Visible-Light Photocatalytic Preparation of 1,4-Ketoaldehydes and 1,4-Diketones from α-Bromoketones and Alkyl Enol Ethers

Article abstract of DOI:10.1021/acs.orglett.9b01275

A Ru²⁺-photocatalyzed, visible-light-mediated ATRA reaction for the straightforward preparation of 1,4-ketoaldehydes, 1,4-diketones, and 1,4-ketoesters, which are of difficult access by other means, is reported herein. This method employs readily accessible α-bromoketones and alkyl vinyl ethers as starting materials, allowing the construction of secondary, tertiary, and challenging quaternary centers. In addition, the synthetic usefulness of this method is illustrated by applying it to the construction of substituted pyrroles.

Full text of DOI:10.1021/acs.orglett.9b01275

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Visible-Light Photocatalytic Preparation of 1,4-Ketoaldehydes and
1,4-Diketones from α‑Bromoketones and Alkyl Enol Ethers
William H. García-Santos, Jeferson B. Mateus-Ruiz, and Alejandro Cordero-Vargas*
́
́
́
Instituto de Química, Universidad Nacional Autonoma de Mexico, Ciudad Universitaria, Ciudad de Mexico 04510, Mexico
S
* Supporting Information
ABSTRACT: A Ru2+-photocatalyzed, visible-light-mediated
ATRA reaction for the straightforward preparation of 1,4-
ketoaldehydes, 1,4-diketones, and 1,4-ketoesters, which are of
difficult access by other means, is reported herein. This method
employs readily accessible α-bromoketones and alkyl vinyl
ethers as starting materials, allowing the construction of
secondary, tertiary, and challenging quaternary centers. In
addition, the synthetic usefulness of this method is illustrated
by applying it to the construction of substituted pyrroles.
We started our study by evaluating the conversion of 2-
he dicarbonyl moiety is present in many natural products,
Tand it is also employed as a precursor for the synthesis of bromoacetophenone 1a into its corresponding 1,4-ketoalde-
hyde 5a, and the representative results are presented in Table
1.14 Initially, we selected vinyl pivalate 2a (4 equiv) as the
radical acceptor, 2 mol % of [Ru(bpy)3]Cl2 (3a) as the
photocatalyst (PC), and DIPEA (4 equiv) as the stoichio-
metric reducing agent in DMF/H2O (4:1, v/v, 0.25 M, entry
1). Under these conditions, the desired product 5a was isolated
in 5% yield. Changing the PC to [Ir(dtbbpy)(ppy)2]PF6 (3b,
entry 2) or switching the acceptor to the less hindered vinyl
acetate (entry 3) also led to a low yield of 5a. Different
solvents were tested, such as DCM, DMSO, and CH3CN. The
latter showed a slight improvement in the yield (19%, entry 4).
Other reducing agents were examined; sodium ascorbate was
the most effective, improving the yield up to 53% (entry 5).
Intriguingly, when ethylvinyl ether (2c) was used as the
acceptor, a similar yield of 5a was observed (46%, entry 6), but
switching back to DIPEA as reductant increased the yield to
79% (entry 7), and the same result was obtained with catalyst
3b (entry 8). The amelioration of the yield with ethyl vinyl
ether can be attributed to the fact that 2c is more electron-rich
than 2a or 2b, favoring the polar effects and making the radical
addition more efficient. Finally, we conducted some control
experiments. When the reaction was performed without any
additive, traces of 5a were observed (entry 9). In addition,
when the reaction was performed in the dark, the starting
material remained unchanged (entry 10).
heterocyles. In particular, 1,4-dicarbonyl compounds are the
direct starting materials for the construction of pyrroles,1
furans,2 thiophenes,3 and cyclopentenones.4 Interestingly,
while many methods for the preparation of diketones5 have
been reported, introducing an acetaldehyde fragment at the α
position of a ketone remains a challenging transformation.
Thus, the number of methods described so far for the synthesis
of 1,4-ketoaldehydes remains scarce; Pan6 reported an
organocatalytic isomerization of allylic alcohols (Scheme 1a);
Jiang and Loh7 utilized the bond cleavage of a cyclopropane
intermediate derived from enaminones (Scheme 1b); Fagnoni8
performed a conjugate radical addition of an acetal derived
radical (Scheme 1c); and very recently, Yu and co-workers9
reported a radical hydroacylation of enals, although the latter
method is limited to the use of cinnamaldehydes as radical
acceptors (Scheme 1d). On the other hand, our group10 and
Reiser11 developed radical-ionic sequences based on the use of
esters, amides, and nitriles as radical precursors. Despite these
advances, the development of general procedures is still highly
desirable. Recently, the photoredox radical reactions12 have
emerged as an alternative for the development of clean, atom-
economic and modulable reactions, which can be applied to
atom transfer radical additions (ATRA).13 In this context, here
we report an ATRA-based, light-mediated photocatalytic
procedure for the preparation of 1,4-ketoaldehydes, 1,4-
diketones, and 1,4-ketoesters.
Subsequently, we evaluated which halogen would serve as
the best radical precursor. Thus, 2-chloroacetophenone (1b)
and 2-iodoacetophenone (1c) were tested with the optimized
reaction conditions. As seen in Scheme 2, 1b reacted very
slowly, obtaining 5a in traces, along with 28% of reduction
product (6a) and starting material (65%). On the other hand,
In this work, we envisaged that, in the presence of the
appropriate photocatalyst (PC), an α-bromoketone radical
precursor 1 would add to an enol ester or enol ether 2, which
would serve as an electron-rich radical acceptor, generating,
after the halogen-atom transfer, an unstable geminal
halohydrine 4. According to our previous work,10 the latter
would collapse to generate the carbonyl moiety, affording the
expected dicarbonyl compound 5 (Scheme 1e).
Received: April 11, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Methods for the Synthesis of 1,4-Ketoaldehydes
Scheme 2. Evaluation of the Halogen Atom in the Radical
Precursor
product formed was acetophenone 6a in 81% yield. This
inefficiency of α-iodoketones to form radicals had been already
observed in our group15 and explained by Curran16 in terms of
the facile formation of I2 and the corresponding enolate
through an ionic mechanism.
With the optimized conditions in hand, we evaluated the
scope of the reaction (Figure 1). Primary acetophenones
afforded the corresponding ketoaldehydes 5b−f in good yields
(68−76%) without any interference of the aromatic ring
substituents. Secondary α-bromoketones also worked with
efficiency. For example, tetralone derivatives 5h and 5i were
obtained in 78 and 75% yields, respectively, whereas 5j was
prepared in 76% yield from 2-bromo-4-chromanone. For the
latter, it is worth mentioning that the reaction was scaled up to
1 g (4.4 mmol) of precursor, without a significant detriment of
the yield (70%). Aliphatic bromoketones were successfully
employed as well as substrates. Thus, cyclopentanone (5k),
cyclohexanone (5l), and cycloheptanone (5m) derivatives
were synthesized in 60−63% yields. Notably, amirine analogue
5n was obtained in 72% yield as a 6:1 mixture of
diastereoisomers from its corresponding α-bromoketone
without alteration of the internal double bond. Remarkably,
this methodology worked for tertiary substrates, rendering
compound 5o in 52% yield. Although the yield is lower in the
latter case, the construction of quaternary centers is worth it.
Next, we changed the radical acceptor in order to prepare
1,4-diketones. Figure 2 shows the results when 2-methox-
ypropene (2d) was used as the radical acceptor. Applying the
same reaction conditions as before, 1,4-diketones 7a−j were
obtained in good yields. Once again, no interference was
observed with other potential radical precursors like chlorine
(7b), as well as different substitution patterns in the aromatic
cycle (7c−f). Secondary α-bromoketones were also employed
as starting material, giving α-tetralone derivatives 7g and 7h in
72 and 67% yields, respectively. α-Bromocyclopentanone and
α-bromocyclohepatnone served also as aliphatic radical
precursors, giving rise to 7i and 7j in 61 and 63% yields,
respectively. As can be noted, the yields are quite similar for
acceptors 2c and 2d, showcasing the generality of the
procedure.
a
Table 1. Screening of the Reaction Conditions
entry acceptor
PC
additive
DIPEA
DIPEA
DIPEA
DIPEA
sodium ascorbate
sodium ascorbate
DIPEA
solvent
yield (%)
1
2
3
4
5
6
7
8
9
10
2a
2a
2b
2a
2a
2c
2c
2c
2c
2c
3a
3b
3a
3a
3a
3a
3a
3b
3a
3a
DMF/H2O
DMF/H2O
DMF/H2O
CH3CN
5
5
5
19
53
46
79
79
traces
NR
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
Furthermore, we prepared more elaborated methyl enol
ethers such as 2e17 and 2f18 according to known procedures in
order to test its reactivity. When 2e was subjected to the
optimized reaction conditions with 1b and 1j, diketones 8
(33%) and 9 (22%, dr 2:1) were obtained in moderate yields.
This is probably due to the higher stability of the generated
benzylic radicals, occasioning a less efficient bromine-atom
transfer.19 Although the yields for the latter experiments are
moderate, the construction of more complex dicarbonyl
compounds like 8 or 9 by other means is not trivial and
would require long routes and complex starting materials.20 On
DIPEA
b
DIPEA
a
Reaction conditions: a degassed mixture of 1a (1 equiv), 2a−c (4
equiv), 3a or 3b (2 mol %) and additive (4 equiv) in the indicated
solvent (0.25 M) was irradiated with blue LED strips for 1 h at rt.
b
Reaction was carried out in the dark.
the starting material was completely consumed when the more
reactive 2-iodoacetophenone 1c was employed, but the major
B
DOI: 10.1021/acs.orglett.9b01275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 1. Scope of the radical precursor. All reactions were run with 50 mg of precursor (1a−p). Reaction conditions: a degassed solution of 1 (1
equiv), 2c (4 equiv), 3a (2 mol %), and DIPEA (4 equiv) in CH3CN (0.25 M) was irradiated by blue LED strips for 1−24 h at room temperature.
(a) The reaction was performed on a 1g (4.4 mmol) scale.
Figure 2. Preparation of 1,4-diketones. All reactions were run with 50 mg of precursor (1a−p). Reaction conditions: a degassed solution of 1 (1
equiv), 2d (4 equiv), 3a (2 mol %), and DIPEA (4 equiv) in CH3CN (0.25 M) was irradiated by blue LED strips for 1−8 h at room temperature.
the other hand, acceptor 2f was highly efficient and afforded 10
in 81% yield, showing that this procedure can be expanded to
the synthesis of ketoesters (Scheme 3).
7g in nearly quantitative yield (97%). Compound 14 was also
prepared in a one-pot protocol: initially, a mixture of 1h and 2c
was treated under the described photoredox conditions. Then,
when 1h was completely consumed (monitored by TLC), the
solvent was switched to methanol and the reaction was directly
treated with NH4(OAc) and AcOH. Under these conditions,
pyrrole 12 was isolated in 68% overall yield (from 1h). This
last sequence shows that our protocol can be a direct and
efficient way to prepare heteropolycyclic compounds (Scheme
4).
As mentioned before, 1,4-ketoaldehydes are valuable starting
materials for the construction of heterocycles, such as pyrroles.
To showcase this application, we treated compound 5j with
benzylamine and a catalytic amount of acetic acid, producing
pyrrole 11 in 98% yield. This reaction was equally efficient
when ammonium acetate was employed as the nitrogen source,
generating compound 1221 from 5a in almost quantitative
yield. In the same way, disubstituted pyrroles 1322 and 1423
were prepared in 97 and 98% yields, respectively, whereas
trisubstituted pyrrole 1524 was straightforwardly forged from
A plausible mechanism of our transformation is depicted in
Scheme 5. Photoexcitation of Ru2+ catalyst with blue LED light
should generate *Ru2+ species, which are reduced by DIPEA,
C
DOI: 10.1021/acs.orglett.9b01275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Dicarbonyl Compounds from Elaborated
Acceptors
Scheme 5. Plausible Mechanism for the formation of 5
Scheme 4. Synthetic Transformations of Dicarbonyl
Compounds
In conclusion, herein we report an efficient photocatalytic
method for the synthesis of 1,4-ketoaldehydes, 1,4-diketones,
and 1,4-ketoesters from readily accessible starting materials,
which would be difficult to obtain by other routes. Our method
is quite general, allowing the construction of secondary,
tertiary, and quaternary carbons, and it shown to be a practical
way for the synthesis of substituted pyrroles.
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.9b01275.
Experimental procedures, characterization and copies of
1H and 13C NMR spectra for new compounds (PDF)
FID files (ZIP)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: acordero@unam.mx.
ORCID
serving as the sacrifice amine, to Ru1+. The latter can perform
an electron transfer to starting material (1a), giving rise to
radical II and regenerating Ru2+. Once the radical II is formed,
the mechanism follows a typical ATRA path, i.e., radical
addition to 2c to produce III, which transfers the bromine
atom from 1a, giving II and ATRA adduct 4. During column
chromatography, 4 can collapse to produce the isolated
dicarbonyl compound. Alternatively, radical III is oxidized to
oxonium IV by either *Ru2+ or DIPEA•+, and hydrolysis of
oxonium ion IV produces 5. It is worth noting that both
adduct 4 and acetal 16 were observed along with 5 during the
Alejandro Cordero-Vargas: 0000-0003-1549-5977
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank DGAPA-UNAM and CONACYT (Project Nos.
IN205318 and A1-S-7825, respectively) for financial support.
W.H.G.-S. and J.B.M.-R. thank CONACYT for graduate
scholarships (Grant Nos. 857265 and 308208, respectively).
́
The authors thank Angeles Pena-Gonzalez, Elizabeth Huerta-
̃
1
́ ́
Salazar, Isabel Chavez-Uribe, and Rocıo Patino-Maya for
̃
reaction (TLC) and in the H NMR crude spectrum. In
addition, 16 was isolated in small amounts for compound 5g
(see the SI for details and characterization); however, after
purification, only 5 was recovered.
technical support (NMR and IR).We also thank Dr. Susana
Porcel (UNAM) and Dr. Fernando Sartillo (BUAP) for helpful
suggestions during the preparation of this manuscript.
D
DOI: 10.1021/acs.orglett.9b01275
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Chem. 2016, 81, 6945. (i) Magagnano, G.; Gualandi, A.; Marchini,
M.; Mengozzi, L.; Ceroni, P.; Cozzi, P. G. Chem. Commun. 2017, 53,
1591. (j) Triandafillidi, I.; Kokotou, M. G.; Kokotos, C. G. Org. Lett.
2018, 20, 36−39.
REFERENCES
■
(1) (a) Bean, G. P. In The Chemistry of Heterocyclic Compounds;
Jones, R. A., Ed.; Wiley-VCH, 1990; Vol. 48, pp 105−294.
(b) Ferreira, V. F.; de Souza, M. C. B. V.; Cunha, A. C.; Pereira, L.
O. R.; Ferreira, M. L. G. Org. Prep. Proced. Int. 2001, 33, 411.
(c) Fuchs, P. J. W.; Zeitler, K. J. Org. Chem. 2017, 82, 7796.
(2) (a) Rao, H. S. P.; Jothilingam, S. J. J. Org. Chem. 2003, 68, 5392.
(b) Khaghaninejad, S.; Heravi, M. M. Adv. Heterocycl. Chem. 2014,
111, 95.
(3) Mortensen, D. S.; Rodríguez, A. L.; Carlson, K. E.; Sun, J.;
Katzenellenbogen, B. S.; Katzenellenbogen, A. J. J. Med. Chem. 2001,
44, 3838.
(4) (a) Paterson, I.; Xuan, M.; Dalby, S. M. Angew. Chem., Int. Ed.
2014, 53, 7286. (b) An, J.; Bagnell, L.; Cablewski, T.; Strauss, C. R.;
Trainor, R. W. J. Org. Chem. 1997, 62, 2505. (c) Geraghty, N. W. A.;
Morris, N. M. Synthesis 1989, 603.
(5) (a) Cowherd, F. G.; Doria, M.-C.; Galeazzi, E.; Muchowski, J. M.
Can. J. Chem. 1977, 55, 2919. (b) Shimizu, M.; Akiyama, T.;
Mukaiyama, T. Chem. Lett. 1984, 13, 1531. (c) Miyashita, M.;
Yanami, T.; Kumazawa, T.; Yoshikoshi, A. J. Am. Chem. Soc. 1984,
106, 2149. (d) Kitahara, H.; Tozawa, Y.; Fujita, S.; Tajiri, A.; Morita,
N.; Asao, T. Bull. Chem. Soc. Jpn. 1988, 61, 3362. (e) Fiandanese, V.;
Marchese, G.; Naso, F. Tetrahedron Lett. 1988, 29, 3587. (f) Lu, X.; Ji,
J.; Ma, D.; Shen, W. J. Org. Chem. 1991, 56, 5774. (g) Echavarren, A.
(14) See the Supporting Information for the full and comprehensive
optimization.
́
(15) Peralta-Hernandez, E.; Cortezano-Arellano, O.; Cordero-
Vargas, A. Tetrahedron Lett. 2011, 52, 6899.
(16) Curran, D. P.; Guthrie, D. B.; Geib, S. J. J. Am. Chem. Soc. 2008,
130, 8437.
(17) (a) Bonvallet, P. A.; Todd, E. M.; Kim, Y. S.; McMahon, R. J. J.
Org. Chem. 2002, 67, 9031. (b) Liu, J.-L.; Zhu, Z.-F.; Liu, F. Org. Lett.
2018, 20, 720.
(18) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002, 124,
12964.
(19) Quiclet-Sire, B.; Zard, S. Z. J. Am. Chem. Soc. 2015, 137, 6762.
(20) (a) Mu, X.-J.; Zou, J.-P.; Wang, Z.-T.; Zhang, W. Tetrahedron
Lett. 2005, 46, 4727. (b) Lin, Q.; Li, Y.; Das, D. K.; Zhang, G.; Zhao,
Z.; Yang, S.; Fang, X. Chem. Commun. 2016, 52, 6459.
(21) Yamamoto, H.; Sasaki, I.; Mitsutake, M.; Karasudani, A.;
Imagawa, H.; Nishizawa, M. Synlett 2011, 2011, 2815.
̈
̈
(22) Cho, H.; Madden, R.; Nisanci, B.; Torok, B. Green Chem. 2015,
17, 1088.
(23) Ivanov, A. V.; Shcherbakova, V. S.; Mikhaleva, A. I.; Trofimov,
B. A. Russ. J. Org. Chem. 2014, 50, 1775.
(24) Tsutsui, H.; Kitamura, M.; Narasaka, K. Bull. Chem. Soc. Jpn.
2002, 75, 1451.
́
M.; Perez, M.; Castano, A. M.; Cuerva, J. M. J. Org. Chem. 1994, 59,
̃
4179. (h) Miyashita, A.; Matsuoka, Y.; Numata, A.; Higashino, T.
Chem. Pharm. Bull. 1996, 44, 448. (i) Yuguchi, M.; Tokuda, M.;
Orito, K. Chem. Lett. 2004, 33, 674. (j) Sauthier, M.; Castanet, Y.;
Mortreux, A. Chem. Commun. 2004, 1520. (k) Nishiyama, Y.;
Kobayashi, A. Tetrahedron Lett. 2006, 47, 5565. (l) Enders, D.; Han,
J.; Henseler, A. Chem. Commun. 2008, 3989. (m) Setzer, P.;
Beauseigneur, A.; Pearson-Long, M. S. M.; Bertus, P. Angew. Chem.,
Int. Ed. 2010, 49, 8691. (n) Xuan, J.; Feng, Z.-J.; Chen, J.-R.; Lu, L.-
Q.; Xiao, W.-J. Chem. - Eur. J. 2014, 20, 3045. (o) Kwon, Y.; Schatz,
D. J.; West, F. G. Angew. Chem., Int. Ed. 2015, 54, 9940. (p) Yin, H.;
Nielsen, D. U.; Johansen, M. K.; Lindhardt, A. T.; Skrydstrup, T. ACS
Catal. 2016, 6, 2982. (q) Miao, C.-B.; Zeng, Y.-M.; Shi, T.; Liu, R.;
Wei, P.-F.; Sun, X.-Q.; Yang, H.-T. J. Org. Chem. 2016, 81, 43.
(r) Geibel, I.; Christoffers, J. Eur. J. Org. Chem. 2016, 2016, 918.
(s) Yang, J.; Mei, F.; Gu, Y. Green Chem. 2018, 20, 1367.
(6) Mondal, K.; Mondal, B.; Pan, S. C. J. Org. Chem. 2016, 81, 4835.
(7) Ni, M.; Zhang, J.; Liang, X.; Jiang, Y.; Loh, T.-P. Chem. Commun.
2017, 53, 12286.
(8) Dondi, D.; Caprioli, I.; Fagnoni, M.; Mella, M.; Albini, A.
Tetrahedron 2003, 59, 947.
(9) Zhao, J.-J.; Zhang, H.-H.; Shen, X.; Yu, S. Org. Lett. 2019, 21,
913.
́
́
́
(10) Peralta-Hernandez, E.; Ble-Gonzalez, E. A.; Gracia-Medrano-
Bravo, V. A.; Cordero-Vargas, A. Tetrahedron 2015, 71, 2234.
̈
(11) Foll, T.; Rehbein, J.; Reiser, O. Org. Lett. 2018, 20, 5794.
(12) For recent reviews on photocatalytic radical reactions, see:
(a) Angnes, R. A.; Li, Z.; Correia, C. R. D.; Hammond, G. B. Org.
Biomol. Chem. 2015, 13, 9152. (b) Goddard, J.-P.; Ollivier, C.;
Fensterbank, L. Acc. Chem. Res. 2016, 49, 1924. (c) Shaw, M. H.;
Twilton, J.; MacMillan, D. W. C. J. Org. Chem. 2016, 81, 6898.
(d) Lee, K. N.; Ngai, M.-Y. Chem. Commun. 2017, 53, 13093.
(e) Matsui, J. K.; Lang, S. B.; Heitz, D. R.; Molander, G. A. ACS Catal.
2017, 7, 2563. (f) Xie, J.; Jin, H.; Hashmi, S. K. Chem. Soc. Rev. 2017,
46, 5193. (g) Khalid, M.; Mohammed, S. Asian J. Chem. 2019, 31, 25.
(13) (a) Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2011, 133, 4160. (b) Wallentin,
C.-J.; Nguyen, J. D.; Finkbeiner, P.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2012, 134, 8875. (c) Pirtsch, M.; Paria, S.; Matsuno, T.; Isobe,
H.; Reiser, O. Chem. - Eur. J. 2012, 18, 7336. (d) Gu, X.; Li, X.; Qu,
Y.; Yang, Q.; Li, P.; Yao, Y. Chem. - Eur. J. 2013, 19, 11878. (e) Arceo,
E.; Montroni, E.; Melchiorre, P. Angew. Chem., Int. Ed. 2014, 53,
12064. (f) Knorn, M.; Rawner, T.; Czerwieniec, R.; Reiser, O. ACS
Catal. 2015, 5, 5186. (g) Huang, M.; Li, L.; Zhao, Z.-G.; Chen, Q.-Y.;
Guo, Y. Synthesis 2015, 47, 3891. (h) Courant, T.; Masson, G. J. Org.
E
DOI: 10.1021/acs.orglett.9b01275
Org. Lett. XXXX, XXX, XXX−XXX