Concise Synthesis of Annulated Pyrido[3,4-b]indoles via Rh(I)-Catalyzed Cyclization

Article abstract of DOI:10.1021/acs.orglett.5b02807

The synthesis of pyridines bearing multiple ring fusions poses a considerable challenge for organic chemists. To address this problem, we describe the synthesis of a small library of pyrido[3,4-b]indoles via an efficient, five-step sequence. The key trans

Full text of DOI:10.1021/acs.orglett.5b02807

Letter
pubs.acs.org/OrgLett
Concise Synthesis of Annulated Pyrido[3,4‑b]indoles via Rh(I)-
Catalyzed Cyclization
Jonathan G. Varelas, Satyam Khanal, Michael A. O’Donnell, and Seann P. Mulcahy*
Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, Rhode Island 02918, United
States
S
* Supporting Information
ABSTRACT: The synthesis of pyridines bearing multiple ring
fusions poses a considerable challenge for organic chemists. To
address this problem, we describe the synthesis of a small
library of pyrido[3,4-b]indoles via an efficient, five-step
sequence. The key transformation is a Rh(I)-catalyzed [2 +
2 + 2] cyclization that forms three rings in one reaction flask.
Our method is high yielding, accommodates a variety of
functional groups, and suffers no entropic costs as ring size increases.
itrogen-containing heterocycles are widely used in drug
discovery for the appropriate balance they offer with
lactam-fused β-carboline (anticancer agent, IC50 = 2.6 μM),7
and a lactone-fused β-carboline (benzodiazepine receptor
antagonist, IC50 = 0.2 nM).8
N
respect to polarity, aqueous solubility, and membrane
permeability. In addition, the diversity in size and shape of
these substructures plays a pivotal role in molecular
recognition. In a recent review,1 the aromatic heterocycle
pyridine was found in nearly 6% of all FDA-approved small
molecule pharmaceuticals. Given this prevalence, organic
chemists have developed numerous methods toward their
synthesis. One goal that still remains underexplored is the
regioselective polyfunctionalization of pyridines. This is
particularly important since nearly 50% of all pyridine-
containing drugs are substituted more than once.
The fusion of additional rings onto the β-carboline core is
difficult to achieve efficiently from a naked scaffold. We
hypothesized that more complex pyridines could be prepared if
the aromatic ring itself was formed very late in the sequence.
Since metal-catalyzed [2 + 2 + 2] cyclization reactions are
widely used to create pyridines in one step,9,10 we envisioned
that additional fused rings could be generated concurrently.11
Using this strategy, we recently reported a three-step synthesis
of an annulated pyrido[3,4-b]indole via palladium-mediated
tandem catalysis.12 While the synthesis of this pyridine was
novel mechanistically, the scope of the methodology is so far
limited to only a single substrate. In this letter, we report a
general method for the synthesis of annulated pyridines via a
late-stage, Rh(I)-catalyzed [2 + 2 + 2] cyclization.
The synthesis of polycyclic systems such as these is difficult
to achieve in one step. In 2002, Witulski reported the synthesis
of annulated β-carbazoles via an intramolecular Cp*Ru(COD)-
Cl-catalyzed [2 + 2 + 2] cyclization.13 Using this work as
inspiration, we sought to replace the terminal alkyne with a
nitrile, thereby providing access to annulated pyrido[3,4-
b]indoles from acyclic precursors in one step.
The synthesis of the required intramolecular substrate
toward these molecules is shown in Scheme 1. We began by
preparing substituted aryl iodide 4 according to a two-step
literature procedure.13 Treatment of iodoaniline 1 with p-
toluenesulfonyl chloride gave the sulfonamide 2, which was
converted to the N-alkynyl sulfonamide 4 under basic
conditions. Upon reacting 4 with alkynyl nitrile 5a under
palladium-catalyzed Sonogashira cross-coupling14 conditions
for 1 h, we obtained diynyl nitrile 6a in 68% yield. This reaction
Commonly known as β-carbolines, pyrido[3,4-b]indoles
contain an indole ring fused to the pyridine scaffold. These
structures have been found to disrupt DNA replication and
transcription,2 elicit strong neuropharmacological effects,3 and
exhibit excellent cytotoxicities against cancer cells, fungi, and
bacteria.4 Natural β-carbolines such as harman and norharman
have received significant attention from the synthetic
community due to their ability to bind to DNA via
intercalation.5 Less common are annulated β-carbolines that
contain an extra carbo- or heterocycle fused to the pyridine
ring. The more notable examples, shown in Figure 1, include
Ambocarb (inhibitor of voltage-gated sodium channels),6
a
Received: September 28, 2015
Figure 1. Annulated pyrido[3,4-b]indoles.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02807
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
8). We observed an additional increase in yield of 8a by
replacing rac-BINAP with S-SEGPHOS (entry 9). Addition of
S-H8-BINAP resulted in a decrease in yield, indicating that the
bite angle of the exogenous ligand is important.
Scheme 1. Synthesis of Ring-Fused Pyridoindole
We next applied this methodology to the synthesis of a
variety of pyrido[3,4-b]indoles bearing annulations of different
size, geometry/conformation, and backbone atom composition
according to Scheme 2. First, we used a collection of six
Scheme 2. Synthesis of Diverse Ring Annulations
was closely monitored by TLC and worked up immediately
after the starting material had been consumed in order to
prevent cyclotrimerization of 6a. Removal of the trimethylsilyl
group proceeded smoothly to give 7a in 89% yield.
With the desired intramolecular substrate 7a in hand, and
given the large precedent for metal-catalyzed [2 + 2+2]
cyclization reactions, we optimized the reaction conditions with
respect to metal catalyst, solvent, concentration, and exogenous
ligand (Table 1). A cobalt complex under microwave irradiation
different alkynyl nitriles as substrates during the Sonogashira
coupling (5a−f, Table 2). With the exception of 5d, the yields
Table 2. Substrate Scope of Methodology
Table 1. Reaction Optimization of Cyclization
yield
a
entry
1
conditions
(%)
20% CpCo(CO)2, μ-wave, ClCH2CH2Cl, 120 °C, 10 min
5% Ir(COD)Cl2, 10% rac-BINAP, toluene
5% Ir(COD)Cl2, 10% rac-BINAP, toluene
10% Cp*Ru(COD)Cl, CH2Cl2
39
17
25
13
19
55
72
71
84
30
b
2
3
4
5
6
7
10% Rh(PPh3)3Cl, CH2Cl2
10% Rh(COD)2BF4, 10% rac-BINAP, CH2Cl2
5% Rh(COD)2BF4, 10% rac-BINAP, CH2Cl2
5% Rh(COD)2BF4, 10% rac-BINAP, CH2Cl2
5% Rh(COD)2BF4, 5% S-SEGPHOS, CH2Cl2
5% Rh(COD)2BF4, 5% S-H8-BINAP, CH2Cl2
c
8
9
10
of this step are consistently good (Table 2). However, the bulk
of the mass balance comes from in situ formation of 8a−f, as we
have observed previously.5 Next, tetrabutylammonium fluoride
mediated desilylation proceeded in excellent yields to afford the
requisite diynyl nitrile cyclization substrates 7a−f. The
instability of these molecules to long-term exposure to air
and moisture prompted us to quickly cyclotrimerize them after
isolation. Applying our optimized Rh(I)-catalyzed [2 + 2 + 2]
cyclization conditions to these substrates led in all cases to the
desired pyrido[3,4-b]indoles 8a−f.
The highest yields for this reaction occurred for rings
containing toluenesulfonyl-protected amines. There appears to
be no limitation in the size of the desired annulation since 5-,
6-, and 7-membered rings can be prepared in excellent yields
(compare entries 1−4). A fused carbocycle and an ester-
functionalized carbocycle both gave slightly poorer yields for
a
All reactions performed at 10 mM substrate concentration and at
b
room temperature unless otherwise noted. 100 mM substrate
concentration. 5 mM substrate concentration.
c
gave only a modest yield of pyrido[3,4-b]indole 8a, despite a
high catalyst loading (entry 1). An iridium(I) complex also gave
a poor yield of 8a and was accompanied by an unidentified
byproduct that formed despite a 10-fold reduction in
concentration (entries 2−3). Both Cp*Ru(COD)Cl and
Rh(PPh3)3Cl, which were the catalysts of choice in Witulski’s
work, also gave a poor yield of 8a (entries 4−5). The cationic
rhodium(I) complex Rh(COD)2BF4, pioneered by Tanaka et
al.,15 gave excellent yields of 8a. Lowering the catalyst loading
and decreasing the substrate concentration resulted in higher
yields and greater turnover numbers, respectively (entries 7−
B
DOI: 10.1021/acs.orglett.5b02807
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
the final step (entries 5 and 6). This was at least in part due to
the incomplete consumption of starting material, despite
heating (40 °C) and longer reaction times (up to 36 h). A
summary of the pyrido[3,4-b]indoles prepared via this method
is shown in Figure 2.
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Figure 2. Summary of annulated pyrido[3,4-b]indoles.
In conclusion, we have described a concise method for the
synthesis of six annulated pyrido[3,4-b]indoles. Each of these
molecules can be prepared in as few as five steps from
commercially available material with good overall yields. While
there appears to be no entropic limitation on annulation size,
efforts to introduce an ether or basic amine functional group
into the backbone were not successful and will require
optimization. Further investigations into the electronic require-
ments of this reaction scheme and the evaluation of these
molecules as biological probes are currently being pursued.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02807.
(15) Tanaka, K.; Shirasaka, K. Org. Lett. 2003, 5, 4697.
Experimental procedures and full characterization
(NMR, IR, and MS) of all newly synthesized compounds
(PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: smulcahy@providence.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported in part by an Institutional
Development Award (IDeA) from the National Institute of
General Medical Sciences of the National Institutes of Health
under Grant Number 5 P20 GM103430, grant support from
the Rhode Island Foundation Medical Research Fund, and
funding from the American Chemical Society Petroleum
Research Fund Undergraduate New Investigator program.
The authors would also like to acknowledge Dr. Tun-Li Shen at
Brown University for HR-MS measurements and the generous
support of Providence College.
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DOI: 10.1021/acs.orglett.5b02807
Org. Lett. XXXX, XXX, XXX−XXX