Ligand-controlled iron-catalyzed coupling of α-substituted β-ketoesters with phenols

Article abstract of DOI:10.1021/ol301297k

A chemo-, regio-, and stereoselective FeCl₃/1,10-phenanthroline- catalyzed cross dehydrogenative coupling (CDC) reaction between phenols and α-substituted β-ketoesters was developed. The reaction creates a new quaternary carbon center within a polycyclic hemiacetal or polycyclic spirolactone architecture. The applicability of the new method to the synthesis of natural products was demonstrated by a possible biomimetic synthesis of the lachnanthospirone core.

Full text of DOI:10.1021/ol301297k

ORGANIC
LETTERS
2012
Vol. 14, No. 13
3324–3327
Ligand-Controlled Iron-Catalyzed Coupling
of r-Substituted β-Ketoesters with Phenols
Regev Parnes, Umesh A. Kshirsagar, Aviya Werbeloff, Clil Regev, and Doron Pappo*
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
pappod@bgu.ac.il
Received May 10, 2012
ABSTRACT
A chemo-, regio-, and stereoselective FeCl3/1,10-phenanthroline-catalyzed cross dehydrogenative coupling (CDC) reaction between phenols and
R-substituted β-ketoesters was developed. The reaction creates a new quaternary carbon center within a polycyclic hemiacetal or polycyclic
spirolactone architecture. The applicability of the new method to the synthesis of natural products was demonstrated by a possible biomimetic
synthesis of the lachnanthospirone core.
The cross-coupling between 1,3-dicarbonyl compounds
and phenols or masked phenols is an important transfor-
mation, because it provides an easy entry to multifunc-
tional synthetic intermediates applicable in the synthesis of
complex phenol based materials. The most useful technol-
ogy to achieve R-arylation of 1,3-dicarbonyls in general,1
and of cyclic-β-ketoesters2 in particular, is based on transi-
tion-metal-catalyzed (mainly Pd and Cu) cross-coupling
between aryl halides and stable enolates. Lead(IV),3
bismuth(V),3 iodine(III),4 and Mn(III)2,5 have also been
found to be effective reagents, with the former two being
applied by Yang and Baran in their syntheses of maoe-
crystal V.3 Other methods, based on aryne coupling6 and
aromatic substitution reactions,7 have also been developed.
The cross dehydrogenative coupling (CDC) reactions
have recently become powerful tools for CꢀC bond
formation.8 These reactions are usually catalyzed by sim-
ple copper or iron ions in the presence of an organic
peroxide, mainly tBuOOH. The reactions are based on
the mechanistic premise that a cation radical intermediate,
generated selectively from the oxidation of a weak CꢀH
bond, reacts with a π-electron-rich nucleophilic cou-
pling partner. Chao-Jun Li9 and others have applied
the CDC reaction for the coupling of a variety of CꢀH
groups, ranging from two sp3 carbons,10 an sp2 and an
sp3 carbon,11 two sp2 carbons,12 or an sp3 and an sp carbon.13
Zhiping Li, for example, prepared polysubstituted benzofurans
(8) (a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b) Liu,
C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
(9) Li, C.-J. Acc. Chem. Res. 2009, 42, 335.
(10) (a) Zhang, Y.; Li, C.-J. Angew. Chem., Int. Ed. 2006, 45, 1949.
(b) Li, Z.; Bohle, D. S.; Li, C.-J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
8928. (c) Zhao, L.; Li, C.-J. Angew. Chem., Int. Ed. 2008, 47, 7075. (d) Li,
Z.; Li, C.-J. J. Am. Chem. Soc. 2005, 127, 3672. (e) Liu, W.; Liu, J.;
Ogawa, D.; Nishihara, Y.; Guo, X.; Li, Z. Org. Lett. 2011, 13, 6272.
(f) Li, Z.; Yu, R.; Li, H. Angew. Chem., Int. Ed. 2008, 47, 7497.
(11) (a) Zhang, Y.; Li, C.-J. Eur. J. Org. Chem. 2007, 4654. (b) Li,
Y.-Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2009,
48, 3817. (c) Song, C.-X.; Cai, G.-X.; Farrell, T. R.; Jiang, Z.-P.; Li, H.;
Gan, L.-B.; Shi, Z.-J. Chem. Commun. 2009, 6002. (d) Guo, X.; Pan, S.;
Liu, J.; Li, Z. J. Org. Chem. 2009, 74, 8848. (e) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2005, 127, 6968. (f) Guo, X.; Li, W.; Li, Z. Eur. J. Org. Chem.
2010, 2010, 5787.
(1) Johansson, C. C. C.; Colacot, T. J. Angew. Chem., Int. Ed. 2010,49,676.
(2) Bhat, V.; Mackay, J. A.; Rawal, V. H. Org. Lett. 2011, 13, 3214.
(3) (a) Gong, J.; Lin, G.; Sun, W.; Li, C.-C.; Yang, Z. J. Am. Chem.
Soc. 2010, 132, 16745. (b) Krawczuk, P. J.; Schone, N.; Baran, P. S. Org.
Lett. 2009, 11, 4774.
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Chem. 1989, 54, 2713.
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J. Am. Chem. Soc. 2010, 132, 13633. (c) Liu, W.; Li, Y.; Liu, K.; Li, Z.
J. Am. Chem. Soc. 2011, 133, 10756.
r
10.1021/ol301297k
Published on Web 06/13/2012
2012 American Chemical Society

by reacting ethyl 3-oxo-3-arylpropanoates with phenols in
the presence of FeCl3•(H2O)6 (10 mol %) and di-tert-
butylperoxide (DTBP).14 The proposed mechanism in-
volvedcoordination of both theβ-ketoester and the phenol
to iron, followed by an intermolecular electron transfer
step and annulation.15 The introduction of ligands into
iron-based CDC reactions has previously met with only
partial success,16 in contrast to the considerable progress in
copper-based CDC transformations,17 which enabled the
development of asymmetric versions of these reactions.18
Here we report a new, synthetically useful technology,
based on iron(III), forthedirectcoupling ofsimplephenols
with either cyclic β-ketoesters or R-substituted β-keto-
esters. The reaction, which involves oxidative coupling and
annulation steps, does not require any preadjustment of the
coupling partners and creates a new quaternary carbon center
within a polycyclic hemiacetal or polycyclic spirolactone
architecture. Moreover, the addition of 1,10-phenanthroline
or 2,20-bipyridine significantly affects the reactivity and
selectivity in this transformation, by favorably promoting
the cross-coupling path over other side reactions, such as
naphthol dimerization or FriedelꢀCrafts alkylation. In addi-
tion, we demonstrate here the synthetic utility of the method-
ology, as well as its biogenesis relevance, by presenting a
single-step synthesis of the central core of lachnanthospirone.
We began our study by coupling methyl 2-oxocyclopen-
tanecarboxylate (1a, 1 mmol) with 2-naphthol (2, 3 mmol)
under conditions similar to those previously reported
[FeCl3•(H2O)6 (10 mol %), DTBP (2 mmol), DCE
(0.5M), 100°C,19 1 h; Scheme1].14 Undertheseconditions,
lactone 3 was isolated in 47% yield, accompanied by large
quantities of BINOL (4), resulting from the oxidative
homocoupling reaction oftwo naphthols. An optimization
study (see Table S1 in the Supporting Information) was
conducted, in which several of the reaction parameters,
such as the metal source and loading, the effect of solvent,
solvent concentration, and temperature on the reaction
were examined. Based on these studies, a new set of con-
ditions was adopted: β-ketoester 1a (1 mmol), naphthol
2 (1.5 mmol), FeCl3•(H2O)6 (10 mol %), and DTBP
(2.5 mmol) were reacted in dichloromethane (0.5 M) at
60 °C for 2 h. Surprisingly, under these conditions, the
annulation step adopted an alternative path, affording
polycylic hemiacetal 5 in 95% isolated yield. It was found
that while the initial oxidative coupling step proceeds
smoothly at 60 °C, the subsequent trans-esterification step
leading to spirolactone 3 is not favored at temperatures
below 80 °C, the point at which the formation of the
hemiacetal is preferred. In addition, it was observed that,
under these mild conditions, the competitive dimerization
side reaction leading to 4 is minimized, and therefore, only
a small excess (1.2 equiv instead of 3 equiv) of naphthol is
required for full conversion of the β-ketoester.
Scheme 1. Cross-Coupling between Methyl 2-Oxocyclo-
pentanecarboxylate (1a) and 2-Naphthol
Next, we examined the reaction between ethyl cyclo-
hexanone-2-carboxylate (6) and naphthol 2. Under the
developed conditions, lower reactivity was observed, and
the hemiacetal coupling product 7 was isolated in a
disappointing yield (35%, Table 1, entry 1). We assumed
that the observed difference in reactivity when switching
from the five- to the six-membered ring β-ketoester could
be a result of different binding affinities to the metal center.
Therefore, a search for a suitable ligand that would
influence the binding properties of the substrates was
undertaken (Table 1). The addition of 2-cyanopyridine
(10 mol %), N,N-dimethylglycine hydrochloride (10 mol %),
TMHD (2,2,6,6-tetramethyl-3,5-heptanedione; 10 mol %),
ethylene glycol (20 mol %), L-proline (5 mol %), or pyridine
(10 mol %) to the reaction mixture either hindered the
reaction or had no effect at all (entries 2ꢀ7), and BINOL
formation dominated. To our delight, however, when
2,20-bipyridine (L1, 5 mol %) or 1,10-phenanthroline (L2,
5 mol %) was introduced, a significant amplification in the
formation of hemiacetal 7 was observed, and the compound
was obtained in 71% and 69% HPLC yields, respectively
(entries 8 and 9). Subsequently, it was found that a second
addition of naphthol (0.5 equiv) after 1 h was needed to
obtain full consumption of 6; under these conditions, hemi-
acetal 7 was isolated in 93% yield. Solvent-free conditions
were also examined (entry 11), and under these conditions
product 7 was isolated in 77% yield. However, these conditions
were found to be less effective for other coupling partners.20
To study the ligand effect in the oxidative coupling
reaction between β-ketoester 6 with 2, a set of comparative
experiments was carried out. In these reactions, equal
amounts of β-ketoester 6 (1.5 equiv) and 2-naphthol 2
(13) (a) Volla, C. M. R.; Vogel, P. Org. Lett. 2009, 11, 1701. (b) Li, Z.;
Li, C.-J. J. Am. Chem. Soc. 2004, 126, 11810. (c) Jiang, H.-F.; Li, J.-H.;
Chen, Z.-W. Tetrahedron 2010, 66, 9721.
(14) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131,
17387.
(15) (a) Barton, D. H. R.; Deflorin, A. M.; Edwards, O. E. J. Chem.
Soc. 1956, 530. (b) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am.
Chem. Soc. 2008, 130, 11546.
(16) (a) Ohta, M.; Quick, M. P.; Yamaguchi, J.; Wunsch, B.; Itami,
K. Chem.;Asian J. 2009, 4, 1416. (b) Yang, L.; Qin, L. H.; Bligh, S. W.;
Bashall, A.; Zhang, C. F.; Zhang, M.; Wang, Z. T.; Xu, L. S. Bioorg.
Med. Chem. 2006, 14, 3496.
(17) Bi, H.-P.; Zhao, L.; Liang, Y.-M.; Li, C.-J. Angew. Chem., Int.
Ed. 2009, 48, 792.
(18) (a) Li, Z.; Li, C.-J. Org. Lett. 2004, 6, 4997. (b) Li, Z.; MacLeod,
P. D.; Li, C.-J. Tetrahedron: Asymmetry 2006, 17, 590. (c) Guo, C.; Song,
J.; Luo, S. W.; Gong, L. Z. Angew. Chem., Int. Ed. 2010, 49, 5558.
(d) Zhang, J.; Tiwari, B.; Xing, C.; Chen, X.; Chi, Y. R. Angew. Chem.,
Int. Ed. 2012, 51, 3649.
(19) Oil bath temperature.
(20) For example see Table S1, entry 18 in the Supporting Information.
Org. Lett., Vol. 14, No. 13, 2012
3325

Table 1. Effect of Additives in the Coupling of Ethyl 2-Oxocy-
clohexanecarboxylate (6) with 2-Naphthol (2)a
entry
additive (X mol %)
yield (%)b
Figure 1. Formation of 7 and 4 as a function of 2,20-bipyridine
(L1) or 1,10-phenanthroline (L2) concentration.
1
none
[39], 35
[35]
2
2-cyanopyridine (10)
N,N-dimethylglycine HCl (10)
TMHD (10)
3
[27]
4
[33]
5
ethylene glycol (20)
L-proline (5)
[42]
6
[25]
[2]c
7
pyridine (10)
8
2,20-bipyridine (L1, 5)
1,10-phenanthroline (L2, 5)
1,10-phenanthroline (L2, 5)
none (solvent-free)
[71]
9
[69], 93d
[53]e
77f
10
11
a Reaction conditions: 6 (1 mmol), 2 (1.7 mmol), FeCl3 (10 mol %),
additive (X mol %), DTBP (2.5 mmol), DCE, 70 °C, 3 h. b Isolated
yields, HPLC yields are given in square brackets and were determined
using mesitylene as the internal standard. c BINOL formation domi-
nated. d Similar reaction conditions, addition of 2 (0.5 mmol) after 1.5 h.
e FeCl3•(H2O)6 (10 mol %) was used. f The reaction was carried out
under solvent-free conditions: 6 (1 mmol), 2 (1.5 mmol), FeCl3 (10 mol %),
DTBP (3 mmol), 70 °C, 8 h.
(1.5 equiv) were coupled with only 1 equiv of DTBP [FeCl3
(10 mol %), DCE, 70 °C] in the presence of various
quantities of phenanthroline or bipyridine (0ꢀ10 mol %).
The reactions were stopped at 1 h, and the yields of both 7
and 4 were determined by HPLC; the results are given in
Figure 1. In the absence of phenanthroline, hemiacetal 7
and 4 were formed in 39% and 29% yields, respectively,
but when 5 mol % of phenanthroline were added, the
reaction proceeded with high chemoselectivity, affording
compound 7 in 45% yield with the formation of only 16%
of 4 (Figure 1b). Significantly, when the concentration of
phenanthroline was increased, the efficiency of the catalyst
was reduced, and at 10 mol % of phenanthroline (1:1 iron/
L2 ratio) the reaction was completely shut down, leaving
the starting materials unchanged. The role of phenanthro-
line in this reaction is not yet fully elucidated, but we
postulate that the phenanthroline ligand competes with
labile naphthyl groups for coordination sites around the
iron, leading to the arrangement of a more organized
complex. As a result, the number of naphthyl groups
attached to the metal is reduced, and the possibility for
homodimerization of two naphthols is decreased.
Figure 2. Scope of the coupling of β-ketoesters with phenols.
Reaction conditions: β-ketoester (1 equiv), phenol (1.2ꢀ
1.7 equiv), FeCl3 (10 mol %), DTBP (2.5 equiv), DCE, 70ꢀ
90 °C, 2ꢀ12 h. See Supporting Information for exact conditions.
Isolated yield of pure compound is presented. For 10, 11, 14, and
17ꢀ25, ligand L2 (5 mol %) was added to the reaction mixture;
yields are given in square brackets. NR = no reaction.
93%, respectively). Other alkyl β-ketoesters were also
effective; benzylester 12 was prepared in 85% yield from
1c, and diastereoisomers 13a and 13b were isolated in 37%
and 43% yields when (ꢀ)-menthyl-chiral auxiliary 1d was
used. 1-Naphthol was found to be unstable under the
reaction conditions, and as a result hemiacetal 14 was
isolated in only 20% yield. Interestingly, the formation
of spirolactone 15 (77% yield) and spirolactone 16 (83%
yield) from the indanone and tetralone derivatives may
be attributed to the low stability of the corresponding
hemiacetals. Moderate stereoselectivity was obtained
when cyclohexanone derivatives bearing alkyl substituents
were reacted. For example, the reaction between ethyl
We then examined the scope of the reaction, applying
the method to a variety of β-ketoesters and to additional
phenol derivatives (Figure 2). Substituted naphthols bear-
ing electron-withdrawing or -donating groups and the
sterically hindered 3-bromo-2-naphthol were all coupled
successfully with 1a, affording polycyclic hemiacetals
(8ꢀ11) in good to high yields (90%, 70%, 95%, and
3326
Org. Lett., Vol. 14, No. 13, 2012

5-methylcyclohexanone-2-carboxylate and 6-bromo-2-
naphthol resulted in the formation of diastereomers 17a
and 17b (52% and 13% yield, respectively, dr = 4:1), and
spirolactone 18, prepared from modified carvone and 2,
was obtained as a single stereoisomer in 39% yield (60%
yield based on starting material recovery). The fact that the
isopropene group was left untouched demonstrates another
aspect of the chemoselectivity of this transformation.15b
In general, the coupling of phenols was found to be
much more difficult than that of naphthols, and unless
activated phenols were used, the yields decreased dramati-
cally.21 The reaction between ethyl 6-(4-chlorophenyl)-2-
oxo-4-phenyl-3-cyclohexene-1-carboxylate and 3-methoxy-
phenol in the presence of phenanthroline (5 mol %)
resulted in the formation of spirolactone 19 in 40% yield.
Moreover, when 3-methoxyphenol was reacted with 1b in the
absence of an additive, the desired coupling product 20a was
isolated in only 42% yield, together with a 25% yield of
4-tert-butyl substituted hemiacetal 20b, resulting from a
FriedelꢀCrafts alkylation prior to the coupling step. The
addition of phenanthroline (5 mol %) reduced the Lewis
acidity of the iron complex, and as a result the FriedelꢀCrafts
reaction became negligible and the desired product 20a was
now isolated in 68% yield. 4-Methoxyphenol is also a suit-
able coupling partner, affording hemiacetal 21 in 66% yield
(50% in the absence of phenanthroline). On the other hand,
2-methoxyphenol failed to react with 1d in the absence
of an additive, and in the presence of phenanthroline
(5 mol %) the desired product 22 was obtained in only 22%
yield as a 2:1 mixture of hemiacetal and free phenol isomers.
We also examined the reaction of ethyl 2-methylaceto-
acetate with phenol derivatives. Under our conditions,
hemiacetal 23 was isolated in 66% yield. When 3-methoxy-
phenol was reacted in the absence of additive, the desired
hemiacetal could not be detected, and when phenanthro-
line (5 mol %) was added, the corresponding unstable
hemiacetal 24 was isolated in only 22% yield. We have also
examined the coupling between ethyl 3-oxo-3-phenylpro-
panoate and 2-naphthol, a reaction which was reported
previously by Li.14 Under our modified conditions benzo-
furan 25 was isolated in 68% yield.
Scheme 2. Formation of Lachnanthospirone Polycyclic Central
Core
coupling step would be phenol 27 and β-ketoester 28a.23
To examine the feasibilty of this hypothesis, the reaction
between indanone derivative 29 and 1-naphthol was cho-
sen as a model system. Indeed, under our general condi-
tions [FeCl3 (10 mol %), L2 (5 mol %), DTBP (2.5 equiv),
DCE, 70 °C], spirolactone 30, which contains the centeral
polycyclic core of lachnanthospirone, was isolated in 43%
yield (not optimized).
In summary, we have developed a novel CDC method
for the coupling of cyclic and acyclic β-ketoesters, based on
an inexpensive, nontoxic iron catalyst, which leads to the
formation of either polyaromatic spirolactones or poly-
aromatic hemiacetal architectures. A ligand effect was
identified, with 1,10-phenanthroline or 2,20-bipyridine
having a significant influence on the efficiency of the
reaction and on the deceleration of side reactions. To
demonstrate the wide applicability of this transformation,
various β-ketoesters were reacted with different phenol
derivatives. The coupling was shown to be chemo-, regio-,
and stereoselective and was successfully applied to the
synthesis of the lachnanthospirone central core via a
possible biomimetic approach. We believe that the power-
ful synthetic tool afforded by our new method can be
applied for the synthesis of many valuable phenolic com-
pounds and is likely to find wide utility in the synthesis of
natural products. Effortstoexpandtherangeofsubstrates,
to apply this methodology in target-oriented syntheses,
and to further study the role of additives in iron-based
CDC reactions are currently underway.
The described method can be applied to the synthesis of
complex natural products, such as lachnanthospirone 26
(Scheme 2). This dimeric pigment22 was isolated from the
seeds of Lachnanthes tinctoria together with lachnantho-
carpone (27) and hemocorin aglycone (28), which pos-
sesses the 9-phenylphenalenone ring system. In the paper
describing the isolation of 26, Edwards et al. proposed that
an unknown oxidative coupling reaction between 27 and
an oxidation product derived from 28 are the precursors of
lachnanthospirone.22 Basedonourstudy, itisnow possible
to propose a biosynthetic route for the synthesis of 26. In
that case, the coupling partners in the key oxidative
Acknowledgment. We wish to thank Dr. Amira Rudi
(BGU) for NMR spectroscopic assistance. This research
was supported bythe Israel ScienceFoundation(grant No.
1406/11).
Supporting Information Available. Table 1S, Full
experimental procedures, characterization data, NMR
spectra, and X-ray crystal data (CIF) for 3, 8, 13a,
and 15. This material is available free of charge via the
Internet at http://pubs.acs.org.
(21) The work that describe the coupling of unactivated phenols with
R-substituted-β-ketoesters will be published elsewhere.
(22) Edwards, J. M.; Mangion, M.; Anderson, J. B.; Rapposch, M.;
Hite, G. Tetrahedron Lett. 1979, 20, 4453.
(23) Intermediate 28a could be obtained from 28 through an oxida-
tive cleavage at C1ꢀC2 follow by Dieckmann condensation.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 13, 2012
3327