Iron-catalyzed direct synthesis of densely Substituted benzofurans and naphthopyrans from phenolic compounds and propargylic alcohols

Article abstract of DOI:10.1002/adsc.201200804

A one-pot cascade reaction for the synthesis of polysubstituted benzofurans and naphthopyrans from simple phenols and propargylic alcohols catalyzed by iron(III) is presented. The results demonstrate that the structural specificity for the formation of fu

Full text of DOI:10.1002/adsc.201200804

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DOI: 10.1002/adsc.201200804
Iron-Catalyzed Direct Synthesis of Densely Substituted
Benzofurans and Naphthopyrans from Phenolic Compounds and
Propargylic Alcohols
Feng-Quan Yuana,b and Fu-She Hana,c,*
a
Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022,
Peopleꢀs Republic of China
Fax : (+86)-431-8526-2926; phone: (+86)-431-8526-2936; e-mail: fshan@ciac.jl.cn
University of Chinese Academy of Sciences, Beijing 100049, Peopleꢀs Republic of China
State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, Peopleꢀs Republic of China
b
c
Received: September 6, 2012; Revised: October 23, 2012; Published online: February 1, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200804.
Abstract: A one-pot cascade reaction for the synthe- propargylic alcohols, the Fe-catalyzed Friedel–Crafts
sis of polysubstituted benzofurans and naphthopyr- (F–C) reaction of phenols with the two types of alco-
ans from simple phenols and propargylic alcohols hols proceeds via different models. Most importantly,
catalyzed by ironACTHNUTRGNE(NUG III) is presented. The results dem- we have demonstrated for the first time that fully
onstrate that the structural specificity for the forma- 2,3,4-substituted naphthopyrans could be synthesized
tion of furan and pyran products is controlled by the efficiently via the iron-catalyzed one-pot cascade re-
structural nature of the propargylic alcohols. Namely, action. Consequently, the results presented herein
benzofurans could be synthesized efficiently from provide straightforward pathways for versatile syn-
phenols and secondary propargylic alcohols in the theses of valuable benzofuran and pyran derivatives
presence of 5 mol% of ironACTHUNTGRNEUNG(III) chloride hexahy- from simple phenolic compounds and propargylic al-
drate (FeCl3·6H2O) catalyst. On the other hand, cohols.
pyran derivatives were obtained exclusively when
tertiary propargylic alcohols were employed. Mecha-
nistic studies revealed that presumably due to the Keywords: benzofurans; iron catalyst; naphthopyr-
discriminated steric effect of secondary and tertiary ans; phenols; propargylic alcohols
Introduction
noble metals such as Pd, Pt, Au, In, and Ru as cata-
lysts. Moreover, the formation of furan and pyran
Benzofuran and pyran derivatives are valuable struc- mixtures was also a concern in some cases. While im-
tural motifs in both naturally occurring and artificial proved procedures via the transition metal-catalyzed
compounds with interesting biological activities and cascade reactions from ortho-halophenols[6] or ortho-
photochromic properties.[1] Particularly, the 3-arylben- dihaloaryl substrates[7] have been disclosed, their ex-
zofuran moiety is ubiquitous in bioactive structures.[2] tensive utilizations were handicapped due to the re-
The most popular methods for accessing such types of quirement for using ortho-disubstituted aryl com-
scaffolds relied mainly on the transition metal-cata- pounds as substrates. However, the commercial avail-
lyzed intramolecular annulation of the pre-prepared ability of such specially substituted substrates is very
ortho-alkynylated phenol derivatives[3] or aryl alkynyl limited. In addition, undesired halogen-containing
ethers.[4] While benzofurans were formed in many of wastes are generated.
these cases, Li[3f] showed that the pyran derivatives
In comparison, the direct construction of benzofur-
could be generated in high selectivity in the presence an and pyran derivatives from simple phenols offers
of FeCl3 catalyst. In addition, the copper-promoted apparent advantages because of their wider availabili-
synthesis of benzofurans using ortho-hydroxybenzo- ty as well as halogen-free natures. So far, the Brønst-
phenones or ortho-hydroxy-a-arylstyrenes has also ed acids such as PPTS salt,[8] TSOH,[9] and boronic
been reported.[5] However, these protocols were mul- acid[10] as well as Lewis acids such as zeolites,[11]
tistep syntheses and required frequently the use of indium,[12] zinc,[13] acidic alumina,[14] and ruthenium
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have been used to catalyze[15] the direct synthesis of
benzofurans or pyrans. However, only very limited
substrate scopes were examined. Recently, Li and co-
workers[16] disclosed a novel protocol for accessing
benzofuran 3-carboxylates via the iron-catalyzed oxi-
dative coupling of phenols and b-keto esters. This
protocol represents one of the few examples for
a more general and direct synthesis of benzofurans
from simple phenols, although an excess of phenol
substrates (3.0 equiv.) paired with the presence of
stoichiometric amounts of organic peroxide (2.0 equiv.
of t-BuOO-t-Bu) have to be employed, and only mod-
erate yields were obtained.
Scheme 1. Initial study on the feasibility of the reaction by
a stepwise procedure.
We have constant interests in the development of
new methods for the synthesis of functionalized het- a single product in high yield at room temperature.
erocycles[17] as well as their downstream application However, the desired benzofuran 4a was not detected.
towards the fabrication of functional materials[18] or Further investigation revealed that by in situ feeding
the synthesis of complex bioactive compounds and of a base such as Et3N (Table 1, entry 1) to the reac-
natural products.[19] On the basis of our extensive ex- tion vessel when the formation of 3a was completed,
perience on N-heterocyclic chemistry,[17–19] we recently 4a could be obtained in 32% yield. Although the
shifted our particular attention to the development of yield was not very satisfactory, the result implies that
a more efficient, general, and practical method for a one-pot synthesis of 4a would be available if the re-
the construction of benzofuran as well as pyran deriv- action parameters could be properly tuned.
atives owing to their great importance in the field of
Thus, we carried out a detailed optimization of the
pharmaceutical and functional materials science (vide reaction conditions. The key of our efforts was fo-
supra). Herein, we demonstrate that FeCl3·6H2O was
a highly active and universally applicable catalyst for
the direct synthesis of both densely substituted benzo-
furan and naphthopyran derivatives from phenols and
propargylic alcohols via a one-pot operation. In addi-
tion to the broad generality and high efficacy, the
methods are also atom-economic and environmentally
benign since only a slight excess (1.2 equiv.) of phenol
substrates was required, coupled with the generation
of only a stoichiometric amount of water as wastes.
More to the point, for the first time, we have estab-
lished an efficient protocol for the synthesis of fully
2,3,4-functionalized naphthopyrans through a one-pot
cascade reaction. Finally, the use of cheap and non-
toxic iron as catalyst also represents an added advant-
age since in pharmaceutical industries, the content of
hazardous metals in an active pharmaceutical ingredi-
ent (API) has to be strictly controlled.[20] As a result,
tedious and expensive purification processes[21] as well
as analysis methods[22] are often required when toxic
metal catalysts are employed.
Table 1. Optimization of the reaction conditions for the one-
pot synthesis of benzofuran from phenols and propargylic
alcohols.[a]
Entry
Catalyst (mol%)
Base
Solvent
Yield[b]
1
2
3
4
5
6
7
8
FeCl3·6H2O (5)
FeCl3·6H2O (5)
FeCl3·6H2O (5)
FeCl3·6H2O (5)
FeCl3·6H2O (5)
FeCl3·6H2O (5)
FeCl3·6H2O (2)
FeCl3 (5)
Et3N
DBACO
KHCO3
K2CO3
K2CO3
–
MeCN
MeCN
MeCN
MeCN
CH2Cl2
DMF
MeCN
MeCN
MeCN
MeCN
32%
76%
75%
77%
n.r.[c]
n.r.[d]
[e]
–
–
K2CO3
–
–
79%
n.r.[d]
n.r.[d]
9
10
FeCl2·4H2O (5)
FeSO4·7H2O (5)
[a]
Reaction conditions: 1a (0.24 mmol, 1.2 equiv.), 2a
(0.2 mmol, 1.0 equiv.), FeCl3·6H2O (5 mol%) in MeCN
(3 mL) at room temperature until 2a had disappeared as
monitored by TLC, then base (1.0 equiv.) was recharged
in situ and heated at 808C for 2–26 h.
Results and Discussion
Our initial study on the feasibility of the iron-cata-
lyzed reaction of phenol and propargylic alcohol to-
wards the synthesis of a 3-arylated benzofuran was
carried out by employing phenol 1a and alcohol 2a as
a model reaction (Scheme 1). After numerous trials,
we found that FeCl3·6H2O was an efficient catalyst
that could affect the formation of F–C product 3a as
[b]
[c]
Isolated yield.
Conversion of 1a and 2a to 3a (see Scheme 1) was com-
peted, but 4a was not formed.
Conversion of 1a and 2a to 3a did not proceed.
Conversion of 3a to 4a was not performed because only
about 50% of 3a was obtained for the F–C reaction after
16 h.
[d]
[e]
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Iron-Catalyzed Direct Synthesis of Densely Substituted Benzofurans and Naphthopyrans
cused on the screening of an appropriate combination complete conversion as well as high yields were ob-
of iron catalyst, base, and solvent that enables the F– served for the reaction of a rich range of substituted
C and the following furan ring formation cyclization phenolic compounds 1a–1k with propargylic alcohol
to occur efficiently through a one-pot operation. 2a (entries 1–11), except for 4-halo-substituted phe-
Some representative results are summarized in nols 1f and 1g (entries 6 and 7). Strangely, incomplete
Table 1. A screening of base (entries 1–4) showed that F–C reaction was observed for these two substrates
organic DABCO (1,4-diazabicycloACTHNUTRGNE[NUG 2.2.2]octane) and either when elongating the reaction time or elevating
inorganic KHCO3 and K2CO3 were effective, afford- the reaction temperature. In addition, the reaction
ing the desired product 4a in ca. 80% yield (entries 2– also exhibited good compatibility for an array of
4). The solvent exhibits a dramatic effect on this propargylic alcohols with various combinations of ar-
transformation. For instance, the formation of 4a was omatic and aliphatic substituents. Namely, alcohols
sluggish when CH2Cl2 was used, although the F–C re- 2b, 2c, and 2d, whose structures were modified by
action for forming 3a was completed (entry 5). Alter- electron-donating OMe, or electron-withdrawing Br
natively, the F–C reaction was completely suppressed and Cl moieties on the phenyl periphery, could be
when DMF was employed (entry 6). A brief examina- converted to the corresponding 3-arylated benzofur-
tion of the loading amount of catalyst showed that ans 4l–4o in good isolated yields (entries 12–15).
the F–C reaction rate was remarkably slowed down Moreover, alcohols with an alkyl group at the alkynyl
when FeCl3·6H2O was decreased from 5 mol% to terminals, e.g., 2e–2g, were also well tolerated (en-
2 mol% (entry 7). About 50% of F–C product 3a was tries 16–19). Finally, the TMS-substituted 2h was also
isolated when the reaction was carried out for a long a viable substrate, affording the desilylated benzofur-
time on a 1-mmol scale. Finally, a comparison of the ans 4t and 4u in high yields (entries 20 and 21). The
catalytic activity of several iron catalysts showed that structures of all the products were characterized by
FeCl3 was equally efficient to FeCl3·6H2O (entry 4 vs. their NMR spectroscopies (see the Supporting Infor-
8), whereas Fe(II) catalysts such as FeCl2·4H2O and mation). Structures of products 4a, 4i, and 4n were
FeSO4·7H2O were ineffective (entries 9 and 10). also confirmed by their single X-ray analyses[23]
Based on an overall consideration of the investigated (Figure 1). It is worth noting that in all these transfor-
parameters, we could establish the optimized condi- mations, the corresponding pyran derivatives were
tions for the one-pot synthesis of benzofuran 4a from not isolated.
phenol 1a and 2a, that is: 1.2:1 equiv. of 1a and 2a in
During the optimization of the reaction conditions,
the presence of 5 mol% of FeCl3·6H2O catalyst at we noted that a sequential addition of FeCl3·6H2O
room temperature in MeCN for 3 h, then K2CO3 catalyst and K2CO3 is essential for effective synthesis
(1.0 equiv.) was recharged in situ and the reaction of benzofurans. To clarify each role played by the
mixture was stirred at 808C for an additional 4 h. Lewis acid and K2CO3 base, we carried out some con-
Under these conditions, 4a could be obtained in 77% trol experiments. The results showed that the propar-
isolated yield (entry 4). These conditions are high- gylation of 1a and 2a occurred smoothly in the pres-
yielding, atom-efficient, and environmentally more ence of 5 mol% of FeCl3·6H2O at room temperature
begin in terms of the substrates and catalyst being to give 3a in 85% isolated yield [Eq. (1)]. In stark
used and the water as the only by-product.
contrast, a simultaneous addition of FeCl3·6H2O and
With the optimized conditions established, we ex- K2CO3 base to the reaction system suppressed com-
amined the substrate scope of this methodology pletely the formation of 3a [Eq. (2)], indicating that
under the optimized conditions. As shown in Table 2, the base exhibits a significant detrimental effect on
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Table 2. Diverse synthesis of 3-arylated benzofurans from various phenols and propargylic alcohols.[a]
[a]
Reaction conditions: phenol 1 (0.6 mmol, 1.2 equiv.), proparyl alcohol 2 (0.5 mmol, 1.0 equiv.), FeCl3·6H2O (5 mol%) in
MeCN (3 mL) at room temperature until 2 had disappeared as monitored by TLC, then K2CO3 (1.0 equiv.) was recharged
in situ and heated at 808C.
Isolated yield.
[b]
[c]
F–C reaction of 1 and 2 was carried out in 6 mL MeCN at 808C.
the F–C reaction. On the other hand, the base-medi- tion were affected independently by FeCl3·6H2O
ated furan ring formation from 3a to benzofuran 4a Lewis acid and K2CO3 base.
can proceed in equally good yields either in the pres-
On the other hand, since several proton transfer
ence or in the absence of FeCl3·6H2O [Eq. (3), 79% processes were involved in the tandem reaction, for
and 80%, respectively]. These results clearly suggest- a better understanding of the mechanism, we investi-
ed that the F–C reaction and the followed cycloaddi- gated the detailed proton transfer behaviour employ-
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Iron-Catalyzed Direct Synthesis of Densely Substituted Benzofurans and Naphthopyrans
Figure 1. X-ray crystal structures of compounds 4a (left), 4i (middle), and 4n (right)
ing an isotopic labelling technique. Accordingly, the not increase significantly. On the other hand, when
reaction of phenol 1a with the deuterated propargylic undeuterated 3a was reacted in the presence of
alcohol D-2a afforded D-3a in 89% yield as a single 5.0 equiv. of D2O as an external proton source [Eq.
product [Eq. (4)]. This result indicates that no proton (5), conditions C), a 1:3.6:3 mixture of 4a:D-4a:diD-
exchange at the propargylic position took place in the 4a was obtained. Notably, the formation of a substan-
F–C reaction although the connection of two aryl tial amount of diD-4a suggests that protonation and
groups and an alkynyl group makes the methine deprotonation of 4a occur reversibly in the reaction
proton rather acidic. Interestingly, the furan ring for- processes.
mation of D-3a in the presence of base afforded a 2:3
Having investigated the generality and mechanism
mixture of 4a and D-4a in 84% total yield with the for the one-pot synthesis of benzofuran derivatives
deuterated D-4a being the major product as deter- from phenols and secondary propargylic alcohols, our
1
mined by the H NMR analysis [Eq. (5), conditions attention was shifted to further expand the utility of
A]. Alternatively, external addition of a large excess this methodology. Thus, the reaction of phenols with
of H2O (5.0 equiv.) as a competitive proton source re- primary and tertiary propargylic alcohols was inspect-
sulted in a slight increase of the undeuterated product ed. Initial studies showed that unlike the secondary al-
4a [Eq. (5), conditions B], forming a 5:4 mixture of cohols, the primary propargylic alcohols were sluggish
4a and D-4a in 77% total yield. The dideuterated for the FeACTHUNTGRNEUNG(III)-catalyzed F-C reaction. Alternatively,
product diD-4a was not observed under both condi- the use of the mesylated surrogates, for example, 5,
tions A and B. These observations imply that both in- led to the etherified products 6a and 6b (Scheme 3).
tramolecular [1,3]-type proton shift and intermolecu- For the tertiary alcohol 7a, we observed two consider-
lar transfer via the deprotonation–protonation process ably different outcomes depending on the structural
from the propargylic position of the 2,3-dihydroben- features of phenols. Namely, elimination of tertiary al-
zofuran intermediate to the benzylic position should cohol 7a to 8a occurred as the major reaction when
be possible (Scheme 2). However, transfer via an in- phenol 1a was used as nucleophile. However, 2-naph-
tramolecular manner should be relatively more fa- thol 1h reacted very efficiently with 7a to give the
vourable because even in the presence of a large naphthopyran 9a in 94% yield in the presence of only
excess of H2O, the yield of the undeuterated 4a did FeCl3·6H2O catalyst without the assistance of base.
Scheme 2. Proposed H-transfer process for the aromatization of the 2,3-dihydrobenzofuran intermediate.
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The structure of 9a was unambiguously confirmed by
the X-ray single crystal analysis[23] (Figure 2, left).
This result implies that the reaction of tertiary alco-
hols with naphthol for the formation of naphthopyran
proceeds via a different reaction model from that of
secondary alcohols for the formation of 3-arylated
benzofurans (see Table 2).
Based on our results for the synthesis of benzofur-
ans (vide supra) together the few related literature re-
ports[10] concerning the Brønsted acids, e.g., boronic
acid-catalyzed reaction of tertiary propargylic alcohols
with aryl nucleophiles, we proposed two tentative
pathways for the formation of naphthopyran 9a
(Scheme 4). Most probably, 7a would form an allenyl
Figure 2. X-ray crystal structures of compounds 9a (left) and
9l (right).
carbocation (10) or propagylic cation (11) under the
effect of FeACTHNUGTRNEUNG(III) (path A). Subsequently, the F–C re-
action of 2-naphthol 1h with the cation occurs at the
less hindered side to provide the ortho-allenylphenol
12. Attributed to the high reactivity as well as the
strained linear configuration of allene moiety, the cy-
AHCTUNGTREGcNNUN lization takes place smoothly via a regiospecific 6-
endo-dig selectivity to give pyran 9a. As another pos-
sible way, 7a and 1h undergoes a sequential F–C reac-
tion (13, path B) and cycloaddition to give pyran 14,
in which the exclusive 6-endo-dig selectivity for 14
can be explained by the steric effect of a quaternary
carbon adjacent to the alkynyl group. Finally, 1,3-mi-
gration of the Me group in 14 furnishs 9a. To clarify
the exact mechanism, we investigated the reaction of
1h with dimethylpropargylic alcohol 7b (Table 3,
entry, 2). Only product 9b was obtained in high yield
while the Me-migrated isomer, i.e., 9a was not detect-
ed. Moreover, we could also obtain the single X-ray
crystal structure of 9l[23] (Figure 2, right) derived from
7b and naphthol 1l (Table 3, entry 12). These results
unambiguously confirmed that the naphthopyrans are
formed through pathway A.
Scheme 3. Reaction of phenols with primary and tertiary
propargylic alcohols in the presence of FeACTHUNRTGNEUNG(III) catalyst.
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Iron-Catalyzed Direct Synthesis of Densely Substituted Benzofurans and Naphthopyrans
Scheme 4. Possible pathway for the formation of naphthopyran 9a.
Having clarified the mechanism for the generation methoxy (9e), ester (9i), and bromo (9f, 9j, and 9k)
of naphthopyran 9a, we then examined the general groups facilitate further diversifying the structures of
applicability of the method because naphthopyran the derived naphthopyrans.
frameworks are of special interest as photochromo-
Finally, based on the mechanistic studies for the
phores. This structural motif exhibits reversible colour formation of naphthopyrans (Scheme 4), we reasoned
changes through the photo-induced ring-opening of that the synthesis of more functionalized pyran deriv-
the pyran ring and the recyclization reaction upon the atives, i.e., introducing a functional group at the 3-po-
cessation of irradiation [Eq. (6)]. Such a facile and sition of the pyran ring would also be possible
unique structural interconversion gives rise to a signifi- through a one-pot cascade reaction. As illustrated in
cant colour change between the two states before and Scheme 5, by choosing appropriately a second electro-
after irradiation and, thereby, making it particularly phile (E+ XÀ) which can be captured by the ortho-alle-
attractive in a wide range of application areas such as nylphenol intermediate 12 during the cycloaddition
ophthalmic glasses, electronic displays, optical reaction, the 3-functionalized naphthopyran deriva-
switches, and memory devices, et al.[8,9,14]
tives 15 might be obtained.
Accordingly, the reaction of naphthol 1h, 7b, and
a second electrophile such as aldehyde, allylic bro-
mide, MeI, NBS, NIS, and I2 was examined under the
identical conditions for the synthesis of naphthopyr-
ans 9a–9n (Table 3). The preliminary results showed
that the presence of aldehyde, allylic bromide, and
MeI did not afford the desired 3-functionalized prod-
ucts and only 9b was obtained in over 80% yield. On
As illustrated in Table 3, we have clearly demon- the other hand, the addition of NBS and NIS resulted
strated that FeCl3·6H2O is a highly efficient catalyst in an intractable mixture. Delightedly, when I2 was
that allows for the direct synthesis of various naph- employed, the desired 3-iodo-substituted product 15b
thopyrans from naphthols and tertiary propargylic al- (Scheme 6) was obtained in 10% yield together with
cohols via the one-pot procedure under mild and very 46% of 3-protonated 9b. Encouraged by this prelimi-
simple conditions-just by stirring a slight excess of nary result, we carried out further optimization of the
naphthol (1.2 equiv.) and propargylic alcohol in the reaction conditions. An extensive trial of various reac-
presence of 5 mol% of FeACTHNUGRTNEUNG(III) catalyst at 808C with- tion parameters led eventually to the discovery of
out the need of any other additives. A rich range of mild and efficient conditions for the one-pot synthesis
propargylic alcohols substituted by a variety of combi- of 15b, i.e., by employing naphthol 1h (1.0 equiv.), ter-
nations of aromatic, aliphatic, and cyclic substituents tiary propargylic alcohol 7b (3.0 equiv.), and I2
(entries 1–8) was well tolerated, affording the 2,2,4- (2.0 equiv.) as substrates, and 10 mol% of FeCl3·6H2O
trisubstituted naphthopyrans in high yields. In addi- as catalyst in toluene (3 mL) at 258C for 10 h, 15b
tion, various naphthols decorated by different func- could be obtained in 81% isolated yield with only
tional groups such as ester (1j), bromo (1k), and a trace amount of 9b being observed in TLC (Table 4,
phenyl (1l) were also viable substrates (entries 9–14). entry 2). The structure of 15b was confirmed by single
Importantly, the flexible incorporation of various crystal X-ray analysis[23] (Figure 3). The excess of 7b
functional groups such as phenoxy (9d, 9k, and 9m),
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Table 3. Diverse syntheses of various naphthopyrans.[a]
Scheme 5. Proposed mechanism for the synthesis of 2,2,3,4-
tetrasubstituted naphthopyrans via a one-pot cascade proce-
dure.
Scheme 6. Initial experiment for the synthesis of 3-iodinated
naphthopyran.
was mainly eliminated to 8b (Scheme 6) and can be
recovered easily by column chromatography.
With the mild, high-yielding conditions for the one-
pot synthesis of 3-iodinated naphthopyran 15b estab-
lished, we then examined the generality of this meth-
odology by varying the structure of propargylic alco-
hols and naphthols. As shown in Table 4, an array of
tertiary propargylic alcohols substituted by a flexible
combination of various aromatic and alphatic, as well
as the heteroatom-hybrid substituents reacted
smoothly to afford the 3-iodinated pyrans in high
yields (15a–15f), albeit a moderated yield was ob-
served for the cyclic alcohols (15g and 15h). In addi-
tion, several substituted naphthols (1k and 1l) were
also viable substrates, affording the desired products
in excellent yields (15i–15l).
Thus, we have established a novel protocol for the
synthesis of 2,2,3,4-tetrasubstituted naphthopyran de-
rivatives via the iron-catalyzed one-step cascade reac-
tion. To the best of our knowledge, such a protocol
has never been reported previously. Of even more in-
terest than this newly developed methodology, the io-
dinated naphthopyrans 15 are anticipated to be at-
tractive compounds in the field of photochromic ma-
terials, because the intrinsically high reactivity of
[a]
Reaction conditions: naphthol 1 (0.6 mmol, 1.2 equiv.),
proparyl alcohol 7 (0.5 mmol, 1.0 equiv.), FeCl3·6H2O (5
mol%) in MeCN (3 mL) at 808C.
Isolated yield.
[b]
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Iron-Catalyzed Direct Synthesis of Densely Substituted Benzofurans and Naphthopyrans
Table 4. Iron-catalyzed efficient synthesis of 3-iodinated na-
thopyrans 15 via the iron-catalyzed one-pot three-compo-
nent reaction.[a]
Figure 3. X-ray crystal structure of compound 15b.
À
Csp2 I bond gives it highly potential for the flexible
incorporation of various functional groups at the C-3
position in 15 via the transition metal-catalyzed cross-
couplings. As a result, the introduction of a substituent
at such a position is highly anticipated to influence
through the steric, electronic, and/or conjugating ef-
fects the photochemical as well as physical properties
of the derived compounds and, thereby, offering op-
portunities for the development of new photochromic
materials. In fact, it has been observed that a subtle
change of the substituents at the 2-position of naph-
thopyrans resulted in a profound change of photo-
chromic properties as seen in some literature re-
ports.[8,14] However, the 3-substituted analogues have
been less investigated due to the lack of a general
method for their synthesis.
Conclusions
In summary, we have demonstrated that, by employ-
ing the iron catalyst, both densely substituted benzo-
furans and naphthopyrans could be synthesized di-
rectly from simple phenolic compounds and propar-
gylic alcohols. Benzofurans were synthesized via
a
two-step one-pot procedure involving the
FeCl3·6H2O-catalyzed F–C reaction followed by
a base-mediated furan ring formation. More impor-
tantly, naphthopyrans can be obtained via a single
step tandem reaction in the presence of only a catalyt-
ic amount of FeACHTUNTRGNEUNG(III) catalyst without the assistance of
any other external additives. Such a general and effi-
cient method has been rarely reported. The chemo-
specific formation of furan and pyran motifs proceed-
ed through different reaction models as controlled by
the structural features of the secondary and tertiary
propargylic alcohols. In addition, the methods are
also atom-economic and environmentally benign be-
cause only a slight excess of phenol substrates
(1.2 equiv.) was used and only water was produced as
stoichiometric waste. Most interestingly, for the first
time, we have established an efficient protocol for the
synthesis of fully 2,3,4-substituted naphthopyrans via
a one-pot reaction. The introduction of an iodo func-
[a]
[b]
Reaction conditions: phenol 1 (0.3 mmol, 1.0 equiv.),
proparyl alcohol 7 (0.9 mmol, 3.0 equiv.), I2 (0.6 mmol,
2.0 equiv.), FeCl3·6H2O (10 mol%) in toluene (3 mL) at
258C.
Isolated yield.
Adv. Synth. Catal. 2013, 355, 537 – 547
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
545

Feng-Quan Yuan and Fu-She Han
FULL PAPERS
(petroleum ether/DCM=10/1, v/v) to give the desired prod-
uct.
tional group at the 3-position should provide a new
entry for the development of naphthopyran-based
photochromic materials. The design and synthesis of
some 3-substituted naphthopyrans and study of their
photochromic properties are currently underway in
our laboratory.
General Procedure for the One-Pot Three-Compon-
ent Synthesis of 3-Iodinated Naphthopyrans (15)
A
toluene solution (3 mL) of propargylic alcohol 7
(0.9 mmol), 2-naphthol 1 (0.3 mmol), I2 (152 mg, 0.6 mmol),
and FeCl3·6H2O (8.1 mg, 0.03 mmol) was stirred in a sealed
Schlenck tube at 258C. After the completion of the reaction
as monitored by TLC, ethyl acetate (30 mL) was added and
the mixture was washed successively with saturated aqueous
Na2S2O3 solution and brine for three times. The organic
layer was then dried over Na2SO4, filtered, and concentrat-
ed. The mixture was purified by silica gel chromatography
(petroleum ether/DCM=10/1, v/v) to give the desired prod-
uct.
Experimental Section
General Methods
All solvents were purified according to the standard meth-
ods prior to use. Phenols and iron catalysts were purchased
from J&K Chemical Ltd or Alfa Aesar, and were used with-
out further purification. FeCl3·6H2O of 99% purity from
ACROS company was used; the FeCl3 used for optimization
of the reaction conditions was purchased from Alfa Aesar
company and had 98% purity. Propargylic alcohols were
prepared according to the known methods.[24] Unless other-
Acknowledgements
1
wise noted, the H NMR spectra were recorded at 400 or
600 MHz in CDCl3 and the 13C NMR spectra were recorded
at 100 or 150 MHz in CDCl3, respectively, with TMS as in-
ternal standard. All shifts are given in ppm. All coupling
constants (J values) are reported in Hertz (Hz). X-ray crys-
tallographic analyses were performed on a Bruker SMART
APEX II CCD diffractometer with graphite-monochromat-
ed Mo-Ka radiation (l=0.71073 ꢂ) operated at 2.0 kW
(50 kV, 40 mA). The structures were solved by direct meth-
ods using the program SHELXL-97 and refined anisotropi-
cally by full matrix least squares on F2 values with
SHELXL-97. High resolution mass spectra was measured by
using IonSpec7.0T MALDI-FTICRMs. Column chromatog-
raphy was performed on silica gel 100 mesh. See the Sup-
porting Information for characterization data, and copies of
1H NMR and 13C NMR spectra of the products.
Financial support from “Hundred Talent Program” of CAS,
and State Key Laboratory of Fine Chemicals (KF1008) is ac-
knowledged.
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asc.wiley-vch.de
547