A visible light photocatalytic cross-dehydrogenative coupling/dehydrogenation/6π-cyclization/oxidation cascade: Synthesis of 12-nitroindoloisoquinolines from 2-aryltetrahydroisoquinolines

Article abstract of DOI:10.1002/chem.201500612

A visible light-induced photocatalytic dehydrogenation/6π-cyclization/oxidation cascade converts 1-(nitromethyl)-2-aryl-1,2,3,4-tetrahydroisoquinolines into novel 12-nitro-substituted tetracyclic indolo[2,1-a]isoquinoline derivatives. Various photocatalysts promote the reaction in the presence of air and a base, the most efficient being 1-aminoanthraquinone in combination with K₃PO₄. Further, the 12-nitroindoloisoquinoline products can be accessed directly from C1-unfunctionalized 2-aryl-1,2,3,4-tetrahydroisoquinolines by extending the one-pot protocol with a foregoing photocatalytic cross-dehydrogenative coupling reaction, resulting in a quadruple cascade transformation.

Full text of DOI:10.1002/chem.201500612

DOI: 10.1002/chem.201500612
Communication
&
Cascade Reactions
A Visible Light Photocatalytic Cross-Dehydrogenative Coupling/
Dehydrogenation/6p-Cyclization/Oxidation Cascade: Synthesis of
12-Nitroindoloisoquinolines from 2-Aryltetrahydroisoquinolines
Fabian Rusch,[a] Lisa-Natascha Unkel,[a] Dirk Alpers,[a] Frank Hoffmann,[b] and
Malte Brasholz*[a]
Chem. Eur. J. 2015, 21, 1 – 6
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Abstract: A visible light-induced photocatalytic dehydro-
genation/6p-cyclization/oxidation cascade converts 1-(ni-
tromethyl)-2-aryl-1,2,3,4-tetrahydroisoquinolines into novel
12-nitro-substituted tetracyclic indolo[2,1-a]isoquinoline
derivatives. Various photocatalysts promote the reaction
in the presence of air and a base, the most efficient being
1-aminoanthraquinone in combination with K3PO4. Fur-
ther, the 12-nitroindoloisoquinoline products can be ac-
cessed directly from C1-unfunctionalized 2-aryl-1,2,3,4-tet-
rahydroisoquinolines by extending the one-pot protocol
with a foregoing photocatalytic cross-dehydrogenative
coupling reaction, resulting in a quadruple cascade trans-
formation.
Scheme 1. CDC reaction between 2-aryl-1,2,3,4-tetrahydroisoquinolines
1 and nitroalkanes 2 and in situ dehydrogenation/6p-cyclization/oxidation
cascade reaction leading to 12-nitro-substituted indoloisoquinolines 4.
The cross-dehydrogenative coupling (CDC)[1] between 2-aryl-
1,2,3,4-tetrahydroisoquinolines 1 and nitroalkanes 2 is a well-
established method for the preparation of 1-(nitroalkyl)-2-aryl-
tetrahydroisoquinolines 3, and various reagents promote this
transformation in high yields (Scheme 1, top). While the reac-
tion can be performed under thermal conditions using stoi-
The crucial role of the base in the reaction 1a+2a!4a
was recognized at an early stage, as product 4a was never de-
tected in its absence. In a preliminary screening, amine bases,
carbonates as well as strong bases such as guanidine, DBU,
KOtBu and K3PO4 were employed in the reaction, along with
[3]
chiometric oxidants such as DDQ,[2] PhI(OAc)3 or catalytic
2+
Ru(bpy)3
as the photocatalyst. These early experiments
[4]
PtCl2 several visible-light photocatalytic methods have as well
showed that Cs2CO3 and K3PO4 are suitable bases while DBU,
KOtBu and Et3N failed to afford product 4a. However, yields
for the overall transformation 1a+2a![3a]!4a remained
low (~10–15%), for which we decided to investigate the
second half reaction 3a!4a first, and Table 1 shows a catalyst
screening in MeCN solution. Metal-based photocatalysts
been developed, employing ruthenium(II)[5] and iridium(III)[6]
photocatalysts, organic photocatalysts such as xanthene dyes[7]
or 9,10-anthraquinone derivatives[8] as well as TiO2.[9] However,
despite the large number of methods available for the prepa-
ration of nitroalkyl amines 3, these products have so far been
void of any synthetic use, with the exception of a single report
by Todd and co-workers who utilized compounds 3 in the syn-
thesis of the anthelmintic praziquantel.[10]
Ru(bpy3)2+ and Ir(dtbbpy)(ppy)2 convert compound 3a into
+
product 4a with 47 and 41% isolated yield (reaction times of
39 and 31 h, respectively), in the presence of 2 equivalents of
As we investigated the photocatalytic CDC reaction 1a!3a K3PO4, under air and using blue LED irradiation (entries 1 and
with nitromethane (2a, 5 equiv) in acetonitrile solution, under 2). Using green LED irradiation under otherwise unchanged re-
aerobic conditions and employing various photocatalysts, we action conditions, organic photocatalysts eosin Y and nile red
observed that in the presence of a base and upon prolonged produce product 4a in 19 and 6% yield, at low conversion
reaction times, initially formed 1-(nitromethyl)-2-phenyl-1,2,3,4- even after 40 h reaction time (entries 3 and 4). Methylene blue
tetrahydroisoquinoline (3a) undergoes an unprecedented sub- along with red LED light irradiation (entry 5) was found to be
sequent oxidative transformation, in situ leading to 12-nitro- ineffective. Finally, various anthraquinone derivatives[11] were
substituted tetracyclic indolo[2,1-a]isoquinoline 4a (Scheme 1, employed in the reaction, with blue fluorescent lamp irradia-
bottom). The novel photocatalytic one-pot reaction 1a+2a! tion (450ꢀ50 nm). While alizarin gives low conversion and
[3a]!4a initially produced product 4a in trace amounts only produces 4a with only 11% isolable yield after 93 h reaction
and consequently, we investigated this transformation in time (entry 6), 1,5-dichloroanthraquinone (DCAQ) offers full
detail. It was further established that it may be classified as conversion of substrate 3a and leads to 4a with 32% yield
a
photocatalytic CDC/dehydrogenation/6p-cyclization/oxida- after 40 h (entry 7). Finally, the red dye 1-aminoanthraquinone
tion cascade.
(1-AAQ, 5 mol%, lmax =465 nm, e=8000) emerged as the opti-
mal catalyst as it gives rise to product 4a with 62% isolated
yield, with full consumption of starting material 3a after 40 h
reaction time and under aerobic conditions (entry 8).
[a] F. Rusch, L.-N. Unkel, D. Alpers, Prof. Dr. M. Brasholz
Department of Chemistry, Institute of Organic Chemistry
University of Hamburg
As mentioned above for the reaction 1a!4a, the reaction
3a!4a does not proceed in the absence of base (entry 12),
and a reduction of the amount of K3PO4 or catalyst loading re-
sults in a decreased yield of 4a (entries 10 and 11). While no
conversion is observed in the dark (entry 13), the reaction pro-
ceeds to some minor extent when irradiated in the absence of
catalyst and under air (17% yield after 48 h, entry 14). When
oxygen is excluded, uncatalyzed conversion of 3a is minimal
Martin-Luther-King-Platz 6, 20146 Hamburg (Germany)
E-mail: malte.brasholz@chemie.uni-hamburg.de
[b] Dr. F. Hoffmann
Department of Chemistry, Institute of Inorganic Chemistry
University of Hamburg, 20146 Hamburg (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201500612.
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Table 1. Optimization of the photocatalytic reaction 3a!4a.[a]
#
Catalyst (mol%)
Ru(bpy)3(BF4)2 (1)
Ir(dtbbpy)(ppy)2(PF6) (1) blue LED
eosin Y (5)
nile red (5)
methylene blue (5)
Alizarin (5)
DCAQ[c] (5)
1-AAQ[d] (5)
1-AAQ (5)
Light source Base
blue LED
t [h] Yield [%][b]
1
2
3
4
5
6
7
8
9
K3PO4 (2) 39
K3PO4 (2) 31
47
41
19
6
green LED
green LED
red LED
blue CFL
blue CFL
blue CFL
blue CFL
blue CFL
blue CFL
blue CFL
–/–
K3PO4 (2) 40
K3PO4 (2) 40
K3PO4 (2) 88
K3PO4 (2) 93
K3PO4 (2) 40
K3PO4 (2) 40
Cs2CO3 (2) 22
K3PO4 (2) 45
K3PO4 (1) 48
trace
11
32
62
52
36
15
0
10 1-AAQ (1)
11 1-AAQ (5)
12 1-AAQ (5)
13 1-AAQ (5)
14 –/–
–/–
48
K3PO4 (2) 48
K3PO4 (2) 48
K3PO4 (2) 48
0
17
8[e]
blue CFL
blue CFL
15 –/–
[a] Reactions were run on 0.2 mmol scale at RT in MeCN (c=0.1m), con-
version monitored by T.L.C. [b] Isolated yield after chromatography.
[c] 1,5-Dichloroanthraquinone. [d] 1-Aminoanthraquinone. [e] Reaction
performed under N2 atmosphere. LED setup used: 5.4 W/0.87 cd/450ꢀ
25 nm or 560ꢀ25 nm; CFL lamps used: 2ꢁ18 W/2ꢁ2.73 cd/450ꢀ50 nm.
(8% yield after 48 h, entry 15). Finally, the optimum conditions
(5 mol% 1-AAQ, 2 equiv K3PO4, blue CFL irradiation) were also
tested in polar solvents other than acetonitrile, and runs in
MeOH, DMSO or DMF (not shown in the table) gave compara-
ble results to MeCN, hence solvent influence on the reaction is
marginal.
Scheme 2. Reaction scope; yields refer to isolated yields after chromatogra-
phy. [a] Compound 4c was prepared using 15 mol% 1,5-AAQ instead of
5 mol% 1-AAQ.
Applying the optimum reaction conditions, various indoloi-
soquinolines 4b–h could be prepared from nitroalkyl amines
3b–h[12] (Scheme 2). Reactions of donor-substituted substrates
efficiently lead to tetracycles 4b–f with yields from 36–69% in
reaction times of 44–88 h. In all cases, conversion was near
quantitative, with the exception of sterically hindered ortho-
substituted compound 4c (77% conversion after 88 h). In addi-
tion, the reaction 3c!4c is more efficiently carried out using
The cyclization reactions of nitroalkyl amines 3 shown in
Scheme 2 generally produce two isolable side products in ad-
dition to the tetracyclic products 4. Dihydroisocarbostyryls 8
are obtained in 10–30% yield from substrates 3a–h (and exclu-
sively in the case of substrate 3i). Notably, when air is replaced
by oxygen, yields of compounds 8 increase.[14] As for the
second side reaction, 12H-substituted indoloisoquinolines 9
are isolated in trace amounts (up to 5%).
15 mol% of 1,5-diaminoanthraquinone (1,5-AAQ, lmax
=
475 nm, e=21800) instead of 1-AAQ.[13] In case of substrates
3g and 3h bearing electron acceptor substituents, cyclization
is less efficient and products 4g,h are isolated in yields of 27%
(after 52 h) and 24% (after 48 h), respectively. Interestingly, the
reaction of 4-nitro-substituted substrate 3i does not lead to
any tetracyclic product, but oxidative C,C-cleavage at C-
1 occurs exclusively in this case, to give the corresponding di-
hydroisocarbostyryl. Open-chain substrate 7 in turn undergoes
quantitative retro-1,4-addition under the standard reaction
conditions. Finally, in addition to substrates 3, N-aryl piperidine
nitroalkyl amines 5[12] can as well be cyclized, and tricyclic
indole products 6a–c are obtained in 30–46% yield, with full
conversion of substrates after elongated reaction times of
131–140 h.
Mechanistically, we propose that the reaction 3!4 is initiat-
ed by photoelectron transfer between amine 3 (exemplary
compound 3d shows Eox = +0.82 V vs. SCE in MeCN)[15] and
the triplet-excited anthraquinone catalyst AQ* to give amine
radical cation 10, which is converted into iminium ion 11 via
H-abstraction by superoxide radical anion (Scheme 3). Facile
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deprotonation of iminium ion 11 generates nitroenamine 12
which undergoes photoinduced conrotatory 6p-electrocyclic
ring closure[16,17] to azomethine ylide 13. Rearomatization of
ylide 13 followed by catalytic oxidation leads to 12-nitroindo-
loisoquinoline 4. Consequently, the proposed overall reaction
pathway 3!4 may be classified as a dehydrogenation/6p-cyc-
lization/oxidation cascade[18] and visible light excitation sus-
tains each of the three individual steps.
Scheme 4. 6p-Cyclization/elimination reaction of nitroenamine 15.
[3]!4, that is, a photochemical CDC/dehydrogenation/6p-cyc-
lization/oxidation quadruple cascade. In order to achieve this
transformation in synthetically useful yields, a catalyst needed
to be identified which additionally displays high productivity
in the upstream CDC reaction, and several donor-substituted
anthraquinone derivatives were probed as catalysts. Reaction
of 2-(4-methylphenyl)-1,2,3,4-tetrahydroisoquinoline (1b) with
5 equiv of nitromethane (2a) and 5 mol% of 1-AAQ in MeCN
solution, under 450 nm irradiation for 72 h in the presence of
air and 3 equiv of K3PO4 leads to full consumption of substrate
1b but conversion of intermediate nitroalkyl amine 3b into
product 4b is largely incomplete (Table 2, entry 1). Increasing
the catalyst loading to 15 mol% slightly improves conversion
of intermediate 3b and product 4b can be isolated in 27%
yield after 72 h (entry 2). It was hypothesized that triplet–triplet
3
Scheme 3. Proposed mechanism of the dehydrogenation/6p-cyclization/oxi-
dation cascade of nitroalkyl amines 3 to products 4.
quenching between the excited AQ* catalyst and the emerg-
ing product 4b (lmax =380 nm, e=14300) could be the cause
of the incomplete conversion of intermediate 3b. Thus, the re-
action was attempted using 1,4-diaminoanthraquinone (1,4-
AAQ) as catalyst, which possesses long-wave absorption
(lmax =545 and 580 nm) along with 530–630 nm irradiation
(entry 3). Yet, under these conditions, conversion of tetrahy-
droisoquinoline substrate 1b into nitroalkyl amine 3b is mini-
mal and no tetracyclic product 4b can be detected. Next,
short-wave absorbing catalyst 1,5-dichloroanthraquinone (1,5-
ClAQ, lmax =345 nm) was employed along with 370 nm excita-
tion, where 6p-cyclization of putative nitroenamine intermedi-
ate 12 should occur at a faster rate than at 450 nm (entry 4).
However, the conversion of 3b into 4b could not be improved
compared to 1-AAQ (entry 2). Gratifyingly, we found that 1,5-
AAQ, (15 mol %) offered full conversion in the CDC reaction
combined with 80% conversion of intermediate nitroalkyl
amine 3b, and product 4b could be isolated in an attractive
53% yield. Applying these conditions, various indoloisoquino-
lines 4a–e could as well be prepared in one-pot fashion, in sat-
isfactory to good yields of 28–44% (entries 7–10).
As for the formation of the 12H-substituted indoloisoquino-
ꢁ
lines 9, we propose an elimination of nitrite anion (NO2 ) from
intermediate 13.[19] The second side reaction leading to dihy-
droisocarbostyryls 8 is likely to be initiated by the deprotona-
tion of radical cation 10 to give a-amino radical 14, which
adds molecular oxygen to give a C1-peroxide intermediate. Its
subsequent CC-cleavage to products 8 is in close analogy to
the known autoxidation of Reissert compounds.[20]
To further support our mechanistic proposal, we prepared
model nitroenamine 15[21] (lmax =355 nm, e=15000) and sub-
jected it to UVA irradiation (370ꢀ30 nm) in the presence of air
and K3PO4. As shown in Scheme 4, compound 15 undergoes
photoinduced cyclization to 1-methyl-2-phenylindole (16) in
35% yield, which is in analogy to the proposed 6p-cyclization/
elimination 12!9 shown in Scheme 3. In addition, a conceiva-
ble radical reaction pathway via an intramolecular cyclization
of the radical cation derived from nitroenamine 15 appeared
unlikely, as enamine 15 shows an oxidation potential Eox = +
1.32 V in cyclic voltammetry (vs. SCE in MeCN).[15] This would
render its one-electron oxidation by Ru(bpy)32+* thermody-
namically impossible (E*red = +0.77 V vs. SCE),[22] however, the
reaction 3a!4a is quite efficiently promoted by this catalyst
(Table 1, entry 1).
In summary, a visible light-induced aerobic photocatalytic
dehydrogenation/6p-cyclization/oxidation cascade was discov-
ered to convert 1-(nitromethyl)-2-aryltetrahydroisoquinolines
into tetracyclic 12-nitroindolo[2,1-a]isoquinoline products. The
cascade reaction can be further extended to encompass an up-
stream cross-dehydrogenative coupling (CDC) between the
parent 2-aryltetrahydroisoquinolines and nitromethane, result-
ing in a quadruple cascade transformation. This operationally
very simple one-pot protocol provides new and valuable indo-
loisoquinoline products in good overall yields and amino-sub-
stituted anthraquinones appear as the ideal organic photocata-
lysts.
After we succeeded in the one-step photocatalytic synthesis
of diverse products 4 and 6 with good yield starting from the
corresponding nitroalkyl amines 3 and 5 (Scheme 2), we re-ex-
amined the initially attempted one-step synthesis of 12-nitroin-
doloisoquinolines 4 starting from the parent 2-aryltetrahydroi-
soquinolines 1 and nitromethane (2a). Table 2 summarizes our
experiments towards the desired one pot reaction 1+2a!
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Unkel, P. Wienefeld, M. Brasholz, Synlett 2014, 2673–2680.
[12] For details on the preparation of nitroalkyl amine substrates 3 and 5,
see Supporting Information.
[13] The meta-methyl-substituted analogue 3j was also reacted giving a mix-
ture of regioisomeric products, see Supporting Information for details.
[14] Reaction of substrate 3a under the optimized conditions (Table 1,
entry 8) but replacing air by an atmosphere of O2 preferentially produ-
ces the corresponding dihydroisocarbostyryl 8a while 4a becomes the
minor product (ratio 2:1).
[15] For results of cyclic voltammetry, see Supporting Information.
[16] Photochemical 6p-cyclisation of related aryl enamines and enaminones:
a) I. Ninomiya, J. Yasui, T. Kiguchi, Heterocycles 1977, 6, 1855–1860;
b) J. C. Arnould, J. Cossy, J. P. Pete, Tetrahedron 1980, 36, 1585–1592;
c) J.-C. Gramain, H.-P. Husson, Y. Troin, Tetrahedron Lett. 1985, 26, 2323–
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Lett. 1987, 28, 817–820.
#
R
Catalyst[a] Mol% lexc [nm] Rel. ratio [%][b]
1:3:4:8:9
Yield
([%])[c]
1
2
3
4
5
6
7
8
9
CH3 1-AAQ
CH3 1-AAQ
CH3 1,4-AAQ 15
CH3 1,5-ClAQ 15
CH3 1,5-AAQ 15
CH3 1,5-AAQ 30
5
15
450ꢀ50 0/52/28/15/5
450ꢀ50 8/39/38/12/3
530-630 92/5/0/3/0
4b (19)
4b (27)
–/–
n.d.
4b (53)
n.d.
4a (34)
4d (43)
4e (44)
4 f (28)
370ꢀ30 0/41/30/19/10
450ꢀ50 0/21/59/18/2
450ꢀ50 10/19/55/14/2
450ꢀ50 26/11/45/18/0
450ꢀ50 8/22/58/12/0
450ꢀ50 10/16/51/23/0
450ꢀ50 17/11/33/39/0
H
1,5-AAQ 15
OMe 1,5-AAQ 15
Ph
1,5-AAQ 15
1,5-AAQ 15
10 Cl
[a] 1-AAQ=1-aminoanthraquinone,
1,5-ClAQ=1,5-dichloroanthraqui-
none, 1,4-AAQ=1,4-diaminoanthraquinone, 1,5-AAQ=1,5-diaminoanthra-
quinone. [b] Determined by 1H NMR. [c] Isolated yield after chromatogra-
phy.
[17] For reviews of nitroenamine chemistry, see: a) S. Rajappa, Tetrahedron
1981, 37, 1453–1480; b) S. Rajappa, Tetrahedron 1999, 55, 7065–7114.
[18] The taxonomy of sequential catalytic protocols has been discussed ear-
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Santos, Coord. Chem. Rev. 2004, 248, 2365–2379; c) K. C. Nicolaou, D. J.
Edmonds, P. G. Bulger, Angew. Chem. Int. Ed. 2006, 45, 7134–7186;
Angew. Chem. 2006, 118, 7292–7344.
[19] A possible Nef-type reaction of nitroalkyl amines 3 to the correspond-
ing aldehydes, followed by intramolecular condensation to compounds
9 was ruled out by control experiments.
Acknowledgements
The authors would like to thank the Deutsche Forschungsge-
meinschaft (DFG) and the Fonds der Chemischen Industrie
(FCI, Sachbeihilfe) for financial support. Experimental contribu-
tions by Mrs. Laura Voigt, Mr. Daniel Felix Euchler and Mr.
Vedran Drenic are gratefully acknowledged.
[20] a) M. D. Rozwadowska, D. Brꢃzda, Tetrahedron Lett. 1978, 19, 589–592;
b) S. Ruchirawat, M. Chuankamnerdkarn, Heterocycles 1978, 9, 1345–
1348; c) M. D. Rozwadowska, D. Brꢃzda, Can. J. Chem. 1980, 58, 1239–
1242.
Keywords: cascade reactions · heterocycles · organocatalysis ·
photocatalysis
[21] J. Barluenga, F. Aznar, R. Liz, M. Bayod, Synthesis 1983, 159–160.
[22] A. Juris, V. Balzani, P. Belser, A. von Zelewsky, Helv. Chim. Acta 1981, 64,
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Received: February 12, 2015
Published online on && &&, 0000
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COMMUNICATION
In one pot: A visible light-induced pho-
tocatalytic cross-dehydrogenative cou-
pling (CDC)/dehydrogenation/6p-cycli-
zation/oxidation cascade converts
common 2-aryl-1,2,3,4-tetrahydroisoqui-
nolines into 12-nitro-substituted tetracy-
clic indolo[2,1-a]isoquinoline derivatives.
Key to this new one-pot transformation
is the presence of K3PO4 as a base and
amino anthraquinone derivatives
appear as superior organic photocata-
lysts.
&
Cascade Reactions
F. Rusch, L.-N. Unkel, D. Alpers,
F. Hoffmann, M. Brasholz*
&& – &&
A Visible Light Photocatalytic Cross-
Dehydrogenative Coupling/
Dehydrogenation/6p-Cyclization/
Oxidation Cascade: Synthesis of 12-
Nitroindoloisoquinolines from 2-
Aryltetrahydroisoquinolines
Cross-Dehydrogenative Coupling
The photocatalytic C1-functionalization of 2-
aryltetrahydroisoquinolines by cross-dehydrogenative
coupling with nitroalkanes is a well-established method for
the preparation of 1-nitroalkyl-2-aryl-
tetrahydroisoquinolines. In their Communication on p. &&
ff., describe M. Brasholz et al. that these primary coupling
products readily undergo a subsequent oxidative cascade
cyclization to furnish 12-nitroindolo[2,1-a]isoquinoline
derivatives. Key to this hitherto unreported one-pot
transformation is the presence of a base like K3PO4 and
aminoanthraquinones emerged as the ideal organic
photocatalysts.
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