Photocycloaddition of Cinnamates in Flow and Development of a Thiourea Catalyst

Article abstract of DOI:10.1002/anie.201504454

Cyclobutanes derived from the dimerization of cinnamic acids are the core scaffolds of many molecules with potentially interesting biological activities. By utilizing a powerful flow photochemistry platform developed in our laboratory, we have evaluated t

Full text of DOI:10.1002/anie.201504454

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201504454
German Edition: DOI: 10.1002/ange.201504454
Flow Chemistry
[2+2] Photocycloaddition of Cinnamates in Flow and Development of
a Thiourea Catalyst**
Reem Telmesani, Sung H. Park, Tessa Lynch-Colameta, and Aaron B. Beeler*
Abstract: Cyclobutanes derived from the dimerization of
cinnamic acids are the core scaffolds of many molecules with
potentially interesting biological activities. By utilizing a power-
ful flow photochemistry platform developed in our laboratory,
we have evaluated the effects of flow on the dimerization of
a range of cinnamate substrates. During the course of the study
we also identified a bis(thiourea) catalyst that facilitates better
reactivity and moderate diastereoselectivity in the reaction.
Overall, we show that carrying out the reaction in flow in the
presence of the catalyst affords consistent formation of
predictable cyclobutane diastereomers.
C
innamic acid derivatives are the building blocks for many
cyclobutane-containing natural products.[1] Truxillic and trux-
inic acids are dimers of cinnamic acid,[2] and there are
a number of related molecules, such as natural products
piperarborenine and incarvillateine and synthetic derivatives,
that exhibit a range of biological activities (Scheme 1).[3–5]
One of the most common and synthetically direct methods
for the synthesis of cyclobutanes is photochemical [2+2]
cycloaddition.[6] However, cinnamate dimerization can pose
a challenge as a consequence of the kinetically favored
isomerization of olefins.[7] Efforts by Lewis et al. revealed that
the addition of Lewis acids (BF3OEt2 or SnCl4) could
facilitate the dimerization of cinnamic acid, but with modest
selectivity and very long reaction times.[8] Some of the greatest
successes in dimerizing cinnamic acid derivatives have been
achieved by carrying out the photochemical reaction in the
solid state.[9,10] More recently, Ramamurthy and co-workers
designed host–guest systems to facilitate dimerization
through templating effects.[11–13] There have also been
a number of tethering approaches to facilitate dimerization
to afford head-to-head cyclobutanes.[14]
Scheme 1. Cyclobutanes with cinnamic acid derived cores.
We recently developed a flow photochemistry platform[15]
which utilizes a xenon(Hg) source that is collimated into
a two-inch beam (Figure 1).[16–18] Through the introduction of
commercially available lenses and UV and IR filters, we are
able to effectively focus the beam with specific wavelengths
[*] R. Telmesani, S. H. Park, T. Lynch-Colameta, Prof. A. B. Beeler
Department of Chemistry, Boston University
590 Commonwealth Ave. Boston, MA 02215 (USA)
E-mail: beelera@bu.edu
Figure 1. A) Xenon(Hg) UV source with collimating lens and UV filter.
B) Conical flow device attached to a glycol recirculating chiller.
C) Batch reaction vial cooled by a Venturi air gun.
[**] Financial support from Boston University is gratefully acknowl-
edged. We thank Dr. Norman Lee (Boston University) for high-
resolution mass spectrometry data. NMR (CHE-0619339) and MS
(CHE- 0443618) facilities at Boston University are supported by the
NSF.
onto a reactor. To best take advantage of this UV source we
designed a cone reactor that would allow for even irradiation
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201504454.
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and could be temperature-controlled by a circulating chiller.
The reactor is wrapped with fluorinated ethylene propylene
(FEP) tubing which sits in small grooves that promote heat
transfer.[15] The cone reactor can be irradiated for long periods
of time while maintaining a set temperature (5–308C). Batch
reactions may also be carried out by placing a reaction vial in
front of the beam. In this case we are able to maintain
temperatures utilizing a Venturi cold air gun.
We began evaluating the reactivity of methyl cinnamate
with our photochemical platform. In batch, we found that the
irradiation (> 225 nm) of methyl cinnamate in acetonitrile for
11 h afforded the head-to-head dimers, b-truxinate and d-
truxinate,[14b] as a 1:1 mixture (14% conversion, 10% yield of
isolated product; Scheme 2). In flow, a minor increase in
With an eye toward developing a controlled dimerization
of cinnamic esters we considered methods that might
facilitate the process. On the basis of results with macro-
molecular host–guest systems[11] and solid-state photodimeri-
zation[9] we postulated that a dual hydrogen-bonding cata-
lyst[19] might be capable of templating two substrates to
facilitate dimerization. Thus, we began evaluating a number
of bis(thioureas)[20] for the [2+2] cycloaddition of methyl
cinnamate.[15] We were pleased to see that thiourea 4 afforded
a moderate increase in conversion (24%) after 2 h residence
time and a notable increase in diastereoselectivity (3:1, d/b).
Initial optimization of the reaction in flow indicated that
we could decrease the loading of thiourea 4 to 8 mol% with
a moderate increase in conversion. As expected, increasing
the residence time and concentration
resulted in higher conversions.[15] We also
evaluated alternative solvents, but
CH3CN was the most effective.[15] We
attribute this, in part, to poor solubility
of either methyl cinnamate or the bis-
(thiourea) in a number of solvents.
Evaluation of the photochemical reac-
tion parameters indicated some loss of
conversion at wavelengths greater than
Scheme 2. Photochemical dimerization of methyl cinnamate.
320 nm, but selectivity was maintained
(Table 2). Notably, there was a dramatic
efficiency was observed after 8 h residence time (18%
conversion, 14% isolated product). In both reactions, the
remaining material was an approximate 1:1 mixture of the
starting material and the corresponding Z isomer. We did not
observe alternative head-tail dimers or dimers incorporating
the Z isomer.[8b]
Table 2: Photochemical conditions for the catalyzed cycloaddition of
methyl cinnamate.[a]
To better understand the photochemical reaction param-
eters we evaluated the effect of the wavelength on the
dimerization in the flow reactor. We observed that the
reactivity declines at wavelengths greater than 320 nm
(Table 1), which correlates well with the observed UV
Table 1: Photochemistry parameters and temperature effects.[a]
Power [W]
l [nm]
Reactor
Conv. [%][a]
d.r. (d/b)[b]
T [oC]
Power [W]
l [nm]
Conv. [%][b]
d.r. (d/b)[c]
500
500
500
500
200
300
400
500
no filter
>305
>320
>370
>305
>305
>305
>305
flow
flow
flow
flow
flow
flow
flow
batch
72
76 (60)
59
16
19
39
48
25
(20)
3:1
3:1
3:1
1:1
3:1
3:1
3:1
2:1
15
15
15
15
15
15
15
0
500
500
500
500
200
300
400
500
no filter
>305
>320
>370
>305
>305
>305
>305
18
20
16
3
10
18
21
29
1:1
1:1
1:1
1:1
1:1
1:1
1:1
1:1
[a] Conversion was determined by 1H NMR spectroscopic analysis of the
crude reaction mixtures. [b] Diastereomeric ratio was determined by
1H NMR spectroscopic analysis of the crude reaction mixtures.
[a] Reactions were carried out in the flow reactor with an 8 h residence
time. [b] Conversion was determined by 1H NMR spectroscopic analysis
of the crude reaction mixtures. [c] Diastereomeric ratio was determined
by 1H NMR spectroscopic analysis of the crude reaction mixtures.
loss of conversion and diastereoselectivity at wavelengths
greater than 370 nm, which corresponds to the absorbance of
thiourea 4.[15] We also observed a significant effect of the
power of the UV source, in contrast to the uncatalyzed
reaction (Table 2).
absorbance of the substrate.[15] We also evaluated the output
power of the UV source and observed similar results with
300–500 Watts and a drop to 10% conversion at 200 Watts
(Table 1). Temperatures of 0–408C did not have an effect on
the conversion or diastereoselectivity (data not shown).
Overall, optimization of the thiourea-promoted reaction
in flow with methyl cinnamate resulted in 76% conversion
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(60% yield of isolated product) and moderate diastereose-
lectivity (d.r. 3:1). The optimized conditions were 8 h resi-
dence time (> 305 nm) in CH3CN (0.8m) and 8 mol%
bis(thiourea) 4. In batch, we observed a notable loss of
conversion (25% conversion, 20% yield of isolated product)
and lower diastereoselectivity (Table 2).
The observed sensitivity to wavelength and power in the
thiourea-promoted reaction suggested a potential triplet
sensitization effect. To better understand these effects[21] we
screened a number of triplet sensitizers. We found that
acetophenone promotes the reaction with 38% conversion
and 2:1 selectivity after 8 h irradiation in flow.[15] These results
are poorer than those observed with bis(thiourea) 4, but
suggest that the reactivity and selectivity of the thiourea-
promoted reactions may be attributed, in part, to triplet
sensitization.[22]
To evaluate whether bis(thiourea) 4 was actively coordi-
nating with the substrate we carried out studies in solution by
NMR spectroscopy.[23] 1H NMR analysis of compound 4 and
methyl cinnamate (1:2 ratio) in both acetone and acetonitrile
showed significant sharpening of the NH signals, thus
indicating strong hydrogen bonding.[15] We also looked for
evidence of intermolecular interactions by utilizing
NOESY.[24] We observed signals corresponding to the inter-
action of the thiourea NH protons with the methyl ester,
alkene, and phenyl protons of methyl cinnamate.[15] We also
observed interactions between the ortho hydrogen atoms of
the phenyl moiety of the photocatalyst and the cinnamate
aromatic hydrogen atoms.[15]
Based on these preliminary results, we propose that
thiourea 4 functions through initial hydrogen bonding of
methyl cinnamate to afford complex 5 (Scheme 3). The
interaction can promote potential excitation by lowering the
HOMO/LUMO gap.[25] Also, potential triplet sensitization by
the bis(thiourea) 4 may be facilitated by a proximity effect as
a result of the coordination.[26] Ultimately, a second molecule
Scheme 4. Evaluation of cinnamate derivatives. For clarity the d isomer
is shown. Reactions were conducted for 8 h in CH3CN. The conversion
was determined by 1H NMR spectroscopic analysis of the crude
reaction mixtures. Yields of isolated products in parentheses refer to
material purified by flash chromatography. The diastereomeric ratio
was determined by 1H NMR spectroscopic analysis of the crude
reaction mixtures.
Scheme 3. Potential reaction pathway through hydrogen bonding of
bis(thiourea) 4. Facial approach affording both b isomer 2 (complex 6)
and the d isomer 3 (complex 7) are illustrated.
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proceeds to react through either unaided approach (7) or
possibly by hydrogen bonding to the second thiourea (6).
We wanted to assess the effect of catalyst 4 on [2+2]
photocycloaddition with a number of cinnamate substrates in
batch and flow. The first aryl-substituted cinnamate we
evaluated was the natural product ferulic acid methyl
ester.[27] In batch, we observed similar results with and
without thiourea 4 (27% and 28% conversion) and both
reactions favored the b isomer (2:1). In flow, the conversion
increased to 50% and the selectivity remained the same. With
addition of catalyst 4 in flow, the conversion increased to 67%
and we observed an increase in the d isomer 8 (d.r. 1:1;
Scheme 4).
Electron-rich pyrinyl and trimethoxy[28] cinnamates also
afforded moderate conversion in favor of the b isomer in
batch with and without thiourea 4. In flow in the absence of 4,
the conversion was significantly higher (58% and 64%).
However, in flow with thiourea 4, there was increased
conversion and moderate selectivity, now favoring the
d isomers (9 and 10, 3:1 and 2:1, respectively). m-Fluoro
and p-bromo cinnamates had similar reactivity, each resulting
in a significant increase in conversion in flow and favoring the
d isomer (11, 12) in the presence of catalyst 4. Although p-
nitro ethyl cinnamate has been shown to be highly reactive in
batch[22] and was similarly reactive in all of our reactions, we
observed an increased selectivity for the d isomer 13 in the
presence of thiourea 4. The reaction with allyl cinnamate
occurred with low conversion and no selectivity without
thiourea 4. In the presence of 4 in flow, there was significant
improvement in the conversion (41%) and good selectivity
(4:1) for the d isomer 14. We did not observe cycloaddition of
the allyl olefin.
We have demonstrated that a flow photochemical plat-
form with a novel cone reactor can facilitate significant
improvement of the [2+2] photocycloaddition of cinnamate
derivatives. We have also discovered a bis(thiourea) that
significantly increases the conversion and diastereoselectivity
with a number of substrates. This study highlights the impact
that flow chemistry can have on photochemical reactions and
will serve as a foundation for the development of the next-
generation catalysts for highly diastereoselective and enan-
tioselective intermolecular [2+2] cycloadditions of cinna-
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Keywords: cinnamates · cyclobutanes · flow chemistry ·
photochemistry · truxinates
How to cite: Angew. Chem. Int. Ed. 2015, 54, 11521–11525
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Received: May 18, 2015
Published online: July 1, 2015
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