Toward a visible light mediated photocyclization: Cu-based sensitizers for the synthesis of [5]helicene

Article abstract of DOI:10.1021/ol300983b

A photochemical synthesis of [5]helicene employing a copper-based sensitizer 7 has been developed that avoids the disadvantages associated with the traditional UV light mediated method. The visible light mediated synthesis uses common glassware and a simple household light bulb without the competing formation of [2 + 2] cycloadducts, regioisomers, or the overoxidation product benzo[ghi]perylene 3. Preliminary results show that the reaction time can be significantly reduced through the use of a continuous flow strategy.

Full text of DOI:10.1021/ol300983b

ORGANIC
LETTERS
2012
Vol. 14, No. 12
2988–2991
Toward a Visible Light Mediated
Photocyclization: Cu-Based Sensitizers
for the Synthesis of [5]Helicene
Augusto C. Hernandez-Perez, Anna Vlassova, and Shawn K. Collins*
ꢀ
Departement de Chimie, Centre for Green Chemistry and Catalysis, Universite de
Montreal, CP 6128 Station Downtown, Montreal, Quebec, Canada H3C 3J7
ꢀ
ꢀ
ꢀ
ꢀ
shawn.collins@umontreal.ca
Received April 16, 2012
ABSTRACT
A photochemical synthesis of [5]helicene employing a copper-based sensitizer 7 has been developed that avoids the disadvantages associated
with the traditional UV light mediated method. The visible light mediated synthesis uses common glassware and a simple household light bulb
without the competing formation of [2 þ 2] cycloadducts, regioisomers, or the overoxidation product benzo[ghi]perylene 3. Preliminary results
show that the reaction time can be significantly reduced through the use of a continuous flow strategy.
The UV light mediated photocyclization of stilbenes
and stilbene-like molecules (photocyclodehydrogenation
reaction), sometimes referred to as the Mallory reaction,1
can be used to prepare a wide variety of polycyclic aro-
matic carbo- and heterocycles. Perhaps the most common
application of the reaction is in the synthesis of helicenes,
3-D polycyclic aromatic systems, which consist of all
ortho-fused aromatic rings that are inherently helically
chiral.2 Since the development of the UV-mediated photo-
cyclization of stilbenes in 1967 by Martin et al., it has been
appliedtothe synthesisofbothsmall and higher helicenes.3
Despite its popularity, the UV-mediated method is not
without its disadvantages. The classical UV-light mediated
photocyclodehydrogenation reaction lacks enantiocon-
trol, there is a need for high dilution conditions to avoid
competitive intermolecular photocycloadditions, and over-
oxidation of the desired products is often problematic.
In addition, there are practical complications which include
the need for a special photochemical apparatus or UV lamps,
protective eyewear, and expensive quartz glassware. Despite
all of the obstacles, the classic photocyclodehydrogenation
reaction remains the go-to method for the synthesis of most
helicenes4 and helicene-like compounds.
One of the simplest helicene scaffolds, [5]helicene, has
been used in the synthesis of molecular springs, mo-
lecular machines, novel dyes, polymers, in asymmetric
catalysis, and in studying molecular recognition.5 The
(1) For reviews, see: (a) Joergensen, K. B. Molecules 2010, 15, 4334–
4358. (b) Mallory, F. B.; Mallory, C. W. Org. React. 1984, 30, 1–456.
For other early contributions to the development of this photochemical
transformation, see: (c) Muszkat, K. A; Fischer, E. J. Chem. Soc. B 1967,
662–678. (d) Cuppen, Th. J. H. M.; Laarhoven, W. H. J. Am. Chem. Soc.
1972, 94, 5914–5915. (e) Wynberg, H.; Groen, M. B. J. Am. Chem. Soc.
1968, 90, 5339–5341.
(2) (a) Hopf, H. In Classics in Hydrocarbon Chemistry: Syntheses,
Concepts, Perspectives; Wiley-VCH: Weinheim, 2000; pp 323ꢀ330. (b)
Smith, P. J.; Liebman, J. F.; Hopf, H.; Stary, I.; Stara, I. G.; Halton, B.
In Strained Hydrocarbons; Dodziuk, H., Ed.; Wiley: 2009; pp 147ꢀ203. (c)
Stara, I. G.; Stary, I. Sci. Synth. 2010, 45b, 885–953.
(4) As the applications of helicenes have grown, more effort has been
placed upon developing new nonphotochemical methods to prepare
helicenes: (a) Urbano, A. Angew. Chem., Int. Ed. 2003, 42, 3986–3989.
Some methods to prepare [5]helicene include successive DielsꢀAlder
reactions: (b) Carreno, M. C.; Garcia-Cerrada, S.; Urbano, A. J. Am.
Chem. Soc. 2001, 123, 7929. Cyclotrimerizations of acetylenes:(c) Teply,
F.; Stara, I.; Stary, I.; Kollarovic, A.; Saman, D.; Rulisek, L.; Fiedler, P.
J. Am. Chem. Soc. 2002, 124, 9175–9180. Carbenoid couplings: (d)
Dubois, F.; Gingras, M. Tetrahedron Lett. 1998, 39, 5039–5040. Radical
cyclizations: (e) Harrowven, D. C.; Nunn, M. I. T.; Fenwick, D. R.
Tetrahedron Lett. 2002, 43, 7345–7347. Olefin metathesis: (f) Collins,
^ ꢀ
S. K.; Grandbois, A.; Vachon, M. P.; Cote, J. Angew. Chem., Int. Ed.
2006, 45, 2923–2926.
(5) Shen, Y.; Chen, C.-F. Chem. Rev. 2011, 112, 1463–1535.
(3) (a) Flammand-Barbieux, M.; Nasielski, J.; Martin, R. H. Tetra-
hedron Lett. 1967, 7, 743–744. (b) Martin, R. H.; Baes, M. Tetrahedron
1975, 31, 2135–2137.
r
10.1021/ol300983b
Published on Web 05/29/2012
2012 American Chemical Society

photochemical synthesis of [5]helicene perhaps best
exemplifies the drawbacks to the UV light mediated
synthesis (Figure 1). The synthesis of [5]helicene 2 from
stilbene precursor 1 is plagued by the formation of an
undesired regioisomer 4 and overoxidation of the
desired product to benzo[ghi]perylene 3. Mallory has
reported that the irradiation of 1 provided the desired
[5]helicene in 25% isolated yield, while the overoxida-
tion product 3 was also formed in 37% yield and the
regioisomeric product dibenzo[b,g]phenanthrene 4 in
38% yield. The difficulty in controlling the second
oxidation of 2 to 3 was noted by Katz et al., who
reported that the judicious choice of substituents
could inhibit the second photocyclization reaction.6
In an effort to develop a practical alternative to the
UV-mediated method, it was believed that the same
stilbene-like precursors could be coerced to form cyclic
products under visible light. As the formation of the
helicene product would now likely arise by a differ-
ent mechanism, the newly developed synthetic route
would not possess the drawbacks associated with the
use of UV light. Herein we describe progress toward
a visible light mediated photocyclization reaction and
the development of a gram scale total synthesis of
[5]helicene 2.
Synthetic photochemistry using visible light has recently
been cited as an emerging synthetic strategy and is
regarded as a “green” technology. The research groups
of MacMillan,7 Yoon,8 and Stephenson9 have recently
reported that sensitizers, such as 5 and 6 (Figure 2), can
be used to photochemically promote reactions (aptly
named photoredox reactions) under mild conditions
using light sources such as simple LED devices, household
lightbulbs, or even direct sunlight.10 Consequently, our
initial investigations sought to employ the same stilbene-
like precursor 1 with reaction conditions that mirrored
the classic photocyclization (utilizing I2 and propylene
oxide 9 as an oxidant system), but with an added sensitizer
(Table 1). We initially chose to investigate complexes that
have been reported to be efficient in other photoredox
processes for related synthetic transformations. These in-
clude the popular [Ru(bpy)3](PF6)2 (5) and [Ir(tbbpy)-
(phpy)]PF6 (6) complexes (Figure 2). Disappointingly, both
catalysts afforded very low conversion of 1 to the desired
[5]helicene, 2. We were then attracted to a Cu-based com-
plex [Cu(DPEPhos)(neo)]BF4 7, reported by McMillin
et al., but never before investigated as a photoredox catalyst.11
Copper based photoactive complexes represent an under-
explored class of catalysts for photoredox chemistry, as they
often are easily prepared, have tunable electronic proper-
ties, and can possess very long excited state lifetimes.12
Upon treating 1 with the Cu-based sensitizer 7 (Table 1,
entry 3) conversion of 1 took place over 5 days to afford 2 in
30ꢀ47% yield. The appropriate control reaction whereby
the same reaction was performed in the absence of light gave
no product 2 (Table 1, entry 4).
Figure 1. Toward a visible light mediated photocyclization.
(6) Liu, L.; Katz, T. J. Tetrahedron Lett. 1991, 32, 6831–6834.
(7) (a) Nicewicz, D. A.; MacMillan, D. W. C. Science 2008, 322, 77–
80. (b) Nagib, D. A.; Scott, M. E.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2009, 131, 10875–10877. (c) Shih, H.-W.; Vander Wal, M. N.;
Grange, R. L.; MacMillan, D. W. C. J. Am. Chem. Soc. 2010, 132,
13600–13603.
(8) (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527–
532. (b) Ischay, M. A.; Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132,
8572–8574. (c) Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2009, 131, 14604–
14605. (d) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am.
Chem. Soc. 2008, 130, 12886–12887. (e) Lu, Z.; Shen, M.; Yoon, T. P.
J. Am. Chem. Soc. 2011, 133, 1162–1164.
Figure 2. Transition metal based sensitizers.
(10) For some other examples of catalysts used for visible light
mediated transformations, see: (a) Su, F.; Mathew, S. C.; Moehlmann,
L.; Antonietti, M.; Wang, X.; Blechert, S. Angew. Chem., Int. Ed. 2011,
50, 657–660. (b) Su, F.; Mathew, S. C.; Lipner, G.; Fu, X.; Antonietti,
M.; Blechert, S.; Wang, X. J. Am. Chem. Soc. 2010, 132, 16299–16301.
(11) (a) Slinker, J. D.; Rivnay, J.; Moskowitz, J. S.; Parker, J. B.;
ꢀ
ꢀ
(9) (a) Condie, A. G.; Gonzalez-Gomez, J.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2010, 132, 1464–1465. (b) Narayanam, J. M. R.;
Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756–
8757. (c) Dai, C.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat. Chem
2011, 3, 140–145. (d) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133, 4160–4163. (e)
Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40,
102–113.
~
Bernhard, S.; Abruna, H. D.; Malliaras, G. G. J. Mater. Chem. 2007, 17,
2976–2988. (b) Cuttell, D. G.; Kuang, S.-M.; Fanwick, P. E.; McMillin,
D. R.; Walton, R. A. J. Am. Chem. Soc. 2002, 124, 6–7.
Org. Lett., Vol. 14, No. 12, 2012
2989

Table 1. Optimization of the Visible Light Mediated Synthesis
of [5]Helicene
Table 2. Optimization of the Visible Light Mediated Synthesis
of [5]Helicene by in Situ Generated Cu-Based Complexes
entry
photocatalyst
oxidant (equiv); time (d)
yield (%)a
1
2
3
4
5
6
7
5
6
7
7
7
7
7
I2 (1), 9 (50); 3
I2 (1), 9 (50); 3
I2 (1), 9 (50); 5
I2 (1), 9 (50); 5
I2 (0.1), O2 (1 atm); 5
DDQ (2); 3
<10
<10
30ꢀ47
0b
38
entry
phosphine
diamine
mol %
yield (%)a,b
21
t-BuOOH (4), Δ; 3
29
1
DPEPhos
ꢀ
neo
10
10
10
10
50
10
25
10
10
25
10
25
32
0c
0d
2
ꢀ
a Isolated yields following flash chromatography. b Reaction per-
formed in the absence of light.
3
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
DPEPhos
XantPhos
XantPhos
XantPhos
XantPhos
neo
4
neo
32
56
40
39
39e
50
57f
36
49
5
neo
Consequently, we began to optimize the synthesis of
[5]helicene 2 with Cu complex 7 in hopes of improving the
isolated yield via solvent effects or alternative oxidants
(Table 1). A number of solvent combinations were sur-
6
bimida
bimida
pypyr
neo
7
8
9
10
11
12
neo
veyed; however none outperformed THF as a solvent.13
A
bimida
bimida
number of alternative oxidants were also investigated
including DDQ and t-BuO2H (21 and 29% isolated yield
of 2 respectively), although neither afforded a superior
yield when compared to molecular iodine (Tabel 1, entries
6ꢀ7). The use of a catalytic amount of iodine was studied,
where molecular oxygen would serve as the stoichiometric
oxidant. Over a reaction time of 5 days,14 comparable
yields were obtained compared to using stoichiometric
amounts of iodine (38 vs 30ꢀ47%).
a Isolated yields after chromatography. b All reactions run at 5 mM.
Attempts at increasing the concentration further led to lower isolated
yields. c Reaction performed in the absence of ligands. d Reaction
performed in the absence of Cu(MeCN)4BF4 e When catalyst was
preformed the isolated yield of 2 was 14%. f When catalyst was pre-
formed the isolated yield of 2 was 56%.
suggest that the actual copper complex 7 is indeed the
active photoredox catalyst. Subsequently, the effect of
catalyst loading was investigated, where the yield of 2
was shown to increase to 56% when 50 mol % of 7 was
used. Whenthe neocuproine ligand10was substituted with
either the N,N0-dimethyl bisimidazole 11 or the pyrimidine
derived ligand 12,13 the yields were again within the same
range asthose obtainedfor the neocuproine complex (40%
for 2 and 39% for 2). However, the best results were
obtained when using XantPhos as the phosphine ligand
to prepare the photoredox catalyst. At a catalyst loading of
10 mol %, the XantPhos/neocuproine catalyst provided a
highly reproducible isolated yield of 50% of [5]helicene.
Changing the amine ligand from 10 to 11 did not result in a
significant increase. When the catalyst loading was in-
creased to 25 mol %, a further increase in yield was
observed to 57%. The visible light mediated reaction was
left for 14 days in an attempt to increase the isolated yield
In an effort to perform a rapid screening of photocata-
lysts based upon 7, an in situ synthesis of the Cu-based
photoredox catalysts was investigated (Table 2). It was
found that a solution of the complex 7, formed in THF
through the sequential addition of DPEPhos and neocu-
proine, could be used directly for the visible light mediated
synthesis of [5]helicene by simple addition of the remaining
reagents and starting material 1. Indeed, the yields for the
isolation of [5]helicene when using preformed catalyst 7
(30ꢀ47%) and via an in situ protocol were comparable
(32%). Using the in situ protocol, two important control
experiments were performed: (1) a reaction in the absence
of both the ligands (entry 2) and (2) a reaction in the
absence of the Cu precursor (entry 3). These experiments
(12) For a review of photoactive Cu complexes, see: (a) McMillin,
D. R.; McNett, K. M. Chem. Rev. 1998, 98, 1201–1220. For recent
examples of novel photoactive Cu complexes, see: (b) Harkins, S. B.;
Peters, J. C. J. Am. Chem. Soc. 2005, 127, 2030–2031. (c) Hashimoto, M.;
Igawa, S.; Yashima, M.; Kawata, I.; Hoshino, M.; Osawa, M. J. Am.
Chem. Soc. 2011, 133, 10348–10351.
(13) Reasons why THF is optimal for the process are still unclear. For
a complete list of solvents studied, see the Supporting Information.
(14) For further information on the effect of the reaction time on the
yield of 1f2, see the Supporting Information.
(16) To date, one of the most efficient syntheses of helicenes on gram
scale is the DielsꢀAlder approach. See refs 4b, 4c, and 5.
(17) (a) Gutierrez, A. C.; Jamison, T. F. Org. Lett. 2011, 13, 6414–
6417. (b) Tucker, J. W.; Zhang, Y.; Jamison, T. F.; Stephenson, C. R. J.
Angew. Chem., Int. Ed. 2012, 51, 4144–4147. (c) Andrews, R. S.; Becker,
J. J; Gagne, M. R. Angew. Chem., Int. Ed. 2012, 51, 4140–4142. (d) Bou-
Hamdan, F. R.; Seeberger, P. H. Chem. Sci. 2012, 3, 1612–1616. (e)
Levesque, F.; Seeberger, P. H. Angew. Chem., Int. Ed. 2012, 51, 1706–
1709.
(15) (a) Zhang, L.; Li, B.; Su, Z. J. Phys. Chem. C 2009, 113, 13968–
13973. (b) Nishikawa, M.; Nomoto, K.; Kume, S.; Inoue, K.; Sakai, M.;
Fujii, M.; Nishihara, H. J. Am. Chem. Soc. 2010, 132, 9579–9581.
2990
Org. Lett., Vol. 14, No. 12, 2012

of the desired helicene. However, no increase in yield was
observed. A control experiment where a 1:1 ratio of 1 and
[5]helicene was submitted to the optimized reaction con-
ditions was performed and no change in the ratio of 1 to 2
was observed, suggesting that the product may be inhibit-
ing further conversion of 1 to [5]helicene.
Scheme 2. Photocyclization of Stilbenes
The synthesis of [5]helicene on a gram scale was
attempted using the optimized protocol (Scheme 1).16
After a 5 day reaction time, the [5]helicene product 2
was isolated in 42% yield. In an effort to develop a more
practical synthetic approach, we performed the synth-
esis of 2 using a continuous flow strategy, since many
photoredox processes have exhibited significant rate
accelerations when using flow chemistry approaches.17
The preliminary experiments demonstrated that a mix-
ture of the catalyst system (formed in situ) and 1 could
be injected through FEP-Teflon tubing while being
irradiated by the same household energy saving light-
bulb at the same concentration (5 mM) used in the
batch reactor. A significant decrease in the reaction
time was observed, as an almost identical yield of 2 was
obtained via the flow process when compared to the
batch reactor in only 10 h (compared to 120 h when
using a round-bottom flask).
In summary, a visible light alternative to traditional UV-
mediated photocyclizations has been developed using the
synthesis of [5]helicene as a model. The synthesis of
[5]helicene via a visible light mediated process using a
Cu-based sensitizer presents several solutions to long-
standing problems associated with the UV-mediated
photocyclization of 1: (1) a significantly higher yield of
2 can be obtained without the formation of any side
products resulting from intermolecular [2 þ 2] cycliza-
tions or from photocyclization at other positions re-
sulting in the formation of regioisomeric products (the
only remaining products are the cis- and trans-isomers
of 1, which can subsequently be recycled), (2) the
reaction does not require the use of expensive quartz
glassware, hazardous UV lamps, or protective eyewear.
The complex 7 was successful in a gram scale synthesis
of [5]helicene in good yield and with much shorter
reaction times when using a flow chemistry strategy.
The success of Cu complexes 7 and 15 should encourage
investigation of other Cu complexes for photoredox
transformations. Given the diverse range of substrates
that can undergo Mallory-type cyclization,1 the inves-
tigation of photoredox catalysis in other cyclization
reactions and application in the synthesis of higher
helicenes is also currently underway.
Scheme 1. Scale-up Synthesis of [5]Helicene Using Either a
Round Bottom Flask or Continuous Flow Strategy
Acknowledgment. The authors thank NSERC of
Canada and the Xerox Research Centre of Canada for
generous support. A.C.H.P. thanks the FQRNT for a
graduate scholarship. The authors thank Prof. Eli Zysman-
Preliminary studies directed toward understanding the
mechanism suggest the newly developed visible light synth-
esis of 2 proceeds via an oxidation mechanism similar to
otherphotoredoxprocesses(Scheme2).18 To provide some
preliminary support for an oxidative pathway, the cycliza-
tion of stilbenes 13 and 15 were also investigated and it was
shown that only the more electron-rich trimethoxy deri-
vative15underwentcyclizationto affordthephenanthrene
16. It should be noted that more detailed investigations are
still necessary to elucidate the mechanistic pathway for the
conversion of 1 to 2.
ꢀ
Colman (Universite de Sherbrooke), Prof. Garry Hanan
ꢀ
ꢀ
(Universite de Montreal), and Dr. Matthew Heuft (Xerox
Research Centre of Canada) for helpful discussions. The
authors also thank Profs. Zysman-Colman and Hanan for
donations of 5 and 6 respectively.
Supporting Information Available. Experimental pro-
cedures and characterization data for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(18) The proposed oxidation of 1 is very similar to what was proposed
for radical cation DielsꢀAlder cycloadditions. See: Lin, S.; Ischay,
M. A.; Fry, C. G.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 19350–
19353.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 12, 2012
2991