Intramolecular Crossed [2+2] Photocycloaddition through Visible Light-Induced Energy Transfer

Article abstract of DOI:10.1021/jacs.7b05277

Herein, we present the intramolecular [2+2] cycloadditions of dienones promoted through sensitization, using a polypyridyl iridium(III) catalyst, to form bridged cyclobutanes. In contrast to previous examples of straight [2+2] cycloadditions, these efficient crossed additions were achieved under irradiation with visible light. The reactions delivered desired bridged benzobicycloheptanone products with excellent regioselectivity in high yields (up to 96%). This process is superior to previous syntheses of benzobicyclo[3.1.1]heptanones, which are readily converted to B-norbenzomorphan analogues of biological significance. Electrochemical, computational, and spectroscopic studies substantiated the mechanism of triplet energy transfer and explained the unusual regiocontrol.

Full text of DOI:10.1021/jacs.7b05277

Subscriber access provided by UNIVERSITY OF CONNECTICUT
Communication
Intramolecular Crossed [2 + 2] Photocycloaddition
Through Visible Light-Induced Energy Transfer
Jiannan Zhao, Jonathan L. Brosmer, Qingxuan Tang, Zhongyue
Yang, Kendall N. Houk, Paula L. Diaconescu, and Ohyun Kwon
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b05277 • Publication Date (Web): 06 Jul 2017
Downloaded from http://pubs.acs.org on July 6, 2017
Just Accepted
“Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted
online prior to technical editing, formatting for publication and author proofing. The American Chemical
Society provides “Just Accepted” as a free service to the research community to expedite the
dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts
appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been
fully peer reviewed, but should not be considered the official version of record. They are accessible to all
readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered
to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published
in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just
Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor
changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers
and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors
or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
Journal of the American Chemical Society is published by the American Chemical
Society. 1155 Sixteenth Street N.W., Washington, DC 20036
Published by American Chemical Society. Copyright © American Chemical Society.
However, no copyright claim is made to original U.S. Government works, or works
produced by employees of any Commonwealth realm Crown government in the course
of their duties.

Page 1 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
Intramolecular Crossed [2 + 2] Photocycloaddition Through Visible
Light–Induced Energy Transfer
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Jiannan Zhao, Jonathan L. Brosmer, Qingxuan Tang, Zhongyue Yang, K. N. Houk, Paula L. Diaconescu,
and Ohyun Kwon*
Department of Chemistry and Biochemistry, University of California, Los Angeles, California 90095ꢀ1569, United States
Supporting Information Placeholder
Scheme 1. Regioselectivity in Intramolecular [2 + 2]
Photocycloadditions
ABSTRACT: Herein, we present the intramolecular [2 + 2]
cycloadditions of dienones promoted through sensitization, using
a polypyridyl iridium(III) catalyst, to form bridged cyclobutanes.
In contrast to previous examples of straight [2 + 2] cycloadditions,
these efficient crossed additions were achieved under irradiation
with visible light. The reactions delivered desired bridged
benzobicycloheptanone products with excellent regioselectivity in
high yields (up to 96%). This process is superior to previous
syntheses of benzobicyclo[3.3.1]heptanones, which are readily
converted to Bꢀnorbenzomorphan analogues of biological
significance. Electrochemical, computational, and spectroscopic
studies substantiated the mechanism of triplet energy transfer and
explained the unusual regiocontrol.
Cyclobutanes are prominent structural components in many
bioactive natural products1 and are also valuable synthetic
intermediates in the preparation of largerꢀring systems.2
Photochemical [2 + 2] cycloaddition is the most frequently used
reaction to access cyclobutaneꢀcontaining structures.3–6 In
addition to conventional UV light–promoted photochemical
transformations,3 [2 + 2] cycloadditions through visible light
photoredox catalysis are also efficient means for construction of
fourꢀmembered carbocycles.4 The scope of these reactions is,
however, limited to a pair of electronꢀdeficient or ꢀrich alkenes
that are amenable to oneꢀelectron redox processes.5 There is also
ongoing interest into the efficacious utilization of energy transfer
pathways in visible light photocatalysis.6 The broad substrate
scope, independent of the electronic nature, makes the energy
transfer process more attractive than the singleꢀelectron transfer
(SET) approach for performing [2 + 2] cycloadditions.
bicycloheptane 2 as the sole regioisomer, presumably facilitated
by the rapid formation of fiveꢀmembered rings and the stability of
the radical intermediates generated through the SET4 or energy
transfer6 process (Scheme 1b). In light of the versatility of energy
transfer as
a
mode of photoactivation, however, the
regioselectivity of the [2 + 2] photocycloadditions should be
altered depending on the stability of the 1,4ꢀdiradical
intermediates. We, therefore, reasoned that the benzoyl tethered
substrate 3a should provide access to the thermodynamically
preferred benzyl radical DR1, which, subsequently, would
undergo ring closure to form the bridged bicyclo[3.3.1]heptanone
4a (Scheme 1c).
In general, intramolecular [2 + 2] cyclizations give rise to either
crossed or straight products, depending on the regioselectivity
(Scheme 1).7 When the tether between the reacting olefinic units
is only two atoms (n = 2), crossed adducts prevail to avoid the
formation of strained fourꢀmembered rings. If the tether is longer
(n = 3 or 4), a straight addition mode is preferred (Scheme 1a).
Typically, these rules can be used to predict the regioselectivity,
and exceptions are rare—even in examples of conventional [2 +
2] photocycloadditions promoted by UV light.8 Although visible
light photocatalysis is enjoying increasing use in stereoselective
[2 + 2] cycloadditions,6 the regioselectivity of the reactions has
been limited previously to the headꢀtoꢀhead mode. Yoon had
demonstrated that the tethered bis(styrene) or bis(enone) 1
undergoes straight cycloaddition, producing the fused
Initially, the [2 + 2] cycloaddition was investigated using the oꢀ
styrenyl enone 3a as the model substrate in dichloromethane and
irradiating with a 12ꢀW white light emitting diode (LED). No
2+
reactions occurred in the presence of Ru(bpy)3 (5a) and
2+
Ru(bpz)3 (5b), which possess triplet energies of 46.5 and 48.4
kcal mol–1, respectively (Table 1, entries
1
and 2).9,10
Consequently, Ir[dF(CF3)ppy]2(dtbbpy)+ 6+ was strategically
chosen as the triplet sensitizer because of its higher triplet energy
(60.1 kcal mol–1) and longꢀlived triplet state (
τ
= 2300 ns).4b,13
To our delight, this iridium complex led to a clean intramolecular
[2 + 2] cycloaddition, which generated the crossed product 4a as a
single regioisomer (Table 1, entry 3).14 A lower concentration of
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 2 of 5
the substrate 3a avoided polymerization and increased the product
elaborate the scope of this reaction, we tested the behavior of the
1
2
3
4
5
6
7
8
yield to 93% after an irradiation time of 24 h (Table 1, entry 4).
naphthalene substrates 3t and 3u (Scheme 2). Surprisingly, the
unusual
Table 2. Scope of Photosensitized [2 + 2] Cycloadditionsa–c
Table 1. Optimization of the Photosensitized [2 + 2]
Cycloaddition and Control Studiesa
white LEDs
catalyst (1 mol%)
white LEDs
6•PF6 (1 mol%)
solvent, 25 o
C
CH2Cl2, 25 o
C
O
O
O
24 h
O
3a
4a, 90% yield
3a
4a
9
Cl
O
+
2+
CF3
X
N
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
tBu
Br
N
X
X
X
X
O
O
O
N
N
N
N
N
F
F
IrIII
N
4b
, 96% yield, 24 h
4c
4d
, 83% yield, 36 h
, 90% yield, 12 h
RuII
N
N
tBu
F
Cl
O
X
CF3
2+
+
O
, 95% yield, 24 h
O
O
5a
5b
6
Ir(dF(CF3)ppy)2(dtbbpy)
(X = CH) Ru(bpy)3
4e
2+
4f
4g
, 93% yield, 12 h
, 46% yield, 20 h
(X = N) Ru(bpz)3
O
entry
catalyst
solvent
conc. [M]
0.1
yieldb
0
1
2
3
4
5
6
7
8c
5a·Cl2·6H2O CH2Cl2
O
N
O
, 0% yield, 24 h
O
O
CH2Cl2
CH2Cl2
CH2Cl2
THF
0.1
0
5b·(PF6)2
6·PF6
6·PF6
6·PF6
6·PF6
none
4i
4j
4h
, 77% yield, 12 h
, 38% yield, 20 h
0.1
78%
93%
48%
76%
0
Ph
0.02
0.02
0.02
0.02
0.02
O
O
, 83% yield
2:1 d.r., 36 h
i-Pr
O
MeCN
CH2Cl2
CH2Cl2
4k
4l
4m
, 82% yield, 24 h
, 95% yield, 12 h
i-Pr
0
6·PF6
aReaction of photocatalyst (0.001 mmol) and 3a (0.1 mmol) was
conducted under irradiation from a 12ꢀW white LED light strip
under N2 at 25 °C for 24 h. Determined from H NMR spectra,
using 2,4ꢀdinitroꢀ1ꢀchlorobenzene as internal standard. cControl
reaction conducted in the dark.
Ph
Me
O
O
O
b
1
4n, 78% yield
1:1 d.r., 24 h
4o
, 92% yield
1:1 d.r., 12 h
4p
, 91% yield, 12 h
Ar
Ar
O
Ph
Tests of alternative solvents (THF, CH3CN) delivered relatively
O
, Ar = 4-ClC6H4
94% yield, 12 h
O
unsatisfactory results (Table 1, entries
5 and 6). Control
4q
, 96% yield, 18 h
4r
4s, Ar = 4-MeOC6H4
experiments confirmed that the cycloaddition did not occur in the
absence of the photocatalyst or in the absence of light (Table 1,
entries 7 and 8).
92% yield, 12 h
aReactions of 3 (0.1 mmol) in the presence of 1 mol% 6·PF6 under N2
with irradiation from a 12ꢀW white LED light strip at a distance of 4
cm. bIsolated yields of cyclic products after 8–36 h.
To test the viability of this method, we turned our attention to
using other styrenyl enones as substrates. Table 2 reveals that
substrates presenting electronꢀwithdrawing, ꢀneutral, and
cDiastereoisomeric ratios determined from H NMR spectra of crude
1
ꢀ
reaction mixtures.
donating substituents on the aromatic ring all tolerated 1 mol% of
the iridium complex 6·PF6, generating the benzobicycloheptanone
derivatives 4b–f in high yields. Positioning a methoxy group at
the para position of the styrene moiety, however, decreased the
yields of 4g and 4h, presumably a result of polymerization of
these more electronꢀrich olefins.15 Unfortunately, the 2ꢀpyridyl
enone substrate 4i was not a suitable reactant. Next, we
investigated the substrate scope with respect to substituents on the
carbon–carbon double bonds. Substrates bearing methyl or phenyl
substituents at the αꢀposition of the styrenic moiety successfully
participated in the reaction, providing access to the cyclobutane
structures 4j and 4k, bearing allꢀcarbon quaternary centers with
excellent regioselectivity. Substitution at the βꢀposition of the
styrenic unit was also tolerated, enabling the construction of
nonsymmetric benzobicyclo[3.1.1]heptanones 4l–o. Reactions
involving αꢀsubstituted enones gave the desired crossed products
4p–4s exclusively. For αꢀaryl enones, the reaction was insensitive
to the electronic nature of the aryl rings (4q–s). To further
bridged cyclobutanone products 4t and 4u were generated through
rearrangement under the optimized conditions. Gratifyingly,
crystals suitable for Xꢀray crystallographic analysis
unambiguously revealed the bridged bicyclic structures of 4q and
4t.16
Scheme 2. Photocycloaddition of NaphthylꢀEnones
ACS Paragon Plus Environment

Page 3 of 5
Journal of the American Chemical Society
O
Scheme 4 outlines our proposed mechanism for the [2 + 2]
white LEDs
1
2
3
4
5
6
7
8
photocycloaddition. Irradiation of the iridium complex with
visible light produces the longꢀlived excited state *Ir(III). The
exergonic energy transfer generates the triplet 3a*, which
undergoes intramolecular cyclization to generate a series of 1,4ꢀ
diradical intermediates (DR1–DR4). Computations revealed that
the benzyl radical DR1 is thermodynamically preferred and
enables the second ring closure to the isolated bridged
cycloadduct 4a. In addition, the mechanism for the formation of
4t and 4u presumably involves crossed [2 + 2] cycloaddition of a
ketene intermediate,24 which might arise from rearrangement of
the diradical intermediate with involvement of the naphthyl
moiety.10
6•PF6 (1 mol%)
CH2Cl2, 25 o
C
O
3t
4t
, 88% yield
white LEDs
6•PF6 (1 mol%)
O
CH2Cl2, 25 o
C
O
3u
4u
, 73% yield
9
10
11
Manipulation of the cyclobutaneꢀbridged tetralones 4 offers
opportunities to generate other cyclobutaneꢀcontaining structures
(Scheme 3). For instance, treatment of the cycloadducts 4 with
hydroxylamine hydrochloride and sodium acetate in methanol
afforded the corresponding ketoximes 7 in excellent yields.17
Subsequent Beckmann rearrangements in the presence of thionyl
chloride provided regioselective access to the lactams 8 via
exclusive alkyl migration.18 Reduction and methylation of 8 gave
the analogues of Bꢀnorbenzomorphan19 9 and 10, respectively,
which are known to possess significant analgesic activity.20
Divergently, the bridged tricycle 8d was a pivotal intermediate in
the synthesis of compound 11 reported by Genentech, who
disclosed its inhibition of NFꢀκB inducing kinase (NIK) and
therapeutic potential for inflammatory disease and cancer.14c,d
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 4. Mechanism of [2 + 2] Photocycloaddition of 3a
Scheme 3. Elaboration of Benzobicyclo[3.3.1]heptanones
In summary, the iridium photocatalyst 6·PF6 enables the
synthesis of bridged benzobicyclo[3.3.1]heptanones through [2 +
2] photocycloadditions under irradiation with visible light. The
excellent regioselectivity observed in this reaction is
a
Mechanistically, our crossed [2 + 2] cycloaddition proceeds via
energy transfer from the triplet sensitizer 6+ to the oꢀstyrenyl
enone 3. In the cyclic voltammograms of 3a, oxidation and
reduction features were observed with halfꢀpeak potentials of
+1.81 V vs SCE and –1.56 V vs SCE, respectively.10 These
electrochemical characteristics ruled out electron transfer
pathways for 3a because the redox potentials of the photocatalyst
6+ indicate that either oxidation or reduction of 3a would be
endergonic.21 We studied the energetics of 3a (singlet) and 3a*
(triplet) computationally using the B3LYP/6ꢀ311+G(2d,p) method
with an implicit CH2Cl2 medium.22 The computed energy gap
(58.5 kcal mol–1) was lower than the triplet energy of
Ir*[dF(CF3)ppy]2(dtbbpy)+ (60.1 kcal mol–1),10 suggesting that
energy transfer from the catalyst to the substrate was feasible.
Stern–Volmer studies23 revealed that the quenching of 6*·PF6 was
linear with respect to the concentration of 3a.10 The energyꢀ
transfer pathway was also supported by the observation that the
reaction worked better in CH2Cl2 than in MeCN or THF. Charged
radical ion intermediates, possibly generated through electron
transfer, would have been strongly destabilized in nonpolar media.
considerable advance in the construction of bridged bicyclic
structures—indeed, it is the first example of exclusive crossed [2
+ 2] cycloaddition promoted by visible light. This approach
provides ready access to bridged benzobicycloheptanone products
that are easily elaborated to biologically active Bꢀ
norbenzomorphan analogues. This additiveꢀfree, atomꢀeconomical
reaction can be performed using simple photochemical equipment
under benign conditions. Detailed mechanistic studies have ruled
out substrate activation by means of SET and, instead, have
confirmed the role of photosensitization through energy transfer.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the
ACS Publication website at DOI: 10.1021/jacs.
Experimental procedures and analytical data (PDF)
Crystallographic data for 4q and 4t (CIF)
AUTHOR INFORMATION
ACS Paragon Plus Environment

Journal of the American Chemical Society
Page 4 of 5
566. (d) Schuster, D. I.; Lem, G.; Kaprinidis, N. A. Chem. Rev. 1993, 93,
Corresponding Author
3. (e) Maradyn, D. J.; Weedon, A. C. J. Am. Chem. Soc. 1995, 117, 5359.
(8) For exceptions, see: (a) LaLonde, R. T.; Aksentijevich, R. I.
Tetrahedron Lett. 1965, 6, 23. (b) Begley, M. J.; Mellor, M.; Pattenden, G.
J. Chem. Soc., Chem. Commun. 1979, 235. (c) Alder, A.; Bühler, N.;
Bellus, D. Helv. Chim. Acta 1982, 65, 2405. (d) Matlin, A. R.; George, C.
F.; Wolff, S.; Agosta, W. C. J. Am. Chem. Soc. 1986, 108, 3385. (e)
Crimmins, M. T.; Hauser, E. B. Org. Lett. 2000, 2, 281. (f) Busqué, F.;
March, P.; Figueredo, M.; Font, J.; Margaretha, P.; Raya, J. Synthesis
2001, 1143. (g) Bach, T.; Kemmler, M.; Herdtweck, E. J. Org. Chem.
2003, 68, 1994. (h) Kohmoto, S.; Hisamatsu, S.; Mitsuhashi, H.;
Takahashi, M.; Masu, H.; Azumaya, I.; Yamaguchi, K.; Kishikawa, K.
Org. Biomol. Chem. 2010, 8, 2174. (i) Weixler, R.; Hehn, J. P.; Bach, T. J.
Org. Chem. 2011, 76, 5924.
1
2
3
4
5
6
7
8
*ohyun@chem.ucla.edu
Notes
The authors declare no competing financial interests.
ACKNOWLEDGMENT
We thank the NIH (GM071779 to O.K.) and the NSF (CHEꢀ
1362999 to P.L.D.; CHEꢀ1361104 to K.N.H.) for financial
support. Calculations were performed on the Hoffman2 cluster at
UCLA and the Extreme Science and Engineering Discovery
Environment (XSEDE), which is supported by the NSF (OCIꢀ
1053575). We also thank Prof. Ellen M. Sletten and Dr. Wei Cao
for help with the Stern–Volmer studies and Prof. Hosea Nelson
and Luke Boralsky for sharing their Rayoner RPRꢀ200 UV reactor.
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(9) UV irradiation of 3a in the absence and presence of photosensitizers
(xanthone, benzophenone and acetone) produced 4a in 10−46% yield.
(10) For details, see the Supporting Information.
(11) (a) Rillema, D. P.; Allen, G.; Meyer, T. J.; Conrad, D. Inorg.
Chem. 1983, 22, 1617. (b) Haga, M.ꢀA.; Dodsworth, E. S.; Eryavec, G.;
Seymour, P.; Lever, A. B. P. Inorg. Chem. 1985, 24, 1901. (c) Teegardin,
K.; Day, J. I.; Chan, J.; Weaver, J. Org. Process Res. Dev. 2016, 20, 1156.
(d) In ref. 6d, the Yoon group calculated values of ET for 5a (46.8 kcal
mol–1) and 5b (47.4 kcal mol–1) based on the emission maxima reported in:
Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.; von
Zelewsky, A. Coord. Chem. Rev. 1988, 84, 85.
REFERENCES
(1) (a) Hansen, T. V.; Stenstrøm, Y. Naturally Occurring Cyclobutanes.
In Organic Synthesis: Theory and Applications; Hudlicky, T., Ed.;
Elsevier: Oxford, U.K., 2001; Vol. 5, p 1. (b) Dembitsky, V. M. J. Nat.
Med. 2008, 62, 1.
(2) (a) Oppolzer, W. Acc. Chem. Res. 1982, 15, 135. (b) Winkler, J. D.;
Bowen, C. M.; Liotta, F. Chem. Rev. 1995, 95, 2003. (c) LeeꢀRuff, E.;
Mladenova, G. Chem. Rev. 2003, 103, 1449. (d) Namyslo, J. C.;
Kaufmann, D. E. Chem. Rev. 2003, 103, 1485. (e) Hoffmann, N. Chem.
Rev. 2008, 108, 1052. (f) Bach, T.; Hehn, J. P. Angew. Chem. Int. Ed.
2011, 50, 1000. (g) Seiser, T.; Saget, T.; Tran, D. N.; Cramer, N. Angew.
Chem. Int. Ed. 2011, 50, 7740.
(3) For selected reviews, see: (a) Bauslaugh, P. G. Synthesis 1970, 287.
(b) Crimmins, M. T.; Reinhold, T. L. Org. React. 1993, 44, 297. (c)
Fleming, S. A.; Bradford, C. L.; Gao, J. J. Regioselective and
Stereoselective [2 + 2] Photocycloadditions. In Organic Photochemistry,
Molecular and Supramolecular Photochemistry; Ramamurthy, V.,
Schanze, K. S., Eds.; Dekker: New York, 1997; Vol. 1, p 187. (d) Bach, T.
Synthesis 1998, 683. (e) Poplata, S.; Tröster, A.; Zou, Y.ꢀQ.; Bach T.
Chem. Rev. 2016, 116, 9748.
(4) For recent reviews, see: (a) Yoon, T. P. ACS Catal. 2013, 3, 895. (b)
Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113,
5322. (c) Xuan, J.; Lu, L.ꢀQ.; Chen, J.ꢀR.; Xiao, W.ꢀJ. Eur. J. Org. Chem.
2013, 6755. (d) Yoon, T. P. Acc. Chem. Res. 2016, 49, 2307.
(12) See ref. 4b for the excitedꢀstate lifetimes of 5a (τ = 1100 ns) and
5b (τ = 740 ns).
(13) (a) Lowry, M. S.; Hudson, W. R.; Pascal, R. A., Jr.; Bernhard, S. J.
Am. Chem. Soc. 2004, 126, 14129. (b) Lowry, M. S.; Goldsmith, J. I.;
Slinker, J. D.; Rohl, R.; Pascal, R. A., Jr.; Malliaras, G. G.; Bernhard, S.
Chem. Mater. 2005, 17, 5712. (c) Singh, A.; Teegardin, K.; Kelly, M.;
Prasad, K. S.; Krishnan, S.; Weaver, J. D. J. Organomet. Chem. 2015, 776,
51. (d) Ref. 11c.
(14) (a) Escale, R.; Girard, A. K. J. P.; Rossi, J. C.; Chapat, J. P. Org.
Magn. Reson. 1981, 17, 217. (b) Liu, Q.; Meng, J.; Liu, Y.; Yang, C.; Xia,
W. J. Org. Chem. 2014, 79, 8143. (c) Staben, S.; Castanedo, G. M.;
Montalbetti, C.; Feng, J. Tricyclic Compounds and Methods of Use
Therefor. U.S. Patent 9,034,866 B2, May 19, 2015. (d) Castanedo, G. M.;
Blaquiere, N.; Beresini, M.; Bravo, B.; Brightbill, H.; Chen, J.; Cui, H.ꢀF.;
Eigenbrot, C.; Everett, C.; Feng, J.; et al. J. Med. Chem. 2017, 60, 627.
(15) Gelation of 3g and 3h was observed upon standing at room
temperature.
(16) CCDC 1543972 (4q) and CCDC 1543973 (4t) contain the
supplementary crystallographic data for this paper. These data can be
obtained free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
(17) The ketoximes 7a and 7d were formed as 4:1 and 7:1 mixtures of
isomers, respectively. Both pairs of isomers were successfully converted
to the lactams 8a and 8d, respectively.
(5) For exception, see: Kranz, D. P.; Griesbeck, A. G.; Alle, R.; Perezꢀ
Ruiz, R.; Neudörfl, J. M.; Meerholz, K.; Schmalz, H.ꢀG. Angew. Chem. Int.
Ed. 2012, 51, 6000.
(6) For examples of visible light–promoted [2 + 2] cycloaddition via
energy transfer, see: (a) Ikezawa, H.; Kutal, C.; Yasufuku, K.; Yamazaki,
H. J. Am. Chem. Soc. 1986, 108, 1589. (b) Barbero, A.; García, C.; Pulido,
F. J. Synlett 2001, 824. (c) Zou, Y.ꢀQ.; Duan, S.ꢀW.; Meng, X.ꢀG.; Hu, X.ꢀ
Q.; Gao, S.; Chen, J.ꢀR.; Xiao, W.ꢀJ. Tetrahedron 2012, 68, 6914. (d) Lu,
Z.; Yoon, T. P. Angew. Chem. Int. Ed. 2012, 51, 10329. (e) Alonso, R.;
Bach, T. Angew. Chem. Int. Ed. 2014, 53, 4368. (f) Kumarasamy, E.;
Raghunathan, R.; Jockusch, S.; Ugrinov, A.; Sivaguru, J. J. Am. Chem.
Soc. 2014, 136, 8729. (g) Hurtley, A. E.; Lu, Z.; Yoon, T. P. Angew. Chem.
Int. Ed. 2014, 53, 8991. (h) Liu, Q.; Zhu, F.ꢀP.; Jin, X.ꢀL.; Wang, X.ꢀJ.;
Chen, H.; Wu, L.ꢀZ. Chem. Eur. J. 2015, 21, 10326. (i) Mojr, V.;
Svobodová, E.; Straková, K.; Neveselý, T.; Chudoba, J.; Dvořáková, H.;
Cibulka, R. Chem. Commun. 2015, 51, 12036. (j) Tröster, A.; Alonso, R.;
Bauer, A.; Bach, T. J. Am. Chem. Soc. 2016, 138, 7808. (k) Blum, T. R.;
Miller, Z. D.; Bates, D. M.; Guzei, I. A.; Yoon, T. P. Science 2016, 354,
1391.
(18) (a) Escale, R.; Khayat, A. E.; Vidal, J.ꢀP.; Girard, J.ꢀP.; Rossi, J.ꢀC.
J. Heterocyclic Chem. 1984, 21, 1033. (b) Crosby, I. T.; Shin, J. K.;
Capuano, B. Aust. J. Chem. 2010, 63, 211.
(19) (a) Mokotoff, M.; Jacobson, A. E. J. Heterocyclic Chem. 1970, 7,
773. (b) Mazzocchi, P. H.; Stahly, B. C. J. Med. Chem. 1979, 22, 455.
(20) For the analgesic activities of Bꢀnorbenzomorphan (ED50 = 20–25
mg kg–1), 9 (ED50 = 47 mg kg–1), 10a (ED50 = 15 mg kg–1), and codeine
(ED50 = 5 mg kg–1), see: Escale, R.; Vidal, J. P.; Rechencq, E.; Boucard,
M.; Girard, J. P.; Rossi, J. C. Eur. J. Med. Chem. 1985, 20, 371.
(21) For the redox potentials of Ir[dF(CF3)ppy]2(dtbbpy)+ 6+
[E1/2(IrIV/*IrIII) = −0.89 vs SCE; E1/2(*IrIII/IrII) = +1.21 vs SCE; E1/2(IrIV/IrIII)
= +1.69; E1/2(IrIII/IrII) = −1.37 vs SCE], see refs. 4b and 13.
(22) Chang, X.ꢀP.; Zheng, Y.; Cui, G.; Fang, W.ꢀH.; Thiel, W. Phys.
Chem. Chem. Phys. 2016, 18, 24713.
(23) Lakowicz, J. R. Principles of Fluorescence Spectroscopy; 3rd ed.;
Springer: New York, 2006.
(7) (a) Srinivasan, R.; Carlough, K. H. J. Am. Chem. Soc. 1967, 89,
4932. (b) Liu, R. S. H.; Hammond, G. S. J. Am. Chem. Soc. 1967, 89,
4936. (c) Gleiter, R.; Sander, W. Angew. Chem. Int. Ed. Engl. 1985, 24,
(24) Lachia, M.; Jung, P. M. J.; De Mesmaeker, A. Tetrahedron Lett.
2012, 53, 4514.
ACS Paragon Plus Environment

Page 5 of 5
Journal of the American Chemical Society
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
ACS Paragon Plus Environment