also be thermodynamically favorable considering the strategy is further effective for electron-neutral and elec-
significant difference in the bond dissociation enthalpies tron-rich aryl bromides, as demonstrated by the installation
of phenyl, tolyl, t-Bu-phenyl, and anisole groups (20–23,
64–79% yield). The presence of ortho methyl or fluorine sub-
stitution on the aryl halide was not problematic (24 and 25,
70% and 60% yield). With respect to heteroaromatic sys-
tems, pyridine rings were incorporated with good efficiency
via the use of the corresponding heteroaryl bromide (26,
65% yield). We were satisfied to see that heteroaryl chlo-
rides were also effective electrophiles in the transformation.
For example, electron-deficient pyridines and pyrimidines
deliver the benzylic amine products in good efficiency (27–
29, 61–83% yield) (35). The collective one step synthesis of
the aryl pyrrolidine products 14–29 from simple N-Boc pyr-
rolidine clearly demonstrates that synthetic streamlining
can be accomplished using this HAT cross-coupling tech-
nology (36).
(BDEs) of hydridic α-amino C–H bonds (α-amino C–H = 89–
94 kcal/mol) and the resultant N–H bond of quinuclidinium
(H–N+ BDE [quinuclidine] = 100 kcal/mol) (31, 32). Concur-
rent with this photoredox cycle, we assumed that our active
Ni(0) species 9—generated in situ via two SET reductions of
(4,7-dOMe-phen)Ni(II)Br2 (4,7-dOMe-phen = 4,7-dimethoxy-
red
1,10-phenanthro-line) by the iridium photocatalyst (E1/2
red
[IrIII/IrII] = –1.37 V vs. SCE in CH3CN, E1/2 [NiII/Ni0] = –1.2
V vs. SCE in DMF) (30, 33)—would undergo oxidative addi-
tion into the aryl halide electrophile 10, forming the elec-
trophilic Ni(II)-aryl intermediate 11. This Ni(II) species
would rapidly intercept radical 7 to generate a Ni(III)-aryl-
alkyl complex 12, which upon reductive elimination would
forge the desired C–C bond to form Ni(I) complex 13 and
benzylic amine 14. Reduction of 13 by 4, the Ir(II) state of
the photocatalyst, would then reconstitute both Ni(0) cata-
lyst 9 and Ir(III) catalyst 1.
We next explored the diversity of amino- and oxy-bearing
C–H nucleophiles that could be employed as substrates in
this photoredox-mediated HAT nickel-catalyzed cross-
We began our investigations into the proposed photore-
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
2

coupling. As demonstrated in Fig. 3, many α-amino methyl- tems as para-xylene is arylated in 54% yield (53). Indeed,
and methylene-containing substrates can be selectively ary- we expect that application of this strategy to a broad range
lated. For example, differentially N-substituted pyrrolidine of α-oxy, α-amino, and benzylic C–H-bearing substrates will
substrates are effective in the transformation, including demonstrate the general utility of this selective C–H aryla-
those bearing tert-butoxycarbonyl (Boc), benzyloxycarbonyl tion protocol.
(Cbz), pivalate (Piv), and tert-butylaminocarbonyl (Bac)
Finally, we recognized that the capacity to control the
groups (14, 30–32, 51–81% yield). Notably, the arylation of regioselectivity of the outlined HAT abstraction along with
N-Boc pyrrolidine can be achieved on gram-scale in a single the opportunity to utilize C–H bonds as latent nucleophiles
batch, delivering 1.34 g of the 2-arylpyrrolidine product 14 brings forward the possibility of enabling multiple native
(78% yield). Cyclic amines of various ring size are readily functionalizations to be conducted in sequence—a strategy
tolerated with azetidine, piperidine, and azepane undergo- that should allow the rapid construction of molecular com-
ing selective C–H arylation (33–35, 42–69% yield). Remark- plexity from a large variety of readily available organic feed-
ably, ring systems that incorporate inductively withdrawing stock chemicals. As one example, we postulated that N-Boc
alcohols and fluorine substituents at the β-amino position proline methyl ester (54) might be differentially arylated via
do not unduly retard the C–H abstraction step (36 and 37, (i) the photoredox-mediated HAT method presented in this
45% yield, >20:1 d.r. and 68% yield, 3:1 d.r.). Moreover, lac- work, followed by (ii) a photoredox-mediated Ni(II) decar-
tams and ureas proved effective latent nucleophiles for this boxylative arylation. As shown in Fig. 4, N-Boc proline me-
coupling, with both N-Me and N-H substrates providing the thyl ester underwent selective arylation at the 5-methylene
corresponding arylated products in good yield (38–42, 62– position using the HAT cross-coupling strategy disclosed
84% yield).
herein (66% yield, 4:1 d.r.). The observed regioselectivity is
The transformation is not restricted to cyclic substrates, usefully complementary to that which would be expected
as a range of acyclic amines have been efficiently functional- using established methods for transition metal-catalyzed
ized using this HAT arylation protocol. For example, prima- cross-coupling. Whereas many current strategies utilize
ry α-amino C–H bonds can be arylated using both N-Boc basic conditions to selectively functionalize acidic hydro-
alkyl amines and ureas (43–45, 47–74% yield). N-Boc butyl- gens (as in enolate arylations), our developed HAT protocol
targets hydridic hydrogen atoms, thereby providing access
to fundamentally distinct product classes. Following the
successful execution of the outlined C–H arylation, the cor-
responding amino acid product 55 successfully underwent
decarboxylative coupling with 2-fluoro-4-bromopyridine at
the 2-position delivering the 2,5-diarylated pyrrolidine ad-
duct in excellent yield (56, 73% yield, 4:1 d.r.). We have also
been able to demonstrate a HAT arylation followed by a
amine, possessing a free N–H bond, undergoes selective α-
arylation in 58% yield (46), leaving this latent functional
handle available for further derivatization without the need
for protection or deprotection steps. For acyclic dialkyl
amines containing methylene C–H bonds, we were delighted
to see that N-Bac substituted amines delivered the α-
arylated products in excellent yield (47–49, 66–82% yield)
while the corresponding Boc systems provided diminished
yet usable efficiencies (20–30% yield). We attribute this in-
teresting reactivity difference to the diminished electron-
withdrawing nature of the Bac group in comparison to Boc,
resulting in an increased rate of hydrogen atom transfer to
the electrophilic amine radical cation 5.
When unsymmetrical amine substrates were exposed to
this HAT protocol, some interesting regioselectivity patterns
were discovered. For example, methyl C–H bonds undergo
preferential coupling over methylene C–H bonds, as shown
with N-Bac butylmethylamine (48, 78% yield, 4:1 r.r.). Fur-
thermore, methyl and methylene C–H bonds react exclusive-
ly over methine C–H bonds, as demonstrated with N-Bac
isopropylmethylamine and N-Boc 2-methylpyrrolidine, re-
spectively (49 and 50, 82% and 62% yield, 1:1 d.r.). This
strategy can also be applied to the HAT arylation of α-oxy
C–H bonds. Tetrahydrofuran (THF) and oxetane both un-
dergo α-oxy arylation in good efficiency (51 and 52, 76%
and 53% yield). Finally, we have been able to demonstrate
that this C–H arylation protocol is effective for benzylic sys-
nickel-catalyzed
C–O
coupling
(37).
N-Boc
3-
hydroxyazetidine can be selectively arylated at the 2-
position in 45% yield (36, Fig. 3), leaving the alcohol un-
touched. The free alcohol can then be subsequently arylated
with 4-bromo-2-methylpyridine to deliver the aryl ether
product in 77% yield (see Supplementary Material).
This HAT strategy represents a powerful demonstration
of the versatility of using sp3
C–H bonds as organometallic
nucleophile equivalents and will likely find application in
the realm of late-stage functionalization. We believe that
this protocol will gain widespread use within the synthetic
community as a complement to existing cross-coupling
technologies.
REFERENCES AND NOTES
1. M. Beller, C. Bolm, Transition Metals for Organic Synthesis, Vol. 1 (Wiley-VCH,
Weinheim, 2004.
2. A. De Meijere, F. Diederich, Metal-Catalyzed Cross-Coupling Reactions, Vol. 1
(Wiley-VCH, Weinheim, 2004).
3. A. de Meijere, F. E. Meyer, Fine feathers make fine birds: The Heck reaction in
modern garb. Angew. Chem. Int. Ed. Engl. 33, 2379–2411 (1995).
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
3

doi:10.1002/anie.199423791
52, 4453–4456 (2013). doi:10.1002/anie.201300459 Medline
4. L. J. Goossen, G. Deng, L. M. Levy, Synthesis of biaryls via catalytic
25. D. Liu, Y. Li, X. Qi, C. Liu, Y. Lan, A. Lei, Nickel-catalyzed selective oxidative
radical cross-coupling: An effective strategy for inert Csp3-H functionalization.
Org. Lett. 17, 998–1001 (2015). doi:10.1021/acs.orglett.5b00104 Medline
decarboxylative
coupling.
Science
313,
662–664
(2006).
doi:10.1126/science.1128684 Medline
5. N. Rodríguez, L. J. Goossen, Decarboxylative coupling reactions: A modern 26. J. M. R. Narayanam, C. R. J. Stephenson, Visible light photoredox catalysis:
strategy for C-C-bond formation. Chem. Soc. Rev. 40, 5030–5048 (2011).
doi:10.1039/c1cs15093f Medline
Applications in organic synthesis. Chem. Soc. Rev. 40, 102–113 (2011).
doi:10.1039/B913880N Medline
6. L. L. Anka-Lufford, M. R. Prinsell, D. J. Weix, Selective cross-coupling of organic
halides with allylic acetates. J. Org. Chem. 77, 9989–10000 (2012).
doi:10.1021/jo302086g Medline
27. C. K. Prier, D. A. Rankic, D. W. C. MacMillan, Visible light photoredox catalysis
with transition metal complexes: Applications in organic synthesis. Chem. Rev.
113, 5322–5363 (2013). doi:10.1021/cr300503r Medline
7. J. C. Lo, J. Gui, Y. Yabe, C.-M. Pan, P. S. Baran, Functionalized olefin cross-
coupling to construct carbon-carbon bonds. Nature 516, 343–348 (2014).
doi:10.1038/nature14006 Medline
28. D. M. Schultz, T. P. Yoon, Solar synthesis: Prospects in visible light
photocatalysis. Science 343, 1239176 (2014). doi:10.1126/science.1239176
Medline
8. Z. Zuo, D. T. Ahneman, L. Chu, J. A. Terrett, A. G. Doyle, D. W. C. MacMillan,
Merging photoredox with nickel catalysis: Coupling of -carboxyl sp3-carbons
with aryl halides. Science 345, 437–440 (2014). doi:10.1126/science.1255525
Medline
29. B. P. Roberts, Polarity-reversal catalysis of hydrogen-atom abstraction
reactions: Concepts and applications in organic chemistry. Chem. Soc. Rev. 28,
25–35 (1999). doi:10.1039/a804291h
30. M. S. Lowry, J. I. Goldsmith, J. D. Slinker, R. Rohl, R. A. Pascal, G. G. Malliaras, S.
Bernhard, Single-layer electroluminescent devices and photoinduced hydrogen
production from an ionic iridium(III) complex. Chem. Mater. 17, 5712–5719
(2005). doi:10.1021/cm051312+
9. V. G. Zaitsev, D. Shabashov, O. Daugulis, Highly regioselective arylation of sp3 C-H
bonds catalyzed by palladium acetate. J. Am. Chem. Soc. 127, 13154–13155
(2005). doi:10.1021/ja054549f Medline
10. S. J. Pastine, D. V. Gribkov, D. Sames, sp3 C-H bond arylation directed by amidine
protecting group: α-arylation of pyrrolidines and piperidines. J. Am. Chem. Soc.
128, 14220–14221 (2006). doi:10.1021/ja064481j Medline
11. J. He, S. Li, Y. Deng, H. Fu, B. N. Laforteza, J. E. Spangler, A. Homs, J.-Q. Yu,
Ligand-controlled C(sp3)-H arylation and olefination in synthesis of unnatural
31. Y.-R. Luo, Handbook of Bond Dissociation Energies in Organic Compounds (CRC
Press, Boca Raton, FL, 2003).
32. W.-Z. Liu, F. G. Bordwell, Gas-phase and solution-phase homolytic bond
dissociation energies of H-N(+) bonds in the conjugate acids of nitrogen bases. J.
Org. Chem. 61, 4778–4783 (1996). doi:10.1021/jo950933r Medline
33. M. Durandetti, M. Devaud, J. Perichon, New J. Chem. 20, 659 (1996).
34. In related studies, we have demonstrated that HAT processes can be achieved
using catalytic quantities of 3-acetoxyquinuclidine in the presence of base.
35. For heteroaryl halides, no product was observed in the absence of nickel catalyst,
supporting the cross-coupling mechanism outlined in Fig. 2. See supplementary
materials for control reactions.
36. K. R. Campos, A. Klapars, J. H. Waldman, P. G. Dormer, C. Y. Chen,
Enantioselective, palladium-catalyzed α-arylation of N-Boc-pyrrolidine. J. Am.
Chem. Soc. 128, 3538–3539 (2006). doi:10.1021/ja0605265 Medline
37. J. A. Terrett, J. D. Cuthbertson, V. W. Shurtleff, D. W. C. MacMillan, Switching on
elusive organometallic mechanisms with photoredox catalysis. Nature 524,
330–334 (2015). doi:10.1038/nature14875 Medline
chiral
α-amino
acids.
Science
343,
1216–1220
(2014).
doi:10.1126/science.1249198 Medline
12. F.-L. Zhang, K. Hong, T.-J. Li, H. Park, J.-Q. Yu, Organic chemistry.
Functionalization of C(sp3)-H bonds using a transient directing group. Science
351, 252–256 (2016). doi:10.1126/science.aad7893 Medline
13. J. J. Topczewski, P. J. Cabrera, N. I. Saper, M. S. Sanford, Palladium-catalysed
transannular C-H functionalization of alicyclic amines. Nature 531, 220–224
(2016). doi:10.1038/nature16957 Medline
14. M. Lee, M. S. Sanford, Platinum-catalyzed, terminal-selective C(sp(3))-H
oxidation of aliphatic amines. J. Am. Chem. Soc. 137, 12796–12799 (2015).
doi:10.1021/jacs.5b09099 Medline
15. J. C. Lewis, P. S. Coelho, F. H. Arnold, Enzymatic functionalization of carbon-
38. D. D. Perrin, W. L. F. Armarego, Purification of Laboratory Chemicals (Pergamon,
Oxford, ed. 3, 1988.
hydrogen bonds. Chem. Soc. Rev.
doi:10.1039/C0CS00067A Medline
40, 2003–2021
(2011).
39. W. C. Still, M. Kahn, A. Mitra, Rapid chromatographic technique for preparative
separations with moderate resolution. J. Org. Chem. 43, 2923–2925 (1978).
doi:10.1021/jo00408a041
16. J. J. Warren, T. A. Tronic, J. M. Mayer, Thermochemistry of proton-coupled
electron transfer reagents and its implications. Chem. Rev. 110, 6961–7001
(2010). doi:10.1021/cr100085k Medline
40. K.-Y. Kim, B. C. Kim, H. B. Lee, H. Shin, Nucleophilic fluorination of triflates by
tetrabutylammonium bifluoride. J. Org. Chem. 73, 8106–8108 (2008).
doi:10.1021/jo8015659 Medline
17. J. M. Mayer, Understanding hydrogen atom transfer: From bond strengths to
Marcus theory. Acc. Chem. Res. 44, 36–46 (2011). doi:10.1021/ar100093z
Medline
41. A. Millet, D. Dailler, P. Larini, O. Baudoin, Ligand-controlled α- and β-arylation of
acyclic N-Boc amines. Angew. Chem. Int. Ed. 53, 2678–2682 (2014).
doi:10.1002/anie.201310904 Medline
18. M. S. Chen, M. C. White, Combined effects on selectivity in Fe-catalyzed
methylene
oxidation.
Science
327,
566–571
(2010).
doi:10.1126/science.1183602 Medline
19. T. Newhouse, P. S. Baran, If C-H bonds could talk: Selective C-H bond oxidation.
Angew. Chem. Int. Ed. 50, 3362–3374 (2011). doi:10.1002/anie.201006368
Medline
42. H. M. L. Davies, C. Venkataramani, Catalytic enantioselective synthesis of β2-
amino acids. Angew. Chem. Int. Ed. 41, 2197 (2002). doi:10.1002/1521-
3773(20020617)41:12<2197::AID-ANIE2197>3.0.CO;2-N
20. K. Qvortrup, D. A. Rankic, D. W. C. MacMillan,
A general strategy for
43. L. R. Steffel, T. J. Cashman, M. H. Reutershan, B. R. Linton, Deuterium exchange
as an indicator of hydrogen bond donors and acceptors. J. Am. Chem. Soc. 129,
12956–12957 (2007). doi:10.1021/ja076185s Medline
44. C. Quinet, L. Sampoux, I. E. Marko, Base-catalysed intramolecular
hydroamination of vinyl sulfides. Eur. J. Org. Chem. 2009, 1806–1811 (2009).
doi:10.1002/ejoc.200900009
45. Z. Zuo, D. W. C. MacMillan, Decarboxylative arylation of α-amino acids via
photoredox catalysis: A one-step conversion of biomass to drug pharmacophore.
J. Am. Chem. Soc. 136, 5257–5260 (2014). doi:10.1021/ja501621q Medline
46. R. K. Dieter, S. J. Li, Copper cyanide-catalyzed palladium coupling of N-tert-
butoxycarbonyl-protected α-lithio amines with aryl iodides or vinyl iodides. J.
Org. Chem. 62, 7726–7735 (1997). doi:10.1021/jo970985b
organocatalytic activation of C-H bonds via photoredox catalysis: Direct
arylation of benzylic ethers. J. Am. Chem. Soc. 136, 626–629 (2014).
doi:10.1021/ja411596q Medline
21. J. D. Cuthbertson, D. W. C. MacMillan, The direct arylation of allylic sp(3) C-H
bonds via organic and photoredox catalysis. Nature 519, 74–77 (2015).
doi:10.1038/nature14255 Medline
22. J. Jin, D. W. C. MacMillan, Alcohols as alkylating agents in heteroarene C-H
functionalization. Nature 525, 87–90 (2015). doi:10.1038/nature14885 Medline
23. J. L. Jeffrey, J. A. Terrett, D. W. C. MacMillan, O-H hydrogen bonding promotes H-
atom transfer from α C-H bonds for C-alkylation of alcohols. Science 349, 1532–
1536 (2015). doi:10.1126/science.aac8555 Medline
24. D. Liu, C. Liu, H. Li, A. Lei, Direct functionalization of tetrahydrofuran and 1,4-
dioxane: Nickel-catalyzed oxidative C(sp3)–H arylation. Angew. Chem. Int. Ed.
47. M. B. Tait, S. Butterworth, J. Clayden, 2,2- and 2,6-Diarylpiperidines by aryl
migration within lithiated urea derivatives of tetrahydropyridines. Org. Lett. 17,
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
4

1236–1239 (2015).doi:10.1021/acs.orglett.5b00199 Medline
48. Y.-F. Wang, K. K. Toh, E. P. J. Ng, S. Chiba, Mn(III)-mediated formal [3+3]-
annulation of vinyl azides and cyclopropanols:
azaheterocycles. J. Am. Chem. Soc.
(2011).doi:10.1021/ja200879w Medline
A
divergent synthesis of
133, 6411–6421
49. J. Luo, J. Zhang, Donor–acceptor fluorophores for visible-light-promoted organic
synthesis: Photoredox/Ni dual catalytic C(sp3)–C(sp2) cross-coupling. ACS
Catal. 6, 873–877 (2016). doi:10.1021/acscatal.5b02204
50. R. B. Bedford, M. Huwe, M. C. Wilkinson, Iron-catalysed Negishi coupling of
benzyl halides and phosphates. Chem. Commun. (Camb.) (5): 600–602
(2009).doi:10.1039/B818961G Medline
ACKNOWLEDGMENTS
The authors are grateful for financial support provided by the NIH General Medical
Sciences (R01 GM078201-05) and gifts from Merck and AbbVie. V.W.S. and
J.A.T. thank Bristol-Myers Squibb for Graduate Fellowships. J.D.C. thanks Marie
Curie Actions for an International Outgoing Fellowship.
SUPPLEMENTARY MATERIALS
www.sciencemag.org/cgi/content/full/science.aaf6635/DC1
Tables S1 and S2
NMR Spectra
References (38–50)
10 March 2016; accepted 14 April 2016
Published online 28 April 2016
10.1126/science.aaf6635
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
5

Fig. 1. Photoredox-mediated hydrogen atom transfer and nickel
catalysis enable highly selective cross-coupling using sp3 C–H
bonds as latent nucleophiles.
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
6

Fig. 2. Photoredox, HAT, and nickel-catalyzed cross-coupling: proposed mechanistic pathway and
catalyst combination. Ac, acetyl; t-Bu, tert-butyl; Boc, tert-butoxycarbonyl; LED, light-emitting diode; SET,
single-electron transfer; HAT, hydrogen atom transfer.
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
7

Fig. 3. Photoredox, HAT, and nickel-catalyzed cross-coupling: Aryl halide and C–H nucleophile scope. All
yields are isolated yields. Reaction conditions as in Fig. 2; see Supplementary Material for experimental details.
Ac, acetyl; t-Bu, tert-butyl; Boc, tert-butoxycarbonyl; Piv, pivalate; Cbz, benzyloxycarbonyl; Bac, tert-
butylaminocarbonyl. *Reaction performed with 4-bromobenzotrifluoride to deliver N-Bac 2-(4-
†
‡
trifluoromethylphenyl)-pyrrolidine. Minor regioisomer is arylated on Me position. Minor regioisomer is arylated
on α-amino methylene position. §Yield determined by 1H NMR.
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
8

Fig. 4. Regioselective arylation: employing C–H arylation and decarboxylative arylation delivers
differentially arylated pyrrolidine product. All yields are isolated yields. See Supplementary Material for
experimental details.
First release: 28 April 2016
www.sciencemag.org
(Page numbers not final at time of first release)
9

Native functionality in triple catalytic cross-coupling: sp3 C−H bonds
as latent nucleophiles
Megan H. Shaw, Valerie W. Shurtleff, Jack A. Terrett, James D.
Cuthbertson and David W. C. MacMillan (April 28, 2016)
published online April 28, 2016
Editor's Summary
This copy is for your personal, non-commercial use only.
Visit the online version of this article to access the personalization and article
tools:
http://science.sciencemag.org/content/early/2016/04/27/science.aaf6635
Article Tools
Obtain information about reproducing this article:
http://www.sciencemag.org/about/permissions.dtl
Permissions
Science (print ISSN 0036-8075; online ISSN 1095-9203) is published weekly, except the last week in
December, by the American Association for the Advancement of Science, 1200 New York Avenue NW,
Washington, DC 20005. Copyright 2016 by the American Association for the Advancement of Science;
all rights reserved. The title Science is a registered trademark of AAAS.