An efficient synthesis of substituted chrysenes

Article abstract of DOI:10.1016/j.tetlet.2016.12.004

Substituted chrysenes have been swiftly synthesised by the 6-endo-dig cyclisation of ethynylnaphthalenes using platinum(II) chloride. Cyclisation precursors were directly prepared from commercially available 2-bromoaldehydes in a telescoped synthetic proc

Full text of DOI:10.1016/j.tetlet.2016.12.004

Accepted Manuscript
An Efficient Synthesis of Substituted Chrysenes
Lee Eccleshare, Sean Selzer, Simon Woodward
PII:
S0040-4039(16)31630-6
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.12.004
TETL 48416
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
24 October 2016
30 November 2016
2 December 2016
Please cite this article as: Eccleshare, L., Selzer, S., Woodward, S., An Efficient Synthesis of Substituted Chrysenes,
Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/j.tetlet.2016.12.004
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Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
An Efficient Synthesis of Substituted Chrysenes
Lee Eccleshare*, Sean Selzer, Simon Woodward[a]
[a] L. Eccleshare, S. Selzer, Prof. Dr. S. Woodward, School of Chemistry, University of Nottingham,
University Park, Nottingham NG7 2RD (United Kingdom)
E-mail: Lee.Eccleshare@outlook.com
Supporting information for this article is available (end of manuscript)
Abstract: Substituted chrysenes have been swiftly synthesised by the 6-endo-dig cyclisation of
ethynylnaphthalenes using platinum(II) chloride. Cyclisation precursors were directly prepared from
commercially available 2-bromoaldehydes in a telescoped synthetic procedure involving a
Cannizzaro triggered cascade and subsequent dehydration and desilylation. This short synthetic
procedure allows rapid access to derivatives of biologically active molecules with useful electronic
properties.
Introduction
Chrysene (C18H12) is a polycyclic aromatic hydrocarbon (PAH) that is formed during incomplete
combustion of carbon rich fuels[1] and was the first PAH to be discovered in uncontaminated soil
samples.[2] Whilst several studies have shown that chrysene and its metabolites,[3] trans-1,2-
dihydroxy-1,2-dihydrochrysene and trans-3,4-dihydroxy-3,4-dihydrochrysene (Scheme 1a) are
carcinogenic and mutagenic,[4] it has also been reported that some substituted chrysenes, due to
their DNA intercalating nature, show anticancer activity.[5] Due to their electronic properties
chrysenes also have synthetic uses as single electron transfer mediators,[6] mechanistic probes[7] and
have applications in the field of organic electronics.[8, 9] The two most common synthetic routes to
chrysenes are the photochemical cyclisations of styrylnaphthalenes[10] and metal catalysed
cyclisations of aromatic acetylenes.[8,11] Our efficient synthesis allows the rapid formation of
substituted chrysenes, under simple, benign conditions from readily available commercial materials.
As we are able to design chrysene substrates with substitution on both terminal rings and also
access substitution patterns that are difficult to control with other synthetic methods[10] (controlled
substitution in the 2- and 4- positions), this work is perfectly complimentary to that which has
already been published.

Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
Scheme 1. a) The numbering of chrysene and a carcinogenic metabolite; b) Compounds from the
preliminary investigation.
Results and Discussion
Recent work carried out within our group[12] highlighted how cascade reactions based around an
unusual Cannizzaro like 1,5-hydride transfer[13] can be used to rapidly develop complex molecules,
such as 1 (Scheme 1b), from commercially available 2-bromoaldehydes. We envisaged using a
platinum(II) chloride catalysed, 6-endo-dig cyclisation[8, 11a] to attain a substituted chrysene from
ethynylnaphthalene 1. Under our initial conditions, heating to reflux with 5 mol% platinum(II)
chloride in toluene, for a protracted reaction time of 65 hours, we observed 58% conversion to the
desilylated chrysene 3a (Scheme 1b). Formation of the silylated chrysene was not observed.
Unsatisfied with the long reaction times and incomplete conversion, more efficient reaction
conditions were sought. The rate of reaction could be significantly increased by microwave heating
to 150 °C in a sealed tube. As the formation of silyl-3a was not observed, it was considered that the
sluggish annulation could be due to a slow desilyation of naphthalene 1 followed by the much faster
annulation of the resultant terminal acetylene. When terminal acetylene 2a, the desilylated
derivative of 1, was subjected to 150 °C microwave heating in the presence of 5 mol% platinum(II)
chloride, complete consumption of the starting material was achieved within 1 hour.
In order to generalise this new synthetic route to chrysenes as efficiently as possible, we telescoped
the synthesis of ethynylnaphthalenes using our Cannizzaro cascade procedure (Scheme 2). The
cascade procedure[12] affords crude 1,2-dihydronaphthalen-1-ol 7 which could be directly
dehydrated using Amberlyst 15® to give silylated ethynylnaphalene 8. Subsequent addition of
tetrabutylammonium fluoride solution to the reaction mixture followed by a single purification leads
directly to ethynylnaphthalene 2 in up to 70% yield in a single synthetic session.

Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
Scheme 2. Telescoped synthesis of ethynylnapthalene 2.
The scope of the telescoped route is shown in Table 1 by the synthesis of a range of
ethynylnaphthalenes (2a-f). When the R2 substituent is an electron withdrawing p-trifluoromethyl
group (2a-c) the aromatic aldehyde can tolerate electron withdrawing, electron donating and
electron neutral substitution and achieve yields of 45-67%. Functional groups are also tolerated in
the R2 position with p-methyl ester (2d) and m-nitrile (2f) substitution giving yields of 61% and 70%,
respectively. Only when using a mildly electron withdrawing R2 substituent, o-fluoro (2e), was a
significant drop in yield observed. This is mainly due to a competing reaction pathway in which the
Cannizzaro cascade forms a fused 8-membered ring in place of the 1,2-dihydronaphthalen-1-ol. This
observation was not unexpected and is in line with our previous work. [12]

Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
Table 1. Scope of the telescoped Cannizzaro cascade procedure.
R1
F
OMe
H
H
H
R2
p-CF3
p-CF3
p-CF3
p-CO2Me
o-F
Product
2a
Yield (%)[b]
58
45
67
61
23
70
2b
2c
2d
2e
H
m-CN
2f
Reaction conditions: i) LiC≡CTMS (6.9 mL of 0.50 M THF-hexane solution) treated with 2-
●
bromoaldehyde (3.24 mmol) at -50 °C; ii) nBuLi (3.40 mmol); iii) CuBr SMe2 (1.63 mmol); iv)
R2ArCClC≡CH, warmed to 0 °C; v) Amberlyst 15® and 3 Å molecular sieves at room temperature; vi)
[a]
TBAF solution (1 M in THF, 6.5 mmol).
Full description of reaction conditions available in
supplementary data. [b] Isolated yield.
Substrates 2a-f were used to assess the generality of the platinum(II) chloride catalysed synthesis of
substituted chrysenes. Using the optimal conditions from our preliminary work, chrysenes 3a-f were
synthesised in 31-81% yield (Table 2). Substrates 2a-b, with the p-trifluoro methyl R2 substituent,
perform well in the cyclisation giving 3a-b in 71% and 66% yields respectively. The closely related 3c
has a slightly lower yield of 51%, this could be in part due to its very poor solubility making
purification challenging. Ester 3d was synthesised in 65% yield, albeit with an extended reaction time
of 2 hours needed to achieve full consumption of the starting material. The highest yielding chrysene
was 4-fluoro substituted 3e attained in an impressive 83% yield.

Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
Table 2. Formation of substituted chrysenes 3a-f.
R1
F
OMe
H
H
H
R2
p-CF3
p-CF3
p-CF3
p-CO2Me
o-F
Product
3a
Yield (%)[a]
71
66
3b
3c
3d
3e
51
65[b]
83
H
m-CN
3f
31[c]
[a]
[b]
Isolated yield. Microwave heating was continued for a total of 2 hours to achieve complete
consumption of starting material. [c] Product was isolated as a 12:1 mixture of regioisomers favouring
substitution at the 3 position versus the 1 position.
Substrate 2f was chosen for this study to assess the regioselectivity of the cyclisation as both
possible chrysene products have published 1H NMR spectroscopic data. [10a] Gratifyingly, inspection
of our own sample showed that we obtained high regioselectivity with a 12:1 ratio favouring the
formation of 3-nitrile substitution over 1-nitrile substitution. The lower yield of chrysene 3f is
thought to be caused by a competing polymerisation pathway involving the nitrile group.
Conclusion
We have developed a new, step efficient, synthetic route to substituted chrysenes. Application of a
one-pot Cannizzaro cascade procedure followed by telescopic dehydration and desilylation gives
swift access to ethylnylnaphthalenes from very simple precursors. Formation of chrysenes can be
achieved via platinum(II) chloride catalysed annulation under microwave heating. This overall
synthetic sequence shows how one-pot reactions can be used to rapidly build up molecular
complexity and access derivatives of valuable biologically active targets.
Acknowledgements
LE would like to thank the University of Nottingham for the provision of a studentship.
Supplementary Material
Full experimental and spectroscopic data for all novel compounds has been made available.

Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
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Eccleshare, Selzer, Woodward – Manuscript for Tetrahedron Lett.
Graphical abstract
Highlights


Telescoped methodology gives easy synthesis of ethynylnaphthalenes (chrysenes
precursors).
Rapid synthesis of complex chrysene precursors from commercially available 2-
bromoaldehydes.


Catalytic annulation of ethynylnaphthalenes into chrysenes with low Pt-loadings (5 mol%).
An unsymmetrical ethynylnaphthalene shows good regioselectivity in chrysene annulation.