Phenanthridine synthesis via [2+2+2] cyclotrimerization reactions

Article abstract of DOI:10.1039/b716519f

A concise synthesis of phenanthridines via a microwave-assisted [2+2+2] cyclotrimerization reaction has been developed. This journal is The Royal Society of Chemistry.

Full text of DOI:10.1039/b716519f

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Phenanthridine synthesis via [2+2+2] cyclotrimerization reactions†
Lakshminath Sripada, Jesse A. Teske and Alexander Deiters*
Received 26th October 2007, Accepted 23rd November 2007
First published as an Advance Article on the web 3rd December 2007
DOI: 10.1039/b716519f
A concise synthesis of phenanthridines via a microwave-
assisted [2+2+2] cyclotrimerization reaction has been deve-
loped.
Four different diyne starting materials carrying various R3
and R4 groups were synthesized (Scheme 2) in order to probe
the tolerance of sterically demanding alkyne substituents and
to induce regioselectivity on the cyclotrimerization reaction. The
synthesis of 10–13 commenced with the ortho-iodo aniline 7 which
underwent a smooth Sonogashira coupling with TMS acetylene
followed by N-acetylation delivering 8 in 88% over two steps.27
In order to provide the terminal alkyne 9, the TMS group was
removed from 8 by treatment with K2CO3–MeOH in 92% yield.28
Both 8 and 9 were then subjected to NH deprotonation with
BuLi at low temperature, followed by alkylation with various
propargyl bromides (R3 = H, CH3, and TMS). All cyclotri-
merization precursors 10–13 were obtained in excellent yields of
89–96%.‡
Phenanthridines are important core structures found in a variety of
natural products and other biologically important molecules with
a wide range of biological activities and applications, including
antibacterial, antiprotozoal, and anticancer agents.1–4 A well
known member of this compound class is ethidium (1), a common
DNA intercalator and stain. Many natural products containing
a phenanthridine core structure are known and representative
examples include trispheridine (2)5 and bicolorine (3),6 shown in
Fig. 1.
Fig. 1 Selected phenanthridines.
The [2+2+2] cyclotrimerization reaction represents a unique
synthetic tool for the assembly of aromatic systems,7–13 and
we envisioned the synthesis of phenanthridines 4 through a
microwave-assisted cyclotrimerization14–17 of a diyne 5 with an
alkyne 6 followed by protecting group removal and oxidation
(Scheme 1). Several cyclotrimerization reaction conditions were
investigated with different catalyst systems based on Co,18,19 Ni,20,21
Rh,22–25 and Ru24,26 and with and without microwave irradiation.
Scheme 2 Synthesis of diyne cyclotrimerization precursors.
We initially screened four different catalyst systems
(RhCl(Ph3P)3,25 Cp*RuCl(COD),24 Ni(CO)2(Ph3P)2,21 and
CpCo(CO)218) for the microwave-mediated cyclotrimerization
of the terminal diyne 10 and 1-hexyne (10 equiv.), revealing
that 10 mol% Wilkinson’s catalyst (RhCl(Ph3P)3) delivered the
cyclotrimerization product 14 with the highest yield (86%). The
other catalysts provided 14 in 60–80% yield. Reactions were
conducted in microwave transparent toluene (0.1 mM) with a
300 W microwave irradiation for 10 min (CEM Discover), leading
to a final reaction temperature of 130 ◦C (IR temperature sensor).
Shorter reaction times or irradiations with less microwave power
led to diminished yields. Importantly, when the cyclotrimerization
10 → 14 was conducted under purely thermal heating, while
mimicking the temperature profile of the microwave reaction
(10 min, 130 ◦C final temperature, 150 ◦C oil bath temperature),
the product 14 was only obtained in 34% yield. The optimized
microwave conditions were then used for the cyclotrimerization
of 10 with a variety of alkynes, probing the functional group
compatibility of the developed reaction conditions. A wide range
of functional groups was tolerated, including a cyano group (in
16), a chloro atom (in 17), a carbamate (in 1829), and a silyl ether
Scheme 1 Retrosynthetic analysis of the phenanthridine skeleton. PG =
protecting group.
Department of Chemistry, North Carolina State University, Raleigh, NC
27695-8204, USA. E-mail: alex_deiters@ncsu.edu; Fax: +1-919-515-5079;
Tel: +1-919-513-2958
† Electronic supplementary information (ESI) available: Experimental
protocols for compounds 10–13; general cyclotrimerization procedure;
analytical data for compounds 14–30, 33–40; 1H NMR spectra for
compounds 10–30 and 33–40. See DOI: 10.1039/b716519f
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The Royal Society of Chemistry 2008
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(in 1930) (Scheme 3). The [2+2+2] cyclotrimerization reaction
of terminal monoalkynes proceeded smoothly delivering 14–22
in 85–89% yield after silica gel chromatography.‡ As expected,
no regioselectivity in the cyclotrimerization step was observed,
leading to the formation of 1 : 1 mixtures of regioisomers at
the 8- and 9-positions. Symmetrical internal alkynes alleviate
the regioselectivity problem, but lead to diminished yields
(30–34%) as seen in the synthesis of 20–22. This low yield is due
to the internal alkynes’ lower reactivity in cyclotrimerization
reactions, which induces the formation of diyne-dimerization
and -trimerization side products typically observed in these
cases.15,24,25 We previously addressed this problem through the
spatial seperation of substrates on a polymeric support.15,26,31,32
Here, we are providing a solution through open-vessel microwave
conditions,33,34 which allowed the slow addition (over 60 min)
of a solution of the diyne (0.01 mM) to the internal alkyne
(0.1 mM) in refluxing toluene (110 ◦C) under microwave
irradiation (300 W). By employing these conditions the yields of
the cyclotrimerization products 20–22 were essentially doubled
(56–65%).
as before, the cyclotrimerization products 23–30 were obtained
under mild conditions in 55–91% yield and with a regioselectivity
of 4 : 1 (Scheme 4).‡ To our surprise, TBS protected propargyl
alcohol led to the formation of 28 with no regioselectivity. By
inserting additional methylene groups between the triple bond
and the OTBS group (in 2936 and 3037), the regioselectivity was
increased to 4 : 1 as in case of the other alkynes.
Scheme 4 Regiodirected [2+2+2] cyclotrimerization. aReaction under
thermal conditions.
In order to increase the selectivity, we investigated the ap-
plication of a sterically more demanding regio-directing group
and selected a TMS group due to its potential conversion into
a proton,26 halide,38 or hydroxy group39 after cyclotrimerization.
The precursors 12 and 13 were synthesized in high yields analogous
to the other diynes. Surprisingly, all cyclotrimerization attempts
with 13 using all four catalyst systems under various conditions
failed (Fig. 2), presumably due to a pronounced strain between
the TMS group and the CH group in position 1 of the met-
allacyclopentadiene intermediate 31 and the cyclotrimerization
product 32.40 In all reaction attempts starting material and
non-characterized byproducts were obtained; only CpCo(CO)2
delivered trace amounts of 32 (with R = Bu).
Scheme
3 Cyclotrimerization reactions of the terminal diyne 10.
aReaction under thermal conditions. bReaction under open-vessel
conditions.
We investigated a potential solution to the regiochemistry
problem through the installation of a regio-directing group,35
as previously demonstrated in the synthesis of indanones via a
[2+2+2] cyclotrimerization reaction.26 Hence, the precursor 11
carrying a methyl group was synthesized (Scheme 2). An initial
catalyst screening with 11 and 1-hexyne revealed that RhCl(Ph3P)3,
Ni(CO)2(Ph3P)2 and CpCo(CO)2 deliver the product 23 as a 1 : 1
mixture of regioisomers. Only Cp*RuCl(COD) displayed a pref-
erence for the formation of the 9- over the 8-isomer in a ratio of
4 : 1 by integration of the 1H NMR signal of the CH3 group. The
9-regioisomer could be easily assigned based on the two singlets
for H-8 and H-10. Thus, 10 mol% of Cp*RuCl(COD) in toluene
was used in the presence of 300 W microwave irradiation leading
Fig. 2 Cyclotrimerization attempts with 13 did not lead to product
formation. M = metal.
The regioselectivity problem was solved using the comple-
mentary silyl modified precursor 12, which led to a smooth
cyclotrimerization reaction with 1-hexyne, yielding 33 in 85%
yield and as a single regiosiomer (Scheme 5). Thus, increasing the
sterical demand from CH3 to Si(CH3)3 led to a substantial increase
in regioselectivity from 4 : 1 to 95 : 5 (as determined by GC). No
cyclotrimerization product 33 was obtained under thermal reac-
tion conditions resembling the temperature profile observed under
◦
to a final reaction temperature of 150 C after 30 min. Without
◦
◦
microwave irradiation (30 min, 150 C final temperature, 165 C
oil bath temperature), the yield dropped to 31% while maintaining
the same ratio of regioisomers. Using the same mono-alkynes
◦
◦
microwave conditions (30 min, 150 C final temperature, 165 C
oil bath temperature). Unfortunately, the microwave-mediated
264 | Org. Biomol. Chem., 2008, 6, 263–265
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Notes and references
‡ The identity of all compounds was confirmed by NMR and HRMS mea-
surements. All yields were determined after flash-column chromatography
on silica gel.
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Acknowledgements
We gratefully acknowledge financial support by the Donors of the
American Chemical Society Petroleum Research Fund and North
Carolina State University. The NCSU Department of Chemistry
MS Facility acknowledges financial support by the North Carolina
Biotechnology Center.
This journal is
The Royal Society of Chemistry 2008
Org. Biomol. Chem., 2008, 6, 263–265 | 265
©