Direct arylation of strong aliphatic C–H bonds

Article abstract of DOI:10.1038/s41586-018-0366-x

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp³-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners^1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks^3–5, the direct functionalization of carbon–hydrogen (C–H) bonds—the most abundant moiety in organic molecules—represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp³)–heteroatom bonds from strong C–H bonds has been reported^6,7. Additionally, valuable technologies have been developed for the formation of carbon–carbon bonds from the corresponding C(sp³)–H bonds via substrate-directed transition-metal C–H insertion⁸, undirected C–H insertion by captodative rhodium carbenoid complexes⁹, or hydrogen atom transfer from weak, hydridic C–H bonds by electrophilic open-shell species^10–14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp³)–H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp³) arylation of a diverse set of aliphatic, C–H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C–H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp³)–C(sp²) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.

Full text of DOI:10.1038/s41586-018-0366-x

Letter
https://doi.org/10.1038/s41586-018-0366-x
Direct arylation of strong aliphatic C–H bonds
Ian B. Perry1,3, thomas F. Brewer1,3, Patrick J. Sarver1, Danielle M. Schultz2, Daniel A. Dirocco2 & David W. C. MacMillan1*
Despite the widespread success of transition-metal-catalysed been merged with transition-metal cross-couplings, and we hoped that
cross-coupling methodologies, considerable limitations still exist such a combination of catalytic processes would enable access to a con-
in reactions at sp3-hybridized carbon atoms, with most approaches siderable breadth of carbon-centred radicals and aryl-functionalized
relying on prefunctionalized alkylmetal or bromide coupling products from abundant feedstocks (Fig. 1). Furthermore, the observed
partners1,2. Although the use of native functional groups (for selectivity of decatungstate for the abstraction of electron-rich, steri-
example, carboxylic acids, alkenes and alcohols) has improved cally accessible C–H bonds25 combined with the steric preference of
the overall efficiency of such transformations by expanding the nickel-catalysed cross-couplings suggested that our proposed dual-
range of potential feedstocks3–5, the direct functionalization of catalytic system could provide site-specific arylation of complex organic
carbon–hydrogen (C–H) bonds—the most abundant moiety in frameworks.
organic molecules—represents a more ideal approach to molecular
A detailed description of our proposed mechanism is illustrated in
construction. In recent years, an impressive range of reactions Fig. 2. Photoexcitation of tetrabutylammonium decatungstate (TBADT, 1)
that form C(sp3)–heteroatom bonds from strong C–H bonds has followed by intersystem crossing would produce the triplet excited
been reported6,7. Additionally, valuable technologies have been state (2) (with a lifetime, τ, of 55 ns)26. Subsequent hydrogen atom
developed for the formation of carbon–carbon bonds from the
corresponding C(sp3)–H bonds via substrate-directed transition-
a
metal C–H insertion8, undirected C–H insertion by captodative
Boc
rhodium carbenoid complexes9, or hydrogen atom transfer from
O
NHAr
H
H
N
H
weak, hydridic C–H bonds by electrophilic open-shell species10–14
.
H
Despite these advances, a mild and general platform for the
coupling of strong, neutral C(sp3)–H bonds with aryl electrophiles
has not been realized. Here we describe a protocol for the direct
C(sp3) arylation of a diverse set of aliphatic, C–H bond-containing
organic frameworks through the combination of light-driven,
polyoxometalate-facilitated hydrogen atom transfer and nickel
catalysis. This dual-catalytic manifold enables the generation of
carbon-centred radicals from strong, neutral C–H bonds, which
thereafter act as nucleophiles in nickel-mediated cross-coupling
with aryl bromides to afford C(sp3)–C(sp2) cross-coupled products.
This technology enables unprecedented, single-step access to a broad
array of complex, medicinally relevant molecules directly from
natural products and chemical feedstocks through functionalization
at sites that are unreactive under traditional methods.
Strong, neutral
99 kcal mol−1
Polarity-matched
92 kcal mol−1
BDE-driven
89 kcal mol−1
Directed
99 kcal mol−1
Boc
O
NHAr
Ar
Ar
N
Ar
Ar
Elusive
transformation
b
Ni
O
O
Metallaphotoredox catalysis has recently emerged as an effective
strategy for C(sp3)–H functionalization15. Specifically, the merger
of photoredox-mediated hydrogen atom transfer (HAT) and
transition-metal catalysis has delivered several methods for the selective
functionalization of activated C–H bonds based on low bond disso-
ciation energies and/or polarity effects (α-heteroatom, benzylic and
formyl)10–14. Inspired by these studies and a strong oxidant-mediated
protocol for C(sp3)–H arylation16, we proposed that combining a HAT
catalyst capable of generating high-energy carbon-centred radicals
from strong, inert C–H bonds with the elementary steps of nickel cata-
lysis (aryl oxidative addition, reductive elimination) would enable the
coupling of aliphatic carbon frameworks with a range of aryl bromide
coupling partners.
W
W
O
O
O
O
O
O
O
O
O
O
O
W
W
O
O
W
O
O
W O
O
O
W
O
O
O
W
O
O
O
O
O
O
O
W
O
W
O
c
Catalytic
manifold
CF3
CF3
H
N
W
Ni
N
Br
We proposed that polyoxometalates (POMs), many of which possess
high-energy excited states able to perform the desired C–H abstraction,
would be ideal cocatalysts for the proposed transformation17. Of par-
ticular interest was the decatungstate anion ([W10O32]4−), a POM that
has been broadly used as an efficient HAT photocatalyst in various oxy-
genations, dehydrogenations, conjugate additions and, more recently,
fluorinations of strong, unactivated, aliphatic C–H bonds18–23 with
bond dissociation energies of up to 100 kcal mol−1 (for cyclohexane,
39 C–H nucleophiles
Single-step C–H arylation
Fig. 1 | Undirected aliphatic C–H arylation. a, Traditional transition-
metal-catalysed C(sp3)–H arylation methods rely on adjacent or distal
functionality to facilitate C–H bond activation. b, This dual-catalytic
approach involves the combination of light-driven, polyoxometalate-
facilitated hydrogen atom transfer and nickel catalysis. c, Use of this
catalytic manifold enables the direct arylation of strong, unactivated C–H
ref. 24). To our knowledge, the decatungstate anion has not previously bonds. Ar, aryl; BDE, bond dissociation energy; Boc, tert-butoxycarbonyl.
1Merck Center for Catalysis at Princeton University, Princeton, NJ, USA. 2Department of Process Chemistry, Merck & Co., Inc., Rahway, NJ, USA. 3These authors contributed equally: Ian B. Perry,
Thomas F. Brewer. *e-mail: dmacmill@princeton.edu
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Letter reSeArCH
Catalytic combination
H
R
W
Ni
Z
5
5
3
Br
C–H nucleophile
Aryl bromide
HAT
[W10O32]
5–H+
9
LnNiI
LnNi0
[W10O32
]
5–H+
Alk
4
4
7
8
t-Bu
t-Bu
Br
Br
N
N
–HBr
Ni
4–
Decatungstate
catalytic cycle
Electron
relay
Nickel
*[W10O32
]
SET
SET
catalytic cycle
oxidant
2
Ni(dtbbpy)Br2
Br
LnNiIII Ar
LnNiI Br
4–
4–
4(Bu4N+)
[W10O32
]
[W10O32
reductant
]
6–2H+
O
Alk
1
12
10
W
O
O
O
O
O
6
O
W
O
O
O
W
W
O
O
O
O
W
O
O
O
O
O
O
O
O
W
O
R
R
W
• Light-enabled
W
O
1 mol% TBADT, 5 mol% Ni(dtbbpy)Br2
O
O
W
O
O
H
+
O
Z
O
O
Z
• Mild conditions
1.1 equiv. K3PO4, acetonitrile (0.1 M)
34 W 390 nm Kessil lamp, fan
Br
W
O
• Broad scope
C–H nucleophile
(5 equiv.)
(hetero)aryl bromide
Arylated product 11
TBADT, 1
Fig. 2 | Reaction scheme and proposed mechanism for C(sp3)–H
arylation via a dual polyoxometalate HAT and nickel catalytic
manifold. The catalytic cycle begins with photoexcitation of the
decatungstate anion 1 to provide triplet excited state 2. HAT from
nucleophile 3 affords reduced photocatalyst 4 and open-shell species 5.
Disproportionation of the reduced decatungstate species regenerates the
active photocatalyst and affords the reducing hexa-anion 6. Ni0 species
7 subsequently captures alkyl radical 5, furnishing Nii-alkyl species 8.
Oxidative addition into aryl electrophile 9 provides Niiii species 10,
which undergoes reductive elimination to afford the product (11) and
Nii–Br species 12. Single electron transfer (SET) between 6 and 12
regenerates 7 and 4, closing both catalytic cycles. Alk, alkyl; dtbbpy,
4,4′-di-tert-butyl-2,2′-bipyridine; equiv., equivalents; L, ligand; TBADT,
tetrabutylammonium decatungstate; t-Bu, tert-butyl.
abstraction from an alkyl nucleophile such as norbornane (3) by excited- As shown in Fig. 3, a diverse array of organic frameworks proved
state decatungstate (2) would readily afford singly reduced decatung- to be competent coupling partners for the C–H arylation protocol.
state (4) and carbon-centred radical 5. Disproportionation of singly Cycloalkanes with various ring sizes ranging from five to eight carbons
reduced decatungstate (4) would regenerate the active HAT photo- were arylated in good yields (13–16, 57%–70% yield). Linear aliphatic
catalyst 1 and concurrently form doubly reduced decatungstate (6)26. systems were likewise successful in the protocol (17–20, 41%–56%
Two successive single-electron reductions of precatalyst Ni(dtbbpy)Br2 yield), with a greater-than-statistical preference observed for arylation
(dtbbpy=4,4′-di-tert-butyl-2,2′-bipyridine) (Ep (Niii/Ni0)=−1.47 V of the less sterically demanding 2-position for all substrates, including
versus Ag/Ag+ in acetonitrile, see Supplementary Information) by n-hexane (SI-1, 48% yield, 60% selectivity). Electron-withdrawing sub-
doubly reduced decatungstate (6) (E1/2red ([W10O32]5−/[W10O32]6−)= stituents further improved this regiocontrol, highlighting the selectivity
−1.52 V versus Ag/Ag+ in acetonitrile, see Supplementary Information) of decatungstate for more hydridic C–H bonds imparted by the elec-
could initially afford Ni0 species 7, which after capture of alkyl radical 5 trophilic nature of its excited state26. Accordingly, we found ketones to
would furnish Nii-alkyl species 8. Subsequent oxidative addition into aryl be particularly effective in modulating regioselectivity, affording prod-
halide 9 by Nii-alkyl species 8 would afford Niiii(aryl)(alkyl) species 10. ucts that are functionalized distal to the electron-withdrawing carbonyl
Reductive elimination would provide the desired cross-coupled product moiety (21, 22, 31–35, 31%–65% yield).
11 as well as Nii species 12. A final single-electron transfer step between
This C–H arylation protocol was also found to effectively function-
this Nii species and the doubly reduced polyoxometalate 6 would regen- alize a range of electronically diverse primary and secondary benzylic
erate the active Ni0 catalyst 7, as well as singly reduced TBADT (4), C–H bonds, which were arylated in moderate to good yields (23–25,
closing both catalytic cycles. An alternative mechanism involving 62%–71% yield, see Supplementary Information for three additional
the oxidative addition of Ni0 catalyst 7 to aryl halide 9 could also be examples). Bridged bicyclic alkanes afforded arylated products with
operative27.
complete exo-selectivity (26–29 and 35, 40%–67% yield), probably
We began our investigation into the proposed transformation owing to selective radical capture by nickel catalyst 7 on the less-
by exposing 5-bromo-2-trifluoromethylpyridine and cyclohexane hindered face. Functionalization of norbornane occurred selectively
to near-ultraviolet light (Kessil 34 W 390 nm light-emitting diodes on the ethylene bridge (26, 61% yield). A bromide substituent on
(LEDs)) in the presence of the commercially available HAT photo
-
the bridging methylene of norbornane was tolerated and, moreover,
catalyst TBADT, Ni(dtbbpy)Br2, and potassium phosphate in aceto- strongly influenced site-selectivity, giving only the anti product (27,
nitrile. To our delight, we observed a 70% analytical yield of the desired 67% yield). Notably, heteroatom-containing bicycles afforded the
cyclohexyl C–H arylation product. Critical to the success of the reac- desired products in moderate to good yields (28 and 29, 40% and 60%
tion was the exclusion of both oxygen and water (see Supplementary yield, respectively). Arylated lactam 29 was subsequently subjected to
Information); however, the use of standard benchtop techniques was ring-opening reductive conditions to afford carbocyclic nucleoside
sufficient in this regard. Moreover, although five equivalents of the analogue 30 (94% yield), highlighting the utility of the C–H arylation
C–H nucleophile affords optimal yields, lower substrate loadings protocol. Intriguingly, adamantane derivatives underwent arylation
can be used albeit with diminished efficiency (see Supplementary predominantly at the methylene position (31 and 32, 48% and 53%
Information).
yield, respectively), an unexpected chemoselectivity given that
With optimized conditions in hand, we next sought to examine the decatungstate-catalysed adamantane functionalization affords 5:1
scope of the transformation with respect to the C–H-bearing partner. selectivity for methine positions when corrected for equivalent
2
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© 2018 Springer Nature Limited. All rights reserved.

reSeArCH Letter
O
O
W
Ni
W
W
O
O
N
CF3
O
O
O
O
t-Bu
t-Bu
O
O
N
CF3
O
H
W
Ni
O
O
O
W
Br
Br
W
N
N
Ni
O
W
O
O
W O
O
O
O
W
O
O
W
O
O
Br
O
O
O
O
O
W
O
W
O
1
C–H nucleophiles
H
Minor regioisomer
R
N
CF3
)-17 49%b R = Me
)-18 56%c R = OAc
)-19 44%d R = Cl
)-20 41%e R = Br
R
N
CF3
(
(
(
(
13 57% n = 0
14 66% n = 1
15 65% n = 2
16 70% n = 3
H
n
Me
Me
n
N
CF3
R
R
O
H
23 69% R = p-Me
24 72% R = o-Me
25 62% R = p-Cl
N
CF3
O
(
(
)-21 51%a n = 0
H
)-22 65%f
n = 1
n
n
N
CF3
N
CF3
N
CF3
O
H
H
O
H
N
Boc
N
Boc
)-31 48%i
(
)-26 61%a,g
(
)-36 53%a
(
N
CF3
O
H
N
CF3
Br
N
CF3
Br
O
Boc
N
Boc
N
H
H
Me
Me
Br
Br
(
)-27 67%a,g
(
)-32 53%j
37 68%
N
CF3
N
CF3
N
CF3
O
O
O
H
O
O
H
H
O
Me
Me
n
n
(
(
(
)-38 n = 1 54%a
(
)-28 40%a,g
(
)-33 42%a,g
55%a
)-39 n = 2
)-40 n = 3
52%a
N
CF3
O
H
Nucleoside
analogue
N
CF3
H
X
H
BocN
X
O
HO
O
O
)-41 X = Cl 50%a,g
NHBoc
O
NaBH4
CF3 MeOH
34 31%k
(
(
70%a,g
)-42 X = Br
N
N
CF3
Boc
Boc
N
H
O
N
N
CF3
O
N
F3C
(
O
BocN
N
H
O
O
Boc
N
Boc
(
)-43 48%l
(
)-29 60%g,h
)-30 94%
(
)-35 61%a,g
Fig. 3 | Scope of the alkyl nucleophile coupling partner. A broad range
of C–H nucleophiles are selectively functionalized by this arylation
protocol. Cyclic, acyclic and bicyclic aliphatic systems are amenable
substrates. Heteroatom and carbonyl substituents electronically influence
regioselectivity, and alkyl halides remain intact. All yields are isolated yields.
Conditions as in Fig. 2. Green circles denote sites where notable amounts
of other regioisomers are observed. See Supplementary Information
for experimental details. Ac, acetyl; Boc, tert-butoxycarbonyl; d.r.,
diastereomeric ratio; Me, methyl; r.r., regioisomeric ratio. a>20:1 r.r.; b70%
selectivity; c53% selectivity; d79% selectivity; e93% selectivity; f1.4:1 r.r.;
g>20:1 d.r.; h2.5:1 r.r.; i79% selectivity, 3:1 d.r. (major); j1.8:1 r.r., 5.4:1 d.r.
(major); k8.8:1 r.r.; l3.4:1 r.r.
hydrogen atoms28. This result further highlights the role of the nickel scaffold among natural products and pharmaceuticals29, was also effec-
catalyst in determining the regioselectivity of C–C bond formation, tively subjected to this dual-catalysis protocol (35, 61% yield).
presumably via reversible radical capture and selectivity-determining
It is important to note that this transformation is not restricted
reductive elimination27. Four-membered rings were also competent to electronically neutral, unactivated C–H systems. Indeed, various
substrates for this arylation protocol, with both an exocyclic ketone and α-heteroatom C–H nucleophiles were readily modified with excellent
a spirocyclic ketone affording the desired product in moderate yields regioselectivity. As follows from the preference of decatungstate for the
(33 and 34, 42% and 31% yield, respectively). Tropinone, a common most hydridic and sterically accessible C–H bond, tert-butoxycarbonyl
7 2
| N A t U r e | V O L 5 6 0 | 2 A U G U S t 2 0 1 8
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Letter reSeArCH
O
O
W
Ni
W
W
O
O
O
O
Z
O
O
t-Bu
O
O
O
H
W
Ni
Br
O
O
O
W
Br
N
W
R
Ni
O
W
O
O
W O
R
O
O
O
N
Br
W
O
W
O
O
O
O
Z
O
O
O
t-Bu
O
W
O
W
O
1
Aryl halide scope
Heteroaryl halide scope
Br
Br
Br
Br
Br
Br
Cl
Br
F
F
Br
Me
N
S
N
N
N
MeO2C
44 68%
F3C
NC
Boc
O
O
45 70%
46 64%
47 60%
59 38%
60 25%
61 49%
62 64%
Br
Br
Br
Br
Br
Br
Br
F3C
Br
Br
H2N
S
N
Ac
N
F
N
N
t-BuO
50 59%
Me
O
O
48 69%
49 63%
51 52%
63 59%
64 27%
65 55%
66 45%
Br
Br
F3C
Br
Br
N
Br
Br
F3C
N
Br
N
NC
F3CO
N
F3C
N
Cl
52 53%
53 60%
54 62%
55 50%
Br
67 52%
68 40%
69 31%
70 55%
Br
Cl
N
Br
Br
N
N
Br
Br
t-Bu
F3C
HO
N
S
S
CO2Me
57 45%
CN
Me Me
56 55%
71 51%
72 54%
73 51%
58 71%
Pharmaceutically relevant aryl halide diversiꢀcation
O
O
O
O
O
O
O
O
S
NH2
S
NH2
S
NH2
S
NH2
• Biorelevant motif
Br
Single-step
alkylation
• Late-stage diversifcation
• Mild, robust conditions
N
N
N
N
O
N
N
N
N
Br
F3C
F3C
F3C
F3C
75b 60%a
75c 67%b
74
Celecoxib–Br
75a 67%
Fig. 4 | Scope of the aryl halide coupling partner. Various electronically
diverse aryl bromides were functionalized in moderate to good yields,
and unprotected polar functionalities such as alcohols and sulfonamides
were well tolerated. Moreover, heteroaryl bromides including indoles,
the transformation. Finally, the dual catalytic manifold was applied to the
synthesis of several analogues of celecoxib. All yields are isolated yields.
Conditions as in Fig. 2. See Supplementary Information for experimental
details. a1.4:1 r.r.; b>20:1 d.r.
pyridines, pyrimidines and thiazoles were competent coupling partners in
(Boc)-protected pyrrolidine was functionalized selectively at the fluorine-bearing aryl bromides were alkylated selectively as well (55
α-amino position (36, 53% yield). Primary α-amino C–H nucleophile and SI-5, 50% and 55% yield, respectively), and free-alcohol-containing
N-Boc dimethylamine was also found to be an effective substrate for substrate 56 was also found to be a competent coupling partner (55%
the transformation (37, 68% yield). In addition to nitrogen-containing yield). ortho-Substituted aryl bromides were likewise alkylated in mod-
nucleophiles, various cyclic ethers were regioselectively functionalized erate to good yields (57 and 58, 45% and 71% yield, respectively). With
in moderate to good yield at the α-oxy position (38–43, 48%–70% respect to heteroaryl bromides, N-Boc-indole 59 underwent the desired
yield). Notable among these substrates, alkyl halides were well toler- transformation in useful efficiency (38% yield). A range of bromopyri-
ated (41 and 42, 50 and 70% yield, respectively), opening avenues for dines were alkylated in useful to good yields as well (60–69, 25%–64%
subsequent synthetic manipulations. N-Boc-morpholine underwent yield). Bromopyrimidines were effective substrates (70 and 71, 55% and
C–H arylation predominantly at the α-amino C–H bond (43, 48% 51% yield, respectively), and both electron-rich and electron-deficient
yield, 3.4:1 regioisomeric ratio (r.r.)). Useful amounts of the α-oxy 2-bromothiazoles afforded the desired product in moderate yields (72
product are generated in this case, in contrast to the quinuclidine- and 73, 54% and 51% yield, respectively). Lastly, the pharmaceutically
mediated triple catalytic arylation reported previously by our relevant aryl halide 74, a precursor to celecoxib was subjected to the
laboratory10 (see Supplementary Information) as well as benzophenone- reaction conditions with various alkyl C–H nucleophiles. Cyclohexane,
mediated cyanation30, wherein exclusive α-amino functionalization cyclohexanone and 7-bromonorbornane were all coupled in good effi-
is observed.
ciencies (75a–c, 60%–67% yield), which demonstrates the utility of the
We next turned our attention to the scope of the aryl halide coupling protocol in cross-coupling complex aryl fragments with structurally
partner. As shown in Fig. 4, a broad range of electron-deficient aryl bro- diverse C–H nucleophiles.
mides provided the desired products in good yield (44–49, 60%–70%
Having demonstrated the applicability of the C–H arylation protocol
yield). Furthermore, neutral and electron-rich substrates displayed to a broad array of C–H nucleophiles and aryl halide electrophiles, we
useful coupling efficiencies (50–54, 52%–62% yield). Chlorine- and next investigated its efficacy on naturally occurring aliphatic systems.
2
A U G U S t 2 0 1 8 | V O L 5 6 0 | N A t U r e | 7 3
© 2018 Springer Nature Limited. All rights reserved.

reSeArCH Letter
a
Minor regioisomer
O
O
O
O
Me
Me
H
Me
H
Me
Me
HO
Me
Me
Me
Me
O
Ar
Me
H
Me
H
Me
O
Me
Me
Me
Me
Me
Me
Me
Me
Eucalyptol: $0.04 per mmol
Fenchone: $0.02 per mmol
Ethyl fenchol: $0.09 per mmol
(
)-Camphene: $0.02 per mmol Sclareolide: $1.07 per mmol
CF3
80a–d
N
Ar
=
N
CF3
N
N
CF3
N
CF3
N
Cl
Me
N
CF3
Me
Me
O
Me
Me
HO
Me
O
80a 41%a
80b 34%a
Me
Me
Ac
O
Me
Me
Me
Me
77 38%a
41% yield, 5.0-mmol scalea
(
)-76 55%
78 52%
72% selectivity, >20:1 d.r.
(
)-79 70%
80c 43%a
80d 31%a,b
3.6:1 r.r., >20:1 d.r.
1.4:1 r.r., >20:1 d.r.
b
Cl
N
Cl
Modular synthesis of
N
epibatidine and analogues
Two-step synthesis of ( )-N-Boc-epibatidine
N
N
Br
(
F
Br
(
Br
Boc
N
Cl
Cl
Boc
N
Boc
N
)-82a 28%a
)-83a 33%a
(
(
)-82b 21%a
)-83b 37%a
)-82c 37%a
W
Ni
H
H
N
N
Br
81
(
)-82a
NBoc
(
(
)-83c 44%a
One-step protection
N-Boc-epibatidine
H
O
Fig. 5 | Functionalization, synthesis and derivatization of natural
products. a, A series of abundantly available terpenoids serve as
competent coupling partners in this dual catalytic protocol, affording
complex arylated scaffolds in good yields. Major and minor isomers
are denoted. b, ( )-N-Boc-epibatidine was synthesized in two steps
from commercially available materials, and subsequently a small library
of analogous compounds was constructed. a>20:1 r.r., >20:1 d.r.;
bcyclopropane carbonyl chloride used as electrophilic coupling partner.
As illustrated in Fig. 5a, various inexpensive, abundant natural prod- the reaction conditions, we observed an unoptimized 28% yield of
ucts were successfully functionalized under our standard conditions, protected epibatidine (82a) in two steps from the commercially avail-
enabling the rapid arylation of complex stereodefined frameworks able unprotected amine (Fig. 5b, see Supplementary Information for
at carbon sites that lack adaptive functional handles. The observed experimental details). To our knowledge, this is the shortest formal
regioselectivities were in accordance with the expected preferences synthesis of ( )-epibatidine in the multitude of reported procedures
of this dual-catalytic manifold, as described above. A moderate yield to date33. Subsequently, we sought to demonstrate that diversification
of heteroarene-coupled eucalyptol was observed (76, 55% yield), was possible by variation of both the alkyl fragment and the aryl bro-
with a strong preference for arylation at the most hydridic mide fragment. A representative sampling of heteroaryl bromides was
and sterically accessible C–H bond. Useful efficiencies were observed coupled with bridged bicyclic amines to afford a small set of analogues
for the terpene fenchone, which was also found to be a suitable in synthetically useful yields (82b to 83c, 21%–44% yield). We have
substrate on 5.0-mmol scale (77, 38% and 41% yield, respectively; developed a robust method for the construction of C(sp3)–C(sp2) bonds
see Supplementary Information for experimental details). A free- from alkane nucleophiles and aryl bromide electrophiles. We believe
alcohol derivative of fenchone was also readily used in this protocol that these results demonstrate the potential to use unactivated C–H
(78, 52% yield), and camphene, a terminal-olefin-containing natural bonds as nucleophiles in transition-metal-catalysed cross-coupling
product, was also an effective substrate for arylation (79, 70% yield). transformations.
Lastly, we sought to illustrate the generality of this method by derivat-
izing the lactone sclareolide with a range of aryl and heteroaryl bro- Data availability
The data that support the findings of this study are available from the correspond-
ing author upon reasonable request.
mides (80a–c, 35%–43% yield). Notably, an alkyl acid chloride provided
the sclareolide-derived ketone in useful efficiency (80d, 33% yield),
which illustrates the capability of our transformation to install a range
of functionality onto complex aliphatic substrates without the need for
directing groups.
Received: 20April 2018;Accepted: 6 June 2018;
Published online 1August 2018.
Finally, we demonstrated the application of this C–H arylation proto-
col towards the rapid generation of complex pharmaceutically relevant
molecules. Our target was the natural product epibatidine, a potent
non-opioid analgesic. Owing to its high toxicity, epibatidine has seen
limited potential as a commercial pharmaceutical31; however, a range
of epibatidine analogues have been investigated in a clinical setting32.
We first targeted the synthesis of ( )-N-Boc-epibatidine from com-
mercially available 7-azabicyclo[2.2.1]heptane. When N-Boc-protected
amine substrate 81 and 2-chloro-5-bromopyridine were subjected to
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Author contributions I.B.P., T.F.B., P.J.S. and D.M.S. performed and analysed
the experiments. I.B.P., T.F.B., P.J.S., D.M.S., D.A.D. and D.W.C.M. designed the
experiments. I.B.P., T.F.B., P.J.S. and D.W.C.M. prepared the manuscript.
Competing interests The authors declare no competing interests.
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Additional information
Supplementary information is available for this paper at https://doi.org/
10.1038/s41586-018-0366-x.
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