Iron-catalyzed oxidative cross-coupling of phenols and alkenes

Article abstract of DOI:10.1021/ol401532a

A novel bioinspired iron-catalyzed oxidative cross-coupling reaction between phenols and conjugated alkenes was developed. This method enables the direct coupling of phenols with styrene, α-alkyl- and α- arylstyrenes, β-alkyl styrenes, and stilbenes, thereby providing a new strategy for the preparation of the pharmacologically important 2,3-dihydrobenzofuran motif. In addition, this study revealed that under a different set of conditions an oxidative/addition dearomatization reaction of 1,1′-bi-2-naphthol (BINOL) with styrene can take place.

Full text of DOI:10.1021/ol401532a

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Iron-Catalyzed Oxidative Cross-Coupling
of Phenols and Alkenes
Umesh A. Kshirsagar, Clil Regev, Regev Parnes, and Doron Pappo*
Department of Chemistry, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
pappod@bgu.ac.il
Received May 31, 2013
ABSTRACT
A novel bioinspired iron-catalyzed oxidative cross-coupling reaction between phenols and conjugated alkenes was developed. This method
enables the direct coupling of phenols with styrene, R-alkyl- and R-arylstyrenes, β-alkyl styrenes, and stilbenes, thereby providing a new strategy
for the preparation of the pharmacologically important 2,3-dihydrobenzofuran motif. In addition, this study revealed that under a different set of
conditions an oxidative/addition dearomatization reaction of 1,10-bi-2-naphthol (BINOL) with styrene can take place.
Oxidative coupling is one of Nature’s most commonly
used synthetic tools for the structural expression of complex
oligo- and polyphenolic assemblies.1 Of particular interest is
the self-coupling of the phenol group of phenyl propanoids
and natural stilbenes with the conjugated alkene unit of a
second molecule. This phenolꢀalkene oxidative coupling
reaction results in the formation of the 2,3-dihydrobenzofur-
an unit(s) found in many natural phenols (as in 1, 2, and 3, in
Scheme 1). Although many plants utilize this metalloenzy-
matic single-electron oxidative oligomerization for the pro-
duction of specific metabolites that are essential for plant
growth and protection,1a,2 a comparable catalytic version of
this oxidative cross-coupling method has not been developed.
Chemists have, however, applied the phenolꢀalkene
oxidative coupling reaction for the self-merging of natural
and natural-like phenylpropanoids and stilbenes.3 Generally,
stoichiometric single-electron metal oxidants, such as AgOAc,4
Ag2O,5 MnO2,6 Ce(IV),7 and FeCl3,6,8 were used, but in
many cases the reactions were not efficient and suffered
from poor regio- and chemoselectivity.3,5,9 In the absence of
a catalytic phenolꢀalkene oxidative cross-coupling reaction
that can offer advanced synthetic opportunities, in terms of
chemo- and stereoselectivity, other approaches, based on
metalloenzymes, such as HRP/H2O2, P450, or laccases were
studied, providing only partial solutions.3,10 The anodic [3 þ 2]
cycloaddition reaction of phenols with alkenes11 can offer
access to a large number of dihydrobenzofuran derivatives
via phenoxonium ion intermediates.
The dihydrobenzofuran structural motif is considered to
be one of the most important heterocycles and is found in
(7) Chen, P.-Y.; Wu, Y.-H.; Hsu, M.-H.; Wang, T.-P.; Wang, E.-C.
Tetrahedron 2013, 69, 653.
(8) Wang, G.-W.; Wang, H.-L.; Capretto, D. A.; Han, Q.; Hu, R.-B.;
Yang, S.-D. Tetrahedron 2012, 68, 5216.
(9) Snyder, S. A.; Kontes, F. J. Am. Chem. Soc. 2009, 131, 1745.
(10) (a) Li, C.; Lu, J.; Xu, X.; Hu, R.; Pan, Y. Green Chem. 2012, 14,
3281. (b) Navarra, C.; Goodwin, C.; Burton, S.; Danieli, B.; Riva, S.
(1) (a) Quideau, S.; Deffieux, D.; Douat-Casassus, C.; Pouysegu, L.
Angew. Chem., Int. Ed. 2011, 50, 586. (b) Riviere, C.; Pawlus, A. D.;
Merillon, J. M. Nat. Prod. Rep. 2012, 29, 1317.
(2) (a) Wink, M. Phytochemistry 2003, 64, 3. (b) Chong, J.; Poutaraud,
A.; Hugueney, P. Plant Science 2009, 177, 143.
(3) S Velu, S.; F Thomas, N.; F Weber, J.-F. Curr. Org. Chem. 2012,
16, 605.
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Tetrahedron 2001, 57, 365.
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Conroy, S. M.; Swenton, J. S. Tetrahedron Lett. 1994, 35, 7529. (c)
Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Swenton, J. S.
J. Org. Chem. 1992, 57, 2135. (d) Kim, S.; Noda, S.; Hayashi, K.; Chiba,
K. Org. Lett. 2008, 10, 1827. (e) Kim, S.; Hirose, K.; Uematsu, J.; Mikami,
Y.; Chiba, K. Chem.;Eur. J. 2012, 18, 6284. (f) Chiba, K.; Fukuda, M.;
Kim, S.; Kitano, Y.; Tada, M. J. Org. Chem. 1999, 64, 7654.
(12) Roupe, K. A.; Remsberg, C. M.; Yanez, J. A.; Davies, N. M.
Curr. Clin. Pharmacol. 2006, 1, 81.
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Yamaguchi, N.; Niwa, M. Tetrahedron 2005, 61, 10285.
r
10.1021/ol401532a
XXXX American Chemical Society

Scheme 1. Fe(II)-Oxidative/Addition Dearomatization and the Fe(III)-Catalyzed Oxidative Cross-Coupling Reactions
many biologically active natural products (as exemplified
in Scheme 1).12 Several synthetic strategies for the prepara-
tion of specific compounds have been developed, as well as
complementary methods based on multistep syntheses to
assemble active dihydrobenzofurans.13,14
Here we present an unpresented efficient catalytic iron-
based phenolꢀalkene oxidative cross-coupling reaction,
which provides direct entry to polysubstituted 2,3-dihydro-
benzofurans. Our regio-, chemo-, and stereoselective method
enables direct coupling of phenols with styrene derivatives in a
formal [3 þ 2] cycloaddition manner (Scheme 1) and thereby
provides a new strategy for the preparation of the pharma-
cologically important 2,3-dihydrobenzofuran motif.12,15
Following strategies similar to those previously em-
ployed for the iron-based cross dehydrogenative coupling
(CDC) reactions16,17 of phenols with β-ketoesters and
R-substituted-β-ketoesters,18,19 we studied the oxidative
Table 1. Optimization Study for the Oxidative Coupling Reac-
tion between 2-Naphthol 4 and Styrene 5a,b
C
7a
8a
9
entry
(mol/L)
[Fe]
FeCl3
(%)
(%)
(%)
c
1
0.5
ꢀ
ꢀ
ꢀ
2
0.5
FeCl2
27
[15]d
ꢀ
28
[15]d
ꢀ
ꢀ
3
0.5
FeCl3 (H2O)6
[40]d
22
3
4
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.5
FeCl2
5
FeCl2 (H2O)4
ꢀ
ꢀ
[25]d
45
3
6
FeCl3
ꢀ
ꢀ
7
FeCl3 (H2O)6
ꢀ
ꢀ
71
3
8e
9f
10g
11h
12i
13
FeCl3 (H2O)6
ꢀ
ꢀ
65
3
FeCl3 (H2O)6
ꢀ
ꢀ
60
3
FeCl3 (H2O)6
ꢀ
ꢀ
42
3
FeCl3
ꢀ
ꢀ
[43]d
[35]d
ꢀ
0.05
0.05
FeCl3
ꢀ
ꢀ
j
no metal
ꢀ
ꢀ
a Conditions: 4 (1 mmol), 5 (0.5 mmol), [Fe] (20 mol %), DTBP
(2 mmol), DCE, 80 °C, 1 h. b Isolated yield. c Only BINOL was formed.
d HPLC yield is given in square brackets. e Similar conditions except 4
(13) (a) Dohi, T.; Hu, Y.; Kamitanaka, T.; Kita, Y. Tetrahedron
2012, 68, 8424. (b) Chen, D. Y.; Youn, S. W. Chem.;Eur. J. 2012, 18,
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Wang, X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
12203. (e) Rousseaux, S.; Davi, M.; Sofack-Kreutzer, J.; Pierre, C.;
Kefalidis, C. E.; Clot, E.; Fagnou, K.; Baudoin, O. J. Am. Chem. Soc.
2010, 132, 10706. (f) Lafrance, M.; Gorelsky, S. I.; Fagnou, K. J. Am.
Chem. Soc. 2007, 129, 14570. (g) Zhang, H.; Ferreira, E. M.; Stoltz,
B. M. Angew. Chem., Int. Ed. 2004, 43, 6144.
(0.5 mmol), 5 (1 mmol). f FeCl3 (H2O)6 (10 mol %) was used. g The
3
reaction was performed at 60 °C. h Solvent-free conditions; 4 (0.5 mmol),
5 (1 mL), FeCl3 (20 mol %), DTBP (1 mmol), 80 °C. i 1,10-Phenanthroline
(10 mol %) was used as an additive in the reaction mixture. j No reaction.
(14) Snyder, S. A.; Gollner, A.; Chiriac, M. I. Nature 2011, 474, 461.
(15) Sun, A. Y.; Simonyi, A.; Sun, G. Y. Free Radical Biol. Med.
2002, 32, 314.
(16) (a) Direct, C. Chem. Rev. 2011, 111, 1293. (b) Liu, C.; Zhang, H.;
Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (c) Yeung, C. S.; Dong,
V. M. Chem. Rev. 2011, 111, 1215. (d) Ashenhurst, J. A. Chem. Soc. Rev.
2010, 39, 540.
(17) (a) DeMartino, M. P.; Chen, K.; Baran, P. S. J. Am. Chem. Soc.
2008, 130, 11546. (b) Richter, J. M.; Whitefield, B. W.; Maimone, T. J.;
Lin, D. W.; Castroviejo, M. P.; Baran, P. S. J. Am. Chem. Soc. 2007, 129,
12857. (c) Baran, P. S.; Richter, J. M. J. Am. Chem. Soc. 2004, 126, 7450.
(d) Li, C.-J. Acc. Chem. Res. 2008, 42, 335. (e) Li, Z.; Li, C.-J. J. Am.
Chem. Soc. 2004, 126, 11810.
(18) (a) Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131,
17387. (b) Parnes, R.; Kshirsagar, U. A.; Werbeloff, A.; Regev, C.;
Pappo, D. Org. Lett. 2012, 14, 3324.
coupling reaction of 2-naphthol (4, 0.5 mmol) and styrene
(5, 1 mmol), with FeCl3 (20 mol %) as the catalyst and
tBuOOtBu (DTBP, 2mmol) astheoxidant inDCE(0.5 M)
at 80 °C (Table 1, entry 1). Unfortunately, under these
conditions only BINOL 6a was obtained. However, un-
expectedly, with FeCl2 (20 mol %) as the catalyst (entry 2),
compound 6a, after being formed, underwent a rapid
oxidative/addition dearomatization20 reaction with styrene to
give a mixture of the constitutional isomers 7a and 8a
(Scheme 1). Although compound 7a was formed as a single
stereoisomer (27% yield),21 compound 8a was isolated
as a mixture of diastereoisomers (28%, 15-epi, dr = 5:1).
The structures of 7a and 8a, as well as other key products in
(19) Kshirsagar, U. A.; Parnes, R.; Goldshtein, H.; Ofir, R.; Zarivach,
R.; Pappo, D. Chem.;Eur. J. 2013, DOI:10.1002/chem.201300389.
(20) (a) Oguma, T.; Katsuki, T. J. Am. Chem. Soc. 2012, 134, 20017.
(b) Rudolph, A.; Bos, P. H.; Meetsma, A.; Minnaard, A. J.; Feringa,
B. L. Angew. Chem., Int. Ed. 2011, 50, 5834. (c) Zhuo, C.-X.; Zhang, W.;
You, S.-L. Angew. Chem., Int. Ed. 2012, 51, 12662.
(21) NOESY experiments failed to provide the data that will enable
the determination of the relative configuration of compound 10a.
B
Org. Lett., Vol. XX, No. XX, XXXX

this work, were determined by 1D and 2D NMR. The
relative configuration of the major diastereoisomer of 8a
was elucidated on the basis of NOE correlations between
Ph-H and H-5. We assumed that, under the Fe(II)/DTBP
conditions, BINOL underwent two single-electron oxida-
tion steps, generating intermediates A and B (Scheme 1).
The latter active intermediates reacted immediately with
styrene in a formal [4 þ 2]-cycloaddition or a [3 þ 2]-
cycloaddition fashion, affording isomers 7a and 8a, re-
spectively (Scheme 1). Interestingly, when BINOL 6a was
subjected to the same reaction conditions in the absence
of a nucleophile, spirolactone 10 was obtained via pinacol-
type rearrangement of intermediate B (Scheme 1), a trans-
formation that was recently reported by Tsubaki.22 More-
over, when naphthol 4 and styrene 5 were reacted in
the presence of the free radical scavenger BHT (3,5-ditert-
butyl-4-hydroxytoluene, 2 equiv), the homocoupling pro-
duct BINOL 6a was obtained as a single product, with no
evidence of 7a and 8a, suggesting that the oxidative/
addition dearomatization coupling of BINOL does indeed
involve a free radical process.
metal (entry 13) or DTBP (not shown), or when the
coupling was performed in the presence of radical
scavenger BHT (2 equiv), the desired coupling product
was not observed.
Next, we investigated the scope of this simple yet highly
effective catalytic phenolꢀalkene oxidative cross-coupling
reaction. The results of our synthetic efforts are shown in
Scheme 2. In general, naphthol derivatives (for example, as
in products 11, 18, and 19) and electron-rich phenols (as in
products 13, 14, and 23) were found to be suitable coupling
partners. Under the oxidative conditions, 4-chlorostyrene
reacted with naphthol 4 to afford 2-(4-chlorophenyl)-1,
2-dihydronaphthofuran 12 in 61% yield (Scheme 2a).
R-Arylstyrenes were found to be excellent coupling
partners (Scheme 2b), and their reactions reached com-
pletion within several minutes, affording the corre-
sponding 2,2-diaryl-2,3-dihydronaphtho- and benzo-
furans 15ꢀ18 in good yields (81%, 75%, 63%, and 44%
respectively).
Better results were obtained when BINOL 6a or 6b was
used instead of naphthol 4. Under the same reaction condi-
tions [5 (2 equiv), FeCl2 (20 mol %), DTBP (2 equiv), DCE
(0.5 M), 80 °C] coupling products 7a and 8a were isolated in
40% and 58% (dr = 5:1) yields, respectively (98% overall
yield), and 7b and 8b in 18% and 68% (dr = 5:1) yields,
respectively.
Scheme 2. Scope of the Phenol-Alkene Oxidative
Cross-Coupling Reactionsa,b
Extensive optimization studies revealed that the reaction
is sensitive to both the iron source and the reaction
concentration. For example, when FeCl3 (H2O)6 (20 mol %,
3
Table 1, entry 3) was used as the catalyst instead of FeCl3 or
FeCl2 (DCE, 0.5 M), the desired dihydronaphthofuran 9
was observed by HPLC together with 7a and 8a. When a
diluted concentration was used (0.05 M), with FeCl2,
FeCl2 (H2O)4, or FeCl3 as the catalyst, dihydronaphtho-
3
furan 9 was obtained as a single product, albeit in low yield
(entries 4ꢀ6). Fortunately, with FeCl3 (H2O)6 (20 mol %)
3
as the catalyst under diluted conditions [naphthol 4
(1 mmol) and styrene 5 (0.05 mmol), DTBP (2 mmol),
DCE (10 mL), 80 °C, 1 h], the desired product 9was isolated
in 71% yield (entry 7). The evidence that 9 was isolated in
low yield when anhydrous FeCl3 (20 mol %) was used as
the catalyst (entry 6) suggests that water might play a role
in the proton transfer process of the reaction.18a Other
reaction parameters were also examined, including inver-
sion of the molar ratio of the coupling partners (entry 8,
65% yield), catalyst loading (entry 9, 60% yield), reducing
the reaction temperature (entry 10, 42% yield), or using
solvent-free conditions (entry 11). The introduction of
1,10-phenanthroline (10 mol %) as an additive, which
was found to be a rewarding tactic for the coupling of
phenols withβ-ketoesters, was alsoexamined(entry 12).18b
Other metal salts, such as Fe(ClO4)3, FeBr3, Fe(acac)3, and
CuBr, failed to promote the transformation, and in control
experiments that were performed either in the absence of
a For the exact conditions see the Supporting Information. b Isolated yields.
The tendency of R-alkylstyrenes to undergo cation-
based reactions reduced the efficiency of these reactions.
A partial solution lay in lowering the reaction tempera-
ture to 60 °C. Under these conditions, compounds 19ꢀ21
(22) Sue, D.; Kawabata, T.; Sasamori, T.; Tokitoh, N.; Tsubaki, K.
Org. Lett. 2009, 12, 256.
Org. Lett., Vol. XX, No. XX, XXXX
C

(Scheme 2c), which have methyl or cyclopropyl and aryl
substituents at C-2 of the furan ring, were isolated in 28%,
65%, and 54% yields, respectively.
Scheme 3. Postulated Mechanism
We then turned our efforts to evaluating stilbenes and
β-alkyl styrenes as partners (Scheme 2d and 2e). Successful
coupling of these partners should provide direct entry to
stilbenoid and phenylpropanoid derivatives, two of the
most important classes of natural phenolic products. For-
tunately, while stilbene was inactive under our general
conditions and 4-methoxystilbene underwent a cationic
self-dimerization reaction and failed to participate in the
oxidative coupling process, the more electron-rich stil-
bene, trans-4,40-dimethoxystilbene, reacted smoothly with
naphthol, p-cresol, and 4-methoxyphenol to afford the
corresponding coupling products 22ꢀ24 in 94%, 29%,
and 63% yields, respectively. Importantly, the cis-4,40-
dimethoxystilbene displayed reactivity similar to that of
the trans isomer, affording 22 in 76% yield. In addition, we
found that β-alkylstyrenes are suitable coupling partners,
enabling entry to dehydrodiisoeugenol 2 analogues. For
example, when trans-p-anethole (p-1-propenylanisole) was
reacted with either 6-bromonaphthol or 4-methoxyphenol,
the coupling products 25 and 28 were isolated in good
yields (74% and 64%, respectively), and when naphthol 4
was coupled with cis-1-(1-hexenyl)-4-methoxybenzene, di-
hydronaphthofuran 26 was obtained in 61% yield. How-
ever, when the benzyl-protected isoeugenol was reacted
with naphthol 9, the corresponding dihydronaphthofuran
27 was obtained in a low yield of 27%, probably due to the
deactivating property of the m-OMe group. In all cases, a
single diastereoisomer was obtained, and based on the
3JH‑2/H‑3 coupling constants the relative configuration was
assigned as anti.
For this reaction, we postulated a chelated radical-
coupling mechanism (Scheme 3a). Thus, in the course of
the reaction, the Fe-chelated species II could be oxidized to
give the electrophilic phenol species IV, which can then
undergo a addition reaction with an alkene group to
afford, after tautomerization, the intermediate V. The reduc-
tive elimination step (from Vto I) might involve the formation
of an iron-chelated benzylic carbocation species VI. Possible
support for the existence of this species may be seen in the fact
that the reaction of naphthol 4 with either cis- or trans-4,40-
dimethoxystilbene afforded only the more energetically
stable anti-22. In addition, the observation that electron-
donating groups, which can stabilize the positive charge
generated in VI, are obligatory in the coupling of stilbenes
(products 22ꢀ24) and β-alkylstyrenes (products 25ꢀ28)
provides further support for the proposed mechanism.
An alternative mechanistic pathway for the reductive
elimination step, which involves β-hydride elimination of
intermediate V to afford Heck-type intermediates such as
29 (Scheme 3b), may also be suggested. According to this
scenario, compound 29 would undergo Lewis acid cata-
lyzed cyclization to afford compound 9. Although such
a cyclization is electronically unfavorable, it has been
documented in the literature as taking place on similar
compounds.23 To examine this hypothesis, 29 was pre-
pared and reacted under our general conditions. First,
under Lewis acidic conditions, in the absence of an oxidant
[FeCl3 (H2O)6 (20 mol %), DCE (0.05 M), 80 °C, 5 h], 29
3
was stable and was fully recovered. In contrast, when the
reaction was performed under oxidative conditions in
the presence of DTBP (2 equiv), anti-3-chloro-2-phenyl-
2,3-dihydronaphthofuran 30 was isolated in 53% yield
(88% yield based on FeCl3 as the limiting reagent). The
fact that dihydronaphthofuran 9 was not observed in either
experiment (by HPLC analysis) challenges a mechanistic
pathway involving a β-hydride elimination step.
In conclusion, a novel metal catalyzed oxidative cross-
coupling reaction of phenols and conjugated alkenes based
on iron chemistry was developed. The highly efficient and
sustainable method enables direct entry to polysubsti-
tuted-2,3-dihydrobenzofurans in a regio-, chemo-, and
stereoselective manner. This valuable synthetic tool, in-
spired by the biosynthetic phenolꢀalkene oxidative cou-
pling reaction, can be applied for diverse syntheses of bio-
active phenolic natural products and other materials con-
taining the 2,3-dihydrobenzofuran structural motif. During
this study an oxidative/addition dearomatization reaction
of 1,10-bi-2-naphthol (BINOL) with styrene was discovered,
a chelated radical-coupling mechanism was proposed, and a
possible mechanistic pathway that involves β-hydride elim-
ination was ruled out. Further exploration of the chemistry’s
scope and limitations is currently underway in our laboratory.
Acknowledgment. We wish to thank Dr. Amira Rudi
(BGU) for NMR spectroscopic assistance. This research
was supported by the Israel Science Foundation (Grant
No. 1406/11).
Supporting Information Available. Full experimental
procedures, characterization data, and NMR spectra.
This material is available free of charge via the Internet
at http://pubs.acs.org.
€
(23) Schadel, U.; Habicher, W. D. Heterocycles 2002, 57, 1049.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX