Alcohols as alkylating agents in heteroarene C-H functionalization

Article abstract of DOI:10.1038/nature14885

Redox processes and radical intermediates are found in many biochemical processes, including deoxyribonucleotide synthesis and oxidative DNA damage. One of the core principles underlying DNA biosynthesis is the radical-mediated elimination of H₂O to deoxygenate ribonucleotides, an example of 'spin-centre shift', during which an alcohol C-O bond is cleaved, resulting in a carbon-centred radical intermediate. Although spin-centre shift is a well-understood biochemical process, it is underused by the synthetic organic chemistry community. We wondered whether it would be possible to take advantage of this naturally occurring process to accomplish mild, non-traditional alkylation reactions using alcohols as radical precursors. Because conventional radical-based alkylation methods require the use of stoichiometric oxidants, increased temperatures or peroxides, a mild protocol using simple and abundant alkylating agents would have considerable use in the synthesis of diversely functionalized pharmacophores. Here we describe the development of a dual catalytic alkylation of heteroarenes, using alcohols as mild alkylating reagents. This method represents the first, to our knowledge, broadly applicable use of unactivated alcohols as latent alkylating reagents, achieved via the successful merger of photoredox and hydrogen atom transfer catalysis. The value of this multi-catalytic protocol has been demonstrated through the late-stage functionalization of the medicinal agents, fasudil and milrinone.

Full text of DOI:10.1038/nature14885

LETTER
doi:10.1038/nature14885
Alcohols as alkylating agents in heteroarene C–H
functionalization
Jian Jin1 & David W. C. MacMillan1
Redox processes and radical intermediates are found in many bio- pathways. Recently, our laboratory introduced a new dual photoredox-
chemical processes, including deoxyribonucleotide synthesis and
oxidative DNA damage1. One of the core principles underlying
DNA biosynthesis is the radical-mediated elimination of H2O to
deoxygenate ribonucleotides, an example of ‘spin-centre shift’2,
during which an alcohol C–O bond is cleaved, resulting in a car-
bon-centred radical intermediate. Although spin-centre shift is a
well-understood biochemical process, it is underused by the syn-
thetic organic chemistry community. We wondered whether it
would be possible to take advantage of this naturally occurring
process to accomplish mild, non-traditional alkylation reactions
using alcohols as radical precursors. Because conventional radical-
based alkylation methods require the use of stoichiometric oxi-
dants, increased temperatures or peroxides3–7, a mild protocol
using simple and abundant alkylating agents would have consid-
erable use in the synthesis of diversely functionalized pharmaco-
phores. Here we describe the development of a dual catalytic
alkylation of heteroarenes, using alcohols as mild alkylating
reagents. This method represents the first, to our knowledge,
broadly applicable use of unactivated alcohols as latent alkylating
reagents, achieved via the successful merger of photoredox and
hydrogen atom transfer catalysis. The value of this multi-catalytic
protocol has been demonstrated through the late-stage functiona-
lization of the medicinal agents, fasudil and milrinone.
organocatalytic platform to enable the functionalization of unacti-
vated sp3 C2H bonds15–17. This catalytic manifold provides access
to radical intermediates via C2H abstraction, resulting in the con-
struction of challenging C2C bonds via a radical–radical coupling
mechanism. With the insight gained from this dual catalytic system
and our recent work on the development of a photoredox-catalysed
Minisci reaction18, we questioned whether it would be possible to
generate alkyl radicals from alcohols and use them as alkylating agents
in a heteroaromatic C–H functionalization reaction (Fig. 1c). While
there are a few early reports of alcohols as alkyl radical precursors
formed via high-energy irradiation (ultraviolet light and gamma
rays)19–21, a general and robust strategy for using alcohols as latent
alkylating agents has been elusive. This transformation would repres-
ent a direct C2H alkylation of heteroaromatics with alcohols via a
spin-centre shift pathway, eliminating H2O as the only by-product.
We recognized that this mild alkylating procedure would serve as a
powerful and general method in late-stage functionalization, using
commercially available and abundant alcohols as latent alkylating
agents.
A detailed description of our proposed dual catalytic mechanism
for the alkylation of heteroarenes with alcohols is outlined in Fig. 2.
Irradiation of Ir(ppy)2(dtbbpy)1 (1) (in which ppy 5 2-phenylpyridine,
dtbbpy 5 4,49-di-tert-butyl-2,29-bipyridine) will generate the long-
During DNA biosynthesis, ribonucleoside diphosphates are con-
verted into their deoxyribonucleoside equivalents via the enzymatic
activity of ribonucleotide reductase (class I–III)8. Crucially, a (39,29)-
spin-centre shift occurs, resulting in b-C–O scission and elimination
of water (Fig. 1a). Considering the efficiency of this mild enzymatic
process to cleave C–O bonds to generate transient radicals, we postulated
whether an analogous chemical process could occur with simple alco-
hols, such as methanol, to access radical intermediates for use in chal-
lenging bond constructions (Fig. 1b). In the medicinal chemistry
community, there is growing demand for the direct introduction of alkyl
groups, especially methyl groups, to heteroarenes, given their influence
ondrugmetabolism and pharmacokineticprofiles9. The open-shelladdi-
tion of alkyl radical intermediates to heteroarenes, known as the Minisci
reaction10, hasbecomeamainstaytransformationwith broadapplication
within modern drug discovery11. Unfortunately, many current methods
are limited in their application to late-stage functionalization of complex
molecules owing to their dependence on the use of strong stoichiometric
oxidants or increased temperatures to generate the requisite alkyl
radicals3–6. A photoredox-catalysed alkylation protocol using peroxides
as the alkyl radical precursors was recently demonstrated7. Given the
state of the art, we questioned whether a general alkylation protocol
could be devised in which a broad range of substituents could be installed
from simple commercial alcohols under mild conditions.
a
PPO
PPO
R
R
O
O
O
HO
OH
RNR class I
–H2O
SCS
b
c
H
H
H
H
HO
C
H
H
Photoredox
R
R
HO Me
Organocatalysis
N
N
H
Me
Methanol
Heteroarene
Methyl adduct
–H2O
R
R
SCS
N
H
N
OH
H
Figure 1
|
Bio-inspired alkylation process using alcohols as spin-centre shift
equivalents via a dual catalytic platform. a, DNA biosynthesis occurs via a
spin-centre shift (SCS) process, catalysed by ribonucleotide reductase (RNR)
class I to generate a carbon-centred radical, after elimination of H2O as a by-
product. b, Alcohols (for example, methanol) as radical intermediates when
spin-centre shift allowed. c, Proposed direct installation of alkyl groups using
alcohols under mild photoredox organocatalytic conditions.
Visible light-mediated photoredox catalysis has emerged in recent
years as a powerful technique in organic synthesis that facilitates
single-electron transfer events with organic substrates12–14. This gen-
eral strategy allows for the development of bond constructions that
are often elusive or currently impossible via classical two-electron
1Merck Center for Catalysis at Princeton University, Princeton, New Jersey 08544, USA.
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RESEARCH LETTER
single-electron transfer event with the excited photocatalyst 2 to regen-
erate the active oxidant Ir(ppy)2(dtbbpy)21 (4), while providing the
desired alkylation product 12.
R
R
N
R
R
NH
OH
NH
OH
N
SCS
–H+
We first examined this new alkylation protocol using isoquinoline
and methanol as the coupling partners, and evaluated a range of
photocatalysts and thiol catalysts. Using Ir(ppy)2(dtbbpy)PF6 (1)
and ethyl 2-mercaptopropionate (5), along with p-toluenesulfonic acid
and blue light-emitting diodes as the light source, we were able to
achieve the desired C–C coupling to provide 1-methylisoquinoline
(15) with a 92% yield (see Supplementary Information). Notably, we
observed none of the desired product in the absence of photocatalyst,
thiol catalyst, acid or light, demonstrating the requirement of all com-
ponents in this dual catalytic protocol. In addition, this method
requires only weak visible light and ambient temperature to install
methyl substituents using methanol as the alkylating agent.
Me
–H2O
11
10
9
Methylated
heteroarene 12
+
+ H
R
SET
NH
Heteroarene 3
IrIII (2)
reductant
IrIV (4)
oxidant
*
8
OH
Photoredox
catalytic
cycle
O
SH
EtO
Me
SET
cat. 5
With the optimal conditions in hand, we sought to evaluate the
generality of this dual catalytic alkylation transformation. As high-
lighted in Fig. 3a, a wide range of heteroaromatics are methylated
under the reaction conditions. Isoquinolines with electron-donating
or -withdrawing substituents (such as methyl substituents, esters and
halides) are functionalized in excellent efficiencies (15–18, 85–98%
yield). Quinolines perform effectively, including those that contain
non-participating functionality (19–23, 65–95% yield), in addition
to phthalazine and phenanthridine coupling partners (24 and 25,
70% and 93% yield). Moreover, a wide range of pyridine derivatives
containing diverse functionality (such as esters, amides, arenes, nitriles
and trifluoromethyl groups) can be converted into the desired methy-
lation products in high yield (26–32, 65–91% yield).
IrIII
(1)
Visible light
source
HAT
Organocatalytic
cycle
Photoredox catalyst
–
PF6
O
t-Bu
t-Bu
N
S
N
N
MeOH
Alcohol 7
EtO
Ir
6
Me
N
Methanol as methylating agent
Ir(ppy)2(dtbbpy)PF6 (1)
Figure 2
|
Proposed mechanism for the direct alkylation of heteroaromatic
Next, we sought to investigate the nature of the alcohol coupling
partner, as demonstrated in Fig. 3b. A broad array of primary alcohols
can effectively serve as alkylating agents in this new alkylation reac-
tion. In contrast to the methylation conditions highlighted above,
alcohols in Fig. 3b typically use methyl thioglycolate 13 as the C–H
abstraction catalyst. Notably, simple aliphatic alcohols such as ethanol
and propanol deliver the alkylated isoquinoline product in high yields
(33 and 34, 95% and 96% yield). Steric bulk proximal to the alcohol
functionality is tolerated, as exemplified by the presence of isopropyl,
b-tetrahydropyran, b-aryl and b-adamantyl substituents (35–38, 87–
92% yield). The presence of an electron-withdrawing trifluoromethyl
(CF3) group distal to the alcohol decreases the rate of the reaction;
however, using the more electrophilic thiol catalyst, 2,2,2-trifluor-
oethanethiol (14), can promote the transformation more efficiently,
possibly owing to the polar effect on the hydrogen atom transfer
transition state (39, 93% yield)26. We found that diols also participate
readily in this alkylation protocol (40 and 41, 88% and 81% yield). It
should be noted that 1,3-butanediol demonstrates exceptional che-
moselectivity and undergoes alkylation exclusively at the primary
C–H bonds via photoredox organocatalysis. The catalytic cycle is initiated via
excitation of photocatalyst 1 to give the excited state 2. A sacrificial amount
of heteroarene 3 oxidizes *IrIII 2 to IrIV 4, which then oxidizes thiol catalyst 5 to
generate thiyl radical 6 and regenerate catalyst 1. Thiyl radical 6 then abstracts a
hydrogen atom from alcohol 7 to form a-oxy radical 8. Radical 8 adds to
heteroarene 3, producing radical cation 9, which after deprotonation forms
a-amino radical 10. Spin-centre shift elimination of H2O forms radical
intermediate 11. Protonation and reduction by *IrIII 2 delivers alkylated
product 12. HAT, hydrogen atom transfer; MeOH, methanol; SET, single-
electron transfer.
lived *Ir(ppy)2(dtbbpy)1 (2) excited state (t 5 557 ns)22. As
*Ir(ppy)2(dtbbpy)1 (2) can function as either a reductant or an oxid-
ant, we postulated that 2 would undergo a single-electron transfer
event with a sacrificial quantity of protonated heteroarene 3 to initiate
the first catalytic cycle and provide the oxidizing Ir(ppy)2(dtbbpy)21
(4). Given the established oxidation potential of Ir(ppy)2(dtbbpy)21
red
(4) (E1/2 5 11.21V versus saturated calomel electrode in CH3CN)22,
we anticipated that single-electron transfer from the thiol catalyst 5 alcohol site. We speculate that the corresponding a-oxy radical at
red
(E1/2 5 10.85V versus saturated calomel electrode for cysteine)23
the secondary alcohol position does not attack the protonated hetero-
to Ir(ppy)2(dtbbpy)21 (4) would occur and, after deprotonation, fur- arene owing to its increased steric hindrance. For these alkylating
nish the thiyl radical 6 while returning Ir(ppy)2(dtbbpy)1 (1) to the agents with several reactive sites (41, 43 and 44), thiol catalyst 5 is
catalytic cycle. At this stage, we presumed that the thiyl radical 6 would the most effective hydrogen atom transfer catalyst—mechanistic
undergo hydrogenatomtransfer with thealcohol7 (a comparablethiol, studies are continuing to determine the origin of these differences
methyl 2-mercaptoacetate S–H bond dissociation energy 5 87 kcal in catalyst reactivity. Ethers, in the form of differentially substituted
mol21 (ref. 24), methanol a-C–H bond dissociation energy 5 96 kcal tetrahydrofurans, are also competent alkylating agents in this dual
mol21 (ref. 25)) to provide the a-oxy radical 8 and regenerate the thiol catalytic platform (42–44, 72–90% yield). In the elimination step, the
catalyst 5, driven by the polar effect in the transition state26. The polar tetrahydrofuran ring opens to reveal a pendent hydroxyl group.
effect is a remarkable property that enables considerably endergonic Interestingly, 3-hydroxytetrahydrofuran and tetrahydrofurfuryl alco-
C–H abstractions that would not be possible otherwise27. The nucleo- hol react regioselectively at the ether a-oxy site distal to the alcohol to
philic a-oxy radical 8 would then add to the protonated electron- afford alkylation products with terminal pinacol motifs. We attribute
deficient heteroarene 3 in a Minisci-type pathway to afford the aminyl this exclusive regioselectivity to a subtle influence on C–H bond
radical cation 9. The resulting a-C–H bond of 9 is sufficiently acidic to dissociation energy owing to the inductive influence of the oxygen
undergo deprotonation to form the a-amino radical 10 (ref. 28). At this atoms. The application of these substrates represents an effective
juncture, intermediate 10 is primed to undergo a spin-centre shift to method to install vicinal diol motifs that would be inaccessible using
eliminate H2O and generate benzylic radical 11. The resulting open- traditional oxidative alkylation methods. Finally, the utility of this
shell species would then undergo protonation followed by a second mild alkylation protocol has been demonstrated by the late-stage
2
|
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LETTER RESEARCH
O
1 mol% photocatalyst 1
5 mol% thiol catalyst 5
O
SH
R1
F3
C
SH
R1
HO R2
Alcohol
EtO
SH
MeO
N
H
N
R2
Me
Thiol cat. 5
TsOH, DMSO, Blue LEDs, 23 °C
Thiol cat. 13
Thiol cat. 14
Heteroarene
Alkylated heteroarene
a
Heteroarenes
Br
Me
CO2Me
Me
N
Me
N
N
N
N
Me
Me
Me
N
Me
Me
19a: 2-Me, 43% yield
19b: 4-Me, 22% yield
15, 92% yield
16, 91% yield
17, 98% yield
18, 85% yield
20, 95% yield
Me
N
Me
Me
Me
Me
N
N
Br
CO2Me
Me
N
Me
N
22, 91% yield
Me
Ph
N
23, 89% yield
Ph
Me
Me
N
21, 93% yield
24, 70% yield
25, 93% yield
26, 82% yield
Me
Me
CF3
CONH2
CN
Me
Ph
N
Me
N
CO2Me
Me
N
N
Me
N
Me
Me
N
Me
27, 81% yield
28, 83% yield
29a: 2-Me, 65% yield
30a: 4-Me, 61% yield
31a: 2-Me, 56% yield
32, 91% yield
29b: 2,6-diMe, 12% yield 30b: 2-Me, 15% yield
30c: 2,4-diMe, 7% yield
31b: 2,6-diMe, 25% yield
Alcohol
Product
Alcohol
Product
c
Ether
Product
b
R
N
R
N
N
R
HO
R
HO
O
OH
33 R = Me
34 R = Et
95% yield
96% yield
42 R = H
43 R = OH
90% yield
72% yield
35, 91% yield
N
N
O
Me
N
HO
O
O
Me
HO
Me
OH
OH
OH
44, 77% yield
Me
36, 87% yield
37, 90% yield
Medicinal agents
d
HN
N
CF3
N
HO
HO
CF3
N
N
O
S
O
39, 93% yield
38, 92% yield
CN
O
N
OH
N
Me
N
H
N
OH
HO
OH
Me
HO
Me
Me
OH
Fasudil derivative
Milrinone derivative
45, 82% yield
46, 43% yield
40, 88% yield
41, 81% yield
Figure 3
|
Substrate scope for the alkylation of heteroaromatic C–H bonds agents in this dual catalytic protocol. c, Ethers are also amenable to the
with alcohols via the dual photoredox organocatalytic platform. A broad
range of heteroaromatics and alcohols are efficiently coupled to produce
alkylated heterocycles under the standard reaction conditions (top,
generalized reaction). a, A variety of isoquinolines, quinolines, phthalazines,
transformation; the products are the corresponding ring-opened alcohols.
d, Two pharmaceuticals, fasudil and milrinone, can be alkylated using this
protocol, demonstrating its utility in late-stage functionalization. Isolated yields
are indicated below each entry. See Supplementary Information for
phenanthridines and pyridines are efficiently methylated using methanol as the experimental details.
alkylating reagent. b, A diverse selection of alcohols serve as effective alkylating
functionalization of several pharmaceutical compounds. Using meth- quenched in the presence of protonated heteroarene 3, but not in the
anol as a simple methylating agent, fasudil, a potent Rho-associated presence of the unprotonated heteroarene or thiol catalyst 5, indicating
protein kinase inhibitor and vasodilator, can be methylated in 82% an oxidative quenching pathway (see Supplementary Information).
yield (product 45). Additionally, milrinone, a phosphodiesterase 3
inhibitor and vasodilator, can be alkylated with 3-phenylpropanol
in 43% yield (product 46).
Furthermore, a series of experiments were conducted to investigate
the proposed spin-centre shift elimination. After exposing hydroxy-
lated intermediate 47 to the reaction conditions, only a modest amount
Mechanistic studies have been conducted to support the proposed of the methylated isoquinoline 15 is observed (8% yield, entry 1,
pathway outlined in Fig. 2. Stern–Volmer fluorescence quenching Fig. 4a). In the absence of an acid additive, only trace yields of the
experiments have demonstrated that the *IrIII excited state 2 is desired product are formed (2% yield, entry 2, Fig. 4a). However, in
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RESEARCH LETTER
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a
1 mol% photocatalyst 1
N
N
2 eq. reductant, 2 eq. acid
DMSO, blue LEDs, 23 °C
Me
47
Entry
OH
15
Acid
Light
Photocatalyst
Reductant
Yield
5. Ji, Y. et al. Innate C–H trifluoromethylation of heterocycles. Proc. Natl Acad. Sci. USA
TsOH
None
TsOH
TsOH
TsOH
8%
2%
1
2
3
4
5
Yes
Yes
Yes
No
Yes
Yes
Yes
Yes
No
None
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˚
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H
¨
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49
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1 mol% photocat. 1
N
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N
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47
OH
50
65% yield
Figure 4
|
Mechanistic studies support spin-centre shift elimination
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via a spin-centre shift pathway to cleave the alcohol C–O bond. c, In the
presence of styrene, 47 is converted to 50, presumably by trapping of radical
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the elimination of oxygen can be achieved in good efficiency (60%
yield, entry 3, Fig. 4a). Crucially, this elimination pathway is shut down
in the absence of either light or photocatalyst (entry 4 or 5, respectively,
Fig. 4a). Therefore, this net reductive process supports the proposed
generation of a-amino radical 48, which could readily form deoxyge-
nated product 15 via a spin-centre shift pathway to b-amino radical
49 (Fig. 4b). This elimination pathway is further corroborated by a
series of radical trapping experiments (Fig. 4c and Supplementary
Information). In the presence of styrene, hydroxymethyl arene 47 is
transformed to adduct 50 (65% yield, Fig. 4c), presumably via the
intermediacy of b-amino radical 49. Finally, while we support the
mechanism outlined in Fig. 2, we cannot rule out the possibility of a
radical chain pathway in which radical 11 abstracts an H-atom from
alcohol 7 or thiol catalyst 5.
In summary, this alkylation strategy represents the first, to our
knowledge, general use of alcohols as simple alkylating agents and
enables rapid late-stage derivatization of medicinally relevant mole-
cules. Given the influence on drug pharmacokinetics and absorption,
distribution, metabolism and excretion (ADME) properties, this
method of installing inert alkyl groups will probably find wide applica-
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and operationally simple alkylation reaction via the synergistic merger
of photoredox and thiol hydrogen atom transfer organocatalysis to
forge challenging heteroaryl C–C bonds using alcohols as latent
nucleophiles. This bio-inspired strategy mimics the key step in
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Supplementary Information is available in the online version of the paper.
Acknowledgements Financial support was provided by NIHGMS (R01
GM103558-03), andgifts from Merck and Amgen. J.J. thanks J. A. Terrett for assistance
in preparing this manuscript.
Author Contributions J.J. performed and analysed experiments. J.J. and D.W.C.M.
designed experiments to develop this reaction and probe its utility, and also prepared
this manuscript.
Received 20 May; accepted 26 June 2015.
Published online 26 August 2015.
Author Information Reprints and permissions information is available at
www.nature.com/reprints. The authors declare no competing financial interests.
Readers are welcome to comment on the online version of the paper. Correspondence
and requests for materials should be addressed to D.W.C.M.
(dmacmill@princeton.edu).
1. Halliwell, B. & Gutteridge, J. M. C. Free Radicals in Biology and Medicine 4th edn
(Oxford Univ. Press, 2007).
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