A mild catalytic system for radical conjugate addition of nitrogen heterocycles

Article abstract of DOI:10.1039/c7sc00243b

The direct addition of pyridine and diazine units to electron-poor alkenes has been achieved via a redox radical mechanism that is enabled by limiting the effective concentration of the hydrogen-atom source. The described method is tolerant of acidic functional groups and is generally applicable to the union of a wide range of Michael acceptors and 6-membered heterocyclic halides.

Full text of DOI:10.1039/c7sc00243b

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DOI: 10.1039/C7SC00243B
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EDGE ARTICLE
A Mild Catalytic System for Radical Conjugate Addition of
Nitrogen Heterocycles
R. A. Aycock,† H. Wang† and N. T. Jui*
Received 00th January 20xx,
Accepted 00th January 20xx
The direct addition of pyridine and diazine units to electron-poor alkenes has been achieved via a redox radical mechanism
that is enabled by limiting the effective concentration of the hydrogen-atom source. The described method is tolerant of
acidic functional groups and is generally applicable to the union of a wide range of Michael acceptors and 6-membered
heterocyclic halides.
DOI: 10.1039/x0xx00000x
www.rsc.org/
Introduction
Pyridines and diazines are critical structural elements in many Because pyridines are weakly nucleophilic, they require
biologically active small molecules[1] and, as a result, significant activation to effectively add to alkenes. Miyaura demonstrated
research effort has been devoted to their preparation.[2] In that rhodium-catalyzed asymmetric conjugate addition of o-
addition to de novo heterocycle assembly, a number of methoxy pyridylboronic acids is efficient, but analogous
powerful methods exist for the functionalization of these coupling of the parent 2-pyridyl boronic acid (devoid of the
heteroarenes. For example, Minisci radical addition is a direct electron-donating blocking group) was unsuccessful.[10] A 2-
and effective synthetic approach to the preparation of alkyl pyridylboronate substrate was utilized in Akita‘s aryl radical
pyridines and diazines,[3] however, the regiochemical outcome conjugate addition system, based on photoredox arylboronate
of these processes is largely dictated by the inherent reactivity oxidation, to give the alkylpyridine in low yield (24%).[11] Nilsson
of a given substrate (or substrate class).[4,5] Catalytic coupling described an effective system for pyridylcuprate Michael
processes of halogenated heteroarene substrates with alkyl addition,[12] but Gilman reagents are extremely acid-sensitive,
metals[6] and, more recently, alkyl halides[7] have been which limits their utility in complex molecule synthesis.
developed for the direct synthesis of alkylated heteroaromatics. Additionally, none of these strategies have demonstrated the
We recently became interested in developing an alternative ability to accomplish diazine conjugate addition. Condon
approach to complex pyridine and diazine synthesis via direct described a Ni-catalyzed reductive Heck process of heteroaryl
union of these heteroaromatic units with alkenes. More halides using electrochemistry, but this system was limited to
specifically, we envision a general strategy for programmed,
regiospecific heteroarene activation that functions through Figure 1. General Strategies for the synthesis of complex heteroarenes
heteroaryl radical intermediates. In contrast to alkyl radicals,
aryl radical species effectively engage a wide range of
unsaturated substrates.[8] Consequently, mild conditions that
deliver these reactive intermediates could enable the
development of many discrete, practical processes for complex
pyridine and diazine synthesis (Figure 1).
Here, we describe the development of a catalytic system for
heteroaryl radical formation and direct coupling with electron-
deficient alkenes, a reductive Meerwein arylation[9] process
(illustrated in Figure 1). Conjugate addition is a highly utilized
strategic disconnection, but direct Michael addition of 6-
membered nitrogen heterocycles remains challenging.
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monosubstituted alkenes.[13] Our strategy for heteroarene
activation is based on single-electron reduction and
fragmentation of heteroaryl halides to regiospecifically afford
the corresponding radical species.[14] Aryl radical addition to
electron-poor alkenes is facile,[15] and this would offer a general
alternative to pyridine and diazine conjugate addition that
operates at room temperature and is tolerant of acidic
functional groups.
Table 2. Heteroaryl radical conjugate addition: Scope of theVaielkweAnreticcleouOpnlliinneg
partnera
DOI: 10.1039/C7SC00243B
Aryl radicals are indispensable intermediates in organic
synthesis, and redox processes of arenediazonium salts[8,9,16] or
arylboronic acids[17] are reliable methods for their formation.
However, these strategies are limited in the context of pyridine
or diazine-based radical generation, due to the instability of the
requisite
heteroaryl-diazonium[18a]
or
-boronic
acid
reagents.[18b] Tin-mediated halogen abstraction delivers
(hetero)aryl radical intermediates[19] but intermolecular alkene
coupling reactions are challenging within this manifold because
hydrogen atom transfer (HAT) to aryl radicals by tin-hydrides is
rapid.[20] Our method for reductive aryl radical generation
involves photoinduced electron transfer. This mode of radical
formation, first described by Beckwith,[21] has been recently
employed by Stephenson,[22] Read de Alaniz and Hawker,[23]
Weaver,[24] and König[25] to accomplish hydrodehalogenation
and a range of C-C bond-formations, mediated by photoredox
catalysts.[26] Notably, Weaver detailed conditions for the
reductive coupling of simple alkenes with 2-haloazoles,
polyfluorinated (hetero)aromatics, and a single example of an
electron-deficient pyrimidine.[24] The successful translation of
this radical strategy to heteroaryl conjugate addition could
streamline the invention of bioactive small molecules.
Table 1. Optimization of conditions for heteroaryl radical conjugate additiona
1 mol%
CO2Me
CO2Me
CO2Me
CO2Me
Ir[dF(CF3)ppy]2dtbbpy+
N
N
I
1.3 equiv amine
Me
Me
solvent
aReaction conditions: 2-iodopyridine (1.0 equiv), Michael acceptor (3.0 equiv),
Ir[dF(CF3)ppy]2dtbbpy•PF6 (1.0 mol%), Hantzsch ester (1.3 equiv), 25% H2O/DMSO
(10 mL/mmol heteroarene), blue light, 23 °C, 18 h. b4:3 diastereomeric ratio (d.r.).
c4:1 d.r. dYield determined by 1H NMR using 1,3,5-trimethoxybenzene as internal
standard. e1:1 d.r.
2-iodopyridine (1)
alkene (2)
(±)-alkylpyridine (3)
blue LED, 23 °C
3b
Entry
Amine
Solvent
Yield of
1c
2c
3c
4
i-Pr2NEt
CH3CN
CH3CN
CH3CN
CH3CN
12%
29%
28%
50%
NBu3
Results and discussion
To assess the feasibility of our design, we studied the radical
NBu3•HCO2H
Hantzschester
Hantzschester
Hantzschester
Hantzschester
Hantzschester
coupling of 2-iodopyridine (1) with the alkylidene malonate 2
(3.0 equivalents). We found that 1 mol% of the iridium-based
photoredox catalyst Ir[dF(CF3)ppy]2dtbbpy•PF6 (among
others)27 is capable of reductive 2-pyridyl radical formation
under irradiation with a commercially available blue LED.
Alkylamines are effective stoichiometric reductants in
photoredox processes, and their use in this context afforded the
5
80%
75%
78%
96%
25% H2O/CH3CN
6
25% H2O/DMF
25% H2O/MeOH
25% H2O/DMSO
7
8
desired radical conjugate addition (RCA) product 3, albeit in low
aReaction conditions: 2-iodopyridine (1.0 equiv), dimethyl ethylidene malonate
(3.0 equiv), Ir[dF(CF3)ppy]2dtbbpy•PF6 (1.0 mol%), amine (1.3 equiv), 25%
H2O/DMSO (10 mL/mmol heteroarene), blue light, 23 °C, 18 h. bYields determined
by GC using dodecane as internal standard. cWith 3.0 equiv amine.
yield (Table 1, entries 1–2). While tributylammonium formate
(the reductant used by Weaver for 2-bromoazole radical
formation,[24a-c] entry 3) was similar in efficiency to the free
base, the use of Hantzsch ester (HEH) delivered
3 in 50% yield
2 | J. Name., 2012, 00, 1-3
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(entry 4). In this system, HEH presumably donates an H-atom conditions select for radical alkene addition. Additionally,
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(to the intermediate radical adduct) and an electron to maintain phenyl rings (entries 4 and 7) and the iDnOdIo: l1e0.1f0u3n9c/tCi7oSnC0in02t4h3Be
redox neutrality. We found that the yield of this process was tryptophan product (entry 15) are unreactive toward aryl
uniformly improved when aqueous solvent mixtures were radical addition in this system.
employed (entries 5–8), and the use of 25% (v/v) H2O/DMSO
afforded the desired product in 96% yield (entry 8).
We then evaluated the ability of our system to perform
radical conjugate addition of other halogenated pyridines and
The scope of this heteroarene conjugate addition protocol diazines to ethyl crotonate (5 equivalents). Under standard
was then investigated. As shown in Table 2, these mild redox conditions, number of stable, commercially available
a
conditions enable the union of 2-pyridyl radical with an array of heteroaryl iodides and bromides similarly function as radical
Michael acceptors with good efficiency. Cyclic ketones and precursors. As shown in Table 3, methyl substitution is tolerated
crotononitrile react to give the corresponding pyridines in good at all positions of 2-pyridyl halides, and the corresponding
yield (entries 1–3, 72–85% yield). Enoates with
a
-phenyl or
a
-
products were formed in good yield (entries 1–4, 53–82%). Also
chloro substitution are effective radical acceptors in this system competent are 3- and 4-iodopyridines (entries 5 and 6), and
(entries 4 and 5, ≥84% yield), giving rise to the complex esters their use in this system provided the products in 52% and 48%
in 4:3 and 4:1 dr, respectively. These radical conditions tolerate yield, respectively.[28] Because reductive radical formation is a
N–H and O–H bonds, as exemplified by the effective coupling of regiospecific process, this approach allows for the predictable
carboxylic acid, benzyl amide, and primary alcohol containing formation of alkylheterocycles as single regioisomers, including
substrates (entries 6,7,14; 68–74% yield). Steric congestion on 3-alkylpyridines, which are not generally accessible via Minisci
the alkene currently diminishes reactivity in this protocol, as radical processes. Phenyl- and chloro-substitution is well
demonstrated by entries 10–12;
b-methyl, -isobutyl, and - tolerated to give the corresponding alkylpyridines in useful yield
isopropyl substitution results in formation of the desired (entries 8, 10, 13; 53–61% yield).
malonate products in decreasing order (89%, 67%, and 50%
Iodopyridines with the electron-withdrawing nitrile (entry 7)
yield respectively). A tryptophan-derived crotonamide was and trifluoromethyl (entry 12) groups were coupled with ethyl
reacted with pyridyl radical to give the radical conjugate crotonate to give the corresponding products in 52% and 68%
addition product in moderate yield (entry 15, 42% yield) as a 1:1 yield, respectively. Iodopyridines containing Boc-protected
mixture of diastereomers. Although pyridine derivatives (like aniline (entry 9) and benzyl alcohol (entry 11) functions were
the products shown here) are effective radical traps, these
Table 3. Photoredox radical conjugate addition: Scope of halogenated heteroarenesa
aReaction conditions: Halogenated heteroarene (1.0 equiv), ethyl crotonate (5.0 equiv), Ir[dF(CF3)ppy]2dtbbpy•PF6 (1.0 mol%), Hantzsch ester (1.3 equiv), 25%
H2O/DMSO (10 mL/mmol heteroarene), blue light, 23 °C, 18 h. b2.0 mol% Ir[dF(CF3)ppy]2dtbbpy•PF6. cReaction conditions: Heteroarene (1.0 equiv), ethyl
crotonate (3.0 equiv), Ir[dF(CF3)ppy]2dtbbpy•PF6 (1.0 mol%), sodium formate (3.0 equiv), 2,4,6-trimethylaniline (1.0 equiv) DMSO (10 mL/mmol heteroarene),
blue light, 23 °C, 18 h. dIr(ppy)2dtbbpy•PF6 (1.0 mol%) was used as catalyst
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Scheme 1. Limiting reductant (Hantzsch ester) solubility improves selectivity
cyclization to afford a mixture of bicyclic producVtisew(4Ar6ti%cle Otonltinael
yield, shown in equation 1). In addition toDtOhIe: 1e0x.1p0e3c9t/Ce7dSpCr0o0d24u3cBt
1 mol% [Ir]+
HEH
CO2Me
CO2Me
CO2Me
CO2Me
5
(arising from 5-exo-trig cyclization), we observed preferential
(2.5:1) formation of the 6-endo product 6 [31]
,
and these data are
N
N
I
N
Me
Me
solvent
consistent with the proposed radical nature of the described
processes.
1.0 equiv
3.0 equiv
A
B
blue LED, 23 °C
% H2O in DMSO product ratio (A:B)
H
H
1 mol% [Ir]+
140
120
100
80
EtO2C
Me
CO2Et
Me
O
O
O
HEH 1.3 equiv
0%
9%
3:1
[eq. 1]
N
N
H
25% DMSO/H2O
blue LED, 23 °C
10:1
18:1
19:1
20:1
N
I
N
60
Me
(HEH)
40
20%
25%
33%
20
4
5 (13% yield)
6 (33% yield)
0
0
20
40
% (v/v) H2O in DMSO
Conclusions
successfully coupled under these conditions without protecting
groups that would be required to participate in anionic
conjugate addition protocols (48% and 74% yield, respectively.
Importantly, substituted iodopyrimidines also undergo radical
formation and conjugate addition in moderate to good yield
(entries 16–18, 68–76% yield). However, when iodopyrazine
and 2-bromopyrimidine were used, the desired product was
formed in trace amounts and a low mass balance was observed.
We identified an alternate set of conditions involving the use of
sodium formate (3.0 equiv) and 2,4,6-trimethylaniline (1.0
equiv) in DMSO solvent, which accomplished the radical
conjugate addition of the parent pyrimidine (entry 15) and
pyrazine (entry 19) elements in moderate yields (39% and 52%,
respectively). While these alternate (sodium formate,
trimethylaniline) conditions were effective in some cases, the
use of Hantzsch ester as terminal reductant/hydrogen-atom
source under aqueous conditions was more generally
applicable. Finally, 2-iodopyrazine and 4-bromoazaindole were
capable RCA substrates and the corresponding products were
delivered in reasonable yield (entries 19 and 20, 52% and 53%
yield, respectively).
In conclusion, we have designed a simple catalytic system that
enables the general, regioselective coupling of pyridine and
diazine units to electron-poor alkenes. This method utilizes
simple alkenes, stable aryl radical precursors (many of the
shown substrates are commercially available), and
a
commercial catalyst. We describe how limiting the effective
concentration of Hantzsch ester enables the employment of
these reactive species in the formation of carbon–carbon bonds
for the preparation of a diverse array of heterocycle-containing
products. Studies to further elucidate the operational
mechanistic details of this process, as well as the development
of related transformations are ongoing in our laboratory.
Acknowledgements
Financial support was provided by Emory University and
Winship Cancer Institute. We gratefully acknowledge Prof. Huw
Davies for generous access to instrumentation and chemicals.
Notes and references
Throughout the course of this study, we observed that the
described aqueous reaction conditions are uniquely effective
for heteroaryl radical conjugate addition. Indeed, the use of
aqueous solvents has improved the efficiency of other radical
processes.[29] In this system, we noticed that the introduction of
water cosolvent resulted in heterogeneous reaction mixtures
that became homogeneous with reaction progress. The
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amounts of water (shown in Scheme 1), and the selectivity for
RCA vs reduction is inversely proportional to HEH solubility
(effective concentration), a principle first described by Stork.[30]
With the model 2-iodopyridine/ethylidene malonate coupling,
the use of 33% (v/v) H2O/DMSO essentially eliminates the
undesired hydrodehalogenation process, giving 20:1 selectivity
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