Synthesis of Chromenoisoxazolidines from Substituted Salicylic Nitrones via Visible-Light Photocatalysis

Article abstract of DOI:10.1021/acs.orglett.9b00097

This effort reports the first redox-neutral visible-light photocatalytic intramolecular dipolar cycloaddition for the diastereoselective synthesis of chromenoisoxazolidines. The authors have found that alkenylphenyl nitrones with a diverse substitution pattern on the aromatic ring and the alkenyl substituent undergo visible-light-promoted cycloadditions in the presence of catalytic amounts of Ru(bpy)₃Cl₂ in high yields and selectivities. Evidence indicates that the proposed redox-neutral pathway is the predominant photoredox mechanism for this transformation.

Full text of DOI:10.1021/acs.orglett.9b00097

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Chromenoisoxazolidines from Substituted Salicylic
Nitrones via Visible-Light Photocatalysis
Graham Haun, Alyson N. Paneque, David W. Almond, Brooke E. Austin, and Gustavo Moura-Letts*
Department of Chemistry and Biochemistry, Rowan University, 201 Mullica Hill Road, Glassboro, New Jersey 08028, United States
S
* Supporting Information
ABSTRACT: This effort reports the first redox-neutral visible-light photocatalytic intramolecular dipolar cycloaddition for the
diastereoselective synthesis of chromenoisoxazolidines. The authors have found that alkenylphenyl nitrones with a diverse
substitution pattern on the aromatic ring and the alkenyl substituent undergo visible-light-promoted cycloadditions in the
presence of catalytic amounts of Ru(bpy)3Cl2 in high yields and selectivities. Evidence indicates that the proposed redox-neutral
pathway is the predominant photoredox mechanism for this transformation.
he dipolar cycloaddition reaction has long been among
antipsychotics, and antianxiolytics.10 These can also be used as
Tthe most influential organic transformations due to its templates for the synthesis of more complex molecules.11
However, the few available methods rely on the intramolecular
cycloaddition of alkenylnitrones through high temperatures or
harsh reagents to achieve moderate efficiencies.5 Moreover,
available methods for their synthesis suffer from substrate
scope, thus severely limiting their applicability. Thus, more
efficient and general methods for the synthesis of such
important scaffolds remain an important synthetic goal.
We are focused on developing novel methods for the
synthesis of complex nitrogen-containing heterocycles.12
Recently we discovered that nitrones undergo regioselective
intermolecular dipolar cycloaddition based upon the sub-
stitution pattern on the dipolarophile. However, inter- and
intramolecular unactivated dipolarophiles are highly unreactive
and therefore poised for the development of suitable
photocatalytic reaction conditions.13
Among the variety of visible-light photocatalytic processes,
redox-neutral photocatalysis may be employed to access stable
radical cations and radical anions that do not provide
fragmentation to give neutral radicals.14 These intermediates
possess reactivity that is inherently different from that of their
ground state, thus providing access to otherwise unprece-
dented transformations.15 We envisioned a visible-light-
promoted redox-neutral photocatalytic dipolar cycloaddition
for the synthesis of chromenoisoxazolidines from alkenylni-
trones.
ability to furnish a variety of highly substituted five-membered
heterocycles.1 The scaffolds obtained through this reaction are
important intermediates in the preparation of natural products
and commercial drugs.2 Moreover, up to three continuous
stereocenters can be formed through this reaction, and the
challenge of controlling regio-, diastereo-, and enantioselectiv-
ities has attracted much attention in recent years.3 Although
some selective methods are available, high regio- and
diastereoselectivities remain elusive.4 Intramolecular dipolar
cycloadditions between nitrones and unactivated alkenes are
poised to provide high selectivities, although reported efforts
rely on high heat or harsh reagents to achieve high reaction
efficiencies.5 Thus, more efficient and milder methods remain
goals in the field of organic chemistry.
Photocatalysis has emerged in the last 15 years as a
promising approach toward the development of otherwise
inefficient or thermodynamically demanding transformations.6
Visible-light-promoted photocatalysis exploits its inexpensive
and mild nature to promote a variety of novel transformations,
thus becoming an emerging field in organic synthesis.7 Among
these, cycloaddition reactions have received considerable
attention, and several efforts have shown that dipolar
cycloadditions are efficiently promoted by visible-light photo-
catalysis for the synthesis of five-membered heterocycles.8
Despite the significant developments, many of these reactions
rely on complex substrates and suffer from poor generality.9
Thus, further development of more efficient and general
visible-light-promoted photocatalytic methods is of fundamen-
tal importance to this field.
Based on our efforts toward better understanding the
selectivity of nitrone cycloadditions, we discovered that 2-
allyloxyphenyl-N-benzylnitrone undergoes very slow conver-
Chromenoisoxazolidines are important molecular scaffolds
in drug discovery for their properties as antidepressants,
Received: January 8, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b00097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 1. Reaction Optimization
a
entry
additive
solvent
t (°C)
concentration (M)
yield (%)
b
1
none
none
none
visible light
visible light
visible light
visible light
visible light
visible light
visible light
visible light
Ru(bpy)3Cl2 5 mol %
Ru(bpy)3Cl2 1 mol %
Ru(bpy)3Cl2 10 mol %
Ir(p-F-ppy)3Cl2 5 mol %
Ru(bpz)3(PF6)2 5 mol %
Ir(L)2(bpy)3(PF6)2 5 mol %
methyl viologen
toluene
toluene
toluene
benzene
CH2Cl2
CH3CN
MeOH
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
rt
0.01
0.01
0.01
0.01
0.01
0.01
0.01
0.02
0
32
88
18
20
32
28
18
15
32
42
98
44
65
71
64
75
14
b
2
60
100
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
b
3
c
4
d
5
d
6
d
7
d
8
d
9
0.03
0.05
d
10
11
12
13
14
15
16
17
18
d
0.005
0.005
0.005
0.005
0.005
0.005
0.005
0.005
d
d
d
d
d
d
,e
d
a
b
c
d
e
Isolated yields. In the absence of light (dark box). 3 days by the windowsill. White LED. L = dfCF3ppy.
sion to the respective chromenoisoxazolidines in 18% yield
over 3 days by the windowsill. Analysis of the reaction
indicated complete selectivity for the cis diastereomer. A survey
of the literature revealed few reports focused on visible-light-
promoted cycloaddition of nitrones, and among those none
had focused on the intra- or intermolecular visible-light-
promoted dipolar cycloaddition of nitrones with unactivated
dipolarophiles.9
increase the reaction productivity to 98% yield at 5 mol %
(entry 12).17 However, at 1 or 10 mol % the yield decreased to
moderate yields (44 and 55%, entries 13 and 14, respectively).
Other commercially available photocatalysts proved to be less
efficient than Ru(bpy)3Cl2 (entries 15−18).
Based on the high conversions and diastereoselectivities, the
next step forward focused on assessing the scope of the
transformation across multiple diversification points. We
anticipated that functional group electronic and steric effects
around the salicylic aromatic ring would provide a thorough
understanding of the reaction scope (Table 2). Moreover,
substituted salicylaldehydes and acetophenones proved ideal at
condensing with benzylhydroxylamine to provide the required
nitrones. Thus, 3-allyl and naphthyl substrates proved to
convert to the corresponding product in very high yields and
with similar high diastereoselectivities for the cis isomer
(entries 2 and 3, 97 and 92% yield, respectively).
Dihalogeneted substrates (diiodo, dichloro, and dibromo)
also reacted in very high yields and provided the respective
chromenoisoxazolidines as single diastereomers (entries 4−6;
95, 94, and 91% yield, respectively). Other substitution
patterns around the nitrone aromatic ring provided the desired
heterocycle in similar high yields (entries 7 and 8, 92 and 96%
yield, respectively). Further exploration of the reaction scope
led to the discovery that phenone-derived nitrones with a
variety of substitution patterns undergo equally high yielding
reactions for the respective cis-chromenoisoxazolidines as
single diastereomers (entries 9−12; 93, 95, 96, and 90%
yield, respectively).
Thus, we decided to focus on the optimization of this
transformation under the proposed reaction conditions (Table
1). The initial discovery highlighted the potential for visible-
light-promoted transformations for this type of substrate. We
found that in the absence of light no conversion was observed
at room temperature (entry 1). However, in the absence of
light and at 60 °C the yield increased to 32% and at 100 °C to
88% (entries 2 and 3, respectively). Although the thermal
transformation is known to work, difficult purifications and
mediocre scopes due to decomposition and lack of functional
group tolerance are unavoidable, thus rendering this approach
inefficient. We then assessed the effect of solvent on the
proposed visible-light transformation. These reactions were
then setup on a photoreactor with a source of white LED. As a
result, different solvents proved a slight preference for polar
aprotic CH3CN at 0.01 M by providing the product in 32%
yield (entry 6; other solvents entries 4, 5, and 7). Despite the
low conversions and relative independence on solvent, the
substrate undergoes slow excitation with fast cyclization to
provide the expected chromenoisoxazolidine. Further efforts
revealed that the productivity is moderate even at lower
concentrations, providing a slightly better 42% yield at 0.005
M (entry 11; other concentrations entries 8−10). Other efforts
for comparable reactions have revealed the need of organic or
inorganic photocatalyst for the efficient promotion of such
transformations.16 These efforts led to the discovery that well-
known photocatalyst Ru(bpy)3Cl2 was able to significantly
This study also aimed at assessing the efficiency of the
visible-light-promoted process on substrates with sterically
demanding allyl ethers (Table 3). As expected, diastereose-
lectivities across the fused ring remain highly selective for the
cis product.18 Substitution at the allylic carbon led to the
production of the expected heterocycle as a 12:1 mixture of
B
DOI: 10.1021/acs.orglett.9b00097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Table 2. Reaction Scope
Table 3. Reaction Scope
a
Reaction conditions: Nitrone (0.1 mmol) and Ru(bpy)3Cl2 (0.005
b
c
mmol) in CH3CN 0.005 M for 24 h. Isolated yields. Reaction crude
was purified by automated chromatography.
diastereomers at the chiral allylic position. The stereoselectivity
observed highly correlates with an expected all-pseudoequato-
rial transition state for this substrate. Moreover, the reaction
yield and overall conversion were not affected by the added
substitution (entry 1, 91% yield). Substrates with methyl
substituents at the 2- and 3-carbon were also very successful at
providing the respective chromenoisoxazolidine in high yields
and diastereoselectivities (entries 2 and 3, 92 and 89% yield,
respectively). Trisubstituted 3,3-dimethylallyl nitrone provided
the product in similar high yields with a slightly prolonged
reaction time (entry 4, 87% yield).
a
Reaction conditions: ntrone (0.1 mmol) and Ru(bpy)3Cl2 (0.005
mmol) in CH3CN 0.005 M for 24 h. bIsolated yields. cReaction crude
was purified by automated chromatography. dNitrone 1a is
particularly sensitive and high purity is required to avoid hydrolysis.
Similarly, sterically demanding 3-phenylallyl and geranyl
nitrones also provided the respective product in high yields
and stereoselectivities (entries 5 and 6, 91 and 88% yield,
C
DOI: 10.1021/acs.orglett.9b00097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
respectively). Tetrasubstituted and bulkier trisubstituted allyl
nitrones failed to react to provide the respective highly
substituted chromenoisoxazolidines in synthetically useful
yields (not shown in the table).
Diversification at the N-alkyl position showed similar success
as N-cyclohexyl, N-phenyl, and N-methyl nitrones provided
the desired heterocycles in similar high yields and selectivities
(entries 7−9, 86, 85, and 84% yield, respectively). Nitrones
with N-bound electron-withdrawing groups (Boc, Cbz)
displayed very low conversion under the proposed reaction
conditions.
The encouraging results shifted the focus toward the study
of the reaction mechanism. Nitrones derived from aromatic
aldehydes are good spin-trapping agents, making them suitable
candidates for photoxidation pathways.19 Moreover, aldoni-
trones with electron-donating groups as the proposed substrate
are reported to undergo less demanding oxidation pathways.20
Mechanistically, the reaction in the absence of a photo-
catalyst must be promoted by the slow excitation of the
substrate to the nitrone triplet state, followed by fast
cyclization and then relaxation to the ground state. Under a
photocatalytic redox-neutral mechanism the substrate plays
both reductant and oxidant roles (Figure 1). Thus, upon
NMR monitoring, thus providing further evidence of a redox-
neutral pathway (SI).
In conclusion, we have developed the first general report for
a redox-neutral visible-light photocatalytic intramolecular
dipolar cycloaddition. The reaction works in high yields for a
wide variety of substrates with multiple diversification points
under very mild conditions. Additionally, the reaction appears
to be highly diastereoselective and stereospecific for the cis
isomer and tolerant for a wide degree of substitution patterns
around the aromatic ring and pendant alkenyl group. Efforts
will continue to focus on further elucidating the proposed
redox-neutral mechanism and establishing novel photoredox
reactions for the synthesis of complex N-containing hetero-
cycles.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b00097.
Experimental protocols and spectroscopic data for each
chromenoisoxazolidine are provided (PDF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: moura-letts@rowan.edu.
ORCID
Gustavo Moura-Letts: 0000-0001-8156-151X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This material is based upon work supported by the National
Science Foundation CAREER award under grant number
CHE-1752085. We are also thankful to Dr. John F. Eng at
Princeton University for his help with HRMS analysis.
REFERENCES
■
(1) (a) Kawade, R. K.; Liu, R.-S. Angew. Chem., Int. Ed. 2017, 56,
2035. (b) Cornil, J.; Gonnard, L.; Bensoussan, C.; Serra-Muns, A.;
Gnamm, C.; Commandeur, C.; Commandeur, M.; Reymond, S.;
Guerinot, A.; Cossy, J. Acc. Chem. Res. 2015, 48, 761. (c) Chakrabarty,
S.; Chatterjee, I.; Wibbeling, B.; Daniliuc, G.; Studer, A. Angew. Chem.,
Int. Ed. 2014, 53, 5964. (d) Zhang, G.; Rucker, G.; Breitmaier, E.;
Nieger, M.; Mayer, R.; Steinbeck, C. Phytochemistry 1995, 40, 299.
(e) Xie, J.; Xue, Q.; Jin, H.; Li, H.; Cheng, Y.; Zhu, C. Chem. Sci.
2013, 4, 1281. (f) Koyama, K.; Hirasawa, Y.; Nugroho, A. E.; Hosoya,
T.; Hoe, T. C.; Chan, K.-L.; Morita, H. Org. Lett. 2010, 12, 4188.
(g) Hong, A. Y.; Vanderwal, C. D. J. Am. Chem. Soc. 2015, 137, 7306.
(h) Krenske, E. H.; Patel, A.; Houk, K. N. J. Am. Chem. Soc. 2013,
135, 17638.
(2) (a) Berthet, M.; Cheviet, T.; Dujardin, G.; Parrot, I.; Martinez, J.
Chem. Rev. 2016, 116, 15235. (b) Yotsu-Yamashita, M.; Kim, Y. H.;
Dudley, S. C.; Choudhary, G.; Pfahnl, A.; Oshima, Y.; Daly, J. W. Proc.
Natl. Acad. Sci. U. S. A. 2004, 101, 4346. (c) Nishikawa, T.; Urabe, D.;
Isobe, M. Heterocycles 2009, 79, 379.
(3) (a) Lee, C.; Choe, S.; Lee, J. W.; Jin, Q.; Lee, M. K.; Hwang, B.
Y. Bull. Korean Chem. Soc. 2013, 34, 1290. (b) Pellissier, H.
Tetrahedron 2012, 68, 2197. (c) Gothelf, K. V.; Jorgensen, K. A.
Chem. Rev. 1998, 98, 863. (d) Stanley, L. M.; Sibi, M. P. Chem. Rev.
2008, 108, 2887. (e) Nair, V.; Suja, T. D. Tetrahedron 2007, 63,
12247. (f) Tiecco, M.; Testaferri, L.; Marini, F.; Sternativo, S.; Santi,
C.; Bagnoli, L.; Temperini, A. Tetrahedron: Asymmetry 2001, 12,
Figure 1. Proposed photoredox-neutral mechanism.
excitation of Ru(bpy)3+2 to *Ru(bpy)3+2, nitrone 1a undergoes
single electron transfer oxidation to form the respective radical
+
cation 3 and Ru(bpy)3 . The radical cation intermediate then
undergoes intramolecular radical addition across the pendant
alkene to form chromenoisoxazolidine radical cation 4. This
intermediate quickly undergoes single electron transfer
reduction to produce product 2a and return the catalyst to
the ground state. In an effort to fully understand the dominant
pathway, tertiary amines were used as potential additives, and
it was discovered that no significant change was observed, thus
eliminating any potential need for a sacrificial reductant and
further validating a redox-neutral pathway. Next, radical-
trapping experiments showed that in the presence of
TEMPO there was complete shutdown of the photoredox
pathway, and no product was observed. This key experiment
provided further evidence of a predominant SET mechanism.
It was also discovered that the proposed photoredox process
1
could not be propagated in the absence of visible light by H
D
DOI: 10.1021/acs.orglett.9b00097
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
3053. (g) Carmona, D.; Lamata, M. P.; Viguri, F.; Rodriguez, R.; Oro,
L. A.; Lahoz, F. J.; Balana, A. I.; Tejero, T.; Merino, P. J. Am. Chem.
Soc. 2005, 127, 13386. (h) Viton, F.; Bernardinelli, G.; Kundig, E. P. J.
Am. Chem. Soc. 2002, 124, 4968. (i) Mita, T.; Ohtsuki, N.; Ikeno, T.;
Yamada, T. Org. Lett. 2002, 4, 2457. (j) Ohtsuki, N.; Kezuka, S.;
Kogami, Y.; Mita, T.; Ashizawa, T.; Ikeno, T.; Yamada, T. Synthesis
2003, 2003, 1462. (k) Kezuka, S.; Ohtsuki, N.; Mita, T.; Kogami, Y.;
Ashizawa, T.; Ikeno, T.; Yamada, T. Bull. Chem. Soc. Jpn. 2003, 76,
2197. (l) Shirahase, M.; Kanemasa, S.; Oderaotoshi, Y. Org. Lett.
2004, 6, 675. (m) Carmona, D.; Lamata, M. P.; Viguri, F.; Ferrer, J.;
Garcıa, N.; Lahoz, F. J.; Martın, M. L.; Oro, L. A. Eur. J. Inorg. Chem.
2006, 2006, 3155.
Prod. Rep. 2004, 21, 752. (i) Desai, M. C.; Lefkowitz, S. L.; Thadeio,
P. F.; Longo, K. P.; Snider, R. M. J. Med. Chem. 1992, 35, 4911.
(11) (a) Bonacorso, H. G.; Ketzer, W. C.; Calheiro, T. P.;
Rodrigues, M. B.; Zanatta, N.; Martins, A. P.; Frizzo, C. P. J. Fluorine
Chem. 2018, 210, 142. (b) Sosnovskikh, W. Y.; Moshkin, V. S.;
Kodess, M. I. Tetrahedron 2008, 64, 7877. (c) Zhao, Q.; Han, F.;
Romero, D. L. J. Org. Chem. 2002, 67, 3317. (d) Broggini, G.; Folcio,
F.; Sardone, N.; Sonzogni, M.; Zecchi, G. Tetrahedron: Asymmetry
1996, 7, 797. (e) Frederickson, M. Tetrahedron 1997, 53, 403.
(12) (a) Lizza, J. R.; Moura-Letts, G. Synthesis 2017, 49, 1231.
(b) Bakanas, I. J.; Moura-Letts, G. Eur. J. Org. Chem. 2016, 5345.
(c) Lizza, J. R.; Patel, S. V.; Yang, C. F.; Moura-Letts, G. Eur. J. Org.
Chem. 2016, 5160. (d) Neuhaus, W. C.; Moura-Letts, G. Tetrahedron
Lett. 2016, 57, 4974. (e) Quinn, D. J.; Haun, G. J.; Moura-Letts, G.
Tetrahedron Lett. 2016, 57, 3844. (f) Costantini, N. V.; Bates, A. D.;
Haun, G. J.; Chang, N. M.; Moura-Letts, G. ACS Sustainable Chem.
Eng. 2016, 4, 1906. (g) Neuhaus, W. C.; Bakanas, I. J.; Lizza, J. R.;
Boon, C., Jr; Moura-Letts, G. Green Chem. Lett. Rev. 2016, 9, 39.
(h) Beebe, A. W.; Dohmeier, E. F.; Moura-Letts, G. Chem. Commun.
2015, 51, 13511.
(4) Quinn, D. J.; Tumbelty, L. N.; Moscarello, E. M.; Paneque, A.
N.; Zinsky, A. H.; Russ, M. P.; Haun, G. J.; Cinti, N. A.; Dare, R. M.;
Moura-Letts, G. Tetrahedron Lett. 2017, 58, 4682.
(5) (a) Yamaguchi, M.; Matsuda, A.; Ichikawa, S. Org. Biomol. Chem.
2015, 13, 1187. (b) Aguiar, A.; Leite, A.; Silva, A. M. N.; Tome, A. C.;
Cunha-Silva, B. D.; Castro, M.; Silva, A. M. G. Org. Biomol. Chem.
2015, 13, 7131. (c) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247.
(d) Jeong, J. H.; Weinreb, S. M. Org. Lett. 2006, 8, 2309. (e) Tamura,
O.; Iyama, N.; Ishibashi, H. J. Org. Chem. 2004, 69, 1475. (f) Dhavale,
D. D.; Jachak, S. M.; Karche, N. P.; Trombini, N. C. Tetrahedron
2004, 60, 3009. (g) White, J. D.; Hansen, J. D. J. Am. Chem. Soc.
2002, 124, 4950. (h) Bhutia, Z. T.; Geethika, P.; Malik, A.; Kumar, A.;
Chatterjee, A.; Roy, B. G.; Banerjee, M. RSC Adv. 2015, 5, 99566.
(i) Furnival, R. C.; Saruengkhanphasit, R.; Holberry, H. E.; Shewring,
J. R.; Guerrand, H. D. S.; Adams, H.; Coldham, I. Org. Biomol. Chem.
2016, 14, 10953. (j) Bakthadoss, M.; Srinivasan, J. RSC Adv. 2015, 5,
67206.
(13) (a) Gesmundo, N. J.; Grandjean, J.-M. M.; Nicewicz, D. A. Org.
Lett. 2015, 17, 1316. (b) Cavanaugh, C. L.; Nicewicz, D. A. Org. Lett.
2015, 17, 6082.
(14) (a) Clark, A. Chem. Soc. Rev. 2002, 31, 1. (b) Pintauer, T.;
Matyjaszewski, K. Chem. Soc. Rev. 2008, 37, 1087. (c) Barton, D. H.
R.; Csiba, M. A.; Jaszberenyi, J. C. Tetrahedron Lett. 1994, 35, 2869.
(d) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson,
C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (e) Wallentin, C.-J.;
Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem. Soc.
2012, 134, 8875. (f) Pirtsch, M.; Paria, S.; Matsuno, T.; Isobe, H.;
Reiser, O. Chem. - Eur. J. 2012, 18, 7336. (g) Iqbal, N.; Choi, S.; Kim,
E.; Cho, E. J. J. Org. Chem. 2012, 77, 11383.
(15) Cismesia, M. A.; Yoon, T. P. Chem. Sci. 2015, 6, 5426.
(16) (a) Campagna, S.; Puntoriero, F.; Nastasi, F.; Bergamini, G.;
Balzani, V. Top. Curr. Chem. 2007, 280, 117. (b) McCusker, J. K. Acc.
Chem. Res. 2003, 36, 876. (c) Bock, C. R.; Connor, J. A.; Gutierrez, A.
R.; Meyer, T. J.; Whitten, D. G.; Sullivan, B. P.; Nagle, J. K. J. Am.
Chem. Soc. 1979, 101, 4815.
̈
̈
(6) (a) Karkas, M. D.; Porco, J. A., Jr; Stephenson, C. R. Chem. Rev.
2016, 116, 9683. (b) Bach, T.; Hehn, J. P. Angew. Chem., Int. Ed.
2011, 50, 1000. (c) Hoffmann, N. Chem. Rev. 2008, 108, 1052.
(d) Takeda, H.; Ishitani, O. Coord. Chem. Rev. 2010, 254, 346−354.
̈
(e) Kalyanasundaram, K.; Gratzel, M. Coord. Chem. Rev. 1998, 177,
347. (f) Narayanam, J. M. R.; Stephenson, C. R. Chem. Soc. Rev. 2011,
40, 102. (g) Xuan, J.; Xiao, W.-J. Angew. Chem., Int. Ed. 2012, 51,
6828. (h) Schultz, D. M.; Yoon, T. P. Science 2014, 343, 1239176.
(7) (a) Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev.
2013, 113, 5322. (b) Shaw, M. H.; Twilton, J.; MacMillan, D. W. C. J.
Org. Chem. 2016, 81, 6898. (c) Romero, N. A.; Nicewicz, D. A. Chem.
Rev. 2016, 116, 10075. (d) Beatty, J. W.; Stephenson, C. R. Acc. Chem.
Res. 2015, 48, 1474. (e) Pitre, S. P.; McTiernan, C. D.; Scaiano, J. C.
Acc. Chem. Res. 2016, 49, 1320. (f) Skubi, K. L.; Blum, T. R.; Yoon, T.
P. Chem. Rev. 2016, 116, 10035.
(17) General protocol for synthesis of chromenoisoxazolidines from
nitrones: In an oven-dried 250 mL round-bottom flask, nitrone (1
mmol, 1 equiv) and Ru(bpy)3Cl2 (0.05 mmol, 0.05 equiv, 5 mol %)
were dissolved in CH3CN (200 mL) 0.005 M under N2 atmosphere.
The resulting mixture was then stirred at room temperature in a
photoreactor with a white LED bulb for 24 h. The resulting crude was
then dried under reduced pressure, and the residue was loaded
directly onto a silica gel column for automated purification.
(18) The isomers isolated in this reaction were characterized by 1D
(8) (a) Rueping, M.; Leonari, D.; Poisson, T. Chem. Commun. 2011,
47, 9615. (b) Zou, Y.-Q.; Lu, L.-Q.; Fu, L.; Chang, N.-J.; Rong, J.;
Chen, J.-R.; Xiao, W.-J. Angew. Chem., Int. Ed. 2011, 50, 7171.
(c) Maity, S.; Zhu, M.; Shinabery, R. S.; Zheng, N. Angew. Chem., Int.
Ed. 2012, 51, 222. (d) Hou, H.; Zhu, S.; Pan, F.; Rueping, M. Org.
Lett. 2014, 16, 2872. (e) Xuan, J.; Xia, X.-D.; Zeng, T.-T.; Feng, Z.-J.;
Chen, J.-R.; Lu, L.-Q.; Xiao, W.-J. Angew. Chem., Int. Ed. 2014, 53,
5653. (f) Zeng, T.-T.; Xuan, J.; Ding, W.; Wang, K.; Lu, L.-Q.; Xiao,
W.-J. Org. Lett. 2015, 17, 4070. (g) Chen, L.; Li, H.; Li, P.; Wang, L.
Org. Lett. 2016, 18, 3646. (h) Alfonzo, E.; Alfonso, F. S.; Beeler, A. B.
Org. Lett. 2017, 19, 2989.
1
and 2D H NMR. The cis stereochemistry was assigned based on
coupling constant and NOE analysis.
(19) (a) Becker, D. A.; Ley, J. J.; Echegoyen, L.; Alvarado, R. J. Am.
Chem. Soc. 2002, 124, 4678. (b) Rosselin, M.; Choteau, F.; Zeamari,
K.; Nash, K. M.; Nash, A.; Das, A.; Lauricella, R.; Lojou, E.; Tuccio,
B.; Villamena, F. A.; Durand, G. J. Org. Chem. 2014, 79, 6615.
(20) Rosselin, M.; Tuccio, B.; Perio, P.; Fabre, P.-L.; Durand, G.
Electrochim. Acta 2016, 193, 231.
(9) (a) Zheng, L.; Gao, F.; Yang, C.; Gao, G.-L.; Zhao, Y.; Gao, Y.;
Xia, W. Org. Lett. 2017, 19, 5086. (b) Jang, G. S.; Lee, J.; Seo, J.; Woo,
K. Org. Lett. 2017, 19, 6448.
(10) (a) Gomez-Canas, M.; Morales, P.; Garcia-Toscano, L.;
Nvarrete, C.; Munoz, E.; Jagerovic, N.; Fernandez-Ruiz, J.; Garcia-
Arencibia, M.; Pazos, M. R. Pharmacol. Res. 2016, 110, 205.
(b) Kwon, Y. J.; Saubern, S.; MacDonald, J. M.; Huang, X.-P.;
Setola, V.; Roth, B. L. Bioorg. Med. Chem. Lett. 2010, 20, 5488.
(c) Liu, L.-X.; Ruan, Y.-P; Guo, Z.-Q; Huang, P.-Q J. Org. Chem.
2004, 69, 6001. (d) Gonzalez, A. S.; Arrayas, R. G.; Rivero, M. R.;
Carretero, J. C. Org. Lett. 2008, 10, 4335. (e) Ruan, S.-T.; Luo, J.-M;
Du, Y.; Huang, P.-Q Org. Lett. 2011, 13, 4938. (f) Tan, C. K.; Yeung,
Y.-Y. Chem. Commun. 2012, 48, 5793. (g) Pansare, S. V.; Paul, E. K.
Org. Biomol. Chem. 2012, 10, 2119. (h) Ma, X. Q.; Gang, D. R. Nat.
E
DOI: 10.1021/acs.orglett.9b00097
Org. Lett. XXXX, XXX, XXX−XXX