An organocatalyst bound α-aminoalkyl radical intermediate for controlled aerobic oxidation of iminium ions

Article abstract of DOI:10.1039/c8ob01032c

A catalyst bound α-aminoalkyl radical intermediate from iminium is developed to control its formation and reactivity with aerobic oxygen. The influence of the catalyst was demonstrated via the ease of radical intermediate formation and its subsequent reactivity, including the first catalyst-controlled enantioselective aerobic oxidation with a chiral phosphite catalyst.

Full text of DOI:10.1039/c8ob01032c

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An organocatalyst bound α-aminoalkyl radical intermediate for
controlled aerobic oxidation of iminium ion
Abdul Motaleb,†a Asish Bera†a and Pradip Maity*a
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
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A catalyst bound α-aminoalkyl radical intermediate from iminium
is developed to control its formation and reactivity with aerobic
oxygen. The catalyst influence was demonstrated via ease of
radical intermediate formation and its subsequent reactivity,
including the first catalyst-controlled enantioselective aerobic
oxidation with a chiral phosphite catalyst.
A diverse pathway to α-aminoalkyl radicals is a major focus for
mild amine functionalization.1 Efficient catalyst systems for
radical intermediates were developed via C-H activation of
both electron rich1,2 and electron poor amines,3
defunctionalization of amino acids4 and α-silylamines,5 and
single electron reduction of imine or iminium.6 However, its
subsequent reactivity remains largely uncontrolled. MacMillan
and others developed an elegant dual catalysis approach with
transition metal (TM), which transform the initially formed
radical to carbon-TM bond for subsequent cross-coupling
reactions.7 Yoon and Ooi group respectively reported a dual
Lewis acid and Brønsted acid catalyzed enantioselective
coupling of α-aminoalkyl radical.8
Figure 1: An organocatalyst bound α-aminoalkyl radical for
catalyst control: Possible formation and reaction course
We began our study to find a suitable catalyst capable of forming
adduct (4) with stable and easy to handle methyl isoquinolinium
triflate (1a). The adduct formation was studied in CDCl3 and
analyzed directly by 1H-NMR anticipating its reversible formation
and instability. Neutral nucleophiles such as PPh3, DABCO, DMAP
did not add, but DBU led to complex NMR, indicating a possible
formation of the unstable cationic adduct. Among anionic
nucleophile, sulfite did not add, but phosphites (DMHP and DPHP)
and thiophenol with K2CO3 led to corresponding adducts,
characterized by 1H-NMR.9
The next goal is to explore the feasibility of radical intermediate (5)
formation from the adduct (4). We initially chose phosphites as a
catalyst since the corresponding radical intermediate should gain
Our interest in finding catalyst control for radical reactions led
us to explore a possible organocatalyst bound α-aminoalkyl
radical formation and its reactivity. In this communication, we
report facile self-photoredox and anionic auto-oxidation processes
for the proposed radical (5) formation and its aerobic oxidation. We
also demonstrate the first catalyst-controlled enantioselective
aerobic oxidation of isoquinolinium with a chiral catalyst.
synergistic stability via captodative effect.10 As
a result, its
formation should be facile and catalyst detachment from radical
intermediate less likely.
Aerobic oxygen was chosen as the coupling partner since a catalyst
release pathway similar to Nef oxidation is viable.11 During
screening under air atmosphere, we were pleasantly surprised to
observe the oxidation product (6a),6b,12 without any radical
generation catalyst and specific light (Table 1, entry 1). The reaction
under dark did not work (entry 2), indicating daylight or hood light
mediated self-photoredox might be operative.13 Optimization of
reaction temperature, base, and solvent led to good yield with 3
equivalent K2CO3 base in MTBE at 40 °C (entry 8). With quinolone
salt (2a), K2CO3 did not result in any oxidation, but stronger KOH
and KOtBu led to efficient product formation in acetonitrile solvent
entry 11, 12).
Table 1: Optimization for phosphite catalyzed aerobic oxidation of
isoquinoline and quinoline salts
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9
2a
2a
2a
2a
K2CO3
KOH
MTBE
THF
0 - r.t.
0 - r.t.
0 - r.t.
0 - r.t.
48
48
24
16
<5
25
88
82
10
11
12
KOH
KOtBu
MeCN
MeCN
aisolated yield; under dark.
N-alkyl salt of isoquinoline, quinoline, and other heteraromatic
compounds was subjected to the optimized reaction condition to
test the generality of our method. A methyl, benzyl, and allyl
substituent on isoquinoline nitrogen are all equally effective (6a-c).
Bromide, phenyl, alkynyl, electron withdrawing nitro, electron rich
methyl all are well tolerated on different position (6d-h) in
moderate to good yields. 5,8-Dibromobo substitution resulted in
lower yield (6j, 47%). Other isoquinoline type heteroaromatics such
as phenanthridinium and dinitrogen phthalazinium salts were also
Entry Starting
Material
Base
Solvent
Temp
(°C)
Time Yield
(%)a
(h)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
K2CO3
K2CO3
-
CHCl3
CHCl3
CHCl3
DCM
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
40
72
72
72
72
72
72
72
48
62
<5b
<5
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
60
56
MeCN
THF
68 oxidized to the corresponding phenanthridinone (6k) and
phthazone (6l) efficiently.
MTBE
MTBE
73
84
Table2: Substrate scope for household light mediated self-photoredox aerobic oxidation of N-heteroaromatic salts
b
c
Conditions: 0.3 mmol scale, for 1 to 6, 2 ml MTBE, K2CO3 base, 40 °C, 16h; for 2 to 7, 2 ml MeCN, KOH or KOtBu base, 16-48 h. aKOtBu as base; 50 °C; 1.5
equiv dimethyl hydrogen phosphite (DMHP) catalyst
including free hydroxyl group at C-8 (7k). Surprisingly, the 8-Br
substrate gave required 7n (56%), along with minor 4-oxo product
(23%). A sterically bulky 9a catalyst yielded the 7n selectively with
good yield (87%). A pyridinium and non-aromatic cyclic iminium
salt did not oxidize in our optimized photoredox reaction condition.
With the successful aerobic oxidation of N-alkyl salts of isoquinoline
in hand, we eagerly explored the possibility of catalyst controlled
oxidative kinetic resolution (Table 2). 1-Phenylethy salt of
isoquinoline (1m) with an α-stereogenic center to nitrogen was
chosen,15 along with TADDOL based phosphite (9a) as a chiral
catalyst.16 Analysis of product at ~50% conversion with 10 mol%
tetramethyl catalyst 9a did not result in any enantioenrichment
(entry 1), but tetraphenyl catalyst (9b) showed promise (entry 2).
Screening of other tetra-aryl catalysts and reaction condition (entry
3-11) led to 70% ee at 45% conversion (s factor = 12.3) with α-
naphthyl substituted catalyst (9e). The recovered enantioenriched
SM was also oxidized under photoredox condition with 20 mol%
Different N-alkyl substitution on quinoline is also compatible, but
KOtBu base results in better yield for benzyl substitution (7c).
Phenyl at 3-position works well with KOtBu base, but electron rich
NMe2 substitution led to
a very slow reaction. Raising the
temperature to 50 °C led to moderate yield (7e, 54%). A major
debrominated product obtained along with the minor required
product (7f) for 3-bromo substitution. Photoredox debromination
of aryl bromides are known, which might be operating here.14
Change of base and reaction temperature did not improve the
result. 4-Methoxy substitution works well with KOtBu (7g), but 4-
methyl quinolinium gave poor yield (<10%) under standard reaction
condition. We suspect possible deprotonation of the 4-methyl
proton in starting salt under basic reaction condition could be a
problem. To circumvent, 1.5 equivalent DMHP was added to
convert all the salt to the intermediate before base mediated
oxidation, which led to 92% yield (7h). Aryl, electron withdrawing as
well as electron donating groups on other ring were well tolerated,
2 | J. Name., 2012, 00, 1-3
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(a) A. L. F. Arriba, F. Urbitsch and D. J. Dixon, Chem.
Commun., 2016, 52, 14434 and reference herein; (b) Y. Jin, L.
Ou, H. Yang and H. Fu, J. Am. Chem. Soc., 2017, 139, 14237.
C. K. Prier, D. A. Rankic and David W. C. MacMillan Chem.
Rev., 2013, 113, 5322.
the corresponding phosphite adduct do not absorb visible light. An
external photoredox catalyst can oxidize the adduct to initiate the
process,2 but it has to be compatible with nucleophile phosphite
catalyst. Instead, we check a possible Nef type anionic auto-
oxidation first to avoid compatibility of dual catalysis.11,12,19
Hydrolytically stable cyclic salts were synthesized (3a-c),20 which
were subjected to DMHP catalyzed reaction condition with a strong
LiHMDS base to deprotonate the α C-H. To our delight, the
corresponding lactams formed in moderate to good yields (Scheme
6A). Acyclic iminium salts were difficult to handle and resulted in
poor yield. To check the efficiency of aerobic auto-oxidation, we
synthesized dimethyl hydrogen phosphite adduct for acylic systems
(Scheme 6B),21 and upon treatment with LiHMDS under air
atmosphere led to a good yield of the corresponding amide.
7
8
(a) L. R. Espelt, I. S. McPherson, E. M. Wiensch and T. P.
Yoon, J. Am. Chem. Soc., 2015, 137, 2452; (b) D. Uraguchi, N.
Kinoshita, T. Kizu and T. Ooi, J. Am. Chem. Soc., 2015, 137
13768.
,
9
DMHP = Dimethyl hydrogen phosphite; DPHP = Diphenyl
hydrogen phosphite.
10 H. Viehe, Z. D. Anousek and R. Merenyi, Acc. Chem. Res.,
1985, 18, 148.
11 (a) S. Umemiya, K. Nishino, I. Sato and Y. Hayashi, Chem. Eur.
J., 2014, 20, 15753; b) J. Li, M. J. Lear, Y. Kawamoto, S.
Umemiya, A. R. Wong, E. Kwon, I. Sato and Y. Hayashi,
Angew. Chem. Int. Ed., 2015, 54, 12986.
12 Base mediated aerobic oxidations with very limited substrate
scope are known with a different mechanistic rationale: (a) S.
Ruchirawat, S. Sunkul, Y. Thebtaranonth, Y. Thirasasna,
Tetrahedron Lett., 1977, 27, 2335; (b) P. Paira, A. Hazra, K. B.
Sahu, S. Banerjee, N. B. Mondal, N. P. Sahu, M. Weber, P.
Luger, Tetrahedron, 2008, 64, 4026 and reference herein.
13 For organic dye catalysed photoredox, see: N. A. Romero, D.
A. Nicewicz, Chem. Rev., 2016, 116, 10075. For direct
photoexitation of catalyst added substrate (enamine), see:
(a) M. Silvi, E. Arceo, I. D. Jurberg, C. Cassani and P.
Melchiorre J. Am. Chem. Soc., 2015, 137, 6120; (b) A.
Scheme 3: (a) Aerobic auto-oxidation of non-aromatic cyclic
Bahamonde and P. Melchiorre J. Am. Chem. Soc., 2016, 138
8019.
,
iminium salt to lactam; (b) Stepwise oxidation to amide
14 J. J. Devery III, J. D. Nguyen, C. Dai and C. R. J. Stephenson,
ACS Catal., 2016, , 5962.
15 (a) S. G. Bujedo, M. Alcarazo, C. Pichon, E. Alvarez, R.
Fernandez and J. M. Lassaletta, Chem. Commun., 2007, 11
1180; (b) L. Benmekhbi, F. Loufi, T. Roisnel and J. P. Hurvois,
J. Org. Chem., 2016, 81, 6721.
16 (a) X. Linghu, R. J. Potnick and S. J. Johnson, J. Am. Chem.
Soc., 2004, 126, 3070; b) A. Falk, L. A. Goderz and G. H.
Schmalz, Angew. Chem. Int. Ed., 2013, 52, 1576.
In conclusion, an organocatalyst bound α-aminoalkyl radical
formation and its aerobic oxidation was achieved without any
other radical generation catalyst. N-alkyl salts of a variety of
heteroaromatic compounds were oxidized in presence of
household light. The catalyst bound α-radical was utilized
successfully for an unprecedented oxidative kinetic resolution
with racemic isoquinolinium salts. Cyclic and acyclic iminiums
were oxidized via an alternative strong base mediated aerobic
auto-oxidation. Full mechanistic studies and catalyst controlled
stereoselective oxidation is currently underway.
6
,
17 Chiral isoquinolone of type 6m was utilized as a chiral
auxiliary for the diastereoselective synthesis of chiral natural
products: (a) D. T. Chu and L. A. Mitscher, U.S. Patent, 1998,
4
, 777, 253; (b) J-J. Youte, D. Barbier, A. Al-Mourabit, D.
The authors gratefully acknowledge the financial support from
SERB (EMR/2015/000711) and CSIR-NCL (MPL030926). A.M.
and A.B. thanks UGC for fellowship.
Gnecco and C. Marazano J. Org. Chem., 2004, 69, 2737.
Bioactive (iso)quinolones have a chiral centre α- to nitrogen:
(c) J. Rujirawanich, S. Kim, A. J. Ma, J. R. Butler, Y. Wang, C.
Wang, M. Rosen, B. Posner, D. Nijhawanc and J. M. Ready, J.
Am. Chem. Soc., 2016, 138, 10561.
18 A. Martin de, P. Nicholas and D. R. Arnold, Can. J. Chem.,
1982, 60, 2165.
19 Although no clear understanding is presented for Nef type
Conflicts of interest
There are no conflicts to declare.
reaction, we presume the radical (5) stability in comparison
to the corresponding carbanion is a key factor. The proposed
captodative stability of radical
approach.
5 could facilitate this
Notes and references
1
(a) K. Nakajima, Y. Miyake and Y. Nishibayashi, Acc. Che. Res.,
2016, 49, 1946; (b) J. Hu, J. Wang, T. H. Nguyen and N.
Zheng, Beilstein J. Org. Chem., 2013, 9, 1977; (c) J. W. Beatty
and C. R. J. Stephenson, Acc. Che. Res., 2015, 48, 1474.
(a) G. Pandey, G. Kumaraswamy and U. T. Bhalerao,
Tetrahedron Lett., 1989, 30, 6059; (b) P. Kohls, D. Jadhav, G.
Pandey and O. Reiser, Org. Lett., 2012, 14, 672.
20 (a) V. K. Aggarwal, I. Bae, H.-Y. Lee and D. T. Williams,
Angew. Chem. Int. Ed., 2003, 42, 3274; (b) J. F. Franz, W. B.
Krausab and Kirsten Zeitler, Chem. Commun., 2015, 51, 8280.
21 G. Keglevich and E. Bálint, Molecules, 2012, 17, 12821.
2
3
4
5
M. H. Shaw, V. W. Shurtleff, J. A. Terrett, J. D. Cuthbertson,
D. W. C. MacMillan, Science, 2016, 352, 1304.
Z. Zuo and D. W. C. MacMillan, J. Am. Chem. Soc., 2014, 136
5257.
U. C. Yoon, P. S. Mariano, Acc. Chem. Res., 1992, 25, 233.
,
4 | J. Name., 2012, 00, 1-3
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A nucleophile catalyst is introduced for facile radical formation and its catalyst controlled aerobic
oxidation