Harnessing the Intrinsic Reactivity of 2-Cyano-Substituted Heteroarenes to Achieve Programmable Double Alkylation

Article abstract of DOI:10.1002/adsc.201901139

Herein, we report our study of tertiary radicals, generated through visible light decarboxylation, alkylating 2-cyanoarenes through radical cross-coupling at the ipso- or the para- positions of the cyano groups. Synthesis of a variety of α-tertiary amines containing quaternary centers is described. The approach enables regioselective sequential double alkylation on either 2-cyanopyridine or 2-cyanopyrimidine with high efficiency. Our report illustrates the synthetic utility of α-heteroatom-substituted tertiary radicals in the synthesis of substituted heteroarenes. (Figure presented.).

Full text of DOI:10.1002/adsc.201901139

Title: Harnessing the Intrinsic Reactivity of 2-Cyano-Substituted
Heteroarenes to Achieve Programmable Double Alkylation
Authors: Zhuming Sun, Jichen Zhao, Huiwen Deng, Li Tian, Bingqing
Tang, Kevin Liu, and Hugh Zhu
This manuscript has been accepted after peer review and appears as an
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201901139
Link to VoR: http://dx.doi.org/10.1002/adsc.201901139

10.1002/adsc.201901139
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Harnessing the Intrinsic Reactivity of 2-Cyano-Substituted
Heteroarenes to Achieve Programmable Double Alkylation
Zhuming Suna, Jichen Zhaoa, Huiwen Denga, Li Tiana, Bingqing Tanga, Kevin K.-C.
Liua and Hugh Y. Zhua*
a
Novartis Institutes for BioMedical Research, 4218 Jinke Road, Pudong New District, Shanghai, China
E-mail: hughzhu@hotmail.com
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. Herein, we report our study of tertiary radicals,
generated through visible light decarboxylation, alkylating
2-cyanoarenes through radical cross-coupling at the ipso-
or the para- positions of the cyano groups. Synthesis of a
variety of α-tertiary amines containing quaternary centers
is described. The approach enables regioselective
sequential double alkylation on either 2-cyanopyridine or
2-cyanopyrimidine with high efficiency. Our report
illustrates the synthetic utility of α-heteroatom-substituted
tertiary radicals in the synthesis of substituted
heteroarenes.
illustrated by Shteingarts, where an alkaline-metal-
mediated 1,2-dicyanobenzene radical anion could be
coupled with a variety of alkyl radicals (Scheme
1A).[7] In the Shteingarts study it was shown that the
alkyl radical added para to the cyclohexadienyl anion
species, which was subsequently oxidized and
deprotonated to afford the re-aromatized product.
In our proposed studies, we rationalized that as
electron-deficient heteroarenes, both 1a and 1b could
not only serve as effective para-coupling partners, but
also act as potential oxidants in a catalytic system.[8]
This alkylation mode leaves the 2-cyano group in 1c
and 1d intact, and as a result different alkyl radical can
subsequently couple via ipso-addition and decyanation
(Scheme 1B). To the best of our knowledge, this would
represent a novel programmable alkylation strategy
towards functionalized heteroarenes. In addition,
tertiary radicals with α-heteroatom substitution have
not been previously explored in literature. These could
be ideal partners for coupling reactions due to their
enhanced stability.[9] The difficulty to access α-
heteroaryl cyclic amine products otherwise was also an
appealing impetus.[10] Herein we report our initial
studies using α-NHBoc and other tertiary radicals to
alkylate various 2-cyanoarenes under mild non-acidic
conditions without addition of external oxidants.
Programmable double alkylation was investigated as
well.
For our exploratory model study, we utilized a
commercially available amino acid 2a (Scheme 2).
When Ir[dF(CF3)ppy]2(dtbbpy)PF6 was applied as the
catalyst, 2a underwent successful decarboxylation to
generate the corresponding tertiary radical, which
subsequently reacted with Michael acceptor 3 to form
Giese product 4 in high yields.[11] Under the same
conditions, the sp3-sp2 radical cross-coupling between
2a and 5-(trifluoromethyl)-2-cyanopyridine 1e was
observed, with a modest 35% yield of 5a (Table 1,
entry 3). Encouraged by this initial result, we reasoned
the bulky t-butyl groups on this photocatalyst could
potentially impede the substrate-photocatalyst
interaction. Subsequent screening of four other
common catalysts (Table 1, entry 1, 2, 4, 5) showed
Keywords: photocatalysis; heterocycles; radical
reactions; C-C coupling
Heterocycles are important pharmacophores in small
molecule drug discovery and hence synthetic methods
to readily modify them are strategically important in
expanding structure-activity relationship (SAR)
studies in modern pharmaceutical research.[1] Recent
innovative photoredox methods have made
tremendous progress in radical-based alkylation on
heteroarenes.[2] These established methods include
photoredox/nickel dual catalysis developed by
MacMillan, Molander and Doyle,[3] photo-Minisci
reactions advanced by Glorius, Overman, Chen and
Wang,[4] and light-mediated alkylation on cyanoarenes
via radical-radical coupling described by MacMillan,
Smith, Opatz and Wang.[5] Based on the latter
methodology, it has been shown that 4-substituted
pyridines can be synthesized from 4-cyanopyridine via
SET reduction to the corresponding radical anion,
followed by radical addition and decyanation (Scheme
1A).[6] By extension, we postulated that that other
cyanoarenes
such
as
2-cyano-3-
(trifluoromethyl)pyridine 1a and 2-cyanopyrimidine
1b could potentially be reduced via SET in an
analogous manner (Scheme 1B). However, the
subsequent cross-coupling on their radical anions
might prefer the para- position of the cyano group over
the ipso-addition and decyanation pathway, due to
their different spin-density properties. Spin-density
controlled regio-selectivity has been previously
1
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10.1002/adsc.201901139
Advanced Synthesis & Catalysis
that in fact fac-Ir(dfppy)3 was the superior catalyst,
yielding 94% of 5a (Table 1, entry 5). In the following
control experiments, we found no reaction occurred
under the 26W CFL exposure or without base (Table
1, entry 6, 7). Switching the base to Cs2CO3, without
N2 bubbling the yields decreased (Table 1, entry 8, 9).
DMF was inferior to DMSO as solvent (Table 1, entry
10). Lower catalyst loading required prolonged
reaction time and resulted in a decreased yield (Table
1, entry 11). Using a 40W blue LED lamp under fan-
cooling, 1e (0.37 mmol), 2a (1.1 mmol), K2HPO4 (0.41
mmol) and fac-Ir(dfppy)3 (7.4 μmol) in DMSO (12
mL) gave the desired product 5a in 87% isolated yield.
Table 1. Photoredox radical coupling of acid 2a and 2-
cyanopyridine 1e to synthesize 5a.
Entry
Photocatalyst
Base
Yield
(%)[a]
1[b]
2
3
Ir[p-F(t-Bu)-ppy]3
Ir(ppy)2(dtbbpy)PF6
Ir[dF(CF3)ppy]2(dtbbpy) K2HPO4
PF6
K2HPO4
K2HPO4
14
22
35
4
Ir[dF(Me)ppy]2(dtbbpy)
PF6
K2HPO4
34
5
fac-Ir(dfppy)3
fac-Ir(dfppy)3
fac-Ir(dfppy)3
fac-Ir(dfppy)3
fac-Ir(dfppy)3
fac-Ir(dfppy)3
fac-Ir(dfppy)3
fac-Ir(dfppy)3
K2HPO4
K2HPO4
No base
Cs2CO3
Cs2CO3
K2HPO4
K2HPO4
K2HPO4
94
0
0
47
12
43
59
87
6[c]
7
8
9[d]
10[e]
11[f]
12[g]
[a]
General conditions: Chemtech (2W) blue LED reactor under
fan-cooling, 2a 0.28 mmol, 1e 0.1 mmol, base 0.1 mmol,
photocatalyst 1.9 μmol, DMSO 3 mL, 30 min N2 bubbling,
overnight rt. Yields were determined by LCMS trace integration
compared to the standard solution of 5a.
[b] Structure of the individual photocatalyst is shown in SI.
[c] Compact fluorescent lightbulb as the light source.
[d] No N2 bubbling.
[e] DMF as the solvent.
[f] 1 mol%, fac-Ir(dfppy)3 loading, 48h.
[g] 40 W Kesil blue LED setup as the light source, isolated yield.
With these optimal conditions in hand, we then
explored the cyanoarene scope with several different
tertiary radicals derived from the corresponding acids
Scheme 1. Proposed 2-cyanoarenes as cross-coupling partners at
para and ipso positions of the cyano groups as a programmable
double alkylation strategy.
(Scheme 3). 1,4-Dicyanobenzene 1d, a well-known
persistent radical source,[5,
formed product with
6]
cyclic acids (5b-c) and α-ether acid (5d). Similarly, 2-
cyano-5-(trifluoromethyl)pyridine 1e reacted with
different acids (5e-f). Its regio-isomer 2-cyano-4-
(trifluoromethyl)pyridine could also couple to a
variety of tertiary radicals (5g-k). In 5j’s case, all
carbon 2-methyl-2-phenylpropanoic acid proceeded
Scheme 2. Giese addition of acid 2a and phenyl vinyl sulfone 3.
Reaction conditions: 40W Kessil blue LED lamp under fan-
cooling, 2a 1.1 mmol, 3 0.37 mmol, K2HPO4 0.41 mmol,
photocatalyst 7.4 μmol, DMSO 12 mL, 30 min N2 bubbling,
overnight rt.
with
a
very
high
yield.
2-Cyano-4-
carbomethoxypyridine and 4-cyano-3-fluoropyridine
were also suitable substrates (5l-m). These examples
demonstrated a facile approach to synthesize
heteroarenes with steric hindered and challenging
substitutions. When natural product Enoxolone was
used to react with 2-cyano-4-(trifluoromethyl)pyridine,
both cyano ipso-substitution product 5n and 6-proton
replaced product 5o were identified. This observation
suggested the multiple roles of 2-cyano-4-
(trifluoromethyl)pyridine. It could function as both the
coupling partner and an oxidant to drive the
photocatalyst mediated oxidation (via anionic radical
formation in the system) to furnish the C(sp2)-H
activated product 5o.
2
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10.1002/adsc.201901139
Advanced Synthesis & Catalysis
Scheme 3. Cyanoarene ipso- cross-coupling with tertiary radicals.
a
Reaction conditions: carboxylic acid 2 (1.0 mmol, 3 equiv),
Scheme 4. Cyanoarene para- cross-coupling with tertiary radicals.
Reaction conditions: carboxylic acid 2 (0.33 mmol, 1 equiv),
arene/heteroarene 1 (1.0 mmol, 3 equiv), potassium phosphate,
dibasic (1.0 mmol, 3 equiv), fac-Ir(dfppy)3 (6.5 µmol, 0.02 equiv),
DMSO (12 mL), blue LED, RT, 16h. All isolated yields calculated
based on acid equiv.
arene/heteroarene 1 (0.33 mmol, 1 equiv), potassium phosphate,
dibasic (1.0 mmol, 3 equiv), fac-Ir(dfppy)3 (6.5 µmol, 0.02 equiv),
DMSO (12 mL), blue LED, RT, 16h. All isolated yields calculated
based on arene equiv.
a
Further study revealed several cyanoarenes only
underwent para-alkylation and afforded the Ar-H
replaced products. Without losing the CN group, only
6a was isolated when 1,2-dicyanobenzene 1f reacted
with 2a (Scheme 4). To optimize the reaction yield, we
increased arene to acid ratio from 1:3 to 3:1 to ensure
enough arenes in the system to act as reactants and
oxidants at the same time. This improved the yield of
6a from 31% to 58% based on limiting reagent 2a.
Similar result was obtained with pyrrolidine acid (6b).
2-Cyano-3-(trifluoromethyl)pyridine 1a and 2,4-di-
cyanopyridine gave excellent yields reacting with
cyclic acids (6c-6f). 2-Cyanopyrimidine and 2-chloro-
3-cyanopyridine were also capable in this “arene-as-
oxidant” coupling (6g-h). The spin-density of the
anionic radical formed likely accounted for the
excellent regio-selectivity in most cases. When
Enoxolone reacted with pyrazinecarbonitrile, the new
C-C bond formed exclusively at the sp2 carbon para to
the nitrile group (6i). However, steric factors might
play a role as well. In the reaction between pyrrolidine
acid 2b and 2-cyano-6-(trifluoromethyl)pyridine 1g,
two isomers were formed. Only 25% of para-
alkylation product 6k was isolated while meta-
alkylation product 6j (47%) accounted for the majority
of the isolated product possibly due to the meta
position was more accessible.
Mechanism for radical ipso-addition to 2-cyano-5-
(trifluoromethyl)pyridine 1e and decyanation was well
[5]
established in literature (Scheme 5A).
The
photocatalyst fac-Ir(dfppy)3 is transformed to its
excited-state Ir(III)* under irradiation. As an excellent
reductant (E1/2red[IrIv/*IrIII] = -1.44 V vs SCE),[5c] it
converts 1e into a persistent radical anion 7a. The
oxidized iridium species Ir(IV) is reduced by the
carboxylic acid 2a, and returns to its baseline state.
The resulting tertiary radical 7b is captured by the
persistent radical 7a. In this event, the spin-density of
7a predicts an ipso-addition to form 7c, which is then
de-cyanated to give 5a. We propose para- alkylation of
1,2-dicyanobenzene 1f starts with
a
similar
photocatalytic cycle (Scheme 5B). However, the spin-
density of radical anion 7d makes it couple with the
tertiary radical 7b at the para-position toward one of
its cyano groups.[12] Our in silico calculation
(DFT/B3LYP)[13] indicates formation of 7e has a 4.1
kcal/mol ∆G# loss. The subsequent 1e- oxidation from
7e to 7f lowers another 10.6 kcal/mol in ∆G#. The de-
protonation and the second oxidation from 7f to 6a
brings in a big ∆G# loss (-33.6 kcal/mol). Thus, these
three thermodynamically downhill events make para-
addition hugely favored. In this pathway, two excess
equivalent of 1,2-dicyanobenzene 1f is needed as an
oxidant to recycle the Ir catalysts. This fully matches
our stoichiometry used (2a 1 equiv, 1f 3 equiv). The
3
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10.1002/adsc.201901139
Advanced Synthesis & Catalysis
alternative SOMO-LUMO guided Minisci type
addition pathway is less likely due to the initial 23.6
kcal/mol ∆G# penalty (Scheme 5C).[13]
Combining these two different coupling modes,
programmable sequential alkylation was achieved on
cyano-heteroarenes 1a and 1b respectively (Scheme 6).
The first step was a para-alkylation, in which the
arenes play a ‘dual role’. It was followed by ipso-
alkylation with either -amino cyclic acid 2a or all-
carbon quaternary acid 2d. These reactions introduced
two highly steric hindered substitutions onto pyridine
and pyrimidine regioselectively. The results
demonstrated the prowess of this photoredox sequence
as an enabling technology in pharmaceutical research
to access previously under-explored structures.
In conclusion, we have described a visible-light
mediated decarboxylative method to generate various
tertiary radicals and coupled them onto cyanoarenes.
We explored substrate scopes of the photoredox ipso-
and para-alkylation reactions, and proposed the
mechanisms for these two modes in this account. Spin-
density calculation could be used to predict this novel
photoredox
para-alkylation
on
cyanoarenes,
expanding its synthetic utility. Our study provided a
mild and practical enhancement to the synthetic
toolbox of substituted heteroarenes, as illustrated by
examples of programmable alkylation on the same
cyano-substituted heteroarenes. These scaffolds
enriched with sp3-carbon and stereocenters could serve
as better starting points for drug candidates.[14]
Experimental Section
General Procedures 1: For ipso-alkylation, to a 40 mL
vial containing a stirring bar were the carboxylic acid (1.0
mmol, 3 equiv), potassium phosphate, dibasic (1.0 mmol, 3
equiv), fac-Ir(dfppy)3 (6.5 µmol, 0.02 equiv) and
arene/heteroarene (0.33 mmol, 1 equiv) mixed in DMSO
(Volume:12 mL, ReagentPlus®, Aldrich). The mixture
was bubbled by industry grade N2 using long-neck
syringes for 30 min. The cap was wrapped by parafilm.
The vial was put on an IKA basic stir plate and was
subjected to the 40W Kesil blue LED exposure. The
distance of the bulb and the vial was roughly 2~4 cm.
Unless noted specifically, the reaction was allowed
overnight i.e., 12~16 h. The reaction mixture was poured
onto brine and water, the crude product was extracted by
ethyl acetate (3 X 40 mL). The organic layer was
combined and was dried with MgSO4, then was filtered
and concentrated in vacuo. The crude product was purified
by column chromatography using a Combiflash
workstation. Some products were further purified by
preparational HPLC.
Scheme 5. A) ipso- Alkylation of 2a (3 equiv) and 1e (1 equiv).
B) para- Alkylation of 2a (1equiv) and 1f (3 equiv). All Ir(IV)
species are formed by arene-driven Ir(III)* oxidation. C) Radical
7b attacking neutral arene 1f results in ∆G# penalty.
General procedures 2: For para-alkylation, carboxylic
acid (1 equiv), arene/heteroarene (3 equiv) and base (1
equiv) were used. Other conditions were the same as in the
general procedures 1.
Acknowledgements
We thank Drs. En Li and Amber Cai for CNIBR Trainee program
(B.T.). We also thank Dr. Richard Robinson (NIBR Cambridge)
for proofreading of the manuscript.
Scheme 6. Programmable alkylation on 1a or 1b. All isolated
yields calculated based on the limiting substrates.
4
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10.1002/adsc.201901139
Advanced Synthesis & Catalysis
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5
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Advanced Synthesis & Catalysis
COMMUNICATION
Harnessing the Intrinsic Reactivity of 2-Cyano-
Substituted Heteroarenes to Achieve Programmable
Double Alkylation
Adv. Synth. Catal. Year, Volume, Page – Page
Zhuming Sun, Jichen Zhao, Huiwen Deng, Li Tian,
Bingqing Tang, Kevin K.-C. Liu, Hugh Y. Zhu*
6
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