Parallel strategies for the synthesis of annulated pyrido[3,4-b]indoles via Rh(I)- and Pd(0)-catalyzed cyclotrimerization

Article abstract of DOI:10.1016/j.tetlet.2018.10.050

Two different pathways for the synthesis of annulated pyrido[3,4-b]indoles are reported using metal-catalyzed cyclotrimerization reactions. A stepwise process using Rh(I)-catalysis in the final step of the synthesis and a multicomponent, tandem catalytic

Full text of DOI:10.1016/j.tetlet.2018.10.050

Tetrahedron Letters xxx (2018) xxx–xxx
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Parallel strategies for the synthesis of annulated pyrido[3,4-b]indoles via
Rh(I)- and Pd(0)-catalyzed cyclotrimerization
Bianca M. Saliba, Satyam Khanal, Michael A. O’Donnell, Kathryn E. Queenan, Junho Song,
⇑
Matthew R. Gentile, Seann P. Mulcahy
Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI 02918, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Two different pathways for the synthesis of annulated pyrido[3,4-b]indoles are reported using metal-cat-
alyzed cyclotrimerization reactions. A stepwise process using Rh(I)-catalysis in the final step of the syn-
thesis and a multicomponent, tandem catalytic approach using Pd(0)-catalysis both lead to complex
nitrogen-containing heterocycles in good yields. Substituent effects are investigated for both pathways,
demonstrating that the Pd(0)-catalyzed approach is more sensitive to electron-withdrawing groups.
Ó 2018 Elsevier Ltd. All rights reserved.
Received 23 September 2018
Revised 15 October 2018
Accepted 23 October 2018
Available online xxxx
Keywords:
Pyridoindole
Cyclotrimerization
Tandem catalysis
Multicomponent
Transition metal catalysis is a fundamental tool in organic syn-
thesis that enables chemists to construct molecules with ever
increasing complexity. Nearly every organic functional group has
some affinity for one or more of the transition metals, and the
resulting complexes often change the reactivity of the functional
group. This can be exploited for synthetic purposes, whereby trans-
formations that are expensive, wasteful, or difficult using tradi-
tional methods can be performed under mild conditions in the
presence of a transition metal [1]. The use of transition metals
for the synthesis of complex nitrogen-containing heterocycles is
especially important given their prevalence in small molecule drug
discovery efforts [2]. We recently reported the synthesis of pyrido
[3,4-b]indoles, also known as b-carbolines, using a strategy that
employs transition metal catalysis to fuse additional rings to the
core pyridine scaffold [3]. While annulations to pyridoindole hete-
rocycles do not appear frequently in the chemical literature, some
notable examples have potent biological effects, including the inhi-
bition of ion channels [4], binding to neurochemical receptors and
DNA [5,6], and cytotoxic and cytostatic activity [7–9]. New meth-
ods to rapidly synthesize these molecules would enable an even
wider study of their biological activity. Furthermore, understand-
ing the mechanism and generality of these transition metal-cat-
alyzed reactions would facilitate the construction of new
heterocycles with increasingly complex architectures. In this Let-
ter, we report two parallel strategies for the synthesis of annulated
pyrido[3,4-b]indoles: 1) a stepwise Rh(I)-catalyzed sequence, and
2) a one-pot tandem catalytic sequence using Pd(0).
Our synthesis of annulated pyrido[3,4-b]indoles used the ret-
rosynthetic strategy outlined in Fig. 1, which made use of a late-
stage cyclotrimerization [10–18] to build the core heterocyclic
framework and a Sonogashira reaction [19] to create a diynylnitrile
substrate from simpler starting materials. Our initial investigations
using this strategy focused on the annulation of different sized
rings to the pyrido[3,4-b]indole by exchanging the alkynylnitrile
tether [3]. In this study, we investigated the effects of substitution
⇑
Corresponding author.
E-mail address: smulcahy@providence.edu (S.P. Mulcahy).
Fig. 1. Retrosynthetic analysis for annulated pyrido[3,4-b]indoles.
https://doi.org/10.1016/j.tetlet.2018.10.050
0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.
Please cite this article in press as: B.M. Saliba et al., Tetrahedron Lett. (2018), https://doi.org/10.1016/j.tetlet.2018.10.050

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B.M. Saliba et al. / Tetrahedron Letters xxx (2018) xxx–xxx
pattern on the starting substrates to determine the electronic
requirements for this sequence.
fonyl protecting group was even observed. Thus, the moderate
yields (ie. 4e, 4f) for this step can be attributed to a combination
of incomplete deprotonation, instability of the products to strongly
basic conditions, and some insolubility of 3 in toluene. It should
also be noted that the Sonogashira reaction had to be closely mon-
itored by TLC and worked up immediately after the starting mate-
rial was completely consumed to avoid lower yields. Removal of
the trimethylsilyl protecting group proceeded smoothly to give ter-
minal alkynamides 7a–g in good yields. These substrates were sen-
sitive to hydrolysis, resulting in the formation of acetamide side
products, so the reaction needed to be performed at lower temper-
atures. Finally, the intramolecular cyclotrimerization reaction pro-
ceeded smoothly in all cases to give the desired targets 8a–g, with
the best yields occurring for electron-rich systems. More moderate
yields were observed for substrates with an electron-withdrawing
group. With the exception of the 8a (rt, CH2Cl2), all diynylnitrile
substrates required refluxing conditions in CHCl3 as solvent and
close monitoring by TLC.
A frustrating problem in the synthesis of annulated pyrido[3,4-
b]indoles via this stepwise approach was the consistently moder-
ate yields for the Sonogashira reaction for some substrates. Upon
closer inspection, much of mass balance came not from decompo-
sition but rather from the formation of 8a–g (Scheme 2). This led
us to believe that palladium itself could catalyze the intramolecu-
lar cyclotrimerization step [22–27], obviating the need for isolation
of two additional intermediates. This result was quite surprising,
since it implied that a single palladium precursor could multitask
within the same reaction flask by participating in more than one
mechanistically unique catalytic cycle [28–34]. We previously
reported a mechanistic study of this transformation for a single
substrate (8a) [35]. Since the reaction was run overnight, had high
catalyst loading, and suffered from some loss of catalytic activity
over time, we searched for an improved experimental procedure
that would have broader utility.
The synthesis of differentially substituted pyrido[3,4-b]indoles
is outlined in Scheme 1. We began by following a two-step litera-
ture procedure [20] to prepare the requisite N-(trimethylsilyl)ethy-
nyl-2-iodoanilines 4a–g in good yield from substituted 2-
iodoanilines. A palladium-catalyzed Sonogashira reaction using a
nitrile-tethered alkyne 5 resulted in the preparation of substrates
6a–g. After removal of the trimethylsilyl group with TBAF, a rho-
dium(I)-catalyzed intramolecular cyclotrimerization [14] reaction
afforded the desired annulated pyrido[3,4-b]indoles 8a–g.
Table 1 shows the yields for each step of this sequence for six
different substrates containing a diversity of functional groups.
Both electron-withdrawing and electron-donating groups resulted
in moderate to good isolated yields for each step in the synthesis
using optimized conditions. The N-alkynylation reaction using
the hypervalent iodine intermediate 3 [21] nearly always resulted
in some recovered starting material despite extensive optimization
of the reaction conditions. In some cases, loss of the p-toluenesul-
I
I
NHTs
NH2
TsCl
2a-g
R2
R2
pyridine
R1
R1
1a-g
i. KHMDS
toluene, –20 °C
ii. TMS
I+Ph
–OTf
3
5
Ts
N
CN
Ts
N
I
Ts
N
CN
Ts
TMS
N
We elected to use microwave acceleration to solve the limita-
tions in our initial synthesis of 8a. Using substrate 4a as our model
system again, we investigated the effect of temperature, time, and
the source of palladium, as shown in Table 2. The results of this
optimization indicate that moderate yields for this reaction could
be achieved. In each case, the most significant byproduct in this
Pd(PPh3)2Cl2
CuI, PPh3
Et3N:DMF (2:1)
R2
R1
TMS
4a-g
R2
R1
6a-g
TBAF
CH2Cl2
–15 °C
Ts
Ts
N
CN
8a-g
N
5 mol% Rh(COD)2BF4
5 mol % S-SEGPHOS
Ts
N
R2
R1
N
N
CHCl3, reflux
Ts
R2
R1
7a-g
Scheme 1. Synthesis of annulated pyrido[3,4-b]indoles via Rh(I)-catalysis.
Scheme 2. One-pot synthesis of annulated pyrido[3,4-b]indoles via Pd(0)-catalysis.
Table 1
Stepwise synthesis of annulated pyrido[3,4-b]indoles.
Entry
R1
=
R2
=
Yield of 2 (%)
Yield of 4
Yield of 6
Yield of 7
Yield of 8
a
b
c
d
e
f
H
Cl
H
H
H
H
H
H
H
Cl
OMe
Me
78
83
71
81
80
99a
61
83
60
74
87
48
38
88
68
72
81
63
82
67
53
89
74
64
88
83
90
79
84b,c
96
65
93
91
CO2Me
F
78
64
g
a
b
c
TsCl, DMAP, CHCl3.
rt, CH2Cl2.
Ref. [3].
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B.M. Saliba et al. / Tetrahedron Letters xxx (2018) xxx–xxx
3
Table 2
Optimization of the one-pot synthesis of annulated pyrido[3,4-b]indole 8a.
Entry
Catalyst (5 mol%)
Temperature (°C)
Time (h)
Isolated yield (%)
1
2
3
4
5
6a
7
8
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
2 Â Pd(PPh3)4
Pd(OAc)2
80
90
100
80
80
80
90
90
1
1
1
2
3
2
1
1
31
36
43
44
36
35
39
53
Pd(PPh3)2Cl2
a
An additional 5% of Pd(PPh3)4 was added after 1 h, then irradiated again.
reaction was intermediate 6a. Higher temperatures resulted in a
higher yield of the derived product 8a, presumably by accelerating
the cyclotrimerization (entries 1–3). Extending the reaction time
did not result in better yields (entries 4–5), nor did adding fresh
catalyst (entry 6) or using Pd(OAc)2 (entry 7). Optimized conditions
were found that employed Pd(PPh3)2Cl2 as catalyst precursor while
being irradiated at 90 °C for 1 h (entry 8).
products in reasonable yields. Coupled with our recent report of
the ability to expand the size of the annulation, these two transi-
tion metal catalyzed pathways provide additional synthetic tools
to construct complex pyrido[3,4-b]indoles in a less time- and
resource-intensive manner.
Acknowledgements
We can now report that the tandem catalytic sequence shown
in Scheme 2 is compatible with a selection of substrates (Table 3).
Treating N-(trimethylsilyl)ethynyl-2-iodoanilines 4b–g with the
alkynylnitrile 5 in the presence of Pd(PPh3)2Cl2 and CuI under
microwave irradiation at 90 °C for 1 h resulted in formation of
8b–e in acceptable yields. Unfortunately, very little product was
formed for substrates with a strong electron withdrawing group
(8f–g). Significant decomposition products were observed in the
synthesis of 8f, which is consistent with the lower yield observed
in the Rh(I)-catalyzed protocol. Homodimerization occurred during
the synthesis of 8g, which suggests that Glaser coupling is faster
than intramolecular cyclization. Attempts to avoid homodimeriza-
tion by using only two equivalents of Et3N did not result in any
product formation.
This research was supported by the National Science Founda-
tion Facilitating Research at Undergraduate Institutions program
(#1565987). Acknowledgement is also made to the Donors of the
American Chemical Society Petroleum Research Fund for partial
support of this research. Research reported in this publication
was also supported in part by the Institutional Development
Award (IDeA) Network for Biomedical Research Excellence from
the National Institute of General Medical Sciences of the National
Institutes of Health under grant number P20GM103430. The
authors would also like to thank Dr. Tun-Li Shen at Brown
University for HR-MS measurements.
Appendix A. Supplementary data
While these yields are indeed modest, our method could be
attractive for certain substrates as a multicomponent coupling.
First, the reaction conditions are an improvement upon our initial
disclosure [35], since half as much catalyst is used and the reaction
time is significantly shorter due to microwave acceleration.
Second, this reaction is unique since a single palladium complex
can form multiple bonds and multiple rings in a single reaction
flask, thereby enabling the synthesis of annulated pyrido[3,4-b]
indoles in as few as three steps from easily accessible starting
materials. Finally, the yields for the one-pot synthesis of 8a–e
using Pd(II)-catalysis (Scheme 2 and Table 3) are on par with the
stepwise method using Rh(I)-catalysis (Scheme 1 and Table 1),
indicating that both pathways are viable depending on the desired
substitution pattern.
Supplementary data (including all experimental details and the
full characterization of all new compounds) to this article can be
found online at https://doi.org/10.1016/j.tetlet.2018.10.050.
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Entry
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a
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Cl
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H
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H
H
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43
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CO2Me
F
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g
0 (98)a
a
Yield of homodimer.
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