Tandem visible light-mediated radical cyclization-divinylcyclopropane rearrangement to tricyclic pyrrolidinones

Article abstract of DOI:10.1021/ol202178t

Visible light promoted single electron reduction of bromocyclopropyl cyclization scaffolds enabled by photoredox catalysis initiates a novel tandem radical cyclization/sigmatropic rearrangement to generate tricyclic pyrrolidinones having considerable mole

Full text of DOI:10.1021/ol202178t

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5468–5471
Tandem Visible Light-Mediated Radical
CyclizationÀDivinylcyclopropane
Rearrangement to Tricyclic
Pyrrolidinones
Joseph W. Tucker and Corey R. J. Stephenson*
Department of Chemistry, Boston University, Boston, Massachusetts 02215,
United States
crjsteph@bu.edu
Received August 10, 2011
ABSTRACT
Visible light promoted single electron reduction of bromocyclopropyl cyclization scaffolds enabled by photoredox catalysis initiates a novel
tandem radical cyclization/sigmatropic rearrangement to generate tricyclic pyrrolidinones having considerable molecular complexity from
simple, readily available starting materials. Furthermore, subtle variations to substrate structure afford a wide array of reaction diversity.
Visible light photoredox catalysis is emerging as a
powerful tool in organic reaction development.1 In
particular, the single electron transfer (SET) processes
enabled by metal polypyridyl catalysts2,3 have recently
found application in a variety of mild oxidation and
reduction reactions.4À7 Specifically, we havedemonstrated
that photoredox catalysis can serve as a more environmen-
tally friendly alternative to typical reaction systems which
(1) For recent reviews on photoredox catalysis in organic synthesis,
see: (a) Yoon, T. P.; Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527.
(b) Narayanam, J. M. R.; Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40,
ꢀ
102. (c) Teply, F. Collect. Czech. Chem. Commun. 2011, 76, 859.
(2) For reviews on the photophysical properties of photoredox
catalysts, see: (a) Kalyanasundaram, K. Coord. Chem. Rev. 1982, 46,
159. (b) Juris, A.; Balzani, V.; Barigelletti, F.; Campagna, S.; Belser, P.;
Von Zelewsky, V. Coord. Chem. Rev. 1988, 84, 85.
(3) (a) Nicewicz, D.; MacMillan, D. W. C. Science 2008, 322, 77.
(b) Ischay, M. A.; Anzovino, M. E.; Du, J.; Yoon, T. P. J. Am. Chem.
Soc. 2008, 130, 12886. (c) Narayanam, J. M. R.; Tucker, J. W.; Ste-
phenson, C. R. J. J. Am. Chem. Soc. 2009, 131, 8756.
(4) For recent examples from the MacMillan group, see: (a) Shih, H.-
W.; Vander Wal, M. N.; Grange, R. L.; MacMillan, D. W. C. J. Am.
Chem. Soc. 2010, 132, 13600. (b) Pham, P. V.; Nagib, D. A.; MacMillan,
D. W. C. Angew. Chem., Int. Ed. 2011, 50, 6119.
(5) For recent examples from the Yoon group, see: (a) Ischay, M. A.;
Lu, Z.; Yoon, T. P. J. Am. Chem. Soc. 2010, 132, 8572. (b) Lu, Z.; Shen,
M.; Yoon, T. P. J. Am. Chem. Soc. 2011, 133, 1162. (c) Hurtley, A. E.;
Cimesia, M. A.; Ischay, M. A.; Yoon, T. P. Tetrahedron 2011, 67, 4442.
(6) For recent examples from our group, see: (a) Condie, A. G.;
(7) For selected recent applications of photoredox catalysis in or-
ꢀ
ganic synthesis, see: (a) Andrews, R. S.; Becker, J. J.; Gagne, M. R.
Angew. Chem., Int. Ed. 2010, 49, 7274. (b) Andrews, R. S.; Becker, J. J.;
ꢀ
Gagne, M. R. Org. Lett. 2011, 13, 2406. (c) Rueping, M.; Vila, C.;
Koenigs, R. M.; Poscharny, K.; Fabry, D. C. Chem. Commun. 2011, 47,
2360. (d) 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. (e) Xuan, J.;
Cheng, Y.; An, J.; Lu, L.-Q.; Zhang, X.-X.; Xiao, W.-J. Chem. Commun.
2011, 47, 8337. (f) Rueping, M.; Zhu, S.; Koenigs, R. M. Chem.
Commun. 2011, 47, 8679.
(8) For recent reviews on radical chemistry, see: (a) Quiclet-Sire, B.;
Zard, S. Z. Pure Appl. Chem. 2011, 83, 519. (b) Beemelmanns, C.;
Reissig, H.-U. Chem. Soc. Rev. 2011, 40, 2199.
(9) (a) Tucker, J. W.; Narayanam, J. M. R.; Krabbe, S. W.; Stephenson,
C. R. J. Org. Lett. 2010, 12, 368. (b) Furst, L.; Matsuura, B. S.; Narayanam,
J. M. R.; Tucker, J. W.; Stephenson, C. R. J. Org. Lett. 2010, 12, 3104.
(c) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2011, 133, 4160. (d) Furst, L.; Narayanam, J. M. R.;
Stephenson, C. R. J. Angew. Chem., Int. Ed. 2011, 50, DOI:10.1002/
anie.201103145.
ꢀ
ꢀ
Gonzalez-Gomez, J. C.; Stephenson, C. R. J. J. Am. Chem. Soc. 2010,
132, 1464. (b) Dai, C.; Narayanam, J. M. R.; Stephenson, C. R. J. Nat.
Chem. 2011, 3, 140. (c) Tucker, J. W.; Narayanam, J. M. R.; Shah, P. S.;
Stephenson, C. R. J. Chem. Commun. 2011, 47, 5040.
r
10.1021/ol202178t
Published on Web 09/22/2011
2011 American Chemical Society

generate alkyl free radical intermediates.8,9 Visible light-
mediated photoredox catalysis is particularly attractive as
the reaction occurs under mild conditions, requiring low
catalyst loadings, and offering good functional group
tolerance and chemoselectivity. In addition, the synthetic
community has long recognized the importance of acces-
sing significant molecular complexity in a single step from
relatively simple starting materials.10 One means of accom-
plishing thisgoalisthroughthoughtful design ofsubstrates
and the use of cascade reactions. Herein, we report the
application of photoredox catalysis to afford fused tricyc-
lic molecular architectures from simple, functionalized
cyclopropane starting materials.
Scheme 2. Access to VCPs and Observed Reactivity
the fused tricyclic pyrrolidinone was generated as the
major product in 52% yield after 12 h. When the reaction
was run at elevated temperature, 40 °C, the yield of the
tricycle improved to 69% (Scheme 2B). In this case, heating
of the reaction medium required only surrounding the
reaction vessel and CFL with aluminum foil and relying
on the light source to heat the medium.17 Furthermore, it is
noteworthy that this transformation results in the generation
of two new ring structures bearing valuable chemical motifs,
specifically a diarylmethane18 and fused pyrrolidinone.19
The substrate scope of this transformation is quite
broad, as demonstrated in Table 1. The reaction is insensi-
tive to substitution about the aryl ring. Both electron-rich
and -deficient aromatic rings undergo the tandem reaction
sequence efficiently. In addition, utilization of trans-1,2-
diaryl substituted cyclopropanes allows access to the com-
plementary regioisomer of the tricyclic product (Table 1,
entries 6À8). Furthermore, tertiary amides having one
propargyl group afforded the rearranged compound in
low yields, due tothe inability of one of the conformational
isomers to undergo the initial cyclization (entry 9). Finally,
diastereomerically pure substrates having differentially
substituted aromatic rings provided a 1:1 mixture of the
constitutional isomers of the rearranged product (entry
10). This is a reflection of the lack of diastereoselectivity of
the radical cyclization step.
Scheme 1. Photoredox Catalysis: Rapid Generation of Plat-
forms for Diversity and Reaction Discovery
We have recently reported the development of a general
radical cyclization reaction, wherein an alkyl radical is
generated via the single electron reduction of alkyl halides.
In this work, we observed efficient formation of com-
pounds which we hypothesized had great potential for
use as a platform for molecular diversity and reaction
discovery,11 in particular bromocyclopropanes and vinyl-
cyclopropanes (VCPs) (Scheme 1).12,13 With this in mind,
we observed that heating of 214 in toluene induced a retro-
ene fragmentation of the cyclopropane ring to afford 3 in
99% yield (Scheme 2A).15 This type of reaction profile is
typical of alkyl substituted VCPs and is often encountered
as an undesired transformation, particularly in the VCP/
cyclopentene rearrangement.16 Therefore, we synthesized
4 in an effort to suppress this retro-ene pathway. Upon
subjecting 4 to the photoredox cyclization conditions,
including irradiation by a household compact fluorescent
lamp (CFL) at room temperature, we observed only trace
amounts of the corresponding VCP product (6). Instead,
In addition to this observed reactivity, subtle structural
changes to the reaction scaffold afforded varied types of
transformations. For instance, an interesting mode of
reactivity was observed when subjecting the corresponding
secondary amide, 7a, and propargyl ester, 7b, to the
optimized reaction conditions. Compounds of this type
have a thermodynamic bias to adopt the (Z) conformation
about the amide/ester bond.20 As a result, they are less
(10) Newhouse, T.; Baran, P. S.; Hoffmann, R. W. Chem. Soc. Rev.
2009, 38, 3010.
(11) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am.
(17) See the Supporting Information for details.
Chem. Soc. 2007, 129, 1413.
(18) (a) Wai, J. S.; Egbertson, M. S.; Payne, L. S.; Fisher, T. E.;
Embrey, M. W.; Tran, L. O.; Melamed, J. Y.; Langford, H. M.; Guare,
J. P., Jr.; Zhuang, L.; Grey, V. E.; Vacca, J. P.; Holloway, M. K.; Naylor-
Olsen, A. M.; Hazuda, D. J.; Felock, P. J.; Wolfe, A. L.; Stillmock,
K. A.; Schleif, W. A.; Gabryelski, L. J.; Yong, S. D. J. Med. Chem. 2000,
43, 4923. (b) Long, Y.-Q.; Jiang, X.-H.; Dayam, R.; Sanchez, T.;
Shoemaker, R.; Sei, S.; Neamati, N. J. Med. Chem. 2004, 47, 2561.
(19) For examples of biologically acive pyrrolidinones, see: (a) Dwoskin,
L. P.; Teng, L.; Buxton, S. T.; Crooks, P. A. J. Pharmacol. Exp. Ther. 1999,
288, 905. (b) Winblad, B. CNS Drug Rev. 2005, 11, 169.
(12) For examples of coupling reaction of cyclopropanes see:
(a) Piers, E.; Jean, M.; Marrs, P. S. Tetrahedron Lett. 1987, 28, 5075.
(b) Charette, A. B.; Giroux, A. J. Org. Chem. 1996, 61, 8718.
(13) For selected reviews on the reactivity of vinylcyclopropanes, see:
(a) Wender, P. A.; Bi, F. C.; Gamber, G. G.; Gosselin, F.; Hubbard,
R. D.; Scanio, M. J. C.; Sun, R.; Williams, T. J.; Zhang, L. Pure Appl.
Chem. 2002, 74, 25. (b) Baldwin, J. E. Chem. Rev. 2003, 103, 1197.
(14) Tucker, J. W.; Nguyen, J. D.; Narayanam, J. M. R.; Krabbe,
S. W.; Stephenson, C. R. J. Chem. Commun. 2010, 46, 4985.
(15) (a) Nakamura, E.; Kubota, K.; Isaka, M. J. Org. Chem. 1992, 57,
5809. (b) Lin, Y.-L.; Turos, E. J. Org. Chem. 2001, 66, 8751.
(16) Hudlicky, T.; Koszyk, F. J. Tetrahedron Lett. 1980, 21, 2487.
€
(20) (a) Blom, C. E.; Gunthard, H. H. Chem. Phys. Lett. 1981, 84,
267. (b) Schnur, D. M.; Yuh, Y. H.; Dalton, D. R. J. Org. Chem. 1989,
54, 3779.
Org. Lett., Vol. 13, No. 20, 2011
5469

ring opening (Figure 1A).21 The same cyclopropyl radical
fragmentation is observed for the corresponding homopro-
pargylic cyclopropyl ketone, 9, with the resulting enone under-
going a further conjugate reduction (Figure 1B). In contrast,
the dialkyl cyclopropane substrate 11 fails to undergo the same
fragmentation process resulting in only the reduction of the
bromocyclopropyl moiety (Figure 1C). Furthermore, elec-
tron-rich aromatics sufficiently stabilize the allylic radical
resulting from the electrocyclic ring opening to promote its
efficient dimerization (Figure 1D). Lastly, subjecting com-
pound 15, having an elongated amide side chain, to the
reaction conditions affords a mixture of compounds 16 and
17 (Figure 1E). In contrast to the five-membered ring VCP, 17
does not spontaneously undergo rearrangement under the
reaction conditions. In addition, heating this isolated product
at 110 °C in DMF afforded no transformation. It is possible
that the increased strain of the five-membered VCP allows for
the more facile rearrangement.
Table 1. Radical Cyclization/Cope Rearrangementa
Several possible mechanisms of this transformation
are outlined in Figure 1. The reaction is initiated by a
5-exo-dig radical cyclization and subsequent quenching
of the vinyl radical by hydrogen-atom abstraction. The
seven-membered ring may then form by a [3,3] sigma-
tropic rearrangement (Figure 1, path b).22 Alterna-
tively, it is possible that the same product could be
formed via a single electron reduction of the VCP
intermediate, followed by a β-scission event and sub-
sequent cyclization and oxidation (Figure 1, path a).5b
However, when the rearrangement of 4 was carried out
on 2.5 mmol scale, small quantities (15 mg, <5%) of the
VCP intermediate 6 were isolated. Mild heating of 6
(40 °C), in DMF in the absence of any redox reaction
conditions, cleanly afforded the desired fused tricycle 5
as the sole product. Based on this observation, a thermal
sigmatropic rearrangement, presumably driven by the
release of the cyclopropyl ring strain, is feasible. How-
ever, we cannot exclude the possibility that the rearran-
gement occurs prior to the quenching of the vinyl
radical. In this case, the high energy intermediate may
initially cyclize onto the aromatic ring which initiates
a β-scission event to form the seven-membered ring
(Figure 1, path c).23 In addition, the inability to isolate
any rearranged product from the reaction of compound
15 helps to discount the SET mechanistic pathway.
Finally, the synthetic utility of this transformation can
be broadened by removal of the propargyl group in the
products to afford N-unprotected lactams. Treatment of
(21) (a) Walborsky, H. M.; Chen, J. J. Am. Chem. Soc. 1970, 92, 7573.
(b) Dembkowsky, L.; Rachon, J. Phosphorus, Sulfur Silicon Relat. Elem.
1994, 91, 251.
a Reaction conditions: cyclopropyl substrate (1.0 equiv), Et3N
(2.0 equiv), Ir(ppy)2(dtbbpy)PF6 (1.0 mol %), visible light, DMF, 40 °C,
4 to 12 h. b Isolated yield after purification by chromatography on SiO2.
c Combined yield of regioisomers (1:1). d The product of electrocyclic ring
opening was isolated in 41% yield (see Figure 1).17
(22) For the rearrangment of aryl-vinylaziridines to form benzazepines,
see: (a) Scheiner, P. J. Am. Chem. Soc. 1967, 32, 2628. (b) Eckelbarger, J. D.;
Wilmot, J. T.; Gin, D. Y. J. Am. Chem. Soc. 2006, 128, 10370.
(23) For examples of radical cyclizations onto unactivated aromatics,
see: (a) Curran, D. P; Liu, H. J. Am. Chem. Soc. 1992, 114, 5863.
(b) Liard, A.; Quiclet-Sire, B.; Saicic, R. N.; Zard, S. Z. Tetrahedron
Lett. 1997, 38, 1759. (c) Ly, T.-M.; Quiclet-Sire, B.; (d) Sortais, B.; Zard,
S. Z. Tetrahedron Lett. 1999, 40, 2533.
likely to undergo the initial cyclization step. Accordingly,
the longer lived radical intermediate undergoes an interesting
fragmentation process, presumably through a 3π electrocyclic
(24) (a) Magnus, P.; Ladlow, M.; Elliott, J.; Kim, C. S. J. Chem. Soc.,
ꢀ
ꢀ
Chem. Commun. 1989, 518. (b) Alcaide, B.; Perez-Castells, J.; Sanchez-
Vigo, B.; Sierra, M. A. J. Chem. Soc., Chem. Commun. 1994, 587.
5470
Org. Lett., Vol. 13, No. 20, 2011

Figure 1. Reaction diversity based upon cyclopropyl substrate and potential mechanistic pathways.
conditions, a significant increase in molecular complexity
can be achieved in a single step under mild and operation-
ally simple reaction conditions.
Scheme 3. Elaboration of Rearranged Product
Acknowledgment. Financial support for this research
from the NSF (CHE-1056568), the Alfred P. Sloan Foun-
dation, Amgen, and Boehringer Ingelheim is gratefully
acknowledged. J.W.T. thanks Vertex, Inc. for a graduate
fellowship. NMR (CHE-0619339) and MS (CHE-0443618)
facilities at Boston University are supported by the NSF.
The authors thank Professor John Porco (Boston
University) and Dr. Marvin Hansen (Eli Lilly) for helpful
discussions and suggestions.
the rearrangement product with Co2(CO)8 followed by the
addition of H2O and DMSO and heating at reflux affords
the secondary amide in good yields.24 Furthermore, partial
reduction by treatment with DIBAL in THF provides the
pyrrole in high yields (Scheme 3).
In conclusion, we report the utilization of photoredox
catalysis to access, via a cascade reaction sequence, the
chemistry of two different valuable synthetic intermedi-
ates, alkyl free radicals, and 1,2-divinyl cyclopropanes.
By subjecting simple starting materials to these reaction
Supporting Information Available. Experimental pro-
cedures, 1H and 13C NMR spectra for all new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Org. Lett., Vol. 13, No. 20, 2011
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