Development, Scope, and Applications of Titanium(III)-Catalyzed Cyclizations to Aminated N-Heterocycles

Article abstract of DOI:10.1002/chem.201805909

The exceptionally mild conditions of a titanium(III)-catalyzed cyclization reaction paired with a convenient acid/base extraction have enabled the straightforward synthesis, isolation, and direct N-functionalization of amino heterocycles such as 3-aminoindoles and -pyrroles. The unprotected heterocycles are ideal building blocks for the installation of aminated indoles and pyrroles into target molecules, but their sensitivity has previously impeded their synthesis by modern catalytic methods. This full paper presents the development and extended scope of the new cyclization methodology. The transformation of the products into fused bis-indoles is also demonstrated along with the discovery of an unusual palladium-catalyzed reductive biphenyl coupling reaction. The titanium(III)-catalyzed cyclization has also been applied to the synthesis of substituted 3-iminoindolines, which are of potential interest for applications in natural product synthesis and exhibit tunable blue-to-green fluorescence properties.

Full text of DOI:10.1002/chem.201805909

A Journal of
Accepted Article
Title: Development, Scope, and Applications of Titanium(III) Catalyzed
Cyclizations to Aminated N-Heterocycles
Authors: Leonardus Hendricus Leijendekker, Jens Weweler, Tobias
Martin Leuther, Daniel Kratzert, and Jan Streuff
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To be cited as: Chem. Eur. J. 10.1002/chem.201805909
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10.1002/chem.201805909
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FULL PAPER
Development, Scope, and Applications of Titanium(III) Catalyzed
Cyclizations to Aminated N-Heterocycles
Leonardus H. Leijendekker,[a] Jens Weweler,[a] Tobias M. Leuther,[a] Daniel Kratzert,[b] and Jan
Streuff*[a]
Abstract: The exceptionally mild conditions of
a
titanium(III)
indole nitration and azidation reactions followed by a reduction to
the free amine,[3] or ionic cyclization reactions.[1,2,5] Modern
catalytic methods, on the other hand, give rise to electron-poor
and/or protected derivatives that require deprotection or
subsequent functional group interconversion steps.[6] To this end,
catalyzed cyclization reaction paired with a convenient acid-base
extraction enable the straightforward synthesis, isolation and direct N-
functionalization of amino heterocycles such as 3-aminoindoles and
3-aminopyrroles. The unprotected heterocycles are ideal building
blocks for the installation of aminated indoles or pyrroles into target
molecules, but their sensitivity has previously impeded the synthesis
by modern catalytic methods. This full paper comprises the
we have developed
a titanium(III) catalyzed imine-nitrile
cyclization reaction that provides free aminoindoles and -pyrroles
in a direct fashion (Scheme 1b). The mild conditions and a
development and extended scope of the new cyclization methodology. convenient acid-base extraction procedure allow the
The transformation of the products into fused bisindoles is
demonstrated along with the discovery of an unusual palladium
catalyzed reductive biphenyl coupling. The titanium(III) catalyzed
cyclization is also applied to the synthesis of substituted 3-
iminoindolines, which are of potential interest for applications in
natural product synthesis and exhibit tunable blue to green
fluorescence properties.
straightforward isolation and an optional direct N-functionalization
of the products. Following our initial communication, we herein
describe the development, extended scope, and application of
this methodology.[7]
a) The challenge: synthesis of free 3-aminoindoles and pyrroles
EWG1
H
N
PG
NH2
R
modern
catalytic
methods
?
EWG2
N
N
H
PG
usual building block
ideal building block
Introduction
(stable)
(labile)
b) This work: titanium(III)-catalyzed cyclization
Aminated indole and pyrrole heterocycles represent a common
structural motif of natural products and synthetic small molecules
with striking biological activity. For example, substituted
3-aminoindoles occur in compounds such as cryptospirolepin, a
potent anti-malaria agent, or are antimitotic agents, tubulin
inhibitors and NMDA receptor antagonists.[1] 3-Aminopyrroles
mark the backbone of a number of small DNA cavity binding
molecules like netropsin, or have been shown to possess strong
anticonvulsant and Lck inhibiting properties.[2] Despite the
importance of 3-aminoindole and 3-aminopyrrole containing
molecules, the number of methods for a straightforward synthesis
and installation of these fragments have remained scarce. One
main reason behind the synthetic challenge is the inherent
instability of the unprotected, electron-rich 3-aminoindoles or 3-
aminopyrroles, which would constitute ideal building blocks
(Scheme 1a). These compounds tend to undergo oxidative
dimerization or similar decomposition reactions, are sensitive to
light and air and cannot be purified by chromatography.[3,4] As a
consequence, the major approaches have remained traditional
purification by
extraction
NH2
N
Cp2TiCl2
(catalyst)
or
R
N
N
R
reductant
direct
N-functionalization
H
Scheme 1. a) Usual and ideal scenarios for the catalytic synthesis of 3-
aminoindole and -pyrrole building blocks. b) Envisioned titanium(III)-catalyzed
cyclization to the unprotected/electron-rich 3-aminoheterocycles.
Titanium(III) catalysis allows the reductive construction of
carbon-carbon and carbon-heteroatom bonds from readily
available functional groups such as epoxides, aziridines, alkyl
halides, carbonyls, nitriles, or Michael-acceptors under mild
conditions.[8,9] Furthermore, low-valent titanium catalyzed radical
reactions can proceed under high catalyst control, leading to
chemo-,
regio-,
stereo-,
and
even
enantioselective
transformations.[10,11] Our group has recently developed a number
of titanium(III) catalyzed reductive cyclizations and cross-
couplings that give rise to 1,2-, 1,4-, or 1,6-difunctionalized
compounds, constituting reductive umpolung reactions.[11b,12,13]
Based on these unique features, we contemplated that low-
valent titanium catalysis would provide an ideal approach for
accessing the elusive aminoindoles and -pyrroles. This was
supported by complementary works by Fürstner, who reported
low-valent titanium promoted and catalyzed McMurry-type
couplings for the synthesis of indoles, pyrroles, or other
heterocycles.[14] In agreement with our previous studies,[12,13] we
hypothesized that the nitrile and the imine of a cyanoarylated or
[a]
[b]
L. H. Leijendekker, J. Weweler, T. M. Leuther, Dr. Jan Streuff
Institut für Organische Chemie
Albert-Ludwigs-Universität Freiburg
Albertstr. 21, 79104 Freiburg im Breisgau, Germany
E-mail: jan.streuff@ocbc.uni-freiburg.de
Dr. D. Kratzert
Institut für Anorganische und Analytische Chemie
Albert-Ludwigs-Universität Freiburg
Albertstr. 21, 79104 Freiburg im Breisgau, Germany
Supporting information for this article is given via a link at the end of
the document.
1
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10.1002/chem.201805909
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cyanoalkenylated imine precursor would each coordinate to an in
situ formed titanium(III) catalyst (Scheme 2). This would trigger a
radical-radical coupling reaction and the resulting imino
heterocycle would then get transformed into the desired product
by ensuing Ti-N cleavages and a tautomerization. In theory, this
required the addition of two equivalents of HCl, which could be
Table 1. Screening of the reaction conditions for the titanium catalyzed
aminoindole cyclization.
N
NH2
Ph
Cp2TiCl2 (catalyst)
reductant (2 equiv)
N
TMSCl, Et3N•HCl
THF, 35 °C, 24 h
then acid-base
extraction
N
H
H
1
Ph
substituted
by
chlorotrimethylsilane
and
triethylamine
2
hydrochloride. Moreover, these additives would improve the
stability and performance of the titanium(III) catalyst.[9m,o]
Entry
mol%
Cp2TiCl2
Reductant
equiv
TMSCl
equiv
Et3N•HCl
Yield
[%][a]
CN
[M]Cl2
2 Cp2TiIIICl
1
5
5
2
1
-
Zn
3.0
3.0
3.0
3.0
3.0
2.0
1.0
0.5
-
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
2.0
1.0
-
61
74
42
29
0
N
R
[M]0
2
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
[TiIII]
3
N
2 Cp2TiIVCl2
NH2
4
N
5
R
[TiIII]
6
5
5
5
5
5
5
87
90
10
0
R
N
N
[TiIV
]
H
7
(after workup)
H
R
8
2 "HCl"
(Et3N•HCl/TMSCl)
N
[TiIV
]
9
10
11
1.0
1.0
42
6
Scheme 2. Simplified catalytic cycle.
Results and Discussion
[a] Yield of isolated product.
3-Aminoindoles. We started the investigation of the
cyclization reaction using imine 1, obtained by condensation of
benzaldehyde with 2-aminobenzonitrile. The reaction was carried
out in THF in presence of 5 mol% of titanocene dichloride as
catalyst, zinc as terminal reducing agent, TMSCl and Et3N•HCl as
additives. The aminoindole 2 was formed and it was discovered
that a simple acid-base extraction provided the product in
analytical purity and 61% yield (Table 1, entry 1). This rapid way
of purification proved to be highly advantageous, since the free
aminoindole showed very limited stability in solution and could not
be purified by chromatography. In agreement with the original
preparation by Fischer,[3c] the product could be crystallized from
benzene if desired. It was possible to enhance the yield by
replacing zinc with manganese (74%, entry 2). We then tested
whether the catalyst amount could be further reduced and
confirmed that no background reaction took place (entries 3–5).
Afterwards, the amounts of TMSCl and Et3N•HCl were
successively optimized to 1.0 and 2.0 equivalents, respectively
(entries 6–11). Using the optimized conditions, the analytically
pure product was isolated in 90% yield (entry 7).
This included chloro or bromo substituents that provide valuable
entry points for subsequent cross-coupling reactions. Of particular
importance was the fact that ortho-bromo and ortho-methyl
substituted 2-aryl-3-aminoindoles 12 and 13, or the 1-naphthyl
derivative 14 could be prepared in high yield as well (83%–93%).
Ortho substitution represented a significant limitation of our
previous cyclization and cross-coupling reactions, usually yielding
only minor amounts of product.[7b,11b,13d–g] The reaction could also
be used to access thiophene and benzodioxole derivatives
(15,16), or products with additional electron-donating substituents
such as methyl or methoxy at the indole core (17,18). Only very
electron-poor substituents and free alcohol functions appeared to
inhibit the reaction. For example, substrates derived from nicotine
aldehyde, vanillin, or salicylic aldehyde as well as
a
cyanobenzaldimine did not undergo the cyclization (19–22).
Overall, the titanium(III) catalysis provided for the first time a
reliable way for accessing the free 3-aminoindoles in high yield
and purity. To demonstrate the synthetic potential of this approach
for the installation of such aminoheterocycles into target
molecules, we sought to combine the aminoindole synthesis with
subsequent N-functionalization reactions (Scheme 4). To begin
with, we isolated and submitted 2 to acetylation conditions using
acetyl chloride. The reaction provided the desired product 23 in
74% yield, but significant double acetylation was observed. The
chemoselectivity could be improved by using acetic anhydride,
In a similar manner, a wide range of free 3-aminoindoles could
be accessed in high yield (Scheme 3). The acid-base extraction
procedure provided a convenient way for the purification of all
products, which could be stored in neat form for 1–5 days at
–20 ºC under argon in the dark. In detail, various electron-
donating, and electron-withdrawing substituents were tolerated in
the para- and meta-position of the 2-phenyl group (3–11).
2
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Cp2TiCl2 (5 mol%)
2
Mn (2 equiv)
NH2
AcCl, Et3N
or
Ac2O
conditions
Boc2O CH2Cl2
23 ºC
Et3N•HCl (2.0 equiv)
TMSCl (1.0 equiv)
N
phthalic
conditions
anhydride
CH2Cl2
0 to 23 ºC
R
THF, 35 °C, 24 h
then acid-base extraction
N
N
R
H
O
H
H
NH2
NH2
NH2
N
Ac
Ph
N
Boc
Ph
N
O
R
Ph
N
N
N
H
N
N
N
H
H
H
H
H
R
3, R = OMe, 75%
4, R = Me, 80%
5, R = F, 78%
6, R = Cl, 64%
7, R = Br, 87%
23
24
25
2, 92%
8, R = Me, 64%
9, R = F, 76%
10, R = Cl, 63%
11, R = Br, 85%
Et3N: 0% DMAP (cat.), THF, 40 ºC: 0%
Et3N, DMAP (cat.): 0%
ZrCl4 (cat.): 87%
AcCl, Et3N: 74%
Ac2O: 77%
NMI (cat.), THF, 23 ºC: 0%
ZnBr2, HMDS, 80 ºC: 32%
[bmim][PF6], 80 ºC: 46%
NH2
NH2
NH2
Scheme 4. Optimization of the conditions for N-acetylation, N-Boc and
N-phthalimide protection reactions.
S
N
H
N
N
H
H
R
benzoylated product 27 could be isolated in 76% yield and small
amounts (5%) of the corresponding bis-benzoylated aminoindole
were formed as well (entry 3). Attempts to enforce a double
benzoylation by using an excess of benzoyl chloride, however,
were unsuccessful. The N-Boc and N-phthalimide protected
products 24 and 25 were obtained in 79% and 42% yield,
respectively (entries 4 and 5). Sequential N-tosyl and N-Fmoc
protections could be carried out giving 28 and 29 in 58% and 82%
yield (entries 6 and 7). A direct treatment of 2 with Burgess
reagent or tosyl isocyanate gave sulfonamide (30) and urea (31),
albeit in low yields of 25% and 38% (entries 8 and 9). Importantly,
our approach could also be applied to the coupling of the crude
aminoindole with an amino acid derivative. As shown in entry 10,
the direct coupling with Boc-Ala-OH proceeded smoothly in
presence of T3P as promoter (73% yield). This result could be of
use for the incorporation of such aminoindoles into peptides and
other biomolecules.
12, R = Br, 83%
13, R = CH3, 92%
14, 85%
15, 85%
Me
MeO
MeO
NH2
NH2
NH2
Ph
Me
O
O
Ph
N
N
H
N
H
H
16, 95%
17, 90%
18, 54%
unsuccessful cyclizations:
NH2
NH2
NH2
OMe
N
H
N
H
N
H
N
OH
R
19
20
21, R = OH
22, R = CN
Scheme 3. Scope of the titanium(III) catalyzed cyclization to free aminoindoles.
The cyclization-N-functionalization sequence further enabled
the preparation of products that were either not stable enough
otherwise to be isolated as free aminoindoles or could not be
received in analytically pure form (Scheme 5). Since the N-
functionalization increased the stability, the products could be
conveniently purified by flash chromatography afterwards. By
applying a combination of the cyclization and the direct Boc-
protection, the indoles 33 and 34 containing a valuable bromo- or
chloro-substituent were received in 84% and 52% yield. The
corresponding 5,6-dimethylated N-Boc-aminoindole 35 was
prepared in 31% yield and the Boc and Ac protected 2(ortho-
bromophenyl)-indoles 36 and 37 were produced in analogy (71%
and 66% yield, respectively). In addition, we demonstrated that 3-
amino-7-azaindoles could be accessed from 2-aminonicotine
nitrile derived imines. 7-Azaindoles find wide use in medicinal and
biological chemistry as well as materials science and coordination
chemistry.[18] Here, the final Boc-protected product 38 was
conveniently isolated by simple filtration (72%). Finally, an N-
acetyl-2-styryl aminoindole (39) was synthesized from an imine
derived from cinnamaldehyde, showing that alkenyl substituents
were tolerated at this position as well. The structure of 39 was
which afforded only the mono-acetylation product 23 in 77% yield.
We then tested subsequent N-Boc or N-phthalimide protections
and found that these could be achieved using optimized reaction
conditions. For example, the Boc-protection did not occur in the
presence of triethylamine or triethylamine-DMAP. But with
zirconium tetrachloride (10 mol%) as promoter, the desired
product 24 was obtained in 87% yield.[15,16] The phthalimide
formation required the use of an additional Lewis-acid (ZnBr2) or
an ionic liquid, the latter of which gave the best result (25, 46%).[17]
Aiming to take advantage of the purification by acid-base
extraction, it was found that the titanium-catalyzed cyclization and
the following N-functionalization could be even carried out in a
single operational sequence. This gave immediate access to a
range of N-derivatized products (Table 2). In detail, the
combination of the titanium(III) catalyzed cyclization and the in-
sequence acetylation with Ac2O gave product 23 in 71% yield
(entry 1). The fact that treatment of 2 with acetyl chloride led to
double-acetylation was utilized to achieve the formation of the bis-
acylated product 26 in 52% yield by employing a five-fold excess
of this reagent (entry 2). Using benzoyl chloride, the mono-
3
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Boc2O
ZrCl4 (10 mol%)
THF
Table 2. Scope of the direct cyclization/N-functionalization sequence:
variation of the N-functionalization.
HN R'
Cp2TiCl2 (5 mol%)
Mn (2.0 equiv)
X
X
CN
N
R
R1
Et3N•HCl (2.0 equiv)
TMSCl (1.0 equiv)
THF, 35 ºC, 24 h
or
N
H
R2
NH2
Ph
0,1
0,1
Ac2O, Et3N
CH2Cl2
N
TiIII-catalysis
R
1
acid-base extraction
Ph
conditions 1[a]
conditions 2
N
N
H
NHBoc
NHBoc
NHBoc
Ph
H
Br
Me
Me
Entry
Conditions 2
Product
Yield
[%][b]
Ph
Ph
N
N
H
N
Cl
H
H
33, 84%
34, 52%
35, 31%
1
2
3
4
5
6
Ac2O, Et3N, CH2Cl2,
0 ºC → 23 ºC
23: R1 = Ac, R2 = H
71
52
76[c]
79
42
58
82
NHBoc
NHAc
NHBoc
AcCl (5.0 equiv), Et3N, 26: R1,R2 = Ac
CH2Cl2, 0 ºC → 23 ºC
Ph
N
N
N
N
H
H
H
Br
Br
BzCl, Et3N, CH2Cl2,
0 ºC → 23 ºC
27: R1 = Bz, R2 = H
36, 71%[a]
37, 66%[a]
38, 72%[b]
Boc2O, ZrCl4 (10 mol%),
THF, 23 ºC
24: R1 = Boc, R2 = H
25: R1 + R2 = Phthaloyl
28: R1 = Ts, R2 = H
NHAc
Phthalic anhydride,
[bmim][PF6], 80 ºC
N
Ph
H
39, 45%
(X-ray)[c]
TsCl, Et3N, CH2Cl2,
0 ºC → 23 ºC
Scheme 5. Scope of the cyclization/N-functionalization sequence: variation of
the 3-aminoindole precursor. Isolated overall yields. [a] Gram scale. [b] Isolated
by filtration. [c] Solvent molecules have been removed. Thermal ellipsoids are
shown at the 50% probability level.
7
8
Fmoc-Cl, THF, 23 ºC
29: R1 = Fmoc, R2 = H
Burgess reagent, CH2Cl2, 30: R1 = SO2NHCO2Me, R2 = H 25
0 ºC → 23 ºC
9
TsNCO, CH2Cl2,
0 ºC → 23 ºC
31: R1 = C(O)NHTs, R2 = H
32: R1 = Boc-Ala, R2 = H
38
73
NHAc
NHAc
Pd/C, H2 (1 atm)
(1)
MeOH, 23 ºC
(82%)
Ph
Ph
10
Boc-Ala-OH, T3P, Et3N,
CH2Cl2, 0 ºC → 23 ºC
N
N
H
H
39
40
[a] For the titanium(III) catalysis conditions, see Scheme 3. [b] Isolated yield
based on 1. [c] 5% of N,N-bis-benzoylated product were isolated in addition.
3-Aminopyrroles. We then probed whether our method could
be applied to the preparation of substituted 3-aminopyrrole
derivatives. This was considerably more challenging than the
synthesis of the 3-aminoindoles, since unprotected 3-
aminopyrroles are known to be even less stable. For example, 3-
aminopyrrole itself, could only be synthesized and characterized
in situ.[3b] 3-Ammoniumpyrrole tautomerizes to the C2-protonated
pyrrole in solvents such as acetonitrile or dichloromethane, which
underlines the electron-rich nature of these compounds.
We chose imines based on aminocyclohexenyl or
aminocyclopentenyl carbonitriles as precursors that contained a
fixed (Z)-configured enamine moiety. The preparation was
conveniently achieved by a Thorpe reaction followed by a
standard imine condensation.[21] Afterwards, the titanium(III)
catalyzed cyclization was carried out using the benzaldehyde-
derived substrate 41 and, gratifyingly, the corresponding 2-phenyl
substituted aminopyrrole 42 could be obtained in pure form using
identical conditions as before (Scheme 6). The fully substituted
aminopyrrole was found to be sufficiently stable for standard
characterization purposes. A 2-(ortho-bromophenyl) derivative
(44) could be prepared in a similar fashion. Here, a reaction
carried out on 4 mmol scale gave an improved yield in comparison
to our previous result.[7a]
confirmed by X-ray analysis.[7a] Importantly, the cyclization-
derivatization sequence could be carried out on gram-scale, as
was exemplified for products 36 and 37.
We aimed to investigate whether aliphatic imines would lead
to 2-alkylated aminoindoles. Previously, we reported that aliphatic
ketones smoothly undergo cyclizations to nitriles, and the groups
of Hirao and Nicholas demonstrated that titanium-catalyzed
pinacol-type couplings proceed smoothly with aliphatic
aldehydes.[11b,19] However, the corresponding aliphatic imines
could either not be prepared or not be obtained in sufficient purity.
For example, the ketimines of acetone, cyclopentanone, or
cyclohexanone did not form, even under aza-Wittig conditions.[20]
A pivalaldimine could not be obtained in sufficient purity and the
material obtained did not undergo the desired cyclization. 2-
(Methyleneamino)benzonitrile prepared from formaldehyde led to
the re-isolation of 2-aminobenzonitrile. Nevertheless, 2-alkylated
aminoindoles were accessible by hydrogenation of the 2-
alkenylated products as shown for 2-styryl aminoindole 39
[Eq. (1)].
4
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NH2
CN
bisindoles 51 and 52 took place, giving 78% and 42% yield,
Cp2TiCl2 (5 mol%)
Mn (2.0 equiv)
respectively (Scheme 8). Starting from pyrrole 45,
a
N
corresponding pyrroloindole 53 could be prepared as well (64%).
Initially, it was our goal to achieve these C-N couplings by a
Hartwig-Buchwald type coupling in presence of catalytic amounts
of Pd2dba3 and Xantphos.[25] To our utmost surprise, an unexpec-
ted reductive homo coupling took place and biphenyl derivative
54 was isolated in 74% yield (Scheme 9). The identity of 54 was
unambiguously established by an X-ray analysis.[26] Since no
reducing agent was added, the mechanism of this overall
reductive coupling remained unclear. In principle, the substrate
itself may have acted as the terminal reductant. As an alternative,
1,4-dioxane could have served as the reducing agent. This was
supported by the fact that the reaction took place only in dioxane.
Other solvents such as toluene or THF showed no formation of
54. Such a scenario was further supported by a recent study on
solvent-induced reduction of palladium aryl species.[27] However,
N
Et3N•HCl (2.0 equiv)
TMSCl (1.0 equiv)
THF, 35 ºC, 24 h
then acid-base
extraction
H
R
R
41: R = H
43: R = Br
42: R = H, 88%
44: R = Br, 91% (4 mmol)
Scheme 6. Synthesis of unprotected 3-aminopyrroles 42 and 44.
When testing other precursors to explore the scope of the
aminopyrrole cyclization, it was found that the product material
isolated after extraction was not sufficiently pure. Without the
possibility of chromatographical purification, we were delighted to
find that the direct in-sequence derivatization could be applied as
well. Using the in situ Boc protection protocol, ortho- and para-
halogenated, as well as para-methylated 2-phenyl-3-
aminopyrroles were prepared in 44–73% yield (45–48, Scheme 7).
Even a cyclopentane-annulated aminopyrrole (49) that was
significantly more strained than the 6-5 bicycle products could be
obtained in 26% yield. We also probed the cyclization to fluorene
spirocycle 50, but no reaction took place. We assumed that the
fluorene unit shielded the top and bottom sides of the iminonitrile
precursor, preventing a coordination to the titanium catalyst. Still,
these results demonstrated the strength of our approach to
access such labile heterocycles. It should be noted that all pyrrole
syntheses and manipulations of the products were carried out in
the dark to avoid a premature decomposition.
R
CuI (2 equiv)
TMEDA (2 equiv)
Cs2CO3 (2 equiv)
R
N
NH
DMSO, 110 ºC 1.5 h
N
N
H
Br
H
R = Boc, 36
R = Ac, 37
R = Boc, 51: 78%
R = Ac, 52: 42%
Boc
N
NHBoc
identical conditions
N
N
H
H
Br
45
53, 64%
To highlight the potential for future applications of the
cyclization, we investigated whether the 2-(ortho-bromoaryl)
substituted amino heterocycles could be cyclized to fused
bisindoles and indolopyrroles. Bisindoles have recently gained
interest in the field of organic field-effect-transistors (OFETs) as a
potential organic semiconductors.[22,23] Using our cyclization it
would be possible to gain access to selectively protected,
unsymmetric derivatives. And indeed, when submitting the Boc
and acetyl protected aminoindoles 36 and 37 to copper-promoted
C-N coupling conditions,[24] the cyclizations to the desired
Scheme 8. Copper-mediated C-N coupling to bisindoles and pyrroloindoles.
NHBoc
Pd2(dba)3 (5 mol%)
Boc
NH
Xantphos (15 mol%)
Cs2CO3 (1.5 equiv)
N
H
H
N
dioxane, 100 ºC, 24 h
(74%)
N
H
Br
NHBoc
36
Cp2TiCl2 (5 mol%)
Mn (2.0 equiv)
Boc2O
ZrCl4 (10 mol%)
BocHN
54
X
X
CN
N
R
Et3N•HCl (2.0 equiv)
TMSCl (1.0 equiv)
THF, 35 ºC, 24 h
THF, 23 ºC
N
0,1
0,1
H
R
acid-base extraction
NHBoc
NHBoc
NHBoc
Br
F
N
N
H
N
H
H
Br
45, 73%[a]
46, 59%
47, 60%
NHBoc
NHBoc
Ph
NHBoc
Ph
Me
N
H
N
N
H
H
X-ray of 54
48, 44%
49, 26%
50, 0%
Scheme 9. Unexpected reductive homo-coupling of 36 and X-ray structure of
54. Thermal ellipsoids are shown at the 50% probability level.
Scheme 7. Application of the cyclization/N-functionalization sequence to N-
Boc-aminopyrroles, isolated yields. [a] Gram scale.
5
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10.1002/chem.201805909
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FULL PAPER
no byproducts of a potential oxidation of the substrate or dioxane
that could have supported either theory were identified by NMR,
GC, or isolation.
Table 3. Optimization of the cyclization to 3-iminoindolines.
NH
catalyst (10 mol%)
reductant (2 equiv)
N
Ph
TMSCl (1.5 equiv)
Et3N•HCl (1.5 equiv)
THF (c = 0.3 M), 24 h
N
N
Ph
3-Iminoindolines. Finally, the transfer of the cyclization
reaction to ketimine substrates was explored. The reaction would
then lead to iminoindoline products that can in principle be
hydrolyzed to 3-indolinones (pseudoindoxyls),[28] a structural motif
of several important natural products.[29] It was found that the
H
55
57
Entry
catalyst
reductant
T [ºC]
Yield [%][a]
1
Cp2TiCl2
Cp2TiCl2
Cp2TiCl2
Cp2TiBr2
Zn
35
60
60
60
60
60
60
60
60
60
80
80
7
synthesis of the ketimine precursors required
a precise
2
Zn
18 (22)[b]
temperature control as exemplified for the formation of 55 in
Scheme 10. At oil bath temperatures lower than 120–130 ºC, the
condensation would not occur, while at temperatures significantly
higher than 135 ºC, undesired quinoline formation set in (56).[30]
p-TsOH (5 mol%)
3
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
Mn
37 (41)[b]
32
4
CN
CN
5
(t-BuCp)2TiCl2
(EtCp)2TiCl2
Cp2Ti(OPh)2
(Cp*)2TiCl2
rac-(ebthi)TiCl2
-
27
MS 4Å
O
+
6
19
toluene, 135 ºC
(oil bath temp.)
Ph
N
Ph
NH2
55, 64%
7
18
Ph
8
7
N
9
29
T >135 ºC
10
11
12
0
N
Ph
56
Cp2TiCl2
47[b]
52[b]
Scheme 10. Formation of ketimine 55 required precise temperature control.
rac-(ebthi)TiCl2
[a] NMR yield determined with 1,2-benzodioxole as internal standard. [b] Yield
of isolated product.
The catalytic cyclization was first attempted under the
conditions that were established for the aldimine cyclizations,
albeit with a catalyst loading of 10 mol% (Table 3, entry 1). The
reaction appeared to be significantly hindered by the additional
methyl group and the desired product 57 was formed only in 7%
yield. In addition, it was found that a severe decomposition of the
substrate to an undefined complex mixture took place even in
absence of the catalyst, an issue that was addressed by careful
optimization of the reaction conditions. The catalysis was able to
outrun the decomposition at an elevated temperature, and at
60 ºC, the desired iminoindoline was formed in 22% yield (entry 2).
The background reactions were further reduced by changing the
reductant to manganese powder (41% yield, entry 3). We also
briefly investigated other catalyst precursors, all of which gave
inferior results (entries 4–9). Again, no product could be observed
in absence of catalyst (entry 10). Increasing the temperature to
80 ºC and using rac-(ebthi)TiCl2 as catalyst under these
conditions then led to satisfying 52% yield (entries 11,12).
Additional optimization attempts (reaction time, concentration,
additive amounts) did not improve the outcome.[7a]
NH
rac-(ebthi)TiCl2 (10 mol%)
N
R3
R1
R2
R1
R2
Mn (2.0 equiv)
R3
R4
TMSCl (1.0 equiv)
Et3N•HCl (2.0 equiv)
THF, 80 ºC
N
N
R4
H
NH
NH
NH
MeO
MeO
MeO
Ph
Ph
Ph
N
N
H
N
H
H
57, 52%
58, 43%
59, 66%
Ac
N
NH
NH
NH
Me
Me
Ph
CO2Me
Ph
N
N
N
CO2Me
H
H
H
60, 41%
61, 55% (Zn)[a]
62, 45% (Zn)[a]
26% (Mn)
30% (Mn)
The optimized conditions were then applied to the synthesis
of six different iminoindolines (Scheme 11). Substitution at the
cyanoaryl moiety with electron-donating methoxy or methyl
groups was well-tolerated and the products 58–60 were isolated
in moderate to good yield (43–66%). Importantly, ketimines
derived from phenyl glyoxylate and from a corresponding
indolylglyoxylate also underwent the cyclization reaction, forming
the 2-methoxycarbonyl iminoindolines 61 and 62.[31] For these
ester-substituted imines, it was empirically found that zinc gave
Scheme 11. Scope of the titanium(III) catalyzed cyclization to 3-iminoindolines.
[a] Reaction carried out with Cp2TiCl2 (10 mol%) and Zn dust (2 equiv).
better results (55% and 45%) than manganese (26% and 30%).
The products 61 and 62 are of particular synthetic intererest,
because the imine hydrolysis gives 2-carboxylated indoxyls,
which are present in natural products such as duocarmycin family
6
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10.1002/chem.201805909
Chemistry - A European Journal
FULL PAPER
members and isatisine A, for example.[28b,32] We also attempted
the asymmetric cyclization of 63. But as in our previous efforts
towards enantioselective imine-nitrile cyclizations, product 58 was
formed only with low enantioselectivity (24% ee) together with a
Table 4. Selected photophysical properties of compounds 57–59 and 61 in
chloroform.
Compound
Absorption
Emission
(exc) [nm] (em) [nm]
Stokes shift
Dl [nm]
69
slightly reduced yield (38%) [Eq. (2)].[7b]
l
(max) [nm]
394
l
l
(R,R)-ebthi-TiCl2 (10 mol%)
Zn (2 equiv)
Et3N•HCl (1 equiv)
TMSCl (1.5 equiv)
57
58
59
61
394
384
370
360
463
491
512
457
NH
MeO
CN
N
MeO
(2)
383
108
Ph
N
THF, 24 h, 35 ºC
H
369
143
Ph
63
58, 38%, 24% ee
361
96
In agreement with the literature, all 3-iminoindoline products
were found to be strongly fluorescent.[28a,c,33] The emission
occurred in the blue-green region with compounds 57 and 61
showing a blue fluorescence, a striking property that was also
observed for related pseudoindoxyls.[34] It may be rationalized by
an equilibrium with the respective 2H-indole tautomer, which
leads to the fluorescence these compounds [Eq. (3)].
Conclusions
NH
NH2
R1
R2
R1
R2
In summary, a mild and broadly applicable titanium(III)-
catalyzed imine-nitrile cyclization has been developed that gives
access to unprotected 3-aminoindoles and 3-aminopyrroles as
(3)
N
N
H
3-iminoindoline
3-amino-2H-indole
well as 3-iminoindolines. This addresses
a longstanding
To investigate the influence of the substitution pattern on the
fluorescence properties, absorption-emission spectra were
recorded for 57, the methoxy derivatives 58, 59 and the ester-
substituted product 61 (Figure 1). Increasing the number of
electron-donating methoxy substituents shifted the absorption
maximum for the first electron excitation to higher energies
(Table 4, entries 1–3). The corresponding emission maxima of the
observed fluorescence spectra were considerably shifted to larger
wavelengths, resulting in an increase of the Stokes-shift. The
installation of an electron-withdrawing group at the 2-position also
increased the absorption energy, while the emission maximum
remained almost unchanged (entry 4). The results demonstrate
that the absorption and emission properties can be independently
adjusted by installing substituents either at the aryl moiety or the
2-position. Hence, these small organic dyes could be of potential
interest for applications as fluorescence probes or as blue-green
emitters for organic functional materials research.
challenge in the synthesis of these otherwise elusive, electron-
rich heterocycles. The isolation of the free products can be
conveniently achieved by an acid-base extraction. As an
alternative, the direct functionalization at the amino group to
produce N-derivatized building blocks can be carried out in a
single sequence. Transformations of the products into
unsymmetrical and selectively protected bisindoles and
pyrroloindoles further highlight the synthetic utility of the approach.
Overall, this particularly mild synthetic method together with the
facile isolation protocol and the demonstrated broad application
range may be of greater value for future applications in areas such
as organic, medicinal, or material chemistry.
Acknowledgements
This work was funded by the Deutsche Forschungsgemeinschaft
(DFG) – project 240508776. The Fonds der Chemischen Industrie
(FCI) is gratefully acknowledged for financial support.
Keywords: catalysis • heterocycles • reduction • titanium •
umpolung
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10.1002/chem.201805909
Chemistry - A European Journal
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Chemistry - A European Journal
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9
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10.1002/chem.201805909
Chemistry - A European Journal
FULL PAPER
Entry for the Table of Contents
FULL PAPER
Leonardus H. Leijendekker, Jens
Weweler, Tobias M. Leuther, Daniel
Kratzert, Jan Streuff*
NH
R'
NH2
TiIII
catalysis
-
TiIII
-
catalysis
CN
R'
R
N
N
R
R' = H
R' ≠ H
N
R
H
H
aminoindoles
aminopyrroles
iminoindolines
(fluorescent)
Page No. – Page No.
Development, Scope, and
Applications of Titanium(III)
Catalyzed Cyclizations to Aminated
N-Heterocycles
A titanium(III) catalyzed imine-nitrile cyclization gives rise to free aminoindoles,
pyrroles, and iminoindolines that are ideal, but fragile building blocks for the
installation of such motifs into target molecules. Herein, the development, extended
scope, and application of this reaction are described. Moreover, the fluorescence
properties of the iminoindoline products are briefly investigated.
10
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