De Novo synthesis of polysubstituted naphthols and furans using photoredox neutral coupling of alkynes with 2-bromo-1,3-dicarbonyl compounds

Article abstract of DOI:10.1021/ol402325z

A conceptually new strategy has been described for the mild, practical, and environmentally friendly preparation of naphthols and furans using a visible-light promoted photoredox neutral approach. These reactions between accessible electron-deficient bromides and commercially available alkynes could be carried out at room temperature in good-to-excellent chemical yields without any external stoichiometric oxidants.

Full text of DOI:10.1021/ol402325z

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
De Novo Synthesis of Polysubstituted
Naphthols and Furans Using Photoredox
Neutral Coupling of Alkynes with
2‑Bromo-1,3-dicarbonyl Compounds
Heng Jiang, Yuanzheng Cheng, Yan Zhang,* and Shouyun Yu*
State Key Laboratory of Analytical Chemistry for Life Science and Institute of Chemical
Biology and Drug Innovation, School of Chemistry and Chemical Engineering,
Nanjing University, Nanjing, 210093, China
yushouyun@nju.edu.cn; njuzy@nju.edu.cn
Received August 14, 2013
ABSTRACT
A conceptually new strategy has been described for the mild, practical, and environmentally friendly preparation of naphthols and furans using a
visible-light promoted photoredox neutral approach. These reactions between accessible electron-deficient bromides and commercially available
alkynes could be carried out at room temperature in good-to-excellent chemical yields without any external stoichiometric oxidants.
Redox reactions constitute one of the most fundamental
chemical transformations in organic synthesis.1 In addi-
tion to redox functional group interconversions, redox
carbonꢀcarbon bond formation has received increasing
attention, especially oxidative coupling.2 However, atom
economy of these transformations is often questionable
when using additional oxidants. Lacking of safe, econom-
ic, chemoselective, and environmentally acceptable oxida-
tive or reductive reagents also restricts their applications in
industrial processes.3 In contrast, neutral redox processes
can address these problems due to the absence of stoichio-
metric redox reagents. As a consequence, intense studies
are now focused on neutral redox reactions in both the
academic and industrial communities.4
Polysubstituted aromatic compounds, especially hetero-
cycles, are frequently encountered in pharmaceuticals and
natural products.5 The preparation of these compounds
via the direct substitution of aromatic rings often suffers
from poor regioselectivity, harsh conditions, or tedious
steps.6 The de novo synthesis of polysubstituted aromatic
compounds from prefunctionalized precursors under mild
(4) For recent selected examples on redox neutral reactions, see: (a)
Das, D.; Sun, A. X.; Seidel, D. Angew. Chem., Int. Ed. 2013, 52, 3765. (b)
Lumbroso, A.; Abermil, N.; Breit, B. Chem. Sci. 2012, 3, 789. (c) Ma, L.;
Chen, W.; Seidel, D. J. Am. Chem. Soc. 2012, 134, 15305. (d) Tang, Q.;
Xia, D.; Jin, X.; Zhang, Q.; Sun, X.-Q.; Wang, C. J. Am. Chem. Soc.
2013, 135, 4628. (e) Leung, J. C.; Geary, L. M.; Chen, T.-Y.; Zbieg, J. R.;
Krische, M. J. J. Am. Chem. Soc. 2012, 134, 15700. (f) Berliner, M. A.;
Dubant, S. P. A.; Makowski, T.; Ng, K.; Sitter, B.; Wager, C.; Zhang, Y.
Org. Process Res. Dev. 2011, 15, 1052.
(5) Majumdar, K. C.; Chattopadhyay, S. K. Heterocycles in Natural
Product Synthesis; Wiley: 2011.
(6) For recent selected examples on direct substitution of aromatic
rings, see: (a) Nagib, D. A.; MacMillan, D. W. C. Nature 2012, 480, 224.
(b) Fujiwara, Y.; Dixon, J. A.; O’Hara, F.; Funder, E. D.; Dixon, D. D.;
(1) (a) Yoshida, J.; Kataoka, K.; Horcajada, R.; Nagaki, A. Chem.
Rev. 2008, 108, 2265. (b) Carey, F. A.; Sundberg, R. J.; Advanced
Organic Chemistry, 5th ed.; Springer: 2007; Chapter 12. (c) Organic
Electrochemistry, 5th ed.; Lund, H., Hammerich, O., Eds.; New York:
Marcel Dekker, 2001.
(2) (a) Shi, W.; Liu, C.; Lei, A. Chem. Soc. Rev. 2011, 40, 2761. (b)
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (c)
Moeller, K. D. Tetrahedron 2000, 56, 9527.
(3) (a) Baumann, M.; Baxendale, I. R.; Ley, S. V.; Nikbin, N.
Beilstein J. Org. Chem. 2011, 7, 442. (b) Carey, J. S.; Laffan, D.;
Thomson, C.; Williams, M. T. Org. Biomol. Chem. 2006, 4, 2337. (c)
Dugger, R. W.; Ragan, J. A.; Ripin, D. H. B. Org. Process Res. Dev.
2005, 9, 253.
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Rodriguez, R. A.; Baxter, R. D.; Herle, B.; Sach, N.; Collins, M. R.;
Ishihara, Y.; Baran, P. S. Nature 2012, 492, 95. (c) Mal, D.; Jana, A. K.;
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r
10.1021/ol402325z
XXXX American Chemical Society

conditions provides one of the major solutions to this
problem.7
III. When aryl ketones are employed, the radical II can go
through oxidative homolytic aromatic substitution (HAS)12
Visible-light photoredox catalysis, which takes advan-
tage of the redox potential of the photocatalyst under
irradiation, has recently emerged as a powerful tool for
promoting useful organic transformations.8 This strategy
has also been employed to construct several valuable
heterocyclic compounds,9 including indoles, benzothio-
phenes, benzothiazoles, tetrahydroimidazoles, and isoxa-
zolidines. To the best of our knowledge, benzene rings and
furans have not been synthesized using this technology.
Herein, we would like to present our efforts in the de novo
synthesis of polysubstituted naphthols and furans via the
photoredox approach under mild conditions.
Compared with alkenes, which have been frequently
used to couple with electron-deficient bromides under photo-
redox catalysis,10 alkynes have seldom been employed in
these transformations.11 It can be envisioned that several
aromatic rings can be achieved using R-bromo-β-ketocarbo-
nyls and alkynes as coupling partners, as shown in Figure 1.
Coupling of an alkyne with the radical I generated from R-
bromo-β-ketones by visible-light mediated reduction could
lead to the formation of sp2 carbon-based radical species II or
Figure 1. Rationale for redox neutral coupling of alkynes with
electron-deficient bromides.
to generate the naphthol motif.13 Instead, when an alkyl
ketone is used, the radical III could attack the carbonyl group
to give the furan framework.14 As a neutral redox transfor-
mation, stoichiometric external oxidants can be avoided.
This idea was first examined using aryl ketobromide 1a
and phenylacetylene 2a as model substrates (Table 1).
When a solution of 1a and 2a in CH3CN was irradiated
by a 13 W white LED in the presence of photocatalyst
Ir(ppy)2(dtbbpy)PF6 (I) and Na2HPO4 for 12 h, the desired
naphthol 3a was isolated in 75% yield (entry 1). EtOH and
CH2Cl2 did not give improved results (entries 2ꢀ3). To our
delight, a 96% yield was achieved when DMSO was used as
solvent (entry 4). The yield was slightly increased to 98%
using DMF as solvent (entry 5). NaHCO3 and K3PO4 were
less effective for this transformation (entries 6ꢀ7). Several
other photocatalysts, such as Ir(ppy)3 (II), Ru(bpy)3(PF6)2
(III), and fluorescein dye, were not superior to Ir(ppy)2-
(dtbbpy)PF6 (I) (entries 8ꢀ10). Control experiments ver-
ified the necessity of a base, irradiation, and a photocatalyst
(entries 11ꢀ13).
(7) For recent selected examples on de novo synthetical strategy, see:
(a) Hoye, T. R.; Baire, B.; Niu, D.; Willoughby, P. H.; Woods, B. P.
Nature 2012, 490, 208. (b) Gati, W.; Rammah, M. M.; Rammah, M. B.;
Couty, F.; Evano, G. J. Am. Chem. Soc. 2012, 134, 9078. (c) Donohoe,
T. J.; Jones, C. R.; Barbosa, L. C. A. J. Am. Chem. Soc. 2011, 133, 16418.
(d) Wang, B.; Hansen, T. M.; Wang, T.; Wu, D.; Weyer, L.; Ying, L.;
Engler, M. M.; Sanville, M.; Leitheiser, C.; Christmann, M.; Lu, Y.;
Chen, J.; Zunker, N.; Cink, R. D.; Ahmed, F.; Lee, C.-S.; Forsyth, C. J.
J. Am. Chem. Soc. 2011, 133, 1484. (e) Henry, G. D. Tetrahedron 2004,
60, 6043.
(8) For selected reviews on visible-light photoredox catalysis, see: (a)
Prier, C. K.; Rankic, D. A.; MacMillan, D. W. C. Chem. Rev. 2013, 113,
€
5322. (b) Hari, D. P.; Konig, B. Angew. Chem., Int. Ed. 2013, 52, 4734. (c)
Shi, L.; Xia, W. Chem. Soc. Rev. 2012, 41, 7687. (d) Xuan, J.; Xiao, W.-J.
Angew. Chem., Int. Ed. 2012, 51, 6828. (e) Tucker, J. W.; Stephenson,
C. R. J. J. Org. Chem. 2012, 77, 1617. (f) Narayanam, J. M. R.;
Stephenson, C. R. J. Chem. Soc. Rev. 2011, 40, 102. (g) Yoon, T. P.;
Ischay, M. A.; Du, J. Nat. Chem. 2010, 2, 527. (h) Zeitler, K. Angew.
€
Chem., Int. Ed. 2009, 48, 9785. (i) Chemical Photocatalysis; Konig, B.,
Ed.; DE GRUYTER: 2013.For pioneering works, see: (j) Nicewicz, D. A.;
MacMillan, D. W. C. Science 2008, 322, 77. (k) Ischay, M. A.; Anzovino,
M. E.; Du, J.; Yoon, T. P. J. Am. Chem. Soc. 2008, 130, 12886. (l)
Narayanam, J. M. R.; Tucker, J. W.; Stephenson, C. R. J. J. Am. Chem.
Soc. 2009, 131, 8756.
To explore the scope of this transformation, a variety of
alkynes were tested, as shown in Figure 2. All the sub-
stituted phenylacetylenes tested so far have worked quite
(9) For synthesis of heterocyclic compounds using visible-light
photoredox, see: (a) Zhu, S.; Das, A.; Bui, L.; Zhou, H.; Curran,
D. P.; Rueping, M. J. Am. Chem. Soc. 2013, 135, 1823. (b) Xie, J.;
Xue, Q.; Jin, H.; Li, H.; Cheng, Y.; Zhu, C. Chem. Sci. 2013, 4, 1281. (c)
(12) (a) Studer, A.; Curran, D. P. Angew. Chem., Int. Ed. 2011, 50,
5018. (b) Santi, R.; Bergamini, F.; Citterio, A.; Sebastiano, R.; Nicolini,
M. J. Org. Chem. 1992, 57, 4250. (c) Snider, B. B.; Zhang, Q.; Dom-
broski, M. A. J. Org. Chem. 1992, 57, 4195.
(13) For recent selected examples on synthesis of naphthols, see: (a)
Xia, Y.; Qu, P.; Liu, Z.; Ge, R.; Xiao, Q.; Zhang, Y.; Wang, J. Angew.
Chem., Int. Ed. 2013, 52, 2543. (b) Liau, B. B.; Milgram, B. C.; Shair,
M. D. J. Am. Chem. Soc. 2012, 134, 16765. (c) Hao, W.-J.; Xu, X.-P.; Bai,
H.-W.; Wang, S.-Y.; Ji, S.-J. Org. Lett. 2012, 14, 4894. (d) Wang, J.-G.;
Wang, M.; Xiang, J.-C.; Zhu, Y.-P.; Xue, W.-J.; Wu, A.-X. Org. Lett.
2012, 14, 6060. (e) Huang, X.; Xun, J. J. Org. Chem. 2007, 72, 3965. (f)
Ciufolini, M. A.; Weiss, T. J. Tetrahedron Lett. 1994, 35, 1127. (g)
Kalogiannis, S.; Spyroudis, S. J. Org. Chem. 1990, 55, 5041. Also see ref
12c.
(14) For recent selected examples on synthesis of furans, see: (a) Lian,
Y.; Huber, T.; Hesp, K. D.; Bergman, R. G.; Ellman, J. A. Angew.
Chem., Int. Ed. 2013, 52, 629. (b) Zheng, M.; Huang, L.; Wu, W.; Jiang,
H. Org. Lett. 2013, 15, 1838. (c) He, C.; Guo, S.; Ke, J.; Hao, J.; Xu, H.;
Chen, H.; Lei, A. J. Am. Chem. Soc. 2012, 134, 5766. (d) Cui, X.; Xu, X.;
Wojtas, L.; Kim, M. M.; Zhang, X. P. J. Am. Chem. Soc. 2012, 134,
19981. (e) Fournier, J.; Arseniyadis, S.; Cossy, J. Angew. Chem., Int. Ed.
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(10) For coupling of alkenes with bromides under visible-light photo-
redox catalysis, see: (a) Wallentin, C.-J.; Nguyen, J. D.; Finkbeiner, P.;
Stephenson, C. R. J. J. Am. Chem. Soc. 2012, 134, 8875. (b) Courant, T.;
Masson, G. Chem.;Eur. J. 2012, 18, 423. (c) Jiang, H.; Huang, C.; Guo,
J.; Zeng, C.; Zhang, Y.; Yu, S. Chem.;Eur. J. 2012, 18, 15158. (d)
Nguyen, J. D.; Tucker, J. W.; Konieczynska, M. D.; Stephenson, C. R. J.
J. Am. Chem. Soc. 2011, 133, 4160. (e) Tucker, J. W.; Narayanam,
J. M. R.; Krabbe, S. W.; Stephenson, C. R. J. Org. Lett. 2010, 12, 368. (f)
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Zhang, Y.; Yu, S. Adv. Synth. Catal. 2013, 355, 809.
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4985. Also see ref 9c.
B
Org. Lett., Vol. XX, No. XX, XXXX

complex and radical species 4 respectively. Radical 4 can
then add onto alkyne 2a to generate the vinyl radical
intermediate 5, which can engage in intramolecular homo-
lytic aromatic substitution (HAS)12 to provide radical
intermediate 6. This can be oxidized by Ir4þ to form cation
Table 1. Reaction Condition Optimizationa
entry
catalyst
base
solvent
yield (%)b
1
I
I
I
I
I
I
I
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
Na2HPO4
NaHCO3
K3PO4
CH3CN
EtOH
CH2Cl2
DMSO
DMF
DMF
75
63
59
96
98
55
35
89
29
47
36
No
No
2
3
4
5
6
7
DMF
8
II
Na2HPO4
Na2HPO4
Na2HPO4
None
DMF
9
III
DMF
10
11
12
13c
fluorescein
DMF
I
DMF
none
Na2HPO4
Na2HPO4
DMF
I
DMF
a Reaction conditions: 1a (0.4 mmol), 2a (0.2 mmol), base (0.24 mmol),
and catalyst (0.002 mmol, 1.0 mol %) in indicated solvent (2.0 mL) were
irradiated by 13 W white LED at rt for 12 h. b Isolated yield. c No
irradiation.
Figure 2. Scope of coupling of bromides with alkynes. All
reactions carried out under optimized conditions. The yields
were isolated yields. a5.0 equiv of bromide 1a was used, and the
reaction time was prolonged to 48 h.
well giving the corresponding naphthols 3aꢀ3f in good-to-
excellent yields. Naphthalene-derived alkynes could also
go through this transformation smoothly to provide bi-
naphthene derivatives 3g and 3h in 83% and 71% yields
respectively. Aliphatic alkynes were also suitable coupling
partners, but with less efficiency than their aromatic
counterparts. The corresponding naphthols 3iꢀ3l were
isolated in 52ꢀ75% yields. Tetrasubstituted naphthol 3m
could also be prepared using this strategy in 43% yield
when 1-phenyl-1-propyne was coupled with 5.0 equiv of
bromide 1a.
Various aryl ketobromides were then explored. tert-Butyl
2-bromo-3-oxo-3-phenylpropanoate 1b worked quite well
to give 3n in excellent yield (95%). 2-Bromide-1,3-diones 1c
and 1d were also appropriate substrates to afford naphthols
3o and 3p in satisfactory yields. It is also worth mentioning
that various aryl groups, such m-MeO-phenyl, 3-furyl, and
2-naphthyl, were compatible in this transformation with
high regioselectivity to give phenol derivatives 3qꢀ3s re-
spectively. Phenol derivatives 3t was also achieved in 72%
yield from ethyl 2-bromo-3-(naphthalen-1-yl)-3-oxopro-
panoate (1h).
intermediate 7 and regenerate Ir3þ. Ultimately, naphthol 3a
can be formed by deprotonation and tautomerization as-
sisted by base.
The success with naphthols inspired us to explore the
possibility of preparing furans using a similar strategy.
Consequently, 2-bromocyclohexane-1,3-dione (8a) and
phenylacetylene (2a) were chosen for further investigation
(Figure 4). Coupling of bromide 8a with phenylacetylene
(2a) afforded furan 9a when the optimized conditions for
naphthols were applied, but only in 22% yield. A change in
the solvent from DMF to EtOH led to an acceptable yield
(60%) beingobtained (forthedetailed conditionscreening,
see the Supporting Information). Mechanistically, the radical
intermediate 11 was generated via a similar pathway to that
by which intermediate 5 was formed. Furan 9a was produced
by addition of radical 11 onto the carbonyl group,14d,15
oxidation of radical 12, and deprotonation of oxonium
cation 13 in the presence of a base.
To find out the scope of this transformation, the reac-
tivity of phenylacetylenes possessing various groups was
then studied systematically. As shown in Figure 5, it was
found that electron-rich phenylacetylenes gave the desired
furans with satisfactory to excellent yields (9b, 9d, 9e).
Acceptable yields were obtained from 54% to 61%
Based on these observations and literature precedents,8,12
a possible, but not exclusive, catalytic cycle is proposed for
this transformation, as shown in Figure 3. First, the photo-
catalyst Ir3þ complex is irradiated to the excited state Ir3þ*
and oxidatively quenched by 1a with generation of the Ir4þ
(15) Chatgilialoglu, C.; Ferreri, C.; Guerra, M.; Timokhin, V.;
Froudakis, G.; Gimisis, T. J. Am. Chem. Soc. 2002, 124, 10765.
Org. Lett., Vol. XX, No. XX, XXXX
C

Figure 3. Proposed mechanism for formation of the naphthols.
Figure 5. Scope of coupling of bromides with alkynes. All
reactions carried out under optimized conditions. The yields
were isolated yields. a4.0 equiv of bromide 8a were used, and the
reaction time was prolonged to 48 h.
Remarkably, the tetrasubstituted furan (9o) could be also
prepared in 48% yield when the internal alkyne was em-
ployed coupled with 4.0 equiv of the bromide 8a.
In summary, we have developed a mild and efficient
synthetic approach to functionalized naphthols and furans
using photoredox coupling of alkynes with 2-bromo-1,3-
dicarbonyl compounds. These reactions, which are of
broad substrate scope, can be carried out at room tem-
perature and afforded good-to-excellent chemical yields of
products under environmentally friendly conditions, with-
out use of any external stoichiometric oxidants. Applica-
tion of inexpensive and readily available electron-deficient
bromides and alkynes as raw materials should also benefit
the future development of industrial processes. Further
exploration of these transformations and mechanistic de-
tails are underway.
Figure 4. Coupling of phenylacetylene with 2-bromocyclohex-
ane-1,3-dione.
(9fꢀ9h) when weak electron-withdrawing groups, such as
p-Ph, m-MeO, and p-F, were attached to the benzene ring.
Strong electron-withdrawing groups, such as p-Cl, p-Br,
and p-CF3, slowed down this transformation significantly
and reduced the yields to 33ꢀ43% (9iꢀ9k). o-MeO-phe-
nylacetylene worked less efficiently (9c, 80% yield) than its
para counterpart due to the additional steric effect.
6-Methoxy-2-naphthylacetylene could undergo this trans-
formation smoothly to provide the desired product 9l in
81% yield. Alkyl and aryl groups in the 5-position of 8a
had no obvious influence on the reaction efficiency, and
excellent yields were obtained (98% for 9m and 92% for 9n).
Acknowledgment. Financial support from the National
Basic Research Program of China (2011CB935800), Na-
tional Natural Science Foundation of China (21121091,
21102072), and the Natural Science Foundation of Jiangsu
Province (BK2012012, SBK201320271).
Supporting Information Available. Full experimental
procedures, characterization data for all the compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX