Photoinduced electron transfer promoted radical ring expansion and cyclization reactions of α-(ω-carboxyalkyl) β-keto esters

Article abstract of DOI:10.1021/ol303460u

Photoinduced electron transfer (PET) promoted decarboxylation of α-(ω-carboxyalkyl) β-keto esters undergoes radical ring expansion and cyclization reactions. This mild and environmentally friendly method can provide one-carbon expanded γ-keto esters and b

Full text of DOI:10.1021/ol303460u

ORGANIC
LETTERS
2013
Vol. 15, No. 3
636–638
Photoinduced Electron Transfer
Promoted Radical Ring Expansion
and Cyclization Reactions of
r‑(ω-Carboxyalkyl) β‑Keto Esters
Keisuke Nishikawa, Tomoki Ando, Kousuke Maeda, Toshio Morita, and Yasuharu Yoshimi*
Department of Applied Chemistry and Biotechnology, Graduate School of Engineering,
University of Fukui, 3-9-1 Bunkyo, Fukui 910-8507, Japan
yyoshimi@u-fukui.ac.jp
Received December 18, 2012
ABSTRACT
Photoinduced electron transfer (PET) promoted decarboxylation of R-(ω-carboxyalkyl) β-keto esters undergoes radical ring expansion and
cyclization reactions. This mild and environmentally friendly method can provide one-carbon expanded γ-keto esters and bicyclic alcohols, and
the product distribution is strongly dependent on the length of the alkyl chain containing the terminal carboxylate group.
Owing to difficulties associated with the use of tradi-
tional methods,1 radical ring expansion reactions are im-
portant processes for the preparation of medium-sized ring
systems. For example, the BeckwithÀDowd ring expansion
reaction is a well-known and efficient method for generating
medium-sized ring cyclic ketones (Scheme 1).2À4 However,
this process requires the use of high temperatures, toxic
reagents such as AIBN and Bu3SnH, and environmentally
unfriendly haloketone substrates. Thus, the development of
reactions of this type that can be carried out under milder
conditions using more benign substrates is a significant goal
in organic synthesis.
Although methods involving PET-promoted BeckwithÀ
Dowd ring expansion reactions of halomethyl substituted
benzocyclic ketones with amines5 and of R-bromomethyl
β-keto esters by using a B12ÀTiO2 hybrid catalyst6 have been
described, both approaches require the use of haloketones as
reactants and generate environmentally unfriendly hydrogen
halides.
Earlier, we observed interesting decarboxylation reac-
tions of aliphatic carboxylic acids, which are promoted
by PET to arene radical cations and produce alkyl free
(5) (a) Hasegawa, E.; Tamura, Y.; Tosaka, E. Chem. Commun. 1997,
1895–1896. (b) Hasegawa, E.; Takizawa, S.; Iwaya, K.; Kurokawa, M.;
Chiba, N.; Yamamichi, K. Chem. Commun. 2002, 1966–1967.
(6) (a) Shimakoshi, H.; Abiru, M.; Izumi, S.; Hisaeda, Y. Chem.
Commun. 2009, 6427–6429. (b) Izumi, S.; Shimakoshi, H.; Abe, M.;
Hisaeda, Y. Dalton Trans. 2010, 39, 3302–3307.
(7) (a) Yoshimi, Y.; Itou, T.; Hatanaka, M. Chem. Commun. 2007,
5244–5246. (b) Itou, T.; Yoshimi, Y.; Morita, T.; Tokunaga, Y.;
Hatanaka, M. Tetrahedron 2009, 65, 263–269. (c) Yoshimi, Y.; Masuda,
M.; Mizunashi, T.; Nishikawa, K.; Maeda, K.; Koshida, N.; Itou, T.;
Morita, T.; Hatanaka, M. Org. Lett. 2009, 11, 4652–4655. (d) Yoshimi,
Y.; Hayashi, S.; Nishikawa, K.; Haga, Y.; Maeda, K.; Morita, T.; Itou,
T.; Okada, Y.; Hatanaka, M. Molecules 2010, 15, 2623–2630. (e)
Yoshimi, Y.; Kobayashi, K.; Kamakura, H.; Nishikawa, K.; Haga,
Y.; Maeda, K.; Morita, T.; Itou, T.; Okada, Y.; Hatanaka, M. Tetra-
hedron Lett. 2010, 51, 2332–2334. (f) Itou, T.; Yoshimi, Y.; Nishikawa,
K.; Morita, T.; Okada, Y.; Ichinose, N.; Hatanaka, M. Chem. Commun.
2010, 6177–6179. (g) Yoshimi, Y.; Hayashi, S.; Nishikawa, N.; Okita,
Y.; Maeda, K.; Morita, T.; Itou, T. Res. Chem. Intermed. 2013, 39, 397–
402. (h) Nishikawa, K.; Yoshimi, Y.; Maeda, K.; Morita, T.; Takahashi,
I.; Itou, T.; Inagaki, S.; Hatanaka, M. J. Org. Chem. 2013, 78, 582–589.
Photoinduced electron transfer (PET) reactions that
generate radical intermediates represent attractive alter-
native approaches for promoting BeckwithÀDowd ring
expansion processes under mild and eco-friendly conditions.
(1) (a) Hesse, M. Ring Enlargement in Organic Chemistry; VCH:
Weinheim, 1991. (b) Yet, L. Tetrahedron 1999, 55, 9349–9403. (c) Yet,
L. Chem. Rev. 2000, 100, 2963–3007. (d) Srikrishna, A. In Radicals in
Orgaic Synthesis; Renaud, P., Sibi, M. P., Eds; Wiley-VCH: Weinheim,
2001; Vol. 2, pp 163À187.
(2) (a) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 3494–
3494. (b) Dowd, P.; Choi, S.-C. J. Am. Chem. Soc. 1987, 109, 6548–6549.
(c) Dowd, P.; Zhang, W. Chem. Rev. 1993, 93, 2091–2115.
(3) Beckwith, A. L. J.; O’Shea, D. M.; Westwood, S. W. J. Am. Chem.
Soc. 1988, 110, 2565–2572.
(4) Wang, C.; Gu, X.; Yu, M. S.; Curan, D. P. Tetrahedron 1998, 54,
8355–8370.
r
10.1021/ol303460u
Published on Web 01/23/2013
2013 American Chemical Society

Table 1. PET-Promoted Radical Ring Expansion of
R-Carboxymethyl β-Keto Ester 1aa
Scheme 1. BeckwithÀDowd Ring Expansion
1a
electron
acceptor
yield of
2a (%)b
radicals.7 Alkyl radicals generated in this manner react
efficiently with a variety of substances, such as thiols and
alkenes, to yield the respective reduction7a,f and addition
products.7c,d,g,h In a recent effort, we observed that PET-
promoted decarboxylations can be applied to BeckwithÀ
Dowd ring expansion reactions of R-(ω-carboxyalkyl)
β-keto esters. The studies described below have led to the
development of a new process that serves as mild and
environmentally friendly method for the preparation of
seven-membered γ-keto esters.
entry
(mM)
arene
Phen
1
1
2
3
4
5
2
2
2
2
2
DCB
DCB
DCB
DCB
DCB
DCB
DCB
DCB
DCN
DCN
83
84
67
60
52
81
58
70
68
78
2
Phen
3
Phen
4
Phen
5
Phen
6c
7d
8
Phen
Phen
biphenyl
Phen
9
10
biphenyl
In an initial phase of the studies exploring the BeckwithÀ
Dowd ring expansion reaction of R-carboxymethyl β-keto
ester 1a, we observed that irradiation of an aqueous
acetonitrile solution (CH3CN/H2O = 9:1), containing phe-
nanthrene (Phen, 20 mM), 1,4-dicyanobenzene (DCB, 20 mM),
and racemic 1a (1 mM), with a 400 W high-pressure
mercury lamp through a Pyrex filter (>280 nm) under an
argon atmosphere for 6 h at room temperature, leads to
formation of the seven-membered γ-keto-ester 2a in 83%
yield as a racemic mixture (entry 1, Table 1) along with near-
quantitative recovery of Phen and DCB. In the absence of
Phen or DCB or both Phen and DCB, a photoreaction does
not take place to recover 1a in a quantitative yield. The
photoreaction using a slightly higher concentration of 1a
(2 mM) also produces 2a in high yield (entry 2), but when
the concentration of 1a is raised to 3À5 mM, 2a is formed in
lower yields (67À52%, respectively) (entries 3À5). We also
observed that the addition of 1 equiv of NaOH to the
reaction mixture leads to a more efficient photoreaction,
which enables production of 2a in a similar yield but with a
shorter irradiation time (3 h) (entry 6). The decreased yield
of 2a (58%) along with the formation of byproduct occurred
in the photoreaction using low concentrations of Phen and
DCB (2 mM) (entry 7). Finally, photoreactions in which
other arenes such as biphenyl and other electron acceptors
such as 1,4-dicyanonaphthalene (DCN) are utilized also give
2a in similar or slightly decreased yields (entries 8À10).
In an effort to elucidate the substrate scope of the
process, photoreactions of R-(ω-carboxyalkyl) β-keto es-
ters 1bÀj, which contain different numbers of methylene
groups in the ring and carboxylic acid side chain, were
carried out using the conditions described above (Table 2).
The results of the study show that irradiation of a solution
containing R-(β-carboxyethyl) β-keto ester 1b (n = 2, m =
2, entry 1), Phen, and DCB does not give rise to formation
of a ring expansion product, but instead products arising
from decarboxylative reduction (4b) and substitution (5b) are
produced. Interestingly, irradiation of a solution containing
R-(γ-carboxypropyl) β-keto ester 1c (n = 3, m = 2, entry 2),
a The photoreaction of 1a was carried out in the presence of an arene
(20 mM) and electron acceptor (20 mM) using a 400-W high-pressure
mercury lamp under an argon atmosphere for 6 h. b Isolated yield. c In
the presence of 2 mM of NaOH, and irradiation time was 3 h. d Con-
centrations of Phen and DCB were 2 mM.
Phen, and DCB results in exclusive formation of a diaste-
reomeric mixture of bicyclic alcohol 3c. In contrast, bicyclic
alcohol 3d, reduction product 4d, and substitution product
5d are generated in nearly equal yields when a solution of
R-(δ-carboxybutyl) β-keto ester 1d (n = 4, m = 2, entry 3),
Phen, and DCB is irradiated. Also, photoreactions of
R-(ω-carboxyalkyl) β-keto ester 1e,gÀj (entries 4, 6À9)
under these conditions yield mixtures containing varying
amounts of the corresponding fused cycloalkanols 3,
reduction products 4, and substitution product 5. Inter-
estingly, unlike the other substrates except 1a, R-carboxy-
methyl β-keto ester 1f (n = 1, m = 1, entry 5) undergoes a
PET promoted reaction to produce the ring expanded
product exclusively. These results show that only BeckwithÀ
Dowd one-carbon ring expansion reactions are efficient, as
exemplified by transformations of 1a and 1f to the respective
seven- or six-membered γ-keto esters.
On the basis of the above results, plausible mechanisms
for the PET-promoted decarboxylative ring expansion and
other reactions can be proposed (Scheme 2). In each route,
initial decarboxylation of the carboxy radical of the sub-
strate 1, formed by single-electron transfer from the carbox-
ylate to the radical cation of Phen, occurs to generate the
corresponding alkyl radical 6.7a In the cases of radicals 6,
containing one, three, and four methylene side chains, exo-
trig cyclization by addition to the ketone takes place to form
bicyclic radical intermediates 7. In contrast, radicals posses-
sing two and five methylene containing side chains cyclize
slowly and, as a result, they are reduced by the radical anion
of DCB or add to the radical anion of DCB more rapidly in
the pathways for formation of the reduction or substitution
products. The cyclopropyl-oxy radicals 7 (n = 1), in which
ring strain exists, undergo β-cleavage to yield the ring
Org. Lett., Vol. 15, No. 3, 2013
637

Table 2. PET-Promoted Reactions of R-(ω-Carboxyalkyl)
β-Keto Ester 1bÀja
Scheme 2. Plausible Mechanism
product yieldsb (%)
entry
carboxylic acid 1
2
3
4
5
1
2
3
4
5
6
7
8
9
1b (n = 2, m = 2)
1c (n = 3, m = 2)
1d (n = 4, m = 2)
1e (n = 5, m = 2)
1f (n = 1, m = 1)
1g (n = 2, m = 1)
1h (n = 3, m = 1)
1i (n = 4, m = 1)
1j (n = 5, m = 1)
À
À
À
À
76
À
À
À
À
À
37
À
35
À
81
30
À
21
43
À
38
27
À
À
À
14
À
71
À
84
20
À
22
43
38
29
a The photoreaction was carried out in the presence of 2 mM of 1.
b Isolated yields.
expanded radicals 8, which is then followed by back electron
transfer (BET) from the radical anion of DCB to form
anions 9 that undergo protonation to yield the ring ex-
panded products 2a,f. The low efficiency of BET in 8 when
the photoreaction is carried out with low concentrations of
Phen and DCB leads to the formation of byproduct and
decreases the yield of 2. In contrast, the relatively more
stable five- and six-membered alkoxy radicals 7 (n = 3 and
4) do not ring open rapidly but instead are captured by BET
from the radical anion of DCB to produce alkoxy anions 10
that serve as precursors of the bicyclic alcohols 3c,d,h,i.
As described earlier,8 electrochemical reactions of the
bromo derivatives of 1 also generate bicyclic alcohols that
are similar to the ones formed in the above PET reactions.
Although the BeckwithÀDowd reaction induced by using
AIBN and Bu3SnH contains the reducing agent Bu3SnH, it
appears that reductants present in reactions promoted by
using both PET (DCB radical anion) and electrochemical
(cathode) oxidations are capable of reducing those inter-
mediate alkoxy radicals 7 that undergo ring opening slowly.
In addition, the results arising from the current effort show
that radicals 6, possessing two and five carbon alkyl side
chains, do not cyclize but rather participate in BET with or
coupling to radical anions of DCB,7b which is similar to the
typical BeckwithÀDowd reaction using AIBN and Bu3SnH.
Finally, in the case of radical 6d,i with a four methylene side
chain, similar rates of cyclization, BET, and substitution
cause formation of a mixture of products containing the
bicyclic alkanol 3d,i, reduction product 4d,i, and substitution
product 5d,i.
In the investigation described above, we have developed a
new method for promoting BeckwithÀDowd ring expansion
reactions of R-carboxymethyl β-keto esters. The process takes
place under mild conditions via a PET-promoted decarbox-
ylation reaction pathway and leads to formation of one-
carbon expanded γ-keto esters. The efficiencies of the reac-
tions are strongly dependent on the length of the alkyl chain
containing the terminal carboxylate group. In addition, the
process can be utilized to prepare bicyclic five- or six-mem-
bered cycloalkanols. Further investigations of the scope and
applications of this new methodology are underway.
Acknowledgment. We are grateful to Prof. Minoru
Hatanaka and Mr. Sho Inagaki at Iwate Medical Uni-
versity, for assistance with HR-MS measurements.
Note Added after ASAP Publication. Table 2 contained
errors in the version Published ASAP on January 23, 2013,
the correct version reposted February 1, 2013.
Supporting Information Available. Experimental pro-
cedures and characterization. This material is available
free of charge via the Internet at http://pubs.acs.org.
(8) Shono, T.; Kise, N.; Uematsu, N.; Morimoto, S.; Okazaki, E.
J. Org. Chem. 1990, 55, 5037–5041.
The authors declare no competing financial interest.
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Org. Lett., Vol. 15, No. 3, 2013