Visible-Light-Mediated Aerobic Tandem Dehydrogenative Povarov/Aromatization Reaction: Synthesis of Isocryptolepines

Article abstract of DOI:10.1002/chem.201903921

A metal-free, photoinduced aerobic tandem amine dehydrogenation/Povarov cyclization/aromatization reaction between N-aryl glycine esters and indoles leads to tetracyclic 11H-indolo[3,2-c]quinolines under mild conditions and with high yields. The reaction can be performed by using molecular iodine along with visible light, or by combining an organic photoredox catalyst with a halide anion. Mechanistic studies reveal that product formation occurs through a combination of radical-mediated oxidation steps with an iminium ion or N-haloiminium ion [4+2]-cycloaddition, and the N-heterocyclic products constitute new analogues of the antiplasmodial natural alkaloid isocryptolepine.

Full text of DOI:10.1002/chem.201903921

A Journal of
Accepted Article
Title: Visible light-mediated aerobic tandem dehydrogenative Povarov/
aromatization reaction: synthesis of isocryptolepines
Authors: Eva Schendera, Lisa-Natascha Unkel, Huyen Quyen Phung
Phan, Gwen Salkewitz, Frank Hoffmann, Alexander Villinger,
and Malte Brasholz
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To be cited as: Chem. Eur. J. 10.1002/chem.201903921
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Visible light-mediated aerobic tandem dehydrogenative
Povarov/aromatization reaction: synthesis of isocryptolepines
Eva Schendera,[a] Lisa-Natascha Unkel,[a] Phung Phan Huyen Quyen,[a] Gwen Salkewitz,[a]
Frank Hoffmann,[b] Alexander Villinger[c] and Malte Brasholz*[a]
Abstract:
A
metal-free, photoinduced aerobic tandem amine
an aerobic photoinduced Cu(II)-mediated reaction has also been
reported.[8]
dehydrogenation/Povarov cyclization/aromatization reaction between
N-aryl glycine esters and indoles leads to tetracyclic 11H-indolo[3,2-
c]quinolines under mild conditions and with high yield. The reaction
can be performed using molecular iodine along with visible light, or
combining an organic photoredox catalyst with halide anion.
Mechanistic studies reveal that product formation occurs through a
combination of radical-mediated oxidation steps with an iminium ion
or N-haloiminium ion [4+2]-cycloaddition, and the N-heterocyclic
products constitute new analogs of the antiplasmodial natural alkaloid
isocryptolepine.
We report here the tandem amine dehydrogenation/imine [4+2]-
cycloaddition/aromatization of glycine esters with indoles. We
developed two photoinduced aerobic and metal-free variants of
this reaction, either using I2 with blue light irradiation, or employing
a system combing an organic photoredox catalyst with a source
of halide anion X− and visible light (Scheme 1d). 11H-indolo[3,2-
c]quinoline products are obtained under mild conditions and with
yields up to 99%. These tetracyclic compounds possess the core
structure of the natural alkaloid isocryptolepine from the west-
african flowering plant Cryptolepis sanguinolenta, which shows
antimalarial activity against plasmodium falciparum.[9] Therefore,
new derivatives of isocryptolepine have been of ongoing interest
in medicinal chemistry research.[10]
The Povarov reaction, i. e. the aza-Diels-Alder reaction of imines
with electron rich alkenes, is a classical and versatile method for
the synthesis of polysubstituted tetrahydroquinolines,[1] and the
pivotal imine [4+2]-cycloaddition can be catalyzed by a range of
Brønsted or Lewis acids[2]. In recent years, dehydrogenative
Povarov reactions have been developed (Scheme 1a), where an
amine-to-imine oxidation precedes the imine [4+2]-cycloaddition
followed by aromatization to quinoline products. These protocols
typically involve the use of metal catalysts like Cu(I) and Cu(II)
salts as well as Fe(II) and Au(I) and Au(III) complexes along with
DDQ, organic peroxides or O2 as the stoichiometric oxidants.[3]
A
thermal double dehydrogenative variant of the Povarov reaction,
including the parallel oxidation of an alkane as the precursor to
the alkene 2π component, has also been introduced,[4] and Huo
et al. remarkably could achieve such a process using the metal-
free system of CBr4 and PPh3 (Scheme 1b).[5] In the arena of
photochemistry, Li and Zhang developed a dual photoredox and
Lewis acid-catalyzed dehydrogenative Povarov reaction between
glycine esters and styrenes (Scheme 1c),[6] and later they also
demonstrated the use of Eosin Y as an organic photocatalyst for
the dehydrogenation of glycine esters in the Brønsted acid-
mediated cycloaddition with dihydrofuran.[7] A single example of
[a]
Prof. Dr. Malte Brasholz
Institute of Chemistry – Organic Chemistry
University of Rostock
Albert-Einstein-Str. 3A, 18059 Rostock, Germany
E-mail: malte.brasholz@uni-rostock.de
Web: https://www.brasholz.chemie.uni-rostock.de
Department of Chemistry – Institute of Inorganic Chemistry
University of Hamburg
Martin-Luther-King-Platz 6, 20146 Hamburg, Germany
Institute of Chemistry – Inorganic Chemistry
University of Rostock
[b]
[c]
Scheme 1. Methods for the tandem dehydrogenative Povarov/aromatization
reaction
Albert-Einstein-Str. 3A, 18059 Rostock, Germany
Supporting information for this article is given via a link at the end of
the document.
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Initially, we observed that reacting p-anisidinyl
glycine ester 1a with N-Boc-indole (2a) in the
presence of small amounts of molecular iodine and
oxygen under blue light irradiation led to the
aromatic N-Boc-protected 11H-indolo[3,2-c]quino-
line-6-carboxylate 4a in mixture with the Boc-
deprotected derivative 4a’, and the reaction was
subsequently optimized as shown in Table 1,
“method A” (see also Table S1, supporting
information). Using 10 mol-% of I2 in MeCN under
air led to a combined yield of cycloadducts 4a,4a’
of 38% after 48 h (entry 1). When the same
reaction was performed in the dark, the dihydro-
11H-indolo[3,2-c]quinoline 3a was formed in 12%
yield along with 5% of product 4a. The
intermediacy of 3a in the reaction was soon
confirmed as its conversion to 4a,4a’ increased
with prolonged reaction time. Increasing quantities
of I2 and oxygen both improved the yields of 4a and
4a’ (entries 3-5), and using 50 mol-% of I2 under O2
atmosphere fully converted indole 2a within 48 h,
to give compound 4a in a high yield of 70% after
chromatography, along with 22% of its Boc-
deprotected congener 4a’. Br2 could be used in
place of I2 (Table S1), however resulting in lesser
conversion and a markedly decreased selectivity.
Under the optimum conditions, no conversion
occurred in the absence of I2 and just 14% in the
absence of O2, while in the case of PMP-glycine
ester 1a, some product formation was also
observed in the dark, which can be attributed to the
particular ease of autoxidation of highly electron-
rich substrate 1a. By comparison, the analogous
dark reaction of the much less activated p-tolyl
glycine ester 1b gave only trace amounts of the
corresponding product 4b (< 5%). (Table S1).
Employing N-tosylindole (2b) in the reaction with
1a under the optimum conditions, none of the
corresponding indolo[3,2-c]quinolines could be
Table 1. Reaction optimization.
conv.
#
R1
conditions
3 (%)b
4 / 4’ (%)b
2a (%)a
method A
1
2
3
4
5
OMe
10 mol-% I2, air, MeCN, 48 h
10 mol-% I2, air, MeCN, 48 h, no light
20 mol-% I2, air, MeCN, 48 h
50 mol-% I2, air, MeCN, 48 h
50 mol-% I2, O2, MeCN, 48 h
38
22
0
12
8
36 / 2
5 / 0
”
”
”
”
38
21 / 8
56 / 26
82
8
100
0
74 / 26
(70c / 22c)
6
OMe
N-tosylindole (2b), N-acetylindole (2c),
1H-indole (2d)
n.d.
14% cycloadducts
from 2c only
method B
7
8
OMe
1 mol-% Acr+-Mes•ClO4,
0
0
0
0 / 0
0 / 0
10 mol-% TBAI, O2, MeCN, 48 h
”
”
1 mol-% TPP•BF4, 10 mol-% TBAI,
O2, MeCN, 48 h
0
9
1 mol-% TPP•BF4, 10 mol-% TBAI,
O2, HFIP/DCE, 48 h
48
68
74
80
0
0 / 48
22 / 30
10 / 52
10
11
12
”
2 mol-% TPP•BF4, 10 mol-% TBAI,
12
12
3
O2, HFIP/DCE, 48 h
”
1 mol-% TPP•BF4, 10 mol-% TBAI,
O2, HFIP/DCE, 72 h
(55c,d
)
Me
1 mol-% TPP•BF4, 10 mol-% TBAI,
O2, HFIP/DCE, 72 h
20 / 56
(75c,d
)
Reactions performed on 0.10 mmol scale of 2a, irradiation with 36 W blue CFL, 450 ± 50 nm.
[a] Conversion determined by 1H-NMR analysis. [b] Yield determined by 1H-NMR against
CH2Br2 as internal standard. [c] Isolated yield after chromatography. [d] Reaction mixture
treated with TFA before isolation. TPP•BF4 = triphenylpyrylium tetrafluoroborate.
detected.
Using
N-acetylindole
(2c),
its
further experimentation (entries 10-11 and Table S1), the best
cycloadducts were formed in only 14% combined yield, while 1H-
indole (2d) underwent decomposition to undefined products
(entry 6).
conditions were using 1 mol-% of TPP•BF4 with irradiation for 72 h,
to give 4a’ as the major product with 52% yield, accompanied by
10% of N-Boc-protected compound 4a. To generate a single
product, the reaction mixture was subsequently treated with TFA,
to furnish compound 4a’ in an isolated yield of 55% after
chromatography. Using glycine ester 1a, a maximum conversion
of indole 2a of 74% could be obtained under these conditions,
however, in case of p-tolyl-substituted 1b, we could demonstrate
that despite incomplete conversion of 2a of 80% (entry 12), an
isolated yield as high as 75% for compound 4b’ could be achieved.
Further, we found that tetrabutylammonium bromide (TBABr)
could be used in place of TBAI (Table S1).
The scope of the visible light-mediated tandem dehydrogenative
Povarov/aromatization reaction is depicted in Scheme 2. Using
method A, various donor-substituted N-aryl glycine esters 1a-1f
were employed in the reaction giving rise to clean and quantitative
conversion of N-Boc-indole (2a) in all cases, and indolo[3,2-
c]quinoline products 4a-4f were isolated in high yields of 59-85%,
We subsequently aimed at developing an alternative
photoorganocatalytic variant of the reaction (Table 1, “method B”),
which potentially would allow replacement of I2 by iodide anion.
While Fukuzumi’s catalyst[11] along with a catalytic quantity of
tetrabutylammonium iodide (TBAI) under O2 in MeCN slowly
converted glycine ester 1a to the corresponding imine (56%
conversion after 48 h) no cycloaddition products were detected
(entry 7). The same reaction with the triphenylpyrylium (TPP+)
cation as organic photocatalyst gave a similar result, however with
quantitative conversion of 1a to the imine. Using 1 mol-% of
TPP•BF4 and 10 mol-% of TBAI in the protic solvent mixture of
hexafluoroisopropanol (HFIP) and dichloroethane (DCE),
conditions similar to those previously used by Muñiz et al. for
photocatalytic Hofmann-Löffler type reactions,[12] glycine ester 1a
and N-Boc-indole (2a) were converted into the Boc-deprotected
aromatic cycloadduct 4a’ with 48% yield after 48 h (entry 9). After
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along with minor quantities of their N-deprotected analogs 4a’-4f’
(9-35%), which were readily separated by column chroma-
tography.[13] Using method B, compounds 4a’-4f’ could be
obtained in 55-75% yield after treatment of the crude product
mixtures with TFA. Notably, the N-phenyl glycine ester 1g did not
provide products the 4g,4g’ under the conditions of method A
(aromatic iodination of the aniline ring occurred), but using
method B, derivative 4g’ could be prepared in 37% yield. Further,
acceptor-substituted glycine esters like the 4-trifluoromethyl-
phenyl and 4-cyanophenyl derivatives 1h and 1i did not react
when employed under conditions A. However, using the
photocatalyst TPP•BF4 with halide anion, this limitation could be
overcome. Thus, product 4h’ was formed in 17% with TPP+/TBAI,
and with a significantly improved yield of 57% with TBABr in place
of TBAI. In case of 4-cyanophenyl glycine ester 1i, the best result
was achieved using the photocatalyst along with TBACl, to furnish
product 4i’ in 54% yield.
Scheme 2. Reaction scope. Yields after chromatography. Method A: 50 mol-% I2, O2, hv 450 nm, MeCN, r.t., 48 h. Method B: 1 mol-% TPP•BF4, 10 mol-% TBAI,
O2, hv 450 nm, HFIP/DCE, r.t., 72 h, then TFA, 50 °C, 6 h.
In addition to N-Boc-indole (2a), N-Boc-5-bromoindole (2e) as
well as the 5- and 7-methoxylated N-Boc-indoles 2f and 2g could
be used, giving rise to polysubstituted indoloquinolines 4j,4j’-4l,l’.
Further, 2-methyl-N-Boc-indole (2h) could successfully be
employed, leading to the cycloadducts 4m-4n with 59% and 31%
yields, but using I2 only. Finally, benzofuran (5) was identified as
another viable 2π component, to generate the benzofuro[2,3-
c]quinoline-6-carboxylates 6a-6c in yields of 42-94%, and the
observed reversal of regioselectivity in these cycloaddition
reactions was unambiguously confirmed by the single crystal X-
ray structure of compound 6c.[13] Again, products 6a-6c were
accessible only under the conditions of method A. We have
further attempted to use N-Boc-pyrrole (7) and benzothiophene
(8) in the reaction, however, no cycloaddition occurred and both
substrates were mostly recovered. The reaction between glycine
ester 1a and 5-cyano-N-Boc-indole (2i) was also not feasible.
With regard to the reaction mechanism, we conducted the control
experiments summarized in Scheme 3. The reaction to products
4a,4a’ starting from glycine ester 1a and N-Boc-indole (2a) could
also be promoted by N-iodosuccinimide (NIS) with blue light
irradiation, while almost no conversion occurred in the dark, which
proved the contribution of radical intermediates (Scheme 3a).
Additionally, the standard reaction between 1a and 2a using I2
was largely quenched in the presence of an equimolar amount of
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TEMPO (Scheme 3b). While no cycloaddition occurred, 56% of
the imine 9a were formed, indicating its role as a key intermediate.
The same experiment under the conditions of method B also
showed radical quenching, even though to slightly lesser extent
(compare Table 1, entry 11).
However, when using HI, NIS and I2 under irradiation, a further
significant increase in conversion was observed, which proved an
additional strong contribution of light-induced radical pathways in
the subsequent oxidation steps to the final products 4a,4a’. Finally,
in order to rule out a conceivable reaction pathway consisting of
a
tandem cross-dehydrogenative coupling (CDC) between
glycine ester 1a and indole, followed by 6π-electron cyclization
and aromatization, we subjected the independently prepared
CDC products 10a and 10b to the typical conditions of method A
(Scheme 3d). These reactions however generated none of
products 3 and 4,4’, but the deeply rearranged[15] 6H-indolo[2,3-
b]quinoline-11-carboxylates 11a and 11b were formed as the only
products and isolated in moderate yields of 38% and 48%,
respectively, their constitution being confirmed by single crystal
X-ray analysis of product 11b.[13]
Scheme 3. Mechanistic control experiments.
Imine 9a, derived from glycine ester 1a by dehydrogenation, was
generally present in all crude reaction mixtures as evident from
NMR analysis. When glycine ester 1a was reacted alone, imine
9a was generated exclusively, both under the conditions of
methods A and B. As shown in Scheme 3c (and Table S2), we
reacted imine 9a with indole 2a under various conditions. While
irradiation of imine 9a in MeCN under O2 with indole 2a alone
gave no conversion, its reactions under both conditions of
methods A and B delivered the products 3a, 4a and 4a’. In order
to establish which species actually activates imine 9a in the [4+2]-
cycloaddition, we added hydroiodic acid (HI), N-iodosuccinimide
(NIS) as well as I2, to find that formation of products 3a and 4a,4a’
occurred in all cases, even in the dark. These results showed that
the imine could be activated via a number of alternative pathways,
including protonation by HI to the iminium ion (9-H)+ as well as N-
iodination with NIS or I2 to give the N-iodoiminium ion (9-I)+, and
possibly also by halogen bonding-activation of 9 in a complex 9•I2
under these model conditions.[14]
Scheme 4. Proposed mechanism.
Based on our observations we propose the mechanism depicted
in Scheme 4. Under the conditions of method A, photolysis of I2
generates the iodine radical I• which abstracts a hydrogen atom
from glycine ester 1, to give HI and the α-amino radical 12, which
is trapped by O2. The resulting peroxyl radical can react with
another molecule of glycine ester 1 in a chain propagation step.[5a]
Elimination of H2O2 from hydroperoxide 13 gives the imine 9,
which undergoes a Brønsted-acid-mediated [4+2]-cyclization with
HI followed by 1,4-hydrogen shift, and a fast oxidation mediated
by I• and O2 leads to the dihydroquinoline 3. The regeneration of
the I2 catalyst can occur through the reaction between HI and
H2O2.16 Conversely, using TPP+ and X− (method B), photoelectron
transfer (PET) between the excited state catalyst (E*red = +2.55 V
vs.SCE)17 and glycine esters 1 (Eox ranging from +0.82 to +1.59
V vs. SCE)18 generates the radical cation 14 which can react with
superoxide to give imine 9. In the protic medium, the major
product-forming pathway similarly is the acid-mediated [4+2]-
cycloaddition and oxidation to 3, however, control experiments
showed that the presence of the halide ion X− contributes to 30-
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35% of total conversion to products 3 and 4 (Table S1), indicating
the existence of a second minor reaction pathway. We propose
that PET between PC* and HX generates X2,[19,20] which in the
presence of trace amounts of H2O gives hypohalite,[12] to convert
imine 9 into the N-haloiminiumion 14. The subsequent [4+2]-
cyclization followed by elimination of HX leads to intermediate 3.
The final comparatively slow oxidation of 3 gives the aromatic
product 4, which undergoes N-Boc-deprotection by HX, the rate
of which depends on the actual acid concentration under the
reaction conditions A or B. Generally, the protic medium of
method B also facilitates an autoxidative product formation in
case of highly electron rich glycine esters like 1a or 1b; this is
however much less pronounced for less activated and acceptor-
substituted systems. In the presence of TPP+, all incident light is
absorbed by the photocatalyst.
The orientation of the C3-nucleophilic indole 2 and imine 9 in the
[4+2]-cycloaddition is polarity-matched, yet it also avoids a steric
clash between the N-Boc-group of the indole and the carboethoxy
function of the imine (such steric hindrance does not occur in
cycloadditions with benzofuran (5) which reacts through a
regioisomeric orientation, which is also in agreement with its
higher charge density at C2).[21] The failure of benzofuran (5) to
undergo the imine [4+2]-cycloaddition under conditions B likely
results from a competing photoelectron transfer to the excited
photocatalyst (Eox of 5 = +1.20 V vs. SCE)[22] impeding further
conversion, and which evidently does not occur with N-Boc-indole
(2a).
450±50 nm) with rapid stirring for 72 h. TFA (169 μL, 2.21 mmol)
was added and the mixture was stirred at 50 °C for 6 h. The
mixture was poured into NaHCO3 aq. and Na2S2O3 aq. followed
by extraction with EtOAc (3×). The combined organic layers were
dried with Na2SO4, filtered and evaporated to dryness. Column
chromatography (silica, Et2O/heptane 1:1) furnished 4b’ (26.0 mg,
75%).
1
4b: Colorless solid, m.p. 103 °C, Rf 0.57 (Et2O/heptane 1:1). H-
NMR (600 MHz, CDCl3) δ = = 1.56 (t, 3J = 7.2 Hz, 3 H, CH3), 1.72
(s, 9 H, tBu), 2.62 (s, 3 H, Ar-CH3), 4.70 (q, 3J = 7.2 Hz, 2 H, CH2),
4
3
7.45 (ddd, J = 1.1 Hz, J = 7.2, 8.2 Hz, 1 H, 8-H), 7.54-7.60 (m,
2 H, 3-H, 9-H), 8.07 (s, 1 H, 1-H), 8.21 (dt, 4J = 0.9 Hz,
3
3J = 8.4 Hz, 1 H, 10-H), 8.23 (d, J = 8.6 Hz, 1 H, 4-H), 8.44 (dt,
4J = 1.0 Hz, 3J = 7.9 Hz, 1 H, 7-H) ppm. 13C-NMR (150 MHz,
CDCl3) δ = 14.5 (q, CH3), 22.4 (q, Ar-CH3), 28.1 (q, tBu), 62.6 (t,
t
CH2), 85.8 (s, Bu), 114.4 (d, C-10), 117.1 (s, C-6a), 119.1 (s,
C-4a), 123.0 (s, C-6b), 123.4 (d, C-7), 123.8 (d, C-1), 124.0 (d,
C-8), 127.7 (d, C-9), 130.8 (d, C-4), 131.2 (d, C-3), 136.9 (s, C-2),
140.3 (s, C-10a), 141.1 (s, C-11a), 144.2 (s, C-6), 144.9 (s,
C-11b), 150.9 (s, NCO), 167.1 (s, CO2R) ppm. IR: 휈̃ = 2980, 2935
(=C-H, -C-H), 1740 (CO), 1250 (C=C), 1150, 1095, 750 cm-1.
HRMS (ESI+): m/z calc.: C24H24N2O4 [M+H]+: 405.1809, found:
405.1825.
4b’: Colorless solid, m.p. 276 °C (dec.), Rf 0.57 (Et2O/heptane
3:1). 1H-NMR (600 MHz, acetone-d6) δ = 1.50 (t, 3J = 7.2 Hz, 3 H,
CH3), 2.62 (s, 3 H, Ar-CH3), 4.62 (d, 3J = 7.1 Hz, 2 H, CH2), 7.35
(ddd, 4J = 1.1 Hz, 3J = 7.1, 8.2 Hz, 1 H, 8-H), 7.52 (ddd, 4J =
1.2 Hz, 3J = 7.1, 8.2 Hz, 1 H, 9-H), 7.65 (dd, 4J = 1.9 Hz, 3J =
In summary, we developed two metal-free protocols for the
photoinduced aerobic tandem amine dehydrogenation/Povarov
cyclization/aromatization reaction between N-aryl glycine esters
and indoles as well as benzofuran, to furnish the corresponding
aromatic [4+2]-cycloadducts with high selectivity and yield. The
indolo[3,2-c]quinoline products resemble new analogs of the
antimalarial natural alkaloid isocryptolepine, and thus they may
be of value in medicinal research.
4
3
8.5 Hz, 1 H, 3-H), 7.73 (dt, J = 1.0 Hz, J = 8.2 Hz, 1 H, 10-H),
8.12 (d, 3J = 8.5 Hz, 1 H, 4-H), 8.30-8.34 (m, 1 H, 1-H), 8.53 (dd,
3
4J = 1.0 Hz, J = 8.2 Hz, 1 H, 7-H), 11.9 (s, 1 H, NH) ppm. 13C-
NMR (150 MHz, acetone-d6) δ = 14.7 (q, CH3), 21.9 (q, Ar-CH3),
62.2 (t, CH2), 112.5 (d, C-10), 113.4 (s, C-6a), 118.4 (s, C-4a),
121.5 (d, C-1), 121.7 (d, C-8), 122.3 (s, C-10a), 124.2 (d, C-7),
126.9 (d, C-9), 131.0 (d, C-4), 131.6 (d, C-3), 138.2 (s, C-2), 140.5
(s, C-6b), 142.2 (s, C-11a), 143.8 (s, C-11b), 145.6 (s, C-6), 168.1
(s, CO2R) ppm. IR: 휈̃ = 2972 (=C-H, -C-H), 1720 (C=O), 1588
(C=N, C-N, NH), 1299, 1239, 1175, 816, 739 (C-H) cm-1. HRMS
(ESI+): m/z calc.: C19H16N2O2 [M+H]+: 305.1290, found: 305.1292.
Experimental section
Typical procedures: synthesis of compounds 4b,4b’
Acknowledgements
Method A: In a 10 mL crimp cap vial, 40.2 mg (208 μmol) of N-
aryl glycine ester 1b and 22.6 mg (104 μmol) N-Boc-Indole (2a)
were dissolved in MeCN (3.50 mL). I2 (13.2 mg, 52.0 μmol) was
added, the vial was sealed and fitted with an O2-balloon (septum
pierced by needle). The mixture was irradiated between two blue
CFL lamps (2×18 W, 450±50 nm) with rapid stirring for 48 h. The
mixture was poured into NaHCO3 aq. and Na2S2O3 aq. followed
by extraction with EtOAc (3×). The combined organic layers were
dried with Na2SO4, filtered and evaporated to dryness. Column
chromatography (silica, Et2O/heptane 1:1) furnished compound
4b (35.8 mg, 85%) and 4b’ (4.4 mg, 14%).
M.B. acknowledges generous support of this project by the
University of Rostock. P.P.H.Q. is grateful for a fellowship by the
„RoHan“ program between the University of Rostock and Vietnam
National University – Hanoi University of Science, which is funded
by the German Academic Exchange Service (DAAD, No.
57315854) and the Federal Ministry for Economic Cooperation
and Development (BMZ) inside the framework "SDG Bilateral
Graduate school program“.
Method B: In a 10 mL crimp cap vial, 44.1 mg (228 μmol) of N-
aryl glycine ester 1b, 24.8 mg (114 μmol) N-Boc-Indole (2a), 4.2
mg (11.0 μmol) TBAI and 0.5 mg (1.0 µmol) TPP•BF4 were
dissolved in DCE (1.90 mL) and HFIP (1.90 mL). The vial was
sealed and fitted with an O2-balloon (septum pierced by needle).
The mixture was irradiated between two blue CFL lamps (2×18 W,
Keywords: Aerobic oxidation • Dehydrogenation • Cycloaddition
• Photochemistry • Heterocycles
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Entry for the Table of Contents
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Eva Schendera, Lisa-Natascha Unkel,
Phung Phan Huyen Quyen,
Gwen Salkewitz, Frank Hoffmann,
Alexander Villinger, Malte Brasholz*
Page No. – Page No.
Visible light-mediated aerobic tandem
dehydrogenative
Povarov/aromatization reaction:
synthesis of isocryptolepines
All metal-free: A photoinduced tandem amine dehydrogenation/Povarov
cyclization/aromatization reaction leads to isocryptolepine analogs with high yield,
using molecular iodine under visible light, or combining an organic photoredox
catalyst with halide anion.
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