Expedient one-pot synthesis of indolo[3,2-c]isoquinolines via a base-promoted N-Alkylation/tandem cyclization

Article abstract of DOI:10.1016/j.tetlet.2015.08.006

A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-indolo[3,2-c]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyano-phenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential

Full text of DOI:10.1016/j.tetlet.2015.08.006

Accepted Manuscript
Expedient one-pot synthesis of indolo[3,2-c]isoquinolines via a base-promoted
N –alkylation/tandem cyclization
Huy H. Nguyen, James C. Fettinger, Makhluf J. Haddadin, Mark J. Kurth
PII:
S0040-4039(15)01287-3
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.08.006
TETL 46590
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Accepted Date:
2 August 2015
6 August 2015
Please cite this article as: Nguyen, H.H., Fettinger, J.C., Haddadin, M.J., Kurth, M.J., Expedient one-pot synthesis
of indolo[3,2-c]isoquinolines via a base-promoted N –alkylation/tandem cyclization, Tetrahedron Letters (2015),
doi: http://dx.doi.org/10.1016/j.tetlet.2015.08.006
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1
Tetrahedron Letters
Expedient one-pot synthesis of indolo[3,2-c]isoquinolines via a base-promoted N–
alkylation/tandem cyclization
Huy H. Nguyena, James C. Fettingera, Makhluf J. Haddadinb, and Mark J. Kurtha*
a Department of Chemistry, University of California, One Shields Avenue, Davis, California 95616, United States
b Department of Chemistry, American University of Beirut, Beirut, 1107 2020 Lebanon
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A transition metal-free, one-pot protocol has been developed for the synthesis of 11H-
indolo[3,2-c]isoquinolin-5-amines via the atom economical annulation of ethyl (2-cyano-
phenyl)carbamates and 2-cyanobenzyl bromides. This method proceeds via sequential N–
alkylation and base-promoted cyclization. Optimization data, substrate scope, mechanistic
insights, and photoluminescence properties are discussed.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
Keyword_1 indolo[3,2-c]isoquinoline
Keyword_2 one-pot
Keyword_3 tandem cyclization
Keyword_4 photoluminescence
Keyword_5 domino process
1. Introduction
revealed only a few synthetic approaches to this unique motif,
and further functionalized derivatives are rarely reported.5 These
Indoles and quinolines are ubiquitous heterocyclic scaffolds
appearing in numerous natural products and synthetic
pharmaceuticals. The family of indoloquinoline alkaloids
depicted in Figure 1 has been isolated from the root bark extracts
of Cryptolepis sanguinolenta (Asclepiadaceae), a Ghanaian
medicinal shrub native to West Africa.1 Well-recognized as
components in traditional folk remedies for malaria, these
alkaloids display interesting pharmacology – for example,
expressing hypotensive, antibacterial, anti-fungal, anti-
plasmodial, antipyretic, and anti-inflammatory activities.2
Further, recent studies have shown that cryptolepine is a potent
cytotoxic agent, which binds to DNA in a base-stacking
intercalation mode.3
existing methods generally require multiple prefunctionalizations
of requisite indole or isoquinoline starting materials (Scheme 1).
For example, Black and co-workers demonstrated a flexible route
to
1
via the acid-catalyzed cyclization of 3-amido-2-
phenylindoles5a and Timari presented a concise synthesis of 2 by
thermal cyclization of 2-azidophenylisoquinoline.5b Both are
effective, but utilize moderately harsh conditions and involve
multi-step precursor preparations.
Figure 1. Bioactive examples of indoloquinoline alkaloids.
Because of their remarkable therapeutic potentials, the synthe-
sis of indoloquinoline derivatives has attracted considerable
attention from the synthetic community.4 In this report, we were
particularly interested in 11H-indolo[3,2-c]isoquinoline, a close
relative of cryptolepine and isocryptolepine. Our literature survey
Scheme 1. Reported indolo[3,2-c]isoquinoline and benzofuro[3,2-
_________
c]isoquinolin-5-amine synthetic methods.
* Corresponding author. Tel.: 530-544-2145; fax: 530-752-8995.
E-mail address: mjkurth@ucdavis.edu (Mark Kurth).

2
Tetrahedron
With the ascendency of organometallic catalysis in modern
group (PG) – one easy to install, compatible with the desired
transformations, and readily removed after cyclization. Among
N–alkyl, N–acyl, and N–carbamoyl PGs, we found N–
ethylcarbamoyl was the most satisfactory as treating ethyl (2-
cyanophenyl)carbamate and the benzylic bromide with
stoichiometric KOtBu or NaH in DMF at 0 C cleanly delivered
8a in quantitative yield within 1.5 h (Scheme 2c). With this result
in hand, we turned our attention to an investigation of optimal
conditions for the annulation using 8a as the model substrate
(Table 1).
organic synthesis, metal-catalyzed cross-coupling C–N/C–C
bond formations have become a powerful tool for constructing
heterocyclic structures.6 In that context, the Maes group described
an interesting assembly of 2 in two steps via a Buchwald–
Hartwig amination followed by a Pd-catalyzed intramolecular
arylation.5c Importantly, the Kalugin group reported the transition
metal-free two-step synthesis of benzofuro[3,2-c]isoquinolin-5-
amine 3 from 2-cyanophenol.5d Building on that work, we
believed that an appropriate method could be developed for the
facile construction of indolo[3,2-c]isoquinoline from readily
available reagents.
Table
1.
Optimization
studies:
base-promoted
heterocyclization of 8a to indoloisoquinolines 9aa
Recently, our group has exploited the atom and step-economy
of tandem/domino and multicomponent reactions to assemble
complex heterocyclic skeletons.7 These strategies provide a rapid
means to introduce molecular complexity by enabling multiple
bond forming events to occur in one simple operation – thus
avoiding the inconvenience of intermediate purifications.8
Herein, we report the base-promoted tandem annulation of ethyl
9a yieldb
t
Time
(h)
Entry
Base
Solvent
9a/9a’c
(2-cyanophenyl)carbamate
derivatives
with
2-(bromo-
(%)
(C)
50
0
methyl)benzonitriles as a one-pot route to amine-functionalized
indoloisoquinolines (Scheme 2a). To the best of our knowledge,
this is the first report on the synthesis of 11H-indolo[3,2-
c]isoquinolin-5-amines.
1
2
3
4
5
6
7
8
9
KOtBu
NaH
DMF
DMF
DMF
DMF
THF
1
1
27
49
–
90:10
NaH
rt
24
0.5
2
26
20:80
NaH
50
80
80
rt
70
90:10
NaH
trace
trace
20
–
–
–
–
–
NaH
MeCN
DMF
DMF
DMF
2
LiHMDS
K2CO3
DBU
24
2
80
rt
NR
trace
24
aReactions were performed using 8a (0.5 mmol), base (0.55 mmol), and
b
solvent (5.0 mL) at different temperatures and reaction time. Isolated yield.
cDetermined by HPLC analysis of the crude reaction mixture. DBU = 1,8-
diazabicyclo[5.4.0]-undec-7-ene.
KOtBu achieved the desired transformation, but afforded 9a in
only 27% yield (entry 1). Examination of other bases revealed
that NaH gave the best efficiency in terms of yield and clean
reaction mixture. Cyclization was sluggish with LiHMDS and
ineffective with K2CO3 and DBU, resulting in low conversion
(entries 7–9). Among the solvents tested, DMF was superior to
THF and MeCN (entries 5,6). Notably, stoichiometric NaH was
essential for complete conversion. Also, prolonged stirring has a
detrimental effect on the overall yield (entry 3) with 9a’, the N-
deprotected indoloisoquinolines, being the major product. When
the reaction was conducted with NaH/DMF at 50 C for 30 min,
the best conversion was achieved with minimal formation of 9a’
(entry 4); therefore, these conditions were found optimal. The
structure of tetracyclic product 9a (Table 1) was unambiguously
established by X-ray crystallographic analysis.10
Scheme 2. (a) Overall transformation; (b) initial approach; and (c)
preparation of ethyl (2-cyanobenzyl)(2-cyanophenyl)carbamate.
2. Results and Discussion
We commenced initial screening by examining the feasibility
of the reaction between 2-aminobenzonitrile and 2-(bromometh-
yl)benzonitrile in the presence of strong base (KOtBu in DMF;
Scheme 2b) – conditions adapted from the work of Li et al.9
Based on Kalugin’s work,5d we envisioned that SN2 displacement
would lead to intermediate 4, which would be subsequently
deprotonated in situ by KOtBu. The resultant benzylic anion
would then attack the aniline ring nitrile and trigger the
annulation process in a cascade fashion. Unfortunately, this N–
alkylation/tandem cyclization furnished the expected tetracyclic
core 5 in low yield and as a complicated reaction mixture. LCMS
analysis revealed a significant amount of aniline remained post-
reaction, suggesting that weak nucleophilicity of the 2-
aminobenzonitrile results in an incomplete SN2 reaction.
Presumably the NH moiety of 4, exhibiting a lower pKa than
benzylic protons, might undergo deprotonation in this basic
environment forming the amide anion, which could then attack
electrophilic sites to form side products. In order to circumvent
these hypothesized difficulties, we decided to modify the NH2
moiety on the starting aniline with an appropriate protecting
This mild and efficient annulation (8a  9a) encouraged us to
explore combining the robust SN2 reaction with the subsequent
cyclization steps to give a one-pot cascade synthesis of 9. With
effective sodium hydride mediation of both steps established (see
Scheme 2 and Table 1), we set out to explore the scope and
generality of this method for transforming appropriate
carbamates 6 and bromides 7 into substituted 11H-indolo[3,2-
c]isoquinolin-5-amines 9.
We first examined the effects of a variety of R1 substituents on
the one-pot process (Scheme 3). Ethyl (2-cyanophenyl)carba-
mates possessing either e-donating or e-withdrawing substituents
are well-tolerated, affording the desired products in moderate to
good yields (9a–h). Aryl halides (F / Cl / Br) are accommodated
by the transformation and provide the possibility of further

3
A plausible mechanism for the base-promoted tandem
functionalization via various coupling reactions. It was found, in
general, that e-rich anilines displayed retarded reactivity,
resulting in lower yields than e-deficient substrates (cf., 9g in
45% vs 9d in 57%). A cyclic--enaminonitrile reacted smoothly
to deliver 9i in 66%, and a pyridyl substrate was converted to
cyclization is depicted in Scheme 5. Initial abstraction of a
benzylic hydrogen by NaH generates benzylic anion intermediate
A, which subsequently attacks the aniline-derived nitrile ( B).
Tautomerization furnishes 3-aminoindole C through which
intramolecular nucleophilic attack onto the benzylic bromide-
derived nitrile delivers D. Finally, tautomerization ( E) and
protonation deliver 9a.
Scheme 5. Proposed mechanistic pathway.
Finally, we examined the photophysical properties of these
novel indoloisoquinolines (UV−vis and fluorescence spectral
data for 9a and 10a in DCM are illustrated in Figure 2).
Compound 9a has a maximum absorption at 341 nm, which can
be ascribed to an aromatic π−π* transition. As expected, removal
of the carbamate moiety increases the availability of π-electrons
on the indolyl nitrogen for easier conjugation with the
isoquinoline, thus possibly explaining the bathochromic shift [9a
(341 nm)  10a (367 nm)]. Both compounds displayed strong
fluorescence in the blue-green region (400-500 nm) and a red-
shift trend was observed for fluorescence (9a  10a || 425 nm 
452 nm).
1
9a
10a
0.1
0.8
0.6
0.4
0.2
Scheme 3. One-pot substrate scope: synthesis of 11H-indolo[3,2-
c]isoquinolin-5-amines. aSee SI for experimental procedures. bIsolated
yield. cThree equivalents of NaH were used. dn.d. = not detected.
0.0
0
300
400
500
600
wavelength, λ [nm]
11H-pyrido[3',2':4,5]pyrrolo-[3,2-c]isoquinolin-5-amine (9n) in
68% yield. A limitation of this protocol was revealed with a
thiophenyl substrate, which failed to undergo cyclization ( 9o)
resulting in recovery of the SN2 intermediate. We next surveyed
benzyl bromide R2 substituents. The presence of an e-
withdrawing fluorine substituent slightly lowers yields (9j-l) and,
in the case of an e-donating methoxy, the SN2 intermediate leads
to 9m in only a trace amount.11
Figure 2. Absorption (dashed lines) and emission (solid lines)
spectra of 9a and 10a (c = 10 μM) in DCM (left). Fluorescence of 9a
and 10a under UV illumination (365 nm) (right).
3. Conclusion
In conclusion, a transition metal-free and operationally simple
one-pot protocol for the synthesis of 11H-indolo[3,2-
c]isoquinolin-5-amines has been developed starting from readily
available ethyl (2-cyanophenyl)carbamates and 2-cyanobenzyl
bromides. This mild and efficient method proceeds via base-
promoted N−alkylation and cyclization steps to forge novel
indoloisoquinolines via a domino process that features atom and
step economy as well as broad substrate scope. Photophysical
studies demonstrate that this class of compounds affords
potentially useful fluorophore properties.
With various analogs of indoloisoquinolines 9 in hand, we set
out to establish a practical N−deprotection method since most
indoles require the free N−H to be biologically active.
Fortunately, removal of the N−ethylcarbamate group can be
achieved by simply treating a solution of 9 with LiOH at ambient
temperature, which affords the free indolyl nitrogen in
quantitative yield (Scheme 4). These conditions were found to be
applicable to substrates with various substituents.
Acknowledgments
The authors dedicate this work to Roland J. Kurth, a
wonderful and gracious mentor, on the occasion of his 89th
birthday. Financial support provided by the National Institutes of
Health (DK072517 and GM089153) and the National Science
Foundation (CHE-080444; for the Dual source X-ray
diffractometer). We also thank Teresa A. Palazzo (Kurth Group),
Scheme 4. N−Deprotection of indoloisoquinolines 9.

4
Tetrahedron
Dong hee Chung (Toney Group), Alexandra L. Holmes
(Kauzlarich Group) at UC Davis for assistance in the collection
of HRMS, UV−Vis, and fluorescence data, respectively.
Supplementary Material
Experimental procedures and characterization data for novel
compounds; X-ray structure of compound 9a. This material is
available
free
of
charge
via
the
Internet
at
http://dx.doi.org/10.1016/j.tetlet####.
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10
The X-ray crystal structure revealed intermolecular N–H···O bonding.
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11
The cyclization was sluggish even in the presence of 3 equivalents of
NaH.

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Expedient one-pot synthesis of indolo[3,2-
c]isoquinolines via a base-promoted N–
alkylation/tandem cyclization
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Huy H. Nguyen, James C. Fettinger, Makhluf J. Haddadin, and Mark J. Kurth*