Evaluating Thiourea Architecture for Intramolecular [2+2] Photocycloaddition of 4-Alkenylcoumarins

Article abstract of DOI:10.1002/adsc.201400677

The efficiency of [2+2] photocycloadditions of 4-alkenylcoumarins was evaluated with various thiourea skeletons to develop thiourea-based catalysts for promoting photochemical reactions. Our results indicate that the excited state chemistry is dependent o

Full text of DOI:10.1002/adsc.201400677

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DOI: 10.1002/adsc.201400677
Evaluating Thiourea Architecture for Intramolecular
[2+2]Photocycloaddition of 4-Alkenylcoumarins
ACHTUNGTRENNUNG
Nandini Vallavoju,a Sermadurai Selvakumar,a Steffen Jockusch,b
Manoj Thathamkulam Prabhakaran,a Mukund P. Sibi,a,*
and Jayaraman Sivagurua,*
a
Department of Chemistry and Biochemistry, North Dakota State University, Fargo, ND 58108-6040, USA
Fax : (+1)-701-231-8831; phone: (+1)-701-205-8338; e-mail: mukund.sibi@ndsu.edu or sivaguru.jayaraman@ndsu.edu
Department of Chemistry, Columbia University, New York, NY 10027, USA
b
Received: July 12, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400677.
Abstract: The efficiency of [2+2]photocycloaddi-
tions of 4-alkenylcoumarins was evaluated with var-
ious thiourea skeletons to develop thiourea-based
catalysts for promoting photochemical reactions.
Our results indicate that the excited state chemistry
is dependent on the nature of the thiourea catalyst
employed to activate the photoactive substrate.
than that of the reactive substrate. The third strategy
involves an energy sharing mechanism where, upon
light excitation, the sensitizer/catalyst and reactant
complex (static/dynamic complex) undergo a photo-
transformation to form the product(s).[5]
We have embraced the energy sharing strategy and
have utilized thiourea-based catalysts[6] to promote
photoreactions with excellent control of product
enantioselectivity.[5b] As an example, we showed that
4-alkenylcoumarin 1a underwent a stereoselective
[2+2]photocycloaddition to form photoproduct 2a
with 94% enantioselectivity with binaphthyl based
thiourea catalysts.[5b] Having deciphered the impor-
tance of binaphthyl based thiourea catalysts we were
interested in evaluating other thiourea skeletons to
Keywords: asymmetric photoreactions; hydrogen
bonding photocatalysis; organophotocatalysis; pho-
tochirogenesis; thiourea photocatalysis
Photochemical transformations are an important class promote photochemical transformations. We were in-
of organic reactions that are often known to generate terested in the role of thioureas not only to achieve
products with unique stereochemistry.[1] For this high enantioselectivity but also high conversions, as it
reason, chemists have developed strategies that are will increase the type of skeletons that could be em-
readily applied in organic synthesis.[2] In recent years, ployed for controlling photoreactions. In this report
there has been tremendous impetus towards develop- we present our findings with six diverse thiourea cata-
ing enantioselective syntheses of complex strained lysts 3b–g in promoting the [2+2]photocycloaddition
compounds by light initiated reactions.[1c,2i] In that of coumarins 1a and 1b. (Scheme 1). The efficiencies
regard three different catalytic strategies have gar- of the new thiourea skeletons were compared to reac-
nered attention, as they are effective in controlling tion efficiency with our previously established catalyst
chemical transformations initiated by light. The first 3a (prepared in one step from commercially available
strategy involves photoredox chemistry[3] where starting material) that gave quantitative conversions
a light absorbing sensitizer performs a one electron upon [2+2]photocycloaddition of 1a leading to 74%
oxidation or reduction of the reactive substrate lead- enantiomeric excess (ee) in the photoproduct 2a.
ing to a radical anion or a radical cation. As these re-
As we had previously established the optimal reac-
active species are in the ground state, their higher po- tion conditions for the enantioselective [2+2]photocy-
tential enables them to react efficiently to form prod- cloaddition of 1a with catalyst 3a, viz. 1:1 mixture of
ucts. The second strategy involves an energy transfer toluene and meta-xylene at À78Æ28C, we employed
mechanism[2h,4] where the excited state energy from the same set of reaction conditions to evaluate the
a light absorbing sensitizer is transferred to the sub- new thiourea skeletons and compare both reaction ef-
strate, producing a singlet or a triplet excited state ficiencies and enantioselectivity (Table 1). Six thiour-
that reacts to form the product. This strategy requires ea skeletons,[7] were examined as they have been
the excited state energy of the sensitizer to be higher shown to be effective in promoting enantioselective
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Nandini Vallavoju et al.
Scheme 1. Enantioselective [2+2]photocycloaddition of coumarin derivatives 1 mediated by thioureas 3.
thermal transformations. These included the atropiso- observed low ee values in the photoproduct. The reac-
meric binaphthyl based bis-aryl thiourea 3b,[7a] the C2- tion efficiency with 3b was 89% and 100% for sub-
symmetrical bis-thioureas 3c[7b] and 3d,[7c] and mono- strates 1a and 1b, respectively (Table 1; entry 3). To
functional chiral thiourea 3e,[7d] Ricciꢁs catalyst 3f[7e,f] our surprise, C2-symmetrical bis-thioureas 3c and 3d,
and 3g.[7g]
as well as aminoindanol derived thiourea 3f gave ex-
To evaluate the efficiency of thiourea catalysts in cellent conversions (Table 1; entries 4, 5 and 7), while
promoting the [2+2]photocycloaddition of coumarins monofunctional chiral thioureas 3e and 3g gave mod-
1a and 1b, we initially scanned different catalysts at erate conversions (Table 1; entries 6 and 8) albeit with
a loading level of 100 mol%. Upon examination of low stereocontrol. This showed that thiourea can be
Table 1, it is quite clear that thioureas display inter- effective in promoting the photochemical transforma-
esting features while promoting photochemical reac- tion. Analysis of Table 1 from a photochemical stand-
tivity and selectivity. We had previously established point makes thioureas 3c and 3f stand out as they do
that thiourea 3a was effective in promoting the photo- not feature a light absorbing chromophore (compared
reaction with an excellent ee value of 74%.[5b] Thiour- to the coumarin functionality), yet were effective in
ea 3a was also equally effective for 1b leading to an promoting the photochemical reaction with excellent
ee value of 86% (Table 1; entry 2) with quantitative conversions. To further evaluate this observation, we
conversions. As we had previously established that 3a carried out the photochemical transformation of 1a
forms both static and dynamic complexes with 1a sub- and 1b with sub-stoichiometric amounts of 3f
strate promoting the photoreaction, we believe that (10 mol%) and compared their reactivity with sub-
a similar scenario manifests in the case of 1b leading stoichiometric amounts of 3a and 3b (Table 2).
to high enantioselectivity in the corresponding photo-
Inspection of Table 2 reveals that even at 10 mol%
product. As we had established the role of the naph- loading, catalyst 3f was effective in promoting the
thalene motif in promoting the intramolecular transformation. For example, the ratio of 1b:2b was
[2+2]photocycloaddition of coumarin 1a, we evaluat- 0:100 (complete conversion) with catalyst 3a under ni-
ed another naphthyl based thiourea 3b, in which we trogen atmosphere compared to 36:64 and 38:62 with
2
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Evaluating Thiourea Architecture
Table 1. Enantioselective intramolecular [2+2]photocycloaddition of 1a with thioureas 3b–3g.[a]
1a
1b
Entry
Catalyst
1a:2a[c]
% Conversion (2a)[d]
% ee (2a)[e]
1b:2b[c]
% Convversion (2b)[d]
% ee (2b)[e]
1
2
3
4
5
6
7
8
none
3a[b]
3b
3c
3d
3e
3f
3g
89:11
11:89
6:94
23:77
11:89
52:48
10:90[g]
33:67[g]
9
racemic
74
28
24 (ent-2a)
24
4
77:23
0:100
0:100
0:100[f]
–
18
100
100
100
–
–
100
–
racemic
86
14
24 (ent-2b)
–
–
22
–
84
89
72
84
45
91
57
–
racemic
racemic
0:100
–
[a]
Reactions were carried out in 1:1 toluene/meta-xylene solvent mixture at À78Æ28C for 3 h with 1 equivalent of the cata-
lyst. All samples were degassed with N2 bubbling for 8–10 min prior to irradiation. Values are an average of two trials.
Values from ref.[5b]
[b]
[c]
[d]
Ratios were obtained from GC analysis.
1
Reaction conversions (%) were determined by H NMR spectroscopy using triphenylmethane as internal standard. The
mass balance was greater than 90% in all the trials.
From GC analysis using chiral stationary phase.
[e]
[f]
1
From H NMR spectroscopy. GC analysis showed a ratio 3:97 for 1b:2b.
[g]
1
From H NMR spectroscopy.
Table 2. Intramolecular [2+2]photocycloaddition of 1 with photophysical studies (Figure 2). Inspection of
10 mol% of catalyst 3 in 1:1 toluene/xylene.[a]
Figure 1 shows that thiourea interacted with the cou-
marin substrate, which was indicated by the upfield
Entry Catalyst Compound Conditions 1:2[b]
ACHTUNGTNER(NUNG % ee,
shift of the C-3 alkene proton resonance of 1b upon
addition of various equivalents of 3f. The strength of
the interaction was computed by non-linear regression
analysis of the NMR titration experiments that re-
vealed a binding constant[8] of 14.8(Æ1.2) MÀ1 in
CDCl3 (Figure 1). UV-Vis spectra of catalyst 3f and
substrate 1b (Figure 2, A) clearly showed that the
coumarin substrate is absorbing the light at the irradi-
ating wavelength (~350 nm) even at 100 mol% cata-
lyst loading. Very weak fluorescence centred around
390 nm was observed from 1b at room temperature in
toluene (Figure 2, B). The excitation matched with
the absorption spectra indicating that the emitting
chromophore has its origin in the coumarin function-
ality (Figure 2, B). Time correlated single photon
counting measurements on 1b in toluene at room
2)[b]
1
2
3
4
5
6
none
3a
3b
1b
1b
1b
1b
N2/4 h
N2/2 h
N2/4 h
N2/4 h
O2/4 h
air/4 h
66:34
0:100
36:64
38:62
(56)[c]
55:45
37:63
68:32
78:22
71:29
racemic
86
28
10
12
3f
12
7
8
9
3f
1a
N2/4 h
O2/4 h
air/4 h
0
0
0
[a]
Solutions were sparged with the appropriate gas for 8–
10 min prior to irradiation. Reactions at À78Æ28C.
Values were determined by GC analysis.
[b]
[c]
Isolated yield, 6 h irradiation.
catalysts 3b and 3f, respectively (Table 2; compare en- temperature showed that the fluorescence lifetime
tries 2–4). In addition, with catalyst 3f the ratio of decay traces overlapped within the instrument re-
1b:2b was unaffected under nitrogen, oxygen and air sponse function indicating very short singlet lifetimes
saturated reaction atmospheres (Table 2; entries 4–6). (<0.1 ns). The short fluorescence lifetime is probably
Similarly, with catalyst 3f the ratio of 1a:2a was unaf- caused by fast intersystem crossing into the triplet
fected under nitrogen, oxygen and air saturated reac- state or fast [2+2]cycloaddition at room temperature.
tion atmospheres (Table 2; entries 7–9). This raises in- To decipher this, we recorded the luminescence in
teresting questions: (a) How does catalyst 3f promote a solid matrix at 77 K, where [2+2]cycloaddition will
the photochemical reaction? and (b) what is the be hindered. Figure 2, C (—) shows the steady-state
mode of reactivity with the coumarin substrate? To luminescence spectrum of 1b in toluene glass at 77 K
address this we utilized coumarin substrate 1b as with two major peaks at ~390 nm and ~500 nm that
a model system to understand the influence of thiour- were assigned to fluorescence and phosphorescence,
ea 3f in promoting the photochemical reaction.
respectively. This peak assignment is consistent with
To understand the nature of the interaction be- the time-resolved luminescence spectrum recorded
tween the coumarin substrate and the thiourea, we 10 ms after the excitation light pulse where only the
carried out NMR titration experiments (Figure 1) and long-lived phosphorescence is detectable (Figure 2, C
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Nandini Vallavoju et al.
Figure 1. 1H NMR spectra (400 MHz; CDCl3) of 1b [0.02M] in the absence and in the presence [0.01–0.04M] of catalyst 3f.
The expanded inset shows the upfield shift of the C-3 alkene proton in 1b upon addition of various equivalents of the thio-
ACHTUNGTRENNUNGurea 3f.
***
). Time correlated single photon counting meas- let-excited state resulting in a 1,4-biradial that cyclizes
urements on 1b in toluene glass at 77 K showed that to form the intramolecular [2+2]photocycloaddition
the fluorescence lifetime decay traces once again product. A similar scenario manifests in the case of
overlapped within the instrument response function coumarin substrate 1a.
indicating very short singlet lifetimes (<0.1 ns) even
Our study has revealed that thioureas can interact
at 77 K. Phosphorescence lifetime measurements at with coumarin substrates and promote photoreac-
77 K showed a biexponential decay with two distinct tion(s) with different modes of activation. The mode
lifetimes 0.9 s and 0.3 s (the biexponential decay of activation depends on the type of chromophore
likely due to matrix inhomogeneity at 77 K) indicat- and/or functionality attached to the thiourea motif
ing a pp* excited state (Figure 2, D).[9] These observa- that anchors the reactive substrate through hydrogen
tions point to a fast decay of the singlet excited state bonding. Manipulating the delicate balance as well as
due to intersystem crossing and/or internal conver- influencing non-bonding interactions that occur be-
sion. Therefore, we conclude that, in the case of 1b, tween the thiourea and reactive substrate can open
photochemical reactivity likely occurs from the triplet up opportunities to develop organo-photocatalysts to
excited state.
enhance both reactivity and selectivity.[6]
Based on the above observations, the role of 3f in
promoting the photoreaction of coumarin 1b can be
elucidated. We believe that 3f interacts with 1a in the
ground state as evidenced by NMR titration experi-
ments. Photoexcitation of 1b in the presence of 3f
(stoichiometric or sub-stoichiometric) results in an ex-
tremely short-lived singlet excited state due to a very
fast intersystem crossing rate and/or internal conver-
sion resulting in the triplet-excited species. The lack
Experimental Section
General Procedure for Photoreactions
Coumarin 1 (0.02M) and thiourea 3a–g (0.002–0.02M) were
dissolved in an appropriate solvent in a Pyrex test tube. The
reaction mixture was degassed by nitrogen (oxygen or air)
of oxygen quenching points to a highly reactive trip- bubbling for 8–10 min. Then the resultant solution was irra-
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Evaluating Thiourea Architecture
***
***
Figure 2. (A) UV-Vis spectra of 1b (–) and 3 f (
) in toluene. (B) Fluorescence emission (—) and excitation (
) of 1b
***
in toluene at room temperature. (C) Time-resolved phosphorescence spectrum (
) and steady state luminescence spec-
trum (—) of 1b in toluene glass at 77 K. (D) Phosphorescence lifetime of 1b in toluene glass at 77 K.
diated in Rayonet reactor (~350 nm) at À78Æ28C for the
specified time intervals. The irradiated samples were ana-
lyzed by gas chromatography to ascertain the reactant to
product ratio as well as the enantiomeric excess in the pho-
toproduct. For conversion and mass balance studies, after ir-
radiation for specific time intervals, an appropriate amount
of internal standard (triphenylmethane) was added to the
reaction mixture. The solvent was evaporated under reduced
pressure in a rotary evaporator and was dried under high
vacuum. The crude reaction mixture was analyzed by
1H NMR spectroscopy (CDCl3 as solvent).
[2] a) Y. Inoue, in: Chiral Photochemistry, Vol. 11, (Eds.: Y.
Inoue, V. Ramamurthy), Marcel Dekker, New York,
2004, pp 129–177; b) T. Mori, R. G. Weiss, Y. Inoue, J.
Am. Chem. Soc. 2004, 126, 8961–8975; c) M. A. Garcia-
Garibay, Acc. Chem. Res. 2003, 36, 491–498; d) J. N.
Gamlin, R. Jones, M. Leibovitch, B. Patrick, J. R. Scheff-
er, J. Trotter, Acc. Chem. Res. 1996, 29, 203–209; e) J. Si-
vaguru, A. Natarajan, L. S. Kaanumalle, J. Shailaja, S.
Uppili, A. Joy, V. Ramamurthy, Acc. Chem. Res. 2003,
36, 509–521; f) M. Sakamoto, M. Kato, Y. Aida, K.
Fujita, T. Mino, T. Fujita, J. Am. Chem. Soc. 2008, 130,
1132–1133; g) A. J.-L. Ayitou, J. Sivaguru, J. Am. Chem.
Soc. 2009, 131, 5036–5037; h) C. Mꢂller, A. Bauer,
M. M. Maturi, M. C. Cuquerella, M. A. Miranda, T.
Bach, J. Am. Chem. Soc. 2011, 133, 16689–16697; i) C. K.
Prier, D. A. Rankic, D. W. C. MacMillan, Chem. Rev.
2013, 113, 5322–5363; j) N. Vallavoju, J. Sivaguru, Chem.
Soc. Rev. 2014, 43, 4084–4101.
Acknowledgements
JS thanks NDSU for financial support and the NSF for gen-
erous support (CHE-1213880) for the purchase of HPLC
and GC columns. MPS thanks NDSU and Arthur C. Cope
Scholar Award for financial support. NV thanks the NDSU
graduate school for a graduate dissertation fellowship. SJ
thanks the NSF for financial support (CHE-1111392). MTP
thanks UGC, India for Raman Postdoctoral Fellowship and
financial support.
[3] a) D. G. Whitten, Acc. Chem. Res. 1980, 13, 83–90;
b) D. A. Nicewicz, D. W. C. MacMillan, Science 2008,
322, 77–80; c) A. Bauer, F. Westkamper, S. Grimme, T.
Bach, Nature 2005, 436, 1139–1140; d) J. Du, K. L.
Skubi, D. M. Schultz, T. P. Yoon, Science 2014, 344, 392–
396; e) J. M. R. Narayanam, J. W. Tucker, C. R. J. Ste-
phenson, J. Am. Chem. Soc. 2009, 131, 8756–8757; f) E.
Arceo, A. Bahamonde, G. Bergonzini, P. Melchiorre,
Chem. Sci. 2014, 5, 2438–2442.
References
[4] a) G. S. Hammond, R. S. Cole, J. Am. Chem. Soc. 1965,
87, 3256–3257; b) Y. Inoue, T. Yokoyama, N. Yamasaki,
A. Tai, J. Am. Chem. Soc. 1989, 111, 6480–6482; c) Y.
[1] a) Y. Inoue, Chem. Rev. 1992, 92, 741–770; b) H. Rau,
Chem. Rev. 1983, 83, 535–547; c) N. Hoffmann, Chem.
Rev. 2008, 108, 1052–1103.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
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These are not the final page numbers!

COMMUNICATIONS
Nandini Vallavoju et al.
Inoue, T. Yokoyama, N. Yamasaki, A. Tai, Nature 1989,
341, 225–226; d) R. Maeda, T. Wada, T. Mori, S. Kono,
N. Kanomata, Y. Inoue, J. Am. Chem. Soc. 2011, 133,
10379–10381; e) R. Alonso, T. Bach, Angew. Chem.
2014, 126, 4457–4460; Angew. Chem. Int. Ed. 2014, 53,
4368–4371.
H. Yue, H. Huang, H. Zong, L. Song, J. Org. Chem.
2013, 78, 9137–9142; c) Y. Sohtome, A. Tanatani, Y. Ha-
shimoto, K. Nagasawa, Tetrahedron Lett. 2004, 45, 5589–
5592; d) M. T. Robak, M. Trincado, J. A. Ellman, J. Am.
Chem. Soc. 2007, 129, 15110–15111; e) M. P. Sibi, K.
Itoh, J. Am. Chem. Soc. 2007, 129, 8064–8065; f) R. P.
Herrera, V. Sgarzani, L. Bernardi, A. Ricci, Angew.
Chem. 2005, 117, 6734–6737; Angew. Chem. Int. Ed.
2005, 44, 6576–6579; g) T. Bui, S. Syed, C. F. Barbas, J.
Am. Chem. Soc. 2009, 131, 8758–8759.
[5] a) J. I. Kim, G. B. Schuster, J. Am. Chem. Soc. 1990, 112,
9635–9637; b) N. Vallavoju, S. Selvakumar, S. Jockusch,
M. P. Sibi, J. Sivaguru, Angew. Chem. 2014, 126, 5710–
5714; Angew. Chem. Int. Ed. 2014, 53, 5604–5608.
[6] a) A. G. Doyle, E. N. Jacobsen, Chem. Rev. 2007, 107,
5713–5743; b) M. S. Taylor, E. N. Jacobsen, Angew.
Chem. 2006, 118, 1550–1573; Angew. Chem. Int. Ed.
2006, 45, 1520–1543; c) A. Wittkopp, P. R. Schreiner,
Chem. Eur. J. 2003, 9, 407–414.
[8] K. A. Conners, Binding Constants, John Wiley, New
York, 1987.
[9] N. J. Turro, V. Ramamurthy, J. C. Scaiano, Modern Mo-
lecular Photochemistry of Organic Molecules, University
Science Books, Sausalito, CA, 2010, pp 265–317 and
pp 383–481.
[7] a) E. M. Fleming, T. McCabe, S. J. Connon, Tetrahedron
Lett. 2006, 47, 7037–7042; b) G. Bian, H. Fan, S. Yang,
6
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Evaluating Thiourea Architecture for Intramolecular
7
ACHTUNGTRENNUNG[2+2]Photocycloaddition of 4-Alkenylcoumarins
Adv. Synth. Catal. 2014, 356, 1 – 7
Nandini Vallavoju, Sermadurai Selvakumar,
Steffen Jockusch, Manoj Thathamkulam Prabhakaran,
Mukund P. Sibi,* Jayaraman Sivaguru*
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