Nitrogen atom insertion into indenes to access isoquinolines

Abstract

We report a convenient protocol for a nitrogen atom insertion into indenes to afford isoquinolines. The reaction uses a combination of commercially available (diacetoxy¬iodo)benzene (PIDA) and ammonium carbamate to furnish a wide range of isoquinolines. Various substitution patterns and commonly used functional groups are well tolerated and the operational simplicity renders this protocol broadly applicable. Furthermore, this strategy enables the facile synthesis of 15N labeled isoquinolines, using 15NH4Cl as a commercial 15N source.

Full text

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Nitrogen atom insertion into indenes to access isoquinolines
Patrick Finkelstein, Julia C. Reisenbauer, Ori Green, Bence Botlik, Andri Florin, and Bill Morandi*[a]
[a] P. Finkelstein, J. C. Reisenbauer, Dr. O. Green, B. Botlik, A. Florin, Prof. Dr. B. Morandi
Laboratorium für Organische Chemie, ETH Zürich
Vladimir-Prelog-Weg 3, HCI, 8093 Zürich (Switzerland)
E-mail: bill.morandi@org.chem.ethz.ch
Supporting information for this article is given via a link at the end of the document.
Abstract: We report a convenient protocol for a nitrogen atom
insertion into indenes to afford isoquinolines. The reaction uses a
combination of commercially available (diacetoxyiodo)benzene
(PIDA) and ammonium carbamate to furnish a wide range of
isoquinolines. Various substitution patterns and commonly used
functional groups are well tolerated and the operational simplicity
renders this protocol broadly applicable. Furthermore, this strategy
enables the facile synthesis of 15N labeled isoquinolines, using
15NH4Cl as a commercial 15N source.
Isoquinoline is an important aromatic N-heterocycle scaffold with
numerous applications in medicinal chemistry,[1–6] materials
science,[7–9] and as a ligand in catalysis.[10–13] Traditionally, this
heterocycle has been synthesized through the assembly of pre-
oxidized building blocks and amines,[14–16] or oxidation of di- or
tetrahydroisoquinoline,[17,18] among other methods.[19,20] A
strategically different approach is the introduction of the key
nitrogen atom at a later stage of a synthetic route, using a pre-
decorated carbocyclic framework. A classical strategy to
accomplish this task relies on the stepwise oxidative cleavage of
an indene skeleton, usually through ozonolysis, followed by
condensation with an amine (Scheme 1A).[21–23] Recently, more
direct methods have emerged, such as an electrochemical
approach using gaseous ammonia as the nitrogen source,[24] but
which is only compatible with electron-rich indenes bearing
additional aryl and alkyl substitutions on the double bond. Finally,
an osmium nitride was shown to stoichiometrically react with 3-
phenyl-1H-indene, which, after a subsequent step gave 1-
phenylisoquinoline.[25] However, the need for stoichiometric metal
and the synthesis of the starting osmium nitride limits synthetic
applications. These challenges highlight the demand for a
synthetically useful and practical approach to directly transform
indenes into isoquinolines.[26]
Our group has recently reported a nitrogen atom insertion method
into silyl-protected indoles, affording either quinazolines or
quinoxalines in a single step.[27] In our proposed mechanism we
postulated nitrogen lone pair participation in the fragmentation of
an N-iodonium-aziridine intermediate. We surmised that indenes,
which possess an acidic C–H moiety in place of the indole
nitrogen atom, could possibly engage in a similar process through
isoelectronic reactive intermediates (Scheme 1B). If successful,
this would result in a simple and efficient conversion of indenes
into isoquinolines.
Here, we report the direct nitrogen atom insertion into a broad
range of indenes and a cyclopentadiene, employing commercially
available (diacetoxyiodo)benzene (PIDA) as the oxidant and
ammonium carbamate as the nitrogen source. We also report an
extension of this protocol to enable the formation of isotopically
labeled isoquinoline structures using commercially accessible
15NH4Cl (Scheme 1C).
Scheme 1. Context of this work.
We chose 3-phenyl-1H-indene 1a as our model substrate and
started our study by using two equivalents of
[bis(trifluoroacetoxy)iodo]benzene (PIFA) as the oxidant and four
equivalents of ammonium carbamate as the nitrogen source. The
combination of a hypervalent iodine compound and an ammonia
source — proposed to generate an iodonitrene in situ — has
been used successfully in several transformations in recent years.
[27–30] Our hypothesis was validated by observing the formation of
the desired 1-phenylisoquinoline product 1b (Table 1, entry 1) in

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methanol at 0 °C after 10 minutes in 77% yield (as determined by
1H-NMR analysis of the crude reaction mixture, for more details
see SI). However, further increasing the amount of oxidant and
ammonia source did not improve the yield (Table 1, entry 2). We
continued by investigating the remaining parameters of the
reaction, starting with different ammonia sources and observed
that these also led to the desired product, albeit in lower quantities
(Table 1, entries 3-4). The reaction also proceeded in aprotic
solvents such as MeCN (Table 1, entry 5), providing a potential
alternative for substrates that are incompatible with protic
conditions. Changing the oxidant had the largest net positive
effect, with both bis(tert-butylcarbonyloxy)iodobenzene and PIDA
increasing the yield to over 90 % (Table 1, entries 6-7). Finally, 2
equivalents of PIDA in combination with 4 equivalents of
ammonium carbamate in MeOH at 0 °C proved to give the highest
yield for our transformation. Other parameters such as the
temperature (0 °C vs. rt) or concentration (0.033 M – 0.20 M) only
had minor effects on the overall outcome of the reaction (see SI).
When scaling up the reaction to 1.0 mmol, we increased the
oxidant loading to 2.5 equivalents to reach full conversion and
thus were able to isolate the product 1b in 63% yield (Table 1,
entry 8). In summary, the transformation of indene 1a into the
corresponding isoquinoline 1b could be achieved open-flask in a
variety of conditions including multiple solvents, oxidants, and
ammonia sources, highlighting the robustness of our protocol.
Table 1. Selected optimization data for the nitrogen insertion into indenes.a
[a] Reaction conditions: indene (0.05 mmol), PIFA (0.10 mmol), ammonium
carbamate (0.20 mmol), methanol-d4 (0.07 M), 0 °C, 10 min. [b] Yields in %
obtained by NMR analysis of the crude reaction mixture using 1,1,2,2-
tetrachloroethane as the internal standard. [c] Isolated yield.
With the optimized conditions in hand, we set out to examine the
functional group tolerance and limitations of our method. For all
reactions, we report the NMR yield on a 0.05-mmol scale and the
isolated yield on a 1.0-mmol scale (Scheme 2). In the following
sections, we discuss the substrate scope based on the NMR
yields.
Unsubstituted indene 2a could successfully be converted into
isoquinoline (2b), however, the lack of a phenyl ring at the 3-
position led to a reduced, yet synthetically useful yield of 58%.
This is an important feature, as recently reported one-step
methods are not compatible with simple unsubstituted indene
substrates.[24,25] We next systematically investigated the effect of
substitutions at the double bond of the five-membered ring. Like
the model system, 3-phenyl-1H-indene (1a), 3-methyl-1H-indene
(3a) gave the product 1-methylisoquinoline (3b) in excellent yield
(88%), possibly hinting at the beneficial effect of a substitution in
the 3-position. A methyl group at the 2-position of the indene (4a)
gave 54% yield of 3-methylisoquinoline (4b), similar to the
unsubstituted system. Next, we installed a phenyl at the 3-position
and compared the results for a methyl group at either the 2- (5a),
or 1-position (6a). Both reactions gave essentially identical yields
(5b: 65% and 6b: 68%), albeit higher than the previous substrates
with no phenyl substitution at the 3-position.
We next compared different substituents on the six-membered
ring. Substrates bearing a bromine atom at any of the four
possible positions on the benzene ring were tolerated in the
reaction (7a, 8a, 9a, and 10a). Similarly diminished yields were
obtained when the bromide was either in the 4- (7b: 34%), 5- (8b:
31%), or 7-position (9b: 34%) of the starting indene, respectively.
In contrast, 6-bromo-1H-indene 10a gave a yield closer to that of
the unsubstituted system (10b: 49% vs 2b: 58%). We observed a
similar yield when subjecting 6-chloro-1H-indene 11a to our
reaction conditions, giving 11b in 47% yield. To investigate a
potential electronic effect at the 6-position of the indene, we
exchanged the halides for an electron-donating methoxy group.
The reaction afforded 6-methoxyisoquinoline 12b in 50% yield,
suggesting that electronic effects at this position do not influence
the reaction’s yield. In comparison, a methoxy group closer to the
reaction center resulted in a slight increase in yield to 58% of 8-
methoxyisoquinoline 13b.
Having established that reactivity could be expected both with or
without substitutions at any position on the indene core, we
explored the functional group tolerance of the reaction. A free
phenol (14a) was well tolerated and gave phenol-containing
isoquinoline 14b in 50% yield. Protecting the phenol with a tri-
isopropyl silyl group (15a) resulted in an even higher yield of
product 15b (87%). Other groups in para position on the phenyl
group were well tolerated, such as a methoxy (16b: 67%) or a
trifluoromethyl group (17b: 93%). Combining these results with
that of our model system 1b, it seems that the reaction yield is not
influenced by the electronics of the pendant aryl substituents.
We further investigated other common functional groups,
including a benzylic pyridine (18a) which was converted into the
corresponding product 18b in 83% yield, an internal alkyne (19a),
which gave the product 19b in 56% yield, and an indene bearing
a ketone (20a) which afforded the desired product 20b in 54%
yield. As aldehydes are prone to oxidize to the nitrile in the
presence of ammonia and an oxidant,[31] we wondered whether
we could achieve both the oxidation and the nitrogen insertion
simultaneously. Indeed, aldehyde 21a was converted to the nitrile
product 21b in 45% yield. Finally, we decided to expand our scope
beyond indenes by testing a cyclopentadiene. We chose
1,2,3,4,5-pentamethyl cyclopentadiene 22a as our substrate, due
to its higher stability compared to the unsubstituted parent
structure. To our delight, 2,3,4,5,6-pentamethyl pyridine 22b was
observed in excellent yield (95%), clearly demonstrating the
possibility to synthesize densely functionalized pyridine products
from cyclopentadienes. Overall, commonly used functional
groups were well tolerated in the reaction and synthetically useful
yields were observed for non-, mono-, and di-substituted indene
cores.

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Scheme 2. Substrate scope. For the scXRD structures, the ellipsoids are shown at 50% probability and hydrogen atoms are omitted for clarity. [a] NMR yield of
0.05-mmol scale crude reaction mixture, using 1,1,2,2-tetrachloroethane as the internal standard. [b] Isolated yield of a 1.00-mmol scale reaction, conditions:
indene (1.0 mmol), PIDA (2.5 mmol), ammonium carbamate (4.0 mmol), methanol (0.07 M), 0 °C for 20 min, then rt for 10 min.
Apart from easily accessing isoquinolines, an appealing
application of our method would be the incorporation of the
heavier 15N isotope, which has a natural abundance of only
around 0.3%. 15N labeled molecules have been used in many
different settings for their nuclear magnetic resonance (NMR) and
mass-related properties, such as in proteomics,[32] as sensitive
protonation probes,[33,34] reaction-progress and complexation
monitoring of COFs,[35,36] and more generally for studies on N-
heterocycles.[37–39] 15N NMR spectroscopy has some significant
advantages compared to the method using the lighter isotope,[40]
but suffers from high costs for the typically laborious syntheses of
15N labeled precursors. Thus, an inexpensive protocol to
incorporate the valuable 15N-label at a later stage in the synthesis
could be attractive to access relevant labeled organic or
organometallic structures.
We thus set out to evaluate whether our protocol could insert 15N
into indenes to form isotopically labeled isoquinolines. Due to the
lack of commercially available 15N ammonium carbamate, we
changed our nitrogen source to NH4Cl and envisaged that adding
a base could unlock the desired reactivity. Surprisingly, when
using four equivalents of NH4Cl as the ammonia source without
any base, we could already see conversion of 1a to the product
1b, albeit in low quantities (Table 2, entry 1). By introducing a
base and changing the equivalents of the reagents, the reaction
was optimized to afford the product 1b in 80% yield on a 0.05-
mmol scale and 49% yield on a 1.0-mmol scale (Table 2, entries
2-7).

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Table 2. Selected optimization data for the nitrogen insertion into indenes using
ammonium chloride.a
[a] Reaction conditions: indene (0.05 mmol), PIDA (0.10 mmol), ammonium
chloride (0.20 mmol), methanol-d4 (0.07 M), 0 °C, 10 min. [b] Yields in %
obtained by NMR analysis of the crude reaction using 1,1,2,2-
tetrachloroethane as the internal standard.
We next used the isotopically labeled salt, 15NH4Cl, to convert 3-
phenyl-1H-indene (1a) into 1-phenylisoquinoline-15N (1c) in 51%
isolated yield (Scheme 3A). We confirmed the incorporation of the
heavier nitrogen isotope by high-resolution mass spectrometry
(HRMS) and NMR analysis. The usual characteristic doublet in
the 1H NMR spectrum of the H at the 3-position of 1b was split
into a doublet of doublets (dd, J = 10.9, 5.7 Hz). We recorded a
15N NMR spectrum, noting a doublet of doublets at δ 306.7 (dd, J
= 10.8, 1.9 Hz). This splitting is caused by the coupling of the
nitrogen with the adjacent hydrogens at the 3- and 4-position of
the isoquinoline, which was also confirmed by 2D 1H-15N-HMBC
experiments (see SI).
After this successful initial example, we next sought to
demonstrate the utility of our labeling method by incorporating 15N
into the isoquinoline-based drug papaverine, which is used to
treat visceral spasms and vasospasms.[41] Having access to an
isotopically labeled drug can greatly help identify metabolic
pathways.[42,43] Subjecting 23a to our reaction conditions, we
obtained the product papaverine-15N (23c) in 38% yield (Scheme
3B). As with 1c, we confirmed the nitrogen isotope incorporation
by HRMS and 1H/15N NMR analyses.
Scheme 3. Isotopically labeled structures. [a] Isolated yields.
In conclusion, we report a facile method to insert a nitrogen atom
into indenes and a cyclopentadiene, granting access to a wide
variety of differently substituted and functionalized isoquinolines
and a densely functionalized pyridine. We could further expand
our method to use 15NH4Cl as the nitrogen source, allowing for the
convenient synthesis of 15N labeled isoquinolines.
Acknowledgements
This work was supported by the Swiss National Science
Foundation (SNSF 184658), ETH Zurich, and the European
Research Council under the European Union’s Horizon 2020
research and innovation program (Shuttle Cat, project ID:
757608). J.C.R. acknowledges a fellowship from the
Stipendienfonds der Schweizerischen Chemischen Industrie
(SSCI). O.G. acknowledges a fellowship from the International
Human Frontier Science Program Organization (grant
LT000861/2020-L). We thank the NMR, MS (MoBiAS), and X-ray
(SMoCC) service departments at ETH Zürich for technical
assistance and the Morandi group for critical proofreading of the
manuscript.
Keywords: Isoquinolines • Skeletal editing • Nitrogen insertion •
15N labeling • Iodonitrene
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Entry for the Table of Contents
Insert graphic for Table of Contents here.
We report a facile and open-flask method to convert indenes into isoquinolines through nitrogen atom insertion using commercially available
reagents. The reaction tolerates various substitution patterns and commonly used functional groups. We could further expand the utility of our
protocol to enable the facile synthesis of 15N labeled isoquinolines, using 15NH4Cl as a commercial 15N source.
Institute and/or researcher Twitter usernames: @morandilab, @PDFinkelstein, @origree1