Azulene Functionalization by Iron-Mediated Addition to a Cyclohexadiene Scaffold

Article abstract of DOI:10.1021/acs.joc.0c01412

The functionalization of azulenes via reaction with cationic η5-iron carbonyl diene complexes under mild reaction conditions is demonstrated. A range of azulenes, including derivatives of naturally occurring guaiazulene, were investigated in reactions with three electrophilic iron complexes of varying electronic properties, affording the desired coupling products in 43-98% yield. The products were examined with UV-vis/fluorescence spectroscopy and showed interesting halochromic properties. Decomplexation and further derivatization of the products provide access to several different classes of 1-substituted azulenes, including a conjugated ketone and a fused tetracycle.

Full text of DOI:10.1021/acs.joc.0c01412

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Article
Azulene Functionalization by Iron-Mediated Addition to a
Cyclohexadiene Scaffold
Petter Dunås, Lloyd C. Murfin, Oscar J. Nilsson, Nicolas Jame, Simon E. Lewis,* and Nina Kann*
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ABSTRACT: The functionalization of azulenes via reaction with cationic
η5-iron carbonyl diene complexes under mild reaction conditions is
demonstrated. A range of azulenes, including derivatives of naturally
occurring guaiazulene, were investigated in reactions with three electrophilic
iron complexes of varying electronic properties, affording the desired
coupling products in 43−98% yield. The products were examined with UV−
vis/fluorescence spectroscopy and showed interesting halochromic proper-
ties. Decomplexation and further derivatization of the products provide
access to several different classes of 1-substituted azulenes, including a
conjugated ketone and a fused tetracycle.
Scheme 1. Electrophilic Aromatic Substitution Reactions for
Functionalizing Azulenes
INTRODUCTION
■
Azulene is a bicyclic nonalternant aromatic hydrocarbon,
isomeric with naphthalene. The π-electrons of azulene are
polarized toward the five-membered ring, resulting in a
relatively large inherent dipole moment and a deep blue
color.1 Their unusual electronic properties make azulenes
interesting as photocatalysts2 and colorimetric indicators3 and
for optoelectronics such as solar cells,4 photoswitches,5 and
organic electronics.6 Azulene derivatives have also found use in
medicine in the form of antiulcer,7 antidiabetic,8 and
anticancer9 agents. The ability to functionalize the azulene
scaffold is thus of great interest.
Azulenes are potent nucleophiles for electrophilic aromatic
substitution (SEAr), with the 1- and 3-positions being the most
reactive toward electrophiles.10 Reported methods for
derivatizing azulenes include (a) the Michael addition,11 (b)
Friedel−Crafts11a,12 and Vilsmeier−Haack reactions,11a,13 (c)
azulene addition to heteroaromatic triflates,14 and (d) the
formation of diazo compounds (Scheme 1).15 Azulenes are
also susceptible to (e) electrophilic halogenations.10e,16 In
addition, cross-coupling reactions have been reported.17 While
these latter reactions are attractive for coupling the azulene to
sp2- and sp-carbons, they generally rely on the use of precious
metal catalysts and require prefunctionalization of the azulene
skeleton.
Scheme 2. Methods for the Formation of Cationic Iron
Carbonyl Dienyl Complexes
Another class of electrophile that could potentially react with
nucleophilic azulenes are cationic η5-iron carbonyl dienyl
complexes (Scheme 2). Such complexes are capable of reacting
with a wide range of nucleophiles to form new carbon−carbon
or carbon−heteroatom bonds.18 Nucleophilic addition pro-
ceeds in a highly selective manner at the opposite face to the
iron carbonyl moiety and at one of the ends of the conjugated
system.18b,19 Substituents on the cation can act to direct the
nucleophilic addition to either termini of the dienyl system;
Received: June 15, 2020
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electron-withdrawing groups will generally favor addition in
the meta position, while electron-donating groups will often
favor the para or ipso addition.20 The cationic complexes can
be formed via hydride abstraction (Scheme 2, path a) or by
acid treatment of a complex possessing a leaving group
(Scheme 2, path b). Once formed, the complex can be isolated
as a shelf-stable fine powder.42
(entry 2). To investigate if solubility issues might play a role in
limiting the yield, the reaction was performed in a 3:1 mixture
of acetone and water, resulting in an enhanced yield of 85%
(entry 3). Adding an amine base such as triethylamine (Et3N)
was not beneficial, neither for methyl acetate as the solvent
(entry 4) nor for acetone (entry 5). A near-quantitative yield
could, however, be attained using acetone with sodium
bicarbonate as the base (entry 6). This last protocol thus
provides a set of green and benign reaction conditions for the
addition reaction.
Azulene itself possesses two nucleophilic carbons, and a
mixture of mono- and disubstituted products is thus to be
expected. To see if azulene could be selectively functionalized
to form either one of these products, the reaction was first
performed using a slight excess of complex 2 relative to
azulene. This afforded an equimolar mixture of the
diastereomeric disubstituted azulenes 4 and 4′ in an 81%
yield (Scheme 3). Using a large excess of azulene instead, a
mixture of mono- and disubstituted products was formed,
where the monosubstituted product 5 could be isolated in a
yield of 48%.
Aromatic nucleophiles that can react with cationic iron
carbonyl dienyl complexes include furan,21 indole,21,22 ani-
line,23 and oxygenated arenes.24 The scope was recently
increased by us to include the selective C- or O-addition of
phenolic nucleophiles.25 Although azulenes, with a nucleophil-
icity similar to that of indoles,10d can be expected to be
efficient nucleophiles, no previous report of their use in this
context has been reported. Herein, we present a convenient
iron-mediated electrophilic C−H functionalization of azulenes
(Scheme 1). The products of this process are valuable in two
contexts. First, they are stimuli-responsive substances with
multimodal outputs (colorimetric, fluorescence, and infrared
spectroscopic). Second, they are versatile substrates for further
synthetic transformations such as cyclizations. The cyclo-
hexadiene also constitutes a proaromatic substituent, which
may be readily converted to a phenyl ring, giving a formal
product of azulene electrophilic arylation, for which there is no
direct SEAr equivalent.
a b
,
Scheme 3. Mono- and Dialkylation of Azulene
RESULTS AND DISCUSSION
■
To investigate if azulenes could react with cationic iron
carbonyl dienyl complexes, we selected guaiazulene 1 as the
nucleophile, due to its low cost and availability from natural
sources. As the electrophile, we selected iron complex 2, which
we have used in earlier studies.25 Optimization of the reaction
conditions for this addition was then performed (Table 1).
Table 1. Optimization of the Addition of Guaiazulene (1) to
a
Cationic Complex 2
a
Products are racemic with the relative stereochemistry shown.
Isolated yields. Excess of 2 (2.2 equiv), 4 equiv NaHCO3. Excess
b
c
d
of azulene (5 equiv), 2 equiv NaHCO3.
b
entry
solvent
base
yield 3 (%)
1
2
3
4
5
6
EtOH
H2O
acetone/H2O (3:1)
MeOAc
acetone
acetone
41
72
85
75
73
The scope of the transformation was then explored further.
In addition to the activated complex (2), electronically neutral
6 and deactivated complex 7 were also selected for evaluation
as electrophiles in the reaction (Figure 1).
Azulenes with extended π-systems are of interest for
optoelectronic applications, as the properties of azulene can
be tuned by extension of the conjugated system.4c Routes to
Et3N
Et3N
NaHCO3
97
a
b
Product 3 is racemic; relative stereochemistry is shown. Yields are
determined by quantitative H NMR using p-xylene as the internal
1
standard.
In our previous studies involving phenolic nucleophiles, we
performed the reaction in ethanol in the absence of base at an
ambient temperature.25 Similar conditions here afforded the
desired addition product 3, albeit in a modest yield (Table 1,
entry 1). Using water as the solvent afforded a heterogeneous
reaction mixture where both guaiazulene and iron complex 2
were insoluble. Nevertheless, the yield was increased to 72%
Figure 1. Cationic iron carbonyl dienyl complexes 2, 6, and 7,
selected as electrophilic coupling partners.
B
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a b
,
functionalizing these types of motifs could thus be valuable. A
selection of 1-substituted azulene nucleophiles (8−11, Figure
2), as well as a 6-substituted azulene (12), was prepared and
explored in reactions with iron complexes 6 and 7.
Scheme 4. Alkylation of Azulene Nucleophiles 8−12
Figure 2. Scope of azulene nucleophiles with extended π-systems.
Azulene is significantly more expensive than guaiazulene. As
nucleophiles 8−11 were prepared from azulene itself, they
were used as the limiting reagent in the ensuing reactions. The
results of their reaction with electrophiles 6 or 7 are shown in
Scheme 4. Treating 1-phenylazulene 8 with 1.1 equiv of iron
complex 6 resulted in the formation of 13 in an excellent yield
of 95%. The less activated iron complex 7 was equally effective
with the same nucleophile, resulting in 94% of adduct 14.
Azulene 9, with a thienyl functionality, reacted with 6 to form
compound 15 in a 73% yield. No other coupling products were
detected, indicating that the thiophene unit does not compete
with azulene as a nucleophile in this case. Azulene 10, with a
pendant alkyne group, and formylated azulene 11 afforded
adducts 16 and 17 in 70 and 50% yields, respectively. These
products contain functional handles, which can be utilized for
further derivatization. As in the case of azulene, 6-phenyl-
azulene 12 possesses two nucleophilic sites and could be
doubly alkylated using an excess of the cationic iron complex 6,
giving rise to an equimolar mixture of diastereomers 18 and
18′ in an 83% yield.
a
Products are racemic with the relative stereochemistry shown.
Isolated yields. 16 h reaction time. 2.2 equiv electrophile, 4 equiv
b
c
d
Naturally occurring guaiazulene (1) is an FDA-approved
additive in cosmetics.26 Being a large-scale commercial
product, it is inexpensive and readily available and therefore
of special interest for synthetic applications. In addition to
guaiazulene itself, seven guaiazulene derivatives (19−25) with
different substitution patterns on the five-membered ring were
prepared to be used as nucleophiles in the addition reaction.
Substituents included both electron-withdrawing and electron-
donating groups, along with some potentially useful synthetic
handles in the form of a boronic ester or a halogen (Figure 3).
Addition of the guaiazulene nucleophiles 1 and 19−25 was
performed using the optimized conditions shown in Table 1.
The results are summarized in Scheme 5. Addition of
guaiazulene itself to electrophilic iron complex 2 proceeded
to give addition product 3 in an excellent yield of 97%.
Complexes 6 and 7 were less reactive, but upon extending the
reaction time from 4 to 16 h, alkylated azulenes 26 and 27
were obtained in yields of 98% and 93%, respectively. A
deactivating effect was seen for the more electron-deficient 1-
formyl-substituted guaiazulene derivative 19, where compound
28 was produced in a 56% yield. The coupling reaction proved
to be sensitive toward substituents in the 2-position of the
guaiazulene scaffold. Guaiazulene derivative 20, with a boronic
NaHCO3.
ester in the 2-position, reacted with iron complex 2 to produce
29 in a 43% yield. 2-Iodoguaiazulene (21) reacted sluggishly,
but a 63% yield of 30 could be attained using a reaction time of
16 h and an excess of cation 2. The bromo-substituted
guaiazulene 22 showed a higher reactivity, resulting in 79% of
product 31 under the standard reaction conditions, with a 4 h
reaction time. This suggests that steric factors may influence
the reaction outcome in the case of 2-substituted azulenes. No
reaction occurred with the tolyl-substituted derivative 23. For
the coupling with 2-aminoguaiazulene (24), competing N-
addition is a possibility.23 The reaction was unsuccessful,
however; while all starting material was consumed, neither C-
or N-addition product could be isolated. To investigate if this
reaction outcome was linked to instability introduced by the
amino group, compound 24 was acetylated to amide 25 and
the latter was subsequently used in a coupling reaction. While
1H NMR analysis of the crude product looked promising, no
product could be isolated in this case.
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Scheme 5. Alkylation of Guaiazulene-Derived
a b
,
Nucleophiles
Figure 3. Guaiazulene (1) and guaiazulene derivatives evaluated as
nucleophilic coupling partners in the addition to iron complexes 2, 6,
and 7.
In our previous research on phenolic nucleophiles, we
developed a shorter route for the coupling reaction starting
from neutral iron cyclohexadiene complexes.25 This method
foregoes the formation and isolation of the cationic iron
carbonyl complex by forming the electrophile in situ from a
neutral precursor using a catalytic amount of acid. We applied
this strategy here and found that guaiazulene could be
alkylated directly from the neutral iron complex 32 (precursor
to cationic complex 2) in the presence of tetrafluoroboric acid
(Scheme 6). When a catalytic amount of acid was used, only a
small amount of product was formed. Upon increasing the
amount of tetrafluoroboric acid to 1.1 equiv, however, the
desired addition product 3 was obtained in an 86% yield. Using
an excess of acid (2 equiv) lowered the yield to 45%, which
may be due to protonation of guaiazulene, reducing its
nucleophilicity. The 86% yield obtained under the optimal
conditions is higher than the combined 76% yield obtained
when preforming the complex,25 followed by the addition of
guaiazulene, opening up for a shorter synthetic path. As the
isolation of the cationic complex includes precipitation using
large amounts of solvent, this variant of the reaction can
significantly reduce the amount of waste created in the
synthesis of products such as 3.
Iron carbonyl complexes are of interest as bioprobes,27
indicating that the azulenes formed in this study could be
useful in their own right. In addition to a strong and distinctive
absorption in the IR region from the iron carbonyl moiety, the
azulene fragment introduces both a fluorophore and a clearly
visible colorimetric indicator, thus potentially allowing multi-
modal chemical sensing. Accordingly, we investigated the UV−
vis, fluorescence, and IR spectroscopic properties of a
representative selection of the novel compounds reported here.
Azulene derivatives are known sometimes to exhibit
halochromism, i.e., to undergo changes in color upon
protonation (at the azulene-1- or 3-position).28,29 Compounds
4/4′, 14, 26, 33, and 34 were assessed for their colorimetric
responses to trifluoroacetic acid (TFA). Exposure to excess
TFA (1000 equiv) resulted in each case in a color change
discernible to the naked eye (Figure S67, see the Supporting
Information (SI)), which became more pronounced when
TFA was used as cosolvent (Figure 4). UV−vis absorption
spectra of the neutral and protonated azulenes were also
a
Products are racemic with the relative stereochemistry shown.
Isolated yields. 4 h reaction time. 16 h reaction time. Excess of 2
b
c
d
e
(1.1 equiv).
acquired (Figure S68). The relationship between azulene
substitution pattern and halochromism has been studied and a
trend can be determined. It has been shown that for some
strongly halochromic azulenes with a particular substituent at
the 2- or 6-position, moving the substituent to the 1- or 3-
position may significantly attenuate the halochromic respon-
se.28b−g This may be due to the change in connectivity
resulting in a different preferred site of protonation. The
tricarbonyliron(diene)-substituted azulenes 4/4′, 14, and 26
exhibit pronounced halochromism regardless of the fact the
substituents are at 1- and 3-positions of the azulene core. This
suggests that in 4/4′, 14, and 26, the azulene core remains the
D
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does not quench the fluorescence of the pendent azulenium
fluorophore. A titration of azulene 4/4′ with TFA was also
performed, monitored by UV−vis and fluorescence spectros-
copy (Figures S69 and S70). A weak second emission
maximum was observed at higher acid concentrations,
implying a possible further reaction under these conditions.
Iron carbonyl diene complexes exhibit strong vibrational
absorption bands in the 2100−1800 cm−1 region, a window
where most biological media are transparent.27a,31 This makes
them interesting in applications such as bioimaging using mid-
IR and Raman spectroscopy.31b Iron carbonyl diene complexes
substituted with fluorescent coumarin moieties have been
suggested as IR-fluorescent probes,27a and we therefore
envision that the azulene-functionalized iron carbonyl
complexes could be useful for similar applications. The IR-
absorption spectra of the azulene addition products were
measured using attenuated total reflection (ATR)-Fourier
transform infrared (FTIR) in the neat state. As expected,
characteristic strong peaks in the 2100−1900 cm−1 region were
observed for all products possessing the iron carbonyl moiety.
To increase the synthetic utility of the formed products, we
investigated the oxidative removal of the iron carbonyl moiety.
Several methods have been developed for this transformation,
where strong oxidative conditions are generally used, including
the use of hydrogen peroxide in aqueous sodium hydroxide,32
cerium ammonium nitrate,33 trimethylamine N-oxide,34 or
cupric chloride.35 Initial application of these methods,
however, showed that these conditions were too harsh for
these compounds, resulting in poor yields, partial degradation
of the oxidatively sensitive azulenes, and in some cases partial
aromatization of the formed cyclohexadiene. Successful
demetallation of the addition products could, however, be
achieved by applying mild, photolytic decomplexation
Scheme 6. Formation of Addition Product Directly from
Neutral Hydroxylated Iron Carbonyl Diene Complex 32
a
a
Isolated yields.
Figure 4. Azulenes (0.5 mM) in CHCl3 (left) and TFA/CHCl3 1:9 v/
v (right). Photo taken 30 min after sample preparation.
preferred site of protonation, as opposed to the
tricarbonyliron(diene) motif.
It is known that for many azulenes, protonation can induce a
significant fluorescence turn-on response,30 whereas fluores-
cence properties of tricarbonyliron(diene) complexes have
been studied only rarely.27a Exposure to UV irradiation is an
established method of cleaving Fe−C bonds in tricarbonyliron-
(diene) complexes (see below), but the reaction time required
for this process is >3 orders of magnitude greater than the
acquisition time for a fluorescence spectrum (days vs seconds).
On the basis of this semiquantitative consideration, we
reasoned that fluorescence spectra could nevertheless be
acquired. Compounds 4/4′, 14, 26, 33, and 34 were all
found to exhibit significant fluorescence enhancement upon
addition of TFA, with 4/4′ showing the greatest turn-on
response (λex = 266 nm, λem = 336 nm; Figure 5), and our
current findings show that the tricarbonyliron(diene) motif
conditions, using a modification of a procedure reported by
36
̈
Knolker. Irradiation of an acetonitrile solution of 13 with a
low-energy UV light (370 nm, 15 W) for 72 h, in the presence
of air, yielded the free diene 33 in a 78% yield (Scheme 7,
entry 1). An advantage of the current procedure is that the
demetallation can be carried out without the need for
specialized equipment. However, it is likely that the reaction
time can be significantly shortened with a more powerful light
source. Notably, this photolytic decomplexation is more
tolerant toward oxidatively labile groups than traditional
Figure 5. Response of azulene 4/4′ to the addition of TFA in CHCl3. (Left) UV−vis spectra of 4/4′ (50 μM) before and after the addition of TFA
in CHCl3 (inset: visible region, 500 μM 4/4′). (Right) Fluorescence response of 4/4′ (5 μM) to TFA. λex = 266 nm (em slit: 5 nm, ex slit: 5 nm).
E
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The C-4 methyl group of guaiazulene is acidic. Upon
deprotonation, the formed anion is stabilized via conjugation
with the electron-poor seven-membered ring. This has been
utilized for condensation reactions with aldehydes under basic
conditions.28a,39 Limited examples of conjugate additions have
also been reported in this context.40 Demetallated guaiazulene
derivative 35 possesses an unsaturated ketone moiety in close
proximity to the C-4 methyl group, which could allow for an
intramolecular conjugate addition. We were pleased to see that
the treatment of 35 with t-BuOK in tetrahydrofuran (THF) at
0 °C yielded a tetracyclic product 37 in a 39% yield (Scheme
9). A strong nuclear Overhauser effect (NOE) interaction
Scheme 7. Photolytic Decomplexation of Addition
Products
a
Scheme 9. Base-Mediated Cyclization of Demetallated
a b
,
Guaiazulene Derivative 35 Forming Tetracycle 37
a
b
Isolated yields. Product 37 is racemic with the relative stereo-
chemistry shown.
between the two ring-junction protons indicates a cis-fused
ring system. The formed tetracyclic compound possesses an
unusual 6/6/5/7 ring system, similar to the carbon skeleton of
swinhoeisterols, isolated from the marine sponge Theonella
swinhoei.41 Swinhoeisterols have been reported to have
cytotoxic properties41 and have recently been the target of a
total synthesis.42 We therefore envision that tetracyclic
structures of this type could be of interest in the synthesis of
natural products and bioactive compounds. A photoswitch
incorporating guaiazulene and cyclohexene was recently
reported by Hecht and co-workers, and compounds such as
35 and 37 may find additional applications in this area.5
a
Isolated yields.
methods. The free diene could also be liberated without
concomitant aromatization. This has previously proved to be
difficult for iron complexes possessing an aromatic substituent,
which is not conjugated to the diene.25,37 Photolytic
demetallation of the methoxy-substituted adduct 14 instead
resulted in the formation of unsaturated ketone 34 in a 74%
yield (Scheme 7, entry 2). This type of reactivity is known
upon decomplexation of 2-methoxy-substituted iron carbonyl
cyclohexadiene complexes38 and provides access to a different
compound class in terms of substituted azulenes. Guaiazulene-
derived adduct 27 could also be demetallated (Scheme 7, entry
3), affording the unsaturated ketone 35 in a 42% yield.
Another product class could be accessed by oxidative
aromatization of diene 33 using 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ), producing 1,3-diphenylazulene (36) in
an 82% yield (Scheme 8).
CONCLUSIONS
■
Azulenes are here shown to be competent nucleophiles in the
addition to cationic iron carbonyl dienyl complexes with
different electronic properties. The reaction proceeds smoothly
at room temperature with acetone as the solvent, using an
inexpensive base (NaHCO3) as the only additive. Apart from
azulene itself, functionalized azulenes with extended con-
jugated systems, as well as derivatives of naturally occurring
guaiazulene, were evaluated as nucleophiles affording the
targeted products in a 43−98% yield. Photolytic decomplex-
ation allowed the oxidative removal of iron under mild
conditions. The synthetic utility of the formed azulenes was
demonstrated via further transformations, including the
formation of a tetracyclic product. UV−vis and fluorescence
properties of selected products were also explored, displaying
some unusual halochromic properties. In conclusion, we
believe that the reported methodology provides a valuable
new method for azulene derivatization and could find
applications in areas such as optoelectronics, sensors,
pharmaceuticals, and natural product synthesis.
Scheme 8. Aromatization of Free Diene
F
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and stirred at room temperature for 24 h. The reaction mixture was
diluted with diethyl ether, filtered through a pad of basic aluminum
oxide, and the solvent was evaporated under a stream of N2 gas.
Purification by flash column chromatography yielded 3 as a blue solid
EXPERIMENTAL SECTION
■
General Considerations. 1-(Azulen-1-yl) tetrahydrothiophenium
hexafluorophosphate,17d neutral iron carbonyl complex 32,25 cationic
iron carbonyl complexes 2,25 6,43 and 744 (starting from commercial
1-methoxy-1,3-cyclohexadiene, technical grade 65%), and guaiazulene
derivatives 11,45 12,46 19,12 20−22,47 and 2348 were synthesized
according to literature procedures. All other solvents and reagents
were purchased from commercial suppliers and used without
purification or drying, unless otherwise stated. Photocatalytic
decomplexation was performed using a low-energy black light lamp
(Velleman lighting, 15 W, 850 lm). Structural assignments were made
with additional information from gradient correlation spectroscopy
(gCOSY), gradient heteronuclear single-quantum coherence
(gHSQC), nuclear Overhauser enhancement spectroscopy
(NOESY), and gradient heteronuclear multiple-bond correlation
(gHMBC) experiments.
1
(41.7 mg, 86%); mp 46−47 °C; H NMR (400 MHz, chloroform-d)
δ 8.02 (d, J = 2.2 Hz, 1H), 7.46 (s, 1H), 7.24 (dd, J = 10.6, 2.2 Hz,
1H), 6.83 (d, J = 10.6 Hz, 1H), 6.31 (dd, J = 4.4, 0.8 Hz, 1H), 5.56
(dd, J = 6.4, 4.4 Hz, 1H), 4.56 (app dt, J = 11.3, 3.9 Hz, 1H), 3.73 (s,
3H), 3.44 (ddd, J = 6.5, 3.3, 1.4 Hz, 1H), 3.00 (hept, J = 6.9 Hz, 1H),
2.96 (s, 3H), 2.87 (dd, J = 15.2, 11.3 Hz, 1H), 2.59 (s, 3H), 1.60
(ddd, J = 15.2, 4.3, 0.9 Hz, 1H), 1.32 (d, J = 6.9 Hz, 6H); 13C{1H}
NMR (101 MHz, chloroform-d) δ 172.6, 144.5, 139.7, 138.5, 136.4,
134.5, 133.7, 131.8, 130.9, 126.8, 124.9, 88.7, 84.7, 69.1, 62.8, 51.6,
39.4, 37.6, 33.7, 27.4, 24.5, 13.1. Signal for Fe−CO not seen; FTIR-
ATR νmax/cm−1 2053 (Fe−CO), 1975 (Fe−CO), 1705 (CO);
HRMS (ESI+) m/z: [M + H]+ calcd for C26H27FeO5 475.1208; found
475.1199.
Analytical Methods. Column chromatography was performed on
a Biotage Isolera Spektra One with Biotage SNAP KP-sil (silica gel)
or KP-C18-HS (C18, reverse phase) columns. NMR spectra, 1H
NMR and 13C NMR, were recorded on an Agilent 400 MHz (101
MHz for 13C NMR). The chemical shifts for 1H and 13C NMR
spectra are reported in parts per million (ppm) using the residual
solvent peak for reference. The following abbreviations are used for
reporting NMR peaks: singlet (s), doublet (d), triplet (t), quartet (q),
heptet (hept), multiplet (m), broad (br), and apparent (app). All
coupling constants (J) are reported in hertz (Hz). For diastereomeric
mixtures, peaks that can be attributed to single diastereomers are
labeled d1/d2. ATR-FTIR spectra were recorded on a PerkinElmer
Spectrum Frontier infrared spectrometer with a pike-GladiATR
module and reported in wavenumber (cm−1). Melting points were
Hexacarbonyl[dimethyl 5,5′-(azulene-1,3-diyl)bis-
(cyclohexa-1,3-diene-1-carboxylate)]diiron (4/4′). Synthesized
according to general procedure B using azulene (12.9 mg, 0.101
mmol), iron complex 2 (93.4 mg, 0.221 mmol), and NaHCO3 (33.8
mg, 0.403 mmol). The product was purified by reversed-phase flash
chromatography (MeOH/H2O 85:15), yielding an equimolar mixture
of diastereomers 4 and 4′ as a blue-green amorphous solid (55.1 mg,
1
81%); H NMR (400 MHz, chloroform-d) δ 8.14 and 8.13 (d1/d2)
(d, J = 9.6 Hz, 2H), 7.50 (app t, J = 9.8 Hz, 1H), 7.41 and 7.38 (d1/
d2) (s, 1H), 7.02 and 7.02 (d1/d2) (app t, J = 9.9 Hz, 2H), 6.35−6.31
(m, 2H), 5.53 and 5.48 (d1/d2) (dd, J = 6.4, 4.4 Hz, 2H), 4.19−4.09
(m, 2H), 3.75 and 3.74 (d1/d2) (s, 6H), 3.44 and 3.40 (ddd, J = 6.4,
3.5, 1.4 Hz, 2H), 2.95 and 2.93 (d1/d2) (dd, J = 15.2, 11.4 Hz, 2H),
1.66 and 1.59 (d1/d2) (dd, J = 15.4, 4.0 Hz, 2H); 13C{1H} NMR (101
MHz, chloroform-d) δ 210.2 (br), 172.7, 172.6, 138.4, 138.4, 135.6,
135.5, 133.5, 133.5, 133.2, 133.1, 131.6, 131.4, 121.9, 121.8, 89.2,
89.2, 84.5, 67.6, 67.4, 63.0, 62.9, 51.9, 37.2, 37.1, 32.8, 32.6; FTIR-
ATR νmax/cm−1 2048 (Fe−CO), 1967 (Fe−CO), 1703 (CO);
HRMS (ESI+) m/z: [M + H]+ calcd for C32H25Fe2O10 681.0147;
found 681.0139.
Tricarbonyl[methyl 5-(azulen-1-yl)cyclohexa-1,3-diene-1-
carboxylate]iron (5). Synthesized according to general procedure
B, using iron complex 2 (21.1 mg, 0.0500 mmol) and azulene (32.0
mg, 0.250 mmol). The product was purified by reversed-phase flash
chromatography (methanol/water, 80:20 → 90:10), yielding 5 as a
blue sticky solid (9.7 mg, 48%); 1H NMR (400 MHz, chloroform-d) δ
8.26 (d, J = 9.1 Hz, 1H), 8.23 (d, J = 8.7 Hz, 1H), 7.70 (d, J = 3.9 Hz,
1H), 7.55 (app t, J = 9.9 Hz, 1H), 7.29 (d, J = 4.0 Hz, 1H), 7.12 (app
t, J = 9.8 Hz, 1H), 7.08 (app t, J = 9.7 Hz, 1H), 6.30 (ddd, J = 4.4, 1.4,
0.9 Hz, 1H), 5.51 (dd, J = 6.4, 4.4 Hz, 1H), 4.20 (app dt, J = 11.4, 3.7
Hz, 1H), 3.73 (s, 3H), 3.46 (ddd, J = 6.4, 3.5, 1.4 Hz, 1H), 2.97 (ddd,
J = 15.3, 11.4, 0.9 Hz, 1H), 1.67 (ddd, J = 15.4, 3.9, 0.9 Hz, 1H);
13C{1H} NMR (101 MHz, chloroform-d) δ 172.6, 141.1, 137.9,
recorded on a Buchi Melting Point B-545. High-resolution mass
̈
spectrometry (HRMS) was performed on an Agilent 1290 infinity LC
system equipped with an autosampler tandem to an Agilent 6520
Accurate Mass Q-TOF LC/MS.29a Fluorescence spectra were
acquired on an Agilent Technologies Cary Eclipse fluorescence
spectrophotometer. UV−vis spectra were acquired on a PerkinElmer
Lambda20 Spectrophotometer, using a Starna Silica (quartz) cuvette
with 10 mm path length, two faces polished.
General Procedure A: Addition of Guaiazulene-Derived
Nucleophiles to Cationic Iron Carbonyl Complexes. Cationic
iron carbonyl complex (1.0 equiv), guaiazulene derivative (1.1 equiv),
NaHCO3 (1.5 equiv), and acetone (2.0 mL) were added to a 5 mL
microwave vial equipped with a stir bar. The vial was capped and
stirred at room temperature for 4 or 16 h. The crude reaction mixture
was diluted with diethyl ether (5.0 mL), filtered through a pad of
basic aluminum oxide, concentrated under a stream of N2 gas, and
purified by reversed-phase flash column chromatography (MeOH/
H2O).
General Procedure B: Addition of Azulene-Derived Nucle-
ophiles to Cationic Iron Carbonyl Complexes. Azulene
derivative (1.0 equiv), cationic iron carbonyl complex (1.1 equiv),
NaHCO3 (2.0 equiv), and acetone (1.0 mL) were added to a 5 mL
microwave vial equipped with a stir bar. The vial was capped and
stirred at room temperature for 5 h. The crude reaction mixture was
diluted with diethyl ether (3.0 mL), filtered through a pad of silica,
concentrated under a stream of N2 gas, and purified by flash column
chromatography.
Tricarbonyl[methyl 5-(5-isopropyl-3,8-dimethylazulen-1-
yl)cyclohexa-1,3-diene-1-carboxylate]iron (3). Starting from
Cationic Iron Carbonyl Complex 2. Synthesized according to general
procedure A using iron complex 2 (42.2 mg, 0.100 mmol),
guaiazulene 1 (21.8 mg, 0.110 mmol), and NaHCO3 (12.6 mg,
0.150 mmol), with a reaction time of 4 h. The product was purified by
reversed-phase chromatography (MeOH/H2O, 60:40 → 85:15),
yielding 3 as a blue solid (47.4 mg, 97%).
Starting from Neutral Iron Carbonyl Complex 32. Iron complex
32 (30.0 mg, 0.102 mmol) and guaiazulene 1 (30.3 mg, 0.153 mmol)
were added to a 5 mL microwave vial equipped with a stir bar.
Acetonitrile (1.0 mL) containing tetrafluoroboric acid diethyl ether
complex (15.3 μL, 0.112 mmol) was added, and the vial was capped
137.0, 134.7, 134.7, 134.4, 133.1, 122.8, 122.0, 117.2, 89.3, 84.6, 67.7,
63.1, 51.8, 37.2, 32.9. Signal for Fe−CO not seen; FTIR-ATR νmax
/
cm−1 2047 (Fe−CO), 1969 (Fe−CO), 1711 (CO); HRMS (ESI+)
m/z: [M + H]+ calcd for C21H17FeO5 405.0425; found 405.0424.
1-Phenylazulene (8). Synthesized according to a literature
procedure.17d To a Radleys Carousel reaction tube equipped with a
stirrer was added 1-(azulen-1-yl) tetrahydrothiophenium hexafluor-
ophosphate (500 mg, 1.39 mmol), phenylboronic acid (203 mg, 1.67
mmol), K3PO4 (589 mg, 2.78 mmol), Xphos (60.2 mg, 0.139 mmol),
and Pd(OAc)2 (12.5 mg, 0.0557 mmol). The vial was capped,
evacuated, and refilled with argon. Dimethylformamide (DMF) (10
mL) was added, and the vial was heated in a heating block at 75° for 6
h. The crude product was diluted with water and extracted with
petroleum ether, and the organic phase was washed with brine and 5%
aqueous lithium chloride. The solvent was evaporated under reduced
pressure, and the crude product was purified by flash column
chromatography (100% petroleum ether), yielding 8 as a blue solid
1
(166.7 mg, 59%). H NMR (400 MHz, chloroform-d) δ 8.57 (d, J =
9.8 Hz, 1H), 8.36 (d, J = 9.4 Hz, 1H), 8.03 (d, J = 3.8 Hz, 1H), 7.65−
7.57 (m, 3H), 7.53−7.48 (m, 2H), 7.45 (d, J = 3.9 Hz, 1H), 7.38−
G
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7.33 (m, 1H), 7.19−7.12 (m, 2H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 141.8, 138.3, 137.7, 137.4, 137.3, 135.8, 135.4, 131.5,
129.9, 128.8, 126.4, 123.5, 123.2, 117.6. Analysis data are in
accordance with published data for this compound.49
MHz, chloroform-d) δ 8.43 (d, J = 9.7 Hz, 1H), 8.23 (d, J = 9.7 Hz,
1H), 7.83 (s, 1H), 7.63−7.58 (m, 2H), 7.57−7.49 (m, 3H), 7.41−
7.35 (m, 1H), 7.07 (app t, J = 9.8 Hz, 1H), 7.04 (app t, J = 9.8 Hz,
1H), 5.22 (dd, J = 6.5, 2.2 Hz, 1H), 3.90 (app dt, J = 11.1, 3.5 Hz,
1H), 3.72 (s, 3H), 3.56 (app dtd, J = 3.4, 2.3, 0.8 Hz, 1H), 2.94 (dd, J
= 6.5, 3.5 Hz, 1H), 2.60 (ddd, J = 14.8, 11.1, 3.7 Hz, 1H), 1.99 (app
dt, J = 15.2, 2.9 Hz, 1H); 13C{1H} NMR (101 MHz, chloroform-d) δ
140.4, 138.6, 137.5, 136.4, 136.0, 135.8, 135.0, 134.7, 133.6, 130.3,
130.0, 128.8, 126.5, 123.1, 122.0, 66.8, 56.0, 54.6, 53.8, 35.4, 35.1,
signal for Fe−CO not seen; FTIR-ATR νmax/cm−1 2035 (Fe−CO),
1946 (Fe−CO); HRMS (ESI+) m/z: [M + H]+ calcd for C26H21FeO4
453.0789; found 453.0787.
1-(2-Thienyl)-azulene (9). Synthesized according to a literature
procedure.17d To a Radleys Carousel reduced volume reaction tube
equipped with a stirrer was added 1-(azulen-1-yl) tetrahydrothiophe-
nium hexafluorophosphate (250 mg, 0.694 mmol), 2-(thiophenebor-
onic acid)pinacol ester (175 mg, 0.833 mmol), K3PO4 (295 mg, 1.39
mmol), Xphos (33.1 mg, 0.0694 mmol), and Pd(OAc)2 (6.2 mg,
0.028 mmol). The vial was capped, evacuated, and refilled with argon.
DMF (5.0 mL) was added, and the vial was heated in a heating block
at 75 °C for 6 h. The crude product was diluted with water and
extracted with petroleum ether, and the organic phase was washed
with brine and 5% aqueous lithium chloride. The solvent was
evaporated under reduced pressure, and the crude product was
purified by flash column chromatography (100% petroleum ether),
Tricarbonyl[2-(3-(cyclohexa-2,4-dien-1-yl)azulen-1-yl)-
thiophene]iron (15). Synthesized according to general procedure B
using azulene derivative 9 (10.5 mg, 0.0499 mmol), iron complex 6
(20.0 mg, 0.0550), and NaHCO3 (8.4 mg, 0.10 mmol) in 0.5 mL
acetone. The product was purified by flash chromatography
(petroleum ether/EtOAc 99:1), yielding 15 as a sticky green solid
1
yielding 9 as a blue-green oil (77.5 mg, 53%). H NMR (400 MHz,
1
(15.6 mg, 73%); H NMR (400 MHz, chloroform-d) δ 8.61 (d, J =
chloroform-d) δ 8.77 (d, J = 9.8 Hz, 1H), 8.32 (d, J = 9.4 Hz, 1H),
8.07 (d, J = 4.0 Hz, 1H), 7.64−7.67 (m, 1H), 7.41 (d, J = 4.0 Hz,
1H), 7.38−7.35 (m, 1H), 7.32−7.29 (m, 1H), 7.23−7.15 (m, 3H);
13C{1H} NMR (101 MHz, chloroform-d) δ 142.3, 139.8, 138.7,
137.5, 137.4, 135.9, 135.1, 127.8, 124.7, 124.5, 123.8, 123.7, 123.7,
117.9. Analysis data are in accordance with published data for this
compound.50
9.6 Hz, 1H), 8.18 (d, J = 9.6 Hz, 1H), 7.86 (s, 1H), 7.53 (app t, J =
9.8 Hz, 1H), 7.36 (dd, J = 5.1, 1.2 Hz, 1H), 7.25 (dd, J = 3.6, 1.2 Hz,
1H), 7.18 (dd, J = 5.1, 3.5 Hz, 1H), 7.07 (app t, J = 9.8 Hz, 1H), 7.06
(app t, J = 9.8 Hz, 1H), 5.63−5.58 (m, 1H), 5.48 (ddd, J = 6.0, 4.1,
1.5 Hz, 1H), 4.02 (app dt, J = 11.1, 3.6 Hz, 1H), 3.35−3.24 (m, 2H),
2.56 (ddd, J = 15.1, 11.1, 3.8 Hz, 1H), 1.83 (dddd, J = 15.2, 3.5, 2.2,
1.1 Hz, 1H); 13C{1H} NMR (101 MHz, chloroform-d) δ 212.2,
139.5, 139.0, 137.0, 135.9, 135.9, 135.2, 134.9, 133.7, 127.8, 124.9,
124.7, 123.4, 122.6, 122.5, 86.4, 84.7, 66.7, 60.7, 35.7, 34.1; FTIR-
ATR νmax/cm−1 2035 (Fe−CO), 1946 (Fe−CO); HRMS (ESI+) m/
z: [M + H]+ calcd for C23H17FeO3S 429.0248; found 429.0246.
Tricarbonyl[((3-(cyclohexa-2,4-dien-1-yl)azulen-1-yl)-
ethynyl)triisopropylsilane]iron (16). Synthesized according to
general procedure B using azulene derivative 10 (11.2 mg, 0.0363
mmol), iron complex 6 (14.5 mg, 0.0398 mmol), and NaHCO3 (6.1
mg, 0.073 mmol) in 0.5 mL acetone. The product was purified by
reversed-phase flash chromatography (MeOH/H2O 70:30 → 100:0),
(Azulen-1-ylethynyl)triisopropylsilane (10). To a microwave
reaction vial was added 1-(azulen-1-yl) tetrahydrothiophenium
hexafluorophosphate (100 mg, 0.278 mmol), CuI (5.3 mg, 0.028
mmol), K3PO4 (64.8 mg, 0.305 mmol), t-BuXphos (11.8 mg, 0.0278
mmol), and Pd(OAc)2 (3.1 mg, 0.014 mmol). The vial was capped,
evacuated, and refilled with argon. (Triisopropylsilyl)acetylene (94
μL, 0.419 mmol) and 2.0 mL DMF were added, and the vial was
heated in a heating block at 80 °C for 16 h. The crude product was
diluted with water and extracted with petroleum ether. The organic
phase was then washed with brine and 5% aqueous lithium chloride.
The solvent was evaporated under reduced pressure, and the crude
product was purified by flash column chromatography (100%
petroleum ether), yielding 10 as a blue oil (23.7 mg, 27%). 1H
NMR (400 MHz, chloroform-d) δ 8.59 (d, J = 9.6 Hz, 1H), 8.28 (d, J
= 9.4 Hz, 1H), 7.98 (d, J = 4.0 Hz, 1H), 7.63 (app t, J = 9.9 Hz, 1H),
7.30−7.18 (m, 3H), 1.22−1.19 (m, 21H); 13C{1H} NMR (101 MHz,
chloroform-d) δ 142.0, 141.3, 140.0, 138.7, 137.3, 136.5, 124.7, 124.2,
117.5, 111.4, 103.3, 94.8, 19.0, 11.7; FTIR-ATR νmax/cm−1 2133
(CC); HRMS (ESI+) m/z: [M + H]+ calcd for C21H29Si 309.2033;
found 309.2048.
1
yielding 16 as a green sticky solid (13.3 mg, 70%); H NMR (400
MHz, chloroform-d) δ 8.45 (d, J = 9.6 Hz, 1H), 8.15 (d, J = 9.6 Hz,
1H), 7.81 (s, 1H), 7.56 (app t, J = 9.8 Hz, 1H), 7.15 (app t, J = 9.9
Hz, 1H), 7.12 (app t, J = 9.9 Hz, 1H), 5.61−5.57 (m, 1H), 5.48 (ddd,
J = 6.0, 4.1, 1.5 Hz, 1H), 3.96 (app dt, J = 11.2, 3.6 Hz, 1H), 3.27−
3.23 (m, 2H), 2.51 (ddd, J = 15.1, 11.2, 3.8 Hz, 1H), 1.79−1.72 (m,
1H), 1.21−1.19 (m, 21H); 13C{1H} NMR (101 MHz, chloroform-d)
δ 212.2, 142.7, 139.0, 137.2, 136.5, 136.3, 135.1, 133.7, 123.8, 123.7,
110.1, 103.1, 95.2, 86.5, 84.8, 77.5, 77.2, 76.8, 66.4, 60.6, 35.6, 34.0,
19.0, 11.7; FTIR-ATR νmax/cm−1 2133 (CC), 2039 (Fe−CO),
1954 (Fe−CO); HRMS (ESI+) m/z: [M + H]+ calcd for
C30H35FeO3Si 527.1705; found 527.1727.
Tricarbonyl[3-(cyclohexa-2,4-dien-1-yl)azulene-1-
carbaldehyde]iron (17). Synthesized according to general proce-
dure B using azulene derivative 11 (26.4 mg, 0.169 mmol), iron
complex 6 (67.7 mg, 0.186 mmol), and NaHCO3 (28.4 mg, 0.338
mmol), with an extended reaction time of 16 h. The product was
purified by reversed-phase flash chromatography (MeOH/H2O
86:14), yielding 17 as a green solid (31.8 mg, 50%); mp 131−134
°C; 1H NMR (400 MHz, chloroform-d) δ 10.87 (s (br), 1H), 9.44 (d,
J = 9.0 Hz, 1H), 8.39 (d, J = 9.7 Hz, 1H), 8.17 (s, 1H), 7.83 (app t, J
= 9.6 Hz, 1H), 7.58−7.42 (m, 2H), 5.65−5.57 (m, 1H), 5.55−5.47
(m, 1H), 3.98 (app dt, J = 11.2, 3.4 Hz, 1H), 3.30−3.23 (m, 2H),
2.56 (ddd, J = 15.1, 11.2, 3.7 Hz, 1H), 1.76 (d, J = 15.4 Hz, 1H);
13C{1H} NMR (101 MHz, DMSO-d6) δ 212.8, 186.2, 141.2, 141.1,
Tricarbonyl[1-(cyclohexa-2,4-dien-1-yl)-3-phenylazulene]-
iron (13). Synthesized according to general procedure B using
azulene derivative 8 (20.6 mg, 0.101 mmol), iron complex 6 (40.5 mg,
0.111 mmol), and NaHCO3 (16.9 mg, 0.202 mmol). The product was
purified by flash chromatography (100% petroleum ether), yielding
1
13 as a blue-green solid (40.6 mg, 95%); mp 51−55 °C; H NMR
(400 MHz, chloroform-d) δ 8.41 (dd, J = 9.7, 0.9 Hz, 1H), 8.23 (d, J
= 9.5 Hz, 1H), 7.84 (s, 1H), 7.61−7.56 (m, 2H), 7.55−7.46 (m, 3H),
7.35 (app ddt, J = 7.9, 6.8, 1.3 Hz, 1H), 7.06 (app t, J = 9.8 Hz, 1H),
7.03 (app t, J = 9.7 Hz, 1H), 5.59 (ddd, J = 6.5, 3.3, 2.0 Hz, 1H), 5.46
(ddd, J = 5.9, 4.1, 1.5 Hz, 1H), 4.06 (dt, J = 11.2, 3.6 Hz, 1H), 3.33
(ddd, J = 6.4, 3.6, 1.4 Hz, 1H), 3.31−3.27 (m, 1H), 2.57 (ddd, J =
15.2, 11.1, 3.8 Hz, 1H), 1.90−1.83 (m, 1H); 13C{1H} NMR (101
MHz, chloroform-d) δ 212.3, 138.6, 137.4, 136.3, 136.1, 135.8, 134.9,
134.9, 133.5, 130.3, 129.9, 128.8, 126.5, 123.1, 122.0, 86.4, 84.7, 66.9,
60.8, 35.7, 34.3; FTIR-ATR νmax/cm−1 2035 (Fe−CO), 1946 (Fe−
CO); HRMS (ESI+) m/z: [M + H]+ calcd for C25H19FeO3 423.0683;
found 423.0695.
141.0, 137.8, 137.2, 136.9, 136.8, 129.6, 128.5, 124.4, 87.3, 85.4, 66.9,
61.9, 34.9, 34.0; FTIR-ATR νmax/cm−1 2032 (Fe−CO), 1944 (Fe−
CO), 1638 (CO); HRMS (ESI+) m/z: [M + H]+ calcd for
C20H15FeO4 375.0320; found 375.0320.
Hexacarbonyl[1,3-di(cyclohexa-2,4-dien-1-yl)-6-
phenylazulene]diiron (18, 18′). Synthesized according to general
procedure A using azulene (21.0 mg, 0.103 mmol), iron complex 6
(82.3 mg, 0.226 mmol), and NaHCO3 (34.5 mg, 0.411 mmol). The
product was purified by reversed-phase flash chromatography
Tricarbonyl[1-(4-methoxycyclohexa-2,4-dien-1-yl)-3-
phenylazulene]iron (14). Synthesized according to general
procedure B using azulene derivative 8 (100 mg, 0.490 mmol), iron
complex 7 (212 mg, 0.539 mmol), and NaHCO3 (82.3 mg, 0.979
mmol) in 4.0 mL acetone. The product was purified by flash
chromatography (petroleum ether/ethyl acetate, 98:2), yielding 14 as
1
a blue-green solid (209 mg, 94%); mp 53−58 °C; H NMR (400
H
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(MeOH/H2O 95:5), yielding an equimolar mixture of diastereomers
18 and 18′ as a green sticky solid (54.8 mg, 83%); H NMR (400
139.5, 138.4, 136.7, 134.4, 133.5, 132.8, 130.9, 126.5, 124.8, 85.8,
1
84.8, 68.5, 60.5, 38.1, 37.6, 35.0, 27.3, 24.5, 13.1; FTIR-ATR νmax/
MHz, chloroform-d) δ 8.14 (d, J = 9.5 Hz, 2H), 7.64−7.59 (m, 2H),
7.52−7.40 (m, 4H), 7.19 (d, J = 10.2 Hz, 2H), 5.68−5.60 (m, 2H),
5.53−5.43 (m, 2H), 4.01 (app dt, J = 11.2, 3.6 Hz, 2H), 3.35−3.24
(m, 4H), 2.60−2.46 (m, 2H), 1.86−1.75 (m, 2H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 212.3, 151.7, 145.2, 134.9, 134.9, 134.3,
134.3, 132.4, 132.2, 132.1, 128.8, 128.4, 128.1, 122.0, 86.3, 86.2, 84.7,
cm−1 2040 (Fe−CO), 1957 (Fe−CO); HRMS (ESI+) m/z: [M +
H]+ calcd for C24H25FeO3 417.1153; found 417.1155.
Tricarbonyl[7-isopropyl-3-(4-methoxycyclohexa-2,4-dien-1-
yl)-1,4-dimethylazulene]iron (27). Synthesized according to
general procedure A using guaiazulene 1 (21.8 mg, 0.110 mmol),
iron complex 7 (39.4 mg, 0.100 mmol), and NaHCO3 (12.6 mg,
0.150 mmol), with a reaction time of 16 h. The product was purified
by reversed-phase chromatography (MeOH/H2O, 60:40 → 85:15),
84.7, 67.1, 67.1, 60.8, 60.8, 36.0, 36.0, 34.0, 33.9; FTIR-ATR νmax
/
cm−1 2037 (Fe−CO), 1942 (Fe−CO); HRMS (ESI+) m/z: [M +
1
H]+ calcd for C34H25Fe2O6 641.0349; found 641.0340.
yielding 27 as a blue solid (41.4 mg, 93%); mp 101−103 °C; H
NMR (400 MHz, chloroform-d) δ 8.01 (d, J = 2.2 Hz, 1H), 7.49 (s,
1H), 7.22 (dd, J = 10.6, 2.2 Hz, 1H), 6.79 (d, J = 10.7 Hz, 1H), 5.26
(dd, J = 6.6, 2.4 Hz, 1H), 4.22 (app dt, J = 11.0, 3.6 Hz, 1H), 3.74 (s,
3H), 3.50 (app dt, J = 3.9, 2.3 Hz, 1H), 2.99 (hept, J = 6.9 Hz, 1H),
2.90 (s, 3H), 2.85 (dd, J = 6.6, 3.4 Hz, 1H), 2.60 (s, 3H), 2.44 (ddd, J
= 14.8, 10.9, 3.9 Hz, 1H), 1.85 (ddd, J = 14.7, 3.7, 2.3 Hz, 1H), 1.32
(d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, chloroform-d) δ 211.7
(br), 144.7, 140.3, 139.6, 138.5, 136.6, 134.6, 133.7, 133.0, 131.1,
126.7, 124.9, 67.2, 57.5, 54.6, 53.6, 38.0, 37.7, 36.2, 27.5, 24.7, 13.2;
FTIR-ATR νmax/cm−1 2036 (Fe−CO), 1958 (Fe−CO); HRMS (ESI
+) m/z: [M + H]+ calcd for C25H27FeO4 447.1258; found 447.1258.
Tricarbonyl[methyl 5-(3-formyl-5-isopropyl-8-methylazu-
len-1-yl)cyclohexa-1,3-diene-1-carboxylate]iron (28). Synthe-
sized according to general procedure A using azulene derivative 19
(23.4 mg, 0.110 mmol), iron complex 2 (42.2 mg, 0.100 mmol), and
NaHCO3 (12.6 mg, 0.150 mmol), with a reaction time of 16 h. The
product was purified by reversed-phase chromatography (MeOH/
H2O 60:40 → 85:15), yielding 28 as a purple solid (27.3 mg, 56%);
7-Isopropyl-1,4-dimethylazulen-2-amine (24). To a micro-
wave reaction vial equipped with a magnetic stirring bar was added 2-
(7-isopropyl-1,4-dimethyl-azulen-2-yl)-4,4,5,5-tetramethyl-1,3,2-diox-
aborolane 20 (111.7 mg, 0.344 mmol), hydroxylamine-O-sulfonic acid
(81.2 mg, 0.718 mmol), acetonitrile (2.0 mL), and 1 M aqueous
NaOH (2.0 mL). The vial was capped and stirred at room
temperature for 24 h. The reaction mixture was diluted with 2 mL
water and extracted with EtOAc (2 × 10 mL), and the organic phase
was dried over Na2SO4 and concentrated under reduced pressure.
The crude product was purified using flash column chromatography
(petroleum ether/EtOAc, 100:0 → 95:5), yielding 24 as a yellow-
brown viscous liquid (26.9 mg, 37%). 1H NMR (400 MHz,
chloroform-d) δ 7.81 (d, J = 1.8 Hz, 1H), 7.12 (dd, J = 10.6, 1.8
Hz, 1H), 6.99 (d, J = 10.6 Hz, 1H), 6.59 (s, 1H), 4.39 (s, 2H), 3.05
(hept, J = 6.9 Hz, 1H), 2.73 (s, 3H), 2.39 (d, J = 0.6 Hz, 3H), 1.35 (d,
J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, chloroform-d) δ 153.4,
141.5, 138.0, 137.3, 135.8, 128.3, 126.7, 126.3, 107.4, 99.7, 38.7, 25.0,
24.2, 8.9; FTIR-ATR νmax/cm−1 3471 (N − H), 3355 (N − H), 1617
(N − H); HRMS (ESI+) m/z: [M + H]+ calcd for C15H20N
214.1596; found 214.1605.
1
mp 74−76 °C; H NMR (400 MHz, chloroform-d) δ 10.27 (s, 1H),
9.60 (s, 1H), 8.10 (s, 1H), 7.57 (dd, J = 10.8, 2.2 Hz, 1H), 7.35 (d, J =
10.7 Hz, 1H), 6.33 (d, J = 4.3 Hz, 1H), 5.66 (dd, J = 6.3, 4.4 Hz, 1H),
4.48 (app dt, J = 11.4, 4.0 Hz, 1H), 3.72 (s, 3H), 3.44 (ddd, J = 6.4,
3.2, 1.4 Hz, 1H), 3.15 (hept, J = 6.9 Hz, 1H), 3.07 (s, 3H), 2.91 (dd, J
= 15.1, 11.3 Hz, 1H), 1.54 (dd, J = 15.1, 4.4 Hz, 1H), 1.37 (d, J = 6.9
Hz, 6H); 13C{1H} NMR (101 MHz, chloroform-d) δ 185.9, 172.3,
149.0, 148.0, 141.6, 141.3, 139.4, 137.3, 137.2, 135.3, 133.0, 124.1,
89.1, 84.8, 67.7, 62.4, 51.7, 39.3, 37.9, 33.8, 27.5, 24.4. Signal for Fe−
CO not seen; FTIR-ATR νmax/cm−1 2050 (Fe−CO), 1974 (Fe−CO),
1707 (CO), 1643 (CO); HRMS (ESI+) m/z: [M + H]+ calcd
for C26H25FeO6 489.1000; found 489.1016.
N-(7-Isopropyl-1,4-dimethylazulen-2-yl)acetamide (25). To
a microwave reaction vial equipped with a magnetic stirring bar was
added 2-(7-isopropyl-1,4-dimethyl-azulen-2-yl)-4,4,5,5-tetramethyl-
1,3,2-dioxaborolane 20 (213.0 mg, 0.657 mmol), hydroxylamine-O-
sulfonic acid (223.0 mg, 1.97 mmol), acetonitrile (3.0 mL), and 1 M
aqueous NaOH (4.0 mL). The vial was capped and stirred at room
temperature for 24 h. The reaction mixture was diluted with water (5
mL) and extracted with dichloromethane. The organic phase was
dried over Na2SO4, and the solvent was evaporated under reduced
pressure. The crude aminoazulene 24 was then redissolved in
dichloromethane (10.0 mL). Acetic anhydride (0.5 mL) and pyridine
(0.5 mL) were added, and the reaction was stirred at room
temperature for 14 h. The reaction mixture was reduced in vacuo,
and the crude product was purified using flash column chromatog-
raphy (20% EtOAc in petroleum ether), yielding 25 as a blue
Tricarbonyl[methyl 5-(5-isopropyl-3,8-dimethyl-2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)azulen-1-yl)cyclohexa-
1,3-diene-1-carboxylate]iron (29). Synthesized according to
general procedure A using azulene derivative 20 (35.7 mg, 0.110
mmol), iron complex 2 (42.2 mg, 0.100 mmol), and NaHCO3 (12.6
mg, 0.150 mmol), with a reaction time of 16 h. The product was
purified by reversed-phase chromatography (MeOH/H2O 60:40 →
1
crystalline solid (60.0 mg, 36%); mp 153−154 °C; H NMR (400
MHz, chloroform-d) δ 8.07 (d, J = 1.9 Hz, 1H), 7.91 (s, 1H), 7.66 (s
(br), 1H), 7.34 (dd, J = 10.8, 1.9 Hz, 1H), 7.09 (d, J = 10.7 Hz, 1H),
3.09 (hept, J = 6.9 Hz, 1H), 2.84 (s, 3H), 2.51 (s, 3H), 2.32 (s, 3H),
1.37 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, DMSO-d6) δ
168.6, 143.9, 140.4, 140.1, 136.2, 134.6, 131.5, 129.9, 126.1, 111.3,
104.7, 37.6, 24.7, 23.9, 23.7, 9.4; FTIR-ATR νmax/cm−1 3302 (N −
H), 1665 (CO); HRMS (ESI+) m/z: [M + H]+ calcd for
C17H22NO 256.1701; found 256.1711.
1
90:10), yielding 29 as a green oil (26.5 mg, 43%); H NMR (400
MHz, chloroform-d) δ 8.01 (d, J = 2.0 Hz, 1H), 7.20 (dd, J = 10.6, 2.1
Hz, 1H), 6.83 (d, J = 10.6 Hz, 1H), 6.30 (d, J = 4.3 Hz, 1H), 5.39
(dd, J = 6.5, 4.3 Hz, 1H), 4.82 (ddd, J = 11.0, 5.7, 2.6 Hz, 1H), 3.73
(s, 3H), 3.37 (ddd, J = 6.4, 2.6, 1.2 Hz, 1H), 3.00 (s, 3H), 2.97 (hept,
J = 6.9 Hz, 1H), 2.76 (dd, J = 15.0, 11.1 Hz, 1H), 2.64 (s, 3H), 1.88
(dd, J = 15.0, 5.8 Hz, 1H), 1.48 (s, 6H), 1.44 (s, 6H), 1.31 (d, J = 6.9
Hz, 6H); 13C{1H} NMR (101 MHz, chloroform-d) δ 210.8 (br),
173.0, 144.6, 140.0, 139.3, 135.0, 134.8, 133.6, 133.2, 131.2, 127.6,
87.9, 85.6, 84.0, 71.4, 62.9, 51.7, 41.4, 37.6, 29.83, 28.55, 25.90, 25.48,
24.58, 13.12. Signal for C-B not seen; FTIR-ATR νmax/cm−1 2045
(Fe−CO), 1968 (Fe−CO), 1708 (CO); HRMS (ESI+) m/z: [M +
H]+ calcd for C32H38BFeO7 601.2059; found 601.2049.
Tricarbonyl[methyl 5-(2-iodo-5-isopropyl-3,8-dimethylazu-
len-1-yl)cyclohexa-1,3-diene-1-carboxylate]iron (30). Synthe-
sized according to general procedure A using azulene derivative 21
(28.6 mg, 0.088 mmol), iron complex 2 (40.9 mg, 0.097 mmol), and
NaHCO3 (11.1 mg, 0.132 mmol), with a reaction time of 16 h. The
product was purified by reversed-phase chromatography (MeOH/
H2O, 60:40 → 90:10), yielding 30 as a blue oil (33.4 mg, 63%);
although stable in neat form, the product was found to be somewhat
unstable in chloroform-d solution. Increased stability was observed
Tricarbonyl[3-(cyclohexa-2,4-dien-1-yl)-7-isopropyl-1,4-
dimethylazulene]iron (26). Synthesized according to general
procedure A using guaiazulene 1 (21.8 mg, 0.110 mmol), iron
complex 6 (36.4 mg, 0.100 mmol), and NaHCO3 (12.6 mg, 0.150
mmol), with a reaction time of 16 h. The product was purified by
reversed-phase chromatography (MeOH/H2O, 60:40 → 85:15),
yielding 26 as a blue sticky solid (41.6 mg, 98%); this product was
also synthesized on a 1 mmol scale, yielding 392 mg of 26 (94%); 1H
NMR (400 MHz, chloroform-d) δ 8.00 (d, J = 2.1 Hz, 1H), 7.53 (s,
1H), 7.21 (dd, J = 10.6, 2.2 Hz, 1H), 6.79 (d, J = 10.6 Hz, 1H), 5.63−
5.57 (m, 1H), 5.49 (ddd, J = 5.9, 4.1, 1.5 Hz, 1H), 4.39 (app dt, J =
11.0, 3.7 Hz, 1H), 3.30−3.22 (m, 2H), 2.99 (hept, J = 6.9 Hz, 1H),
2.90 (s, 3H), 2.59 (d, J = 0.7 Hz, 3H), 2.42 (ddd, J = 15.2, 11.0, 4.0
Hz, 1H), 1.73 (dddd, J = 15.2, 3.7, 2.2, 1.1 Hz, 1H), 1.31 (d, J = 6.9
Hz, 6H); 13C{1H} NMR (101 MHz, chloroform-d) δ 212.3, 144.5,
I
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Article
when the CDCl3 was filtered through a plug of basic aluminum oxide
prior to use; H NMR (400 MHz, chloroform-d) δ 8.13 (d, J = 2.1
3H), 2.36−2.25 (m, 1H); 13C{1H} NMR (101 MHz, chloroform-d) δ
199.7, 153.9, 138.9, 137.1, 136.7, 136.3, 136.2, 136.1, 133.7, 130.3,
129.9, 129.6, 129.4, 128.8, 126.7, 123.6, 122.5, 37.3, 35.2, 31.9; FTIR-
ATR νmax/cm−1 1674 (CO); HRMS (ESI+) m/z: [M + H]+ calcd
for C22H19O 299.1436; found 299.1440.
1
Hz, 1H), 7.34 (dd, J = 10.7, 2.1 Hz, 1H), 6.98 (d, J = 10.7 Hz, 1H),
6.33 (d, J = 4.3 Hz, 1H), 5.66 (dd, J = 6.5, 4.3 Hz, 1H), 4.97 (ddd, J =
11.0, 6.4, 2.5 Hz, 1H), 3.74 (s, 3H), 3.13 (d, J = 5.6 Hz, 1H), 3.09−
2.97 (m, 4H), 2.65 (dd, J = 14.8, 11.2 Hz, 1H), 2.59 (s, 3H), 1.97
(dd, J = 14.8, 6.3 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 210.9 (br), 173.0, 143.3, 141.8, 136.2,
134.9, 133.8, 133.2, 129.0, 128.8, 126.4, 105.7, 88.9, 86.4, 67.5, 63.2,
51.8, 40.5, 37.7, 29.0, 26.8, 24.7, 16.3; FTIR-ATR νmax/cm−1 2048
(Fe−CO), 1972 (Fe−CO), 1706 (CO); HRMS (ESI+) m/z: [M +
H]+ calcd for C26H26FeIO5 601.0174; found 601.0177.
4-(5-Isopropyl-3,8-dimethylazulen-1-yl)cyclohex-2-en-1-
one (35). Synthesized according to the general procedure, using 41.4
mg (0.0928 mmol) of compound 27, dissolved in 42 mL of
acetonitrile in a 500 mL round-bottom flask. The crude product was
purified by flash chromatography (petroleum ether/EtOAc 93:7),
yielding 35 as a blue sticky oil (11.4 mg, 42%); 1H NMR (400 MHz,
chloroform-d) δ 8.13 (d, J = 2.2 Hz, 1H), 7.47 (s, 1H), 7.33 (dd, J =
10.7, 2.2 Hz, 1H), 7.10 (ddd, J = 10.1, 3.0, 1.2 Hz, 1H), 6.92 (d, J =
10.7 Hz, 1H), 6.16 (dd, J = 10.1, 2.5 Hz, 1H), 4.76 (app ddt, J = 7.9,
5.0, 2.8 Hz, 1H), 3.05 (hept, J = 6.9, 1H) 3.02 (s, 3H), 2.65−2.57 (m,
4H), 2.55−2.44 (m, 2H), 2.23−2.11 (m, 1H), 1.35 (d, J = 6.9 Hz,
6H); 13C{1H} NMR (101 MHz, chloroform-d) δ 199.9, 155.4, 144.7,
140.1, 138.1, 137.8, 135.2, 134.1, 131.6, 128.8, 128.0, 127.3, 125.0,
37.8, 37.4, 37.0, 33.9, 27.5, 24.7, 13.1; FTIR-ATR νmax/cm−1 1679
(CO); HRMS (ESI+) m/z: [M + H]+ calcd for C21H25O 293.1905;
found 293.1904.
Tricarbonyl[methyl 5-(2-bromo-5-isopropyl-3,8-dimethyla-
zulen-1-yl)cyclohexa-1,3-diene-1-carboxylate]iron (31). Syn-
thesized according to general procedure A using azulene derivative
22 (10.0 mg, 0.0361) mmol, iron complex 2 (13.9 mg, 0.0329), and
NaHCO3 (5.5 mg, 0.066 mmol) in 0.5 mL acetone, with a reaction
time of 4 h. The product was purified by reversed-phase
chromatography (MeOH/H2O 60:40 → 90:10), yielding 31 as a
blue solid (14.4 mg, 79%). Although stable in neat form, the product
was found to be somewhat unstable in chloroform-d solution.
Increased stability was observed when the CDCl3 was filtered through
1,3-Diphenylazulene (36).16b To a 5 mL microwave vial
equipped with a stir bar, containing 27.4 mg (0.0970 mmol) of
compound 33, was added 24.2 mg (0.107 mmol) DDQ. The vial was
put under an atmosphere of nitrogen. Toluene (1.0 mL) was added,
and the solution was stirred at room temperature for 40 min. The
reaction mixture was diluted with ethyl acetate (20 mL) and washed
with 1 M aqueous NaOH (3 × 20 mL) followed by brine (1 × 20
mL). The organic phase was dried over Na2SO4, filtered, and
concentrated under reduced pressure. The product was purified by
flash chromatography (petroleum ether/EtOAc 99:1), yielding 36 as a
blue-green solid (22.3 mg, 82%); 1H NMR (400 MHz, chloroform-d)
δ 8.57 (dd, J = 9.8, 1.2 Hz, 2H), 8.15 (s, 1H), 7.69−7.66 (m, 4H),
7.60 (t, J = 9.8, 1.2 Hz, 1H), 7.56−7.50 (m, 4H), 7.40 (app ddt, J =
7.9, 6.9, 1.3 Hz, 2H), 7.14 (dd, J = 9.8, 9,8 Hz, 2H); 13C{1H} NMR
(101 MHz, chloroform-d) δ 139.1, 137.4, 137.3, 136.8, 136.3, 130.7,
130.0, 128.8, 126.6, 123.6. Analysis data are in accordance with
published data for this compound.16b
(7aS,11aR)-4-Isopropyl-2-methyl-7,7a,8,10,11,11a-hexahy-
dro-9H-naphtho[1,2,3-cd]azulen-9-one (37). In a 2 mL micro-
wave vial equipped with a stir bar, compound 35 (9.3 mg, 0.032
mmol) was dissolved in THF (1 mL). The vial was capped and cooled
in an ice bath. t-BuOK was added as a 1 M solution in THF (100 μL,
0.100 mmol). The solution was left to stir at 0 °C for 20 min, after
which it was poured into 1 M aqueous HCl (10 mL) and extracted
with EtOAc (3 × 10 mL). The combined organic extracts were dried
over Na2SO4, filtered, and the solvent was removed under a stream of
nitrogen. The product was purified by flash chromatography
(petroleum ether/EtOAc 90:10), yielding 37 as a blue sticky oil
(3.6 mg, 39%); 1H NMR (400 MHz, chloroform-d) δ 8.09 (d, J = 1.8
Hz, 1H), 7.54 (s, 1H), 7.36 (dd, J = 10.5, 1.8 Hz, 1H), 6.77 (d, J =
10.5 Hz, 1H), 3.61 (app dt, J = 5.7, 4.5 Hz, 1H), 3.25 (dd, J = 16.8,
4.4 Hz, 1H), 3.04 (hept, J = 6.9 Hz, 1H), 2.91 (dd, J = 16.8, 6.6 Hz,
1H), 2.84−2.75 (m, 1H), 2.67 (s, 3H), 2.49−2.42 (m, 2H), 2.41−
2.36 (m, 2H), 2.32 (dd, J = 14.3, 8.6 Hz, 1H), 2.25−2.18 (m, 1H),
1.35 (d, J = 6.9 Hz, 6H); 13C{1H} NMR (101 MHz, chloroform-d) δ
212.3, 144.0, 139.3, 135.8, 134.2, 133.4, 133.3, 133.0, 125.8, 124.5,
122.7, 44.6, 38.7, 38.7, 38.3, 37.7, 34.7, 30.4, 24.90, 24.91, 12.9; FTIR-
ATR νmax/cm−1 1709 (CO); HRMS (ESI+) m/z: [M + H]+ calcd
for C21H25O 293.1905; found 293.1904.
1
a plug of basic aluminum oxide prior to use; mp 147−149 °C; H
NMR (400 MHz, chloroform-d) δ 8.10 (d, J = 2.2 Hz, 1H), 7.33 (dd,
J = 10.7, 2.1 Hz, 1H), 6.99 (d, J = 10.7 Hz, 1H), 6.30 (dd, J = 4.3, 1.1
Hz, 1H), 5.61 (dd, J = 6.4, 4.4 Hz, 1H), 4.90 (ddd, J = 10.9, 5.9, 2.6
Hz, 1H), 3.73 (s, 3H), 3.15 (ddd, J = 6.5, 2.7, 1.3 Hz, 1H), 3.09−2.97
(m, 4H), 2.65 (dd, J = 14.7, 11.3 Hz, 1H), 2.55 (s, 3H), 1.93 (ddd, J
= 14.8, 6.0, 0.9 Hz, 1H), 1.33 (d, J = 6.9 Hz, 6H); 13C{1H} NMR
(101 MHz, methylene chloride-d2) δ 173.1, 144.3, 142.3, 136.5,
135.1, 133.4, 133.2, 129.6, 129.4, 125.1, 124.7, 88.2, 87.2, 67.6, 63.8,
51.9, 40.0, 38.1, 29.0, 27.6, 24.8, 12.7. Signal for Fe−CO not seen;
FTIR-ATR νmax/cm−1 2047 (Fe−CO), 1968 (Fe−CO), 1705 (C
O); HRMS (ESI+) m/z: [M + H]+ calcd for C26H26BrFeO5
553.0313; found 553.0324.
General Procedure for the Photocatalytic Decomplexation,
Exemplified by the Formation of 1-(Cyclohexa-2,4-dien-1-yl)-3-
phenylazulene (33). To a 100 mL borosilicate glass round-bottom
flask equipped with a magnetic stirring bar, 25.0 mg (0.0592 mmol) of
13 was added and dissolved in 24 mL of acetonitrile. The flask was
sealed with a rubber septum, which was pierced with a syringe needle
open to the atmosphere. The flask was placed 5 cm from a low-energy
black light lamp (Velleman lighting, 15 W, 850 lm) in a container
lined with aluminum foil. The reaction mixture was irradiated
(emission maximum of 370 nm; for emission spectrum, see Figure
S71) without the use of any filter under stirring in room temperature,
cooled by a stream of air, for 72 h. The solvent was removed under
reduced pressure, and the residue was redissolved in dichloromethane,
filtered through a plug of silica, and the solvent was evaporated under
a stream of nitrogen. The crude product was purified by reversed-
phase flash chromatography (methanol/water, 84:16), yielding 33 as a
1
green sticky solid (13.1 mg, 78%); H NMR (400 MHz, chloroform-
d) δ 8.49 (d, J = 9.8 Hz, 1H), 8.36 (d, J = 9.7 Hz, 1H), 8.04 (s, 1H),
7.64−7.61 (m, 2H), 7.57−7.45 (m, 3H), 7.40−7.32 (m, 1H), 7.14−
7.02 (m, 2H), 6.16−6.04 (m, 2H), 6.04−5.99 (m, 1H), 5.94−5.88
(m, 1H), 4.34 (app ddt, J = 12.5, 9.2, 3.0 Hz, 1H), 2.68 (dddd, J =
17.3, 9.2, 4.9, 1.3 Hz, 1H), 2.57 (dddd, J = 17.2, 13.3, 3.8, 2.3 Hz,
1H); 13C{1H} NMR (101 MHz, chloroform-d) δ 138.4, 137.6, 136.8,
136.6, 136.0, 135.6, 133.7, 132.9, 131.1, 130.1, 129.9, 128.7, 126.4,
126.2, 124.3, 124.2, 123.0, 122.0, 32.1, 31.6; HRMS (ESI+) m/z: [M
+ H]+ calcd for C22H19 283.1486; found 283.1483.
ASSOCIATED CONTENT
4-(3-Phenylazulen-1-yl)cyclohex-2-en-1-one (34). Synthe-
sized according to the general procedure, using 25.0 mg (0.0553
mmol) of compound 14 dissolved in 25 mL of acetonitrile. The crude
product was purified by flash chromatography (petroleum ether/
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.joc.0c01412.
1
EtOAc 93:7), yielding 34 as a green sticky solid (12.2 mg, 74%); H
NMR (400 MHz, chloroform-d) δ 8.53 (d, J = 10.0 Hz, 1H), 8.36 (d,
J = 9.4 Hz, 1H), 7.87 (s, 1H), 7.65−7.56 (m, 3H), 7.52−7.46 (m,
2H), 7.38−7.33 (m, 1H), 7.19−7.11 (m, 3H), 6.23 (ddd, J = 10.1,
2.5, 0.6 Hz, 1H), 4.46 (ddt, J = 8.3, 5.3, 2.8 Hz, 1H), 2.69−2.47 (m,
Spectroscopic data for all products; NMR assignments
and stereochemical elucidation of 37; colorimetric
response to TFA and UV−vis/fluorescence spectra for
J
https://dx.doi.org/10.1021/acs.joc.0c01412
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
J. Org. Chem. 2020, 85, 70−78. (d) Murfin, L. C.; Weber, M.; Park, S.
selected compounds; and emission spectrum of lamp
used for photolytic decomplexations (PDF)
́
J.; Kim, W. T.; Lopez-Alled, C. M.; McMullin, C. L.; Pradaux-
̈
Caggiano, F.; Lyall, C. L.; Kociok-KohnKociok-Kohn, G.; Wenk, J.;
Bull, S. D.; Yoon, J.; Kim, H. M.; James, T. D.; Lewis, S. E. Azulene-
Derived Fluorescent Probe for Bioimaging: Detection of Reactive
Oxygen and Nitrogen Species by Two-Photon Microscopy. J. Am.
Chem. Soc. 2019, 141, 19389−19396. (e) Fang, H.; Gan, Y. T.; Wang,
S. R.; Tao, T. A selective and colorimetric chemosensor for fluoride
based on dimeric azulene boronate ester. Inorg. Chem. Commun. 2018,
95, 17−21. (f) Lichosyt, D.; Wasiłek, S.; Dydio, P.; Jurczak, J. The
Influence of Binding Site Geometry on Anion-Binding Selectivity: A
Case Study of Macrocyclic Receptors Built on the Azulene Skeleton.
AUTHOR INFORMATION
Corresponding Authors
■
Simon E. Lewis − Centre for Sustainable Circular Technologies
and Department of Chemistry, University of Bath, Bath BA2
7AY, U.K.; orcid.org/0000-0003-4555-4907;
Email: S.E.Lewis@bath.ac.uk
Nina Kann − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0002-4457-5282;
Email: kann@chalmers.se
́
Chem. − Eur. J. 2018, 24, 11683−11692. (g) Lopez-Alled, C. M.;
Sanchez-Fernandez, A.; Edler, K. J.; Sedgwick, A. C.; Bull, S. D.;
̈
McMullin, C. L.; Kociok-Kohn, G.; James, T. D.; Wenk, J.; Lewis, S.
E. Azulene-boronate esters: colorimetric indicators for fluoride in
drinking water. Chem. Commun. 2017, 53, 12580−12583. (h) Birzan,
L.; Cristea, M.; Drahici, C. C.; Tecuceanu, V.; Hanganu, A.;
Ungureanu, E. M.; Razus, A. C. 4-(Azulen-1-y1) six-membered
heteroaromatics substituted in 2-and 6-positions with 2-(2-furyl)vinyl,
2-(2-thienyl)vinyl or 2-(3-thienyl) vinyl moieties. Tetrahedron 2017,
73, 2488−2500. (i) Lichosyt, D.; Dydio, P.; Jurczak, J. Azulene-Based
Macrocyclic Receptors for Recognition and Sensing of Phosphate
Anions. Chem. − Eur. J. 2016, 22, 17673−17680. (j) Wakabayashi, S.;
Uchida, M.; Tanaka, R.; Habata, Y.; Shimizu, M. Synthesis of Azulene
Derivatives That Have an Azathiacrown Ether Moiety and Their
Selective Color Reaction Towards Silver Ions. Asian J. Org. Chem.
Authors
Petter Dunås − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0002-3779-3265
Lloyd C. Murfin − Department of Chemistry, University of
Bath, Bath BA2 7AY, U.K.; orcid.org/0000-0003-4780-
9539
Oscar J. Nilsson − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0003-2716-2563
Nicolas Jame − Department of Chemistry and Chemical
Engineering, Chalmers University of Technology, SE-41296
Gothenburg, Sweden; orcid.org/0000-0002-0550-5134
́
2013, 2, 786−791. (k) Lopez-Alled, C. M.; Murfin, L. C.; Kociok-
̈
Kohn, G.; James, T. D.; Wenk, J.; Lewis, S. E. Colorimetric detection
of Hg2+ with an azulene-containing chemodosimeter via dithioacetal
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.joc.0c01412
hydrolysis. Analyst 2020, 6262−6269.
̈
(4) (a) Cowper, P.; Pockett, A.; Kociok-Kohn, G.; Cameron, P. J.;
Lewis, S. E. Azulene - Thiophene - Cyanoacrylic acid dyes with
donor-π-acceptor structures. Synthesis, characterisation and evalua-
tion in dye-sensitized solar cells. Tetrahedron 2018, 74, 2775−2786.
(b) Xin, H. S.; Ge, C. W.; Jiao, X. C.; Yang, X. D.; Rundel, K.;
McNeill, C. R.; Gao, X. K. Incorporation of 2,6-Connected Azulene
Units into the Backbone of Conjugated Polymers: Towards High-
Performance Organic Optoelectronic Materials. Angew. Chem., Int. Ed.
2018, 57, 1322−1326. (c) Xin, H. S.; Gao, X. K. Application of
Azulene in Constructing Organic Optoelectronic Materials: New
Tricks for an Old Dog. ChemPlusChem 2017, 82, 945−956.
(d) Nishimura, H.; Ishida, N.; Shimazaki, A.; Wakamiya, A.; Saeki,
A.; Scott, L. T.; Murata, Y. Hole-Transporting Materials with a Two-
Dimensionally Expanded π-System around an Azulene Core for
Efficient Perovskite Solar Cells. J. Am. Chem. Soc. 2015, 137, 15656−
15659. (e) Puodziukynaite, E.; Wang, H. W.; Lawrence, J.; Wise, A. J.;
Russell, T. P.; Barnes, M. D.; Emrick, T. Azulene Methacrylate
Polymers: Synthesis, Electronic Properties, and Solar Cell Fabrication.
J. Am. Chem. Soc. 2014, 136, 11043−11049.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The Swedish Research Council (N.K., grant 2015-05360), the
Swedish Research Council Formas (N.K., grant 2015-1106),
and the Engineering and Physical Sciences Research Council
(S.E.L., grant EP/L016354/1) are gratefully acknowledged for
funding. We thank Dr. Andrew Paterson, Chemspeed
Technologies, for his discussions and Jennifer Tamayo
́
̃
Nunez for her assistance in preparing one of the azulenes.
REFERENCES
■
(5) Hou, I. C. Y.; Berger, F.; Narita, A.; Mullen, K.; Hecht, S.
̈
(1) (a) Liu, R. S. H. Colorful azulene and its equally colorful
derivatives. J. Chem. Educ. 2002, 79, 183−185. (b) Michl, J.;
Thulstrup, E. W. Why is Azulene Blue and Anthracene White -
Simple MO Picture. Tetrahedron 1976, 32, 205−209. (c) Wheland, G.
W.; Mann, D. E. The Dipole Moments of Fulvene and Azulene. J.
Chem. Phys. 1949, 17, 264−268.
Proton-Gated Ring-Closure of a Negative Photochromic Azulene-
Based Diarylethene. Angew. Chem., Int. Ed. 2020, 59, 18532−18536.
(6) Vlasceanu, A.; Koerstz, M.; Skov, A. B.; Mikkelsen, K. V.;
Nielsen, M. B. Multistate Photoswitches: Macrocyclic Dihydroazu-
lene/Azobenzene Conjugates. Angew. Chem., Int. Ed. 2018, 57, 6069−
6072.
(7) Zhang, L. Y.; Yang, F.; Shi, W. Q.; Zhang, P.; Li, Y.; Yin, S. F.
Synthesis and antigastric ulcer activity of novel 5-isopropyl-3,8-
dimethylazulene derivatives. Bioorg. Med. Chem. Lett. 2011, 21, 5722−
5725.
(2) Ghasimi, S.; Landfester, K.; Zhang, K. A. I. Water Compatible
Conjugated Microporous Polyazulene Networks as Visible-Light
Photocatalysts in Aqueous Medium. ChemCatChem 2016, 8, 694−
698.
́
(3) (a) Murfin, L. C.; Lopez-Alled, C. M.; Sedgwick, A. C.; Wenk, J.;
(8) Ikegai, K.; Imamura, M.; Suzuki, T.; Nakanishi, K.; Murakami,
T.; Kurosaki, E.; Noda, A.; Kobayashi, Y.; Yokota, M.; Koide, T.;
Kosakai, K.; Ohkura, Y.; Takeuchi, M.; Tomiyama, H.; Ohta, M.
Synthesis and biological evaluation of C-glucosides with azulene rings
as selective SGLT2 inhibitors for the treatment of type 2 diabetes
mellitus: Discovery of YM543. Bioorg. Med. Chem. 2013, 21, 3934−
3948.
James, T. D.; Lewis, S. E. A simple, azulene-based colorimetric probe
for the detection of nitrite in water. Front. Chem. Sci. Eng. 2020, 14,
90−96. (b) Murfin, L. C.; Chiang, K. T.; Williams, G. T.; Lyall, C. L.;
Jenkins, A. T. A.; Wenk, J.; James, T. D.; Lewis, S. E. A Colorimetric
Chemosensor Based on a Nozoe Azulene That Detects Fluoride in
Aqueous/Alcoholic Media. Front. Chem. 2020, 8, No. 10. (c) Xin, H.
S.; Li, J.; Yang, X. D.; Gao, X. K. Azulene-Based BN-Heteroaromatics.
K
https://dx.doi.org/10.1021/acs.joc.0c01412
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
́
(9) Chen, C. H.; Lee, O.; Yao, C. N.; Chuang, M. Y.; Chang, Y. L.;
Chang, M. H.; Wen, Y. F.; Yang, W. H.; Ko, C. H.; Chou, N. T.; Lin,
M. W.; Lai, C. P.; Sun, C. Y.; Wang, L. M.; Chen, Y. C.; Hseu, T. H.;
Chang, C. N.; Hsu, H. C.; Lin, H. C.; Chang, Y. L.; Shih, Y. C.; Chou,
S. H.; Hsu, Y. L.; Tseng, H. W.; Liu, C. P.; Tu, C. M.; Hu, T. L.; Tsai,
Y. J.; Chen, T. S.; Lin, C. L.; Chiou, S. J.; Liu, C. C.; Hwang, C. S.
Novel azulene-based derivatives as potent multi-receptor tyrosine
kinase inhibitors. Bioorg. Med. Chem. Lett. 2010, 20, 6129−6132.
(10) (a) Razus, A. C.; Birzan, L. Synthesis of azulenic compounds
substituted in the 1-position with heterocycles. Monatsh. Chem. 2019,
150, 139−161. (b) Shoji, T.; Ito, S. Advances in Heterocyclic Chemistry;
In Scriven, E. F. V.; Scriven, E. F. V.; Ramsden, C. A., Eds.; Elsevier
Science Publishing Co Inc., 2018; Vol. 126, pp 1−54. (c) Ito, S.;
Shoji, T.; Morita, N. Recent Advances in the Development of
Methods for the Preparation of Functionalized Azulenes for
Electrochromic Applications. Synlett 2011, 2279−2298. (d) Kedzior-
ek, M.; Mayer, P.; Mayr, H. Nucleophilic Reactivities of Azulene and
Fulvenes. Eur. J. Org. Chem. 2009, 2009, 1202−1206. (e) Anderson,
A. G.; Nelson, J. A. Electrophilic Substitution of Azulene. J. Am. Chem.
Soc. 1950, 72, 3824−3825.
(11) (a) Devendar, B.; Wu, C. P.; Chen, C. Y.; Chen, H. C.; Chang,
C. H.; Ku, C. K.; Tsai, C. Y.; Ku, C. Y. Synthesis, characterization and
applications of densely functionalized pyridazines and fulvene-type
compounds containing azulene moiety. Tetrahedron 2013, 69, 4953−
4963. (b) Dyker, G.; Muth, E.; Hashmi, A. S. K.; Ding, L. Gold(III)
chloride-catalyzed addition reactions of electron-rich arenes to methyl
vinyl ketone. Adv. Synth. Catal. 2003, 345, 1247−1252.
(12) Okajima, T.; Kurokawa, S. Facile conversion of 1-methyl group
of guaiazulene into 1-formyl group. Chem. Lett. 1997, 69−70.
(13) Shoji, T.; Inoue, Y.; Ito, S. First synthesis of 1-(indol-2-
yl)azulenes by the Vilsmeier-Haack type arylation with triflic
anhydride as an activating reagent. Tetrahedron Lett. 2012, 53,
1493−1496.
(18) (a) Bromfield, K. M.; Graden, H.; Ljungdahl, N.; Kann, N.
Synthetic applications of cationic iron and cobalt carbonyl complexes.
Dalton Trans. 2009, 5051−5061. (b) Pearson, A. J. Iron Compounds in
Organic Synthesis; Academic Press Ltd.: London, 1994.
́
(19) Gree, R. Acyclic butadiene iron tricarbonyl complexes in
organic-synthesis. Synthesis 1989, 341−355.
(20) (a) Birch, A. J.; Bandara, B. M. R.; Chamberlain, K.; Chauncy,
B.; Dahler, P.; Day, A. I.; Jenkins, I. D.; Kelly, L. F.; Khor, T. C.;
Kretschmer, G.; Liepa, A. J.; Narula, A. S.; Raverty, W. D.; Rizzardo,
E.; Sell, C.; Stephenson, G. R.; Thompson, D. J.; Williamson, D. H.
Organometallic compounds in organic-synthesis. 11. The strategy of
lateral control of reactivity - tricarbonylcyclohexadieneiron complexes
and their organic synthetic equivalents. Tetrahedron, Supplement 1981,
37, 289−302. (b) Birch, A. J.; Kelly, L. F. Tricarbonyliron
methoxycyclohexadiene and dienyl complexes - preparation, proper-
ties and applications. J. Organomet. Chem. 1985, 285, 267−280.
(21) Kane-Maguire, L. A. P.; Mansfield, C. A. Cationic Metal-Dienyl
Complexes as Electrophilic Reagents on Aromatic Molecules. J. Chem.
Soc., Chem. Commun. 1973, 540−541.
(22) Kane-Maguire, L. A. P.; Mansfield, C. A. Kinetics of
nucleophilic attack on coordinated organic moieties. Part 4.
Mechanisms of addition of indole and substituted indoles to
tricarbonyl(cyclohexadienyl)-iron and tricarbonyl(cyclohexadienyl)-
ruthenium cations. J. Chem. Soc., Dalton Trans. 1976, 2192−2196.
(23) Birch, A. J.; Liepa, A. J.; Stephenson, G. R. Organometallic
compounds in organic synthesis. Some tricarbonyl(cyclohexadienyl)
iron cations and nitrogen containing nucleophiles. Tetrahedron Lett.
1979, 3565−3568.
(24) Mansfield, C. A.; Al-Kathumi, K. M.; Kane-Maguire, L. A. P.
Cationic metal π-enyl complexes as electrophilic reagents on aromatic
molecules. J. Organomet. Chem. 1974, 71, C11−C13.
̈
(25) Dunås, P.; Paterson, A. J.; Kociok-Kohn, G.; Lewis, S. E.; Kann,
N. Selective Iron-Mediated C- and O-Addition of Phenolic
Nucleophiles to a Cyclohexadiene Scaffold Using Renewable
Precursors. ACS Sustainable Chem. Eng. 2019, 7, 7155−7162.
(26) Gordon, M. The Azulenes. Chem. Rev. 1952, 50, 127−200.
(27) (a) Glowacka, P. C.; Maindron, N.; Stephenson, G. R.; Romieu,
A.; Renard, P. Y.; Emery, F. D. Synthesis and photophysical properties
of iron-carbonyl complex-coumarin conjugates as potential bimodal
IR-fluorescent probes. Tetrahedron Lett. 2016, 57, 4991−4996.
(b) Anson, C. E.; Creaser, C. S.; Malkov, A. V.; Mojovic, L.;
Stephenson, G. R. Flavonoid derivatives as organometallic bioprobes.
J. Organomet. Chem. 2003, 668, 101−122. (c) Stephenson, G. R.;
Anson, C. E.; Creaser, C. S.; Daul, C. A. Spectroscopic, Structural and
DFT Study of the Responses of Carbonylmetal Crown Ether
Complexes to Alkali Metal Cations. Eur. J. Inorg. Chem. 2011,
2086−2097.
(14) Shoji, T.; Ito, S.; Higashi, J.; Morita, N. Synthesis of 1-
Heteroaryl- and 1,3-Bis(heteroaryl)azulenes: Electrophilic Hetero-
arylation of Azulenes with the Triflates of N-Containing Hetero-
arenes. Eur. J. Org. Chem. 2011, 5311−5322.
(15) Tskhovrebov, A. G.; Naested, L. C. E.; Solari, E.; Scopelliti, R.;
Severin, K. Synthesis of Azoimidazolium Dyes with Nitrous Oxide.
Angew. Chem., Int. Ed. 2015, 54, 1289−1292.
(16) (a) Oda, M.; Thanh, N. C.; Ikai, M.; Fujikawa, H.; Nakajima,
K.; Kuroda, S. Synthesis and properties of N,N,N′,N′-tetrasubstituted
1,3-bis(5-aminothien-2-yl)azulenes and their application as a hole-
injecting material in organic light-emitting devices. Tetrahedron 2007,
63, 10608−10614. (b) Thanh, N. C.; Ikai, M.; Kajioka, T.; Fujikawa,
H.; Taga, Y.; Zhang, Y. M.; Ogawa, S.; Shimada, H.; Miyahara, Y.;
Kuroda, S.; Oda, M. Synthesis of N,N,N′,N′-tetrasubstituted 1,3-
bis(4-aminophenyl)azulenes and their application to a hole-injecting
material in organic electroluminescent devices. Tetrahedron 2006, 62,
11227−11239. (c) Muthyala, R. S.; Liu, R. S. H. Synthesis of
fluorinated azulenes. J. Fluorine Chem. 1998, 89, 173−175.
(17) (a) Shi, X. Z.; Sasmal, A.; Soule, J. F.; Doucet, H. Metal-
Catalyzed C-H Bond Activation of 5-Membered Carbocyclic Rings: A
Powerful Access to Azulene, Acenaphthylene and Fulvene Derivatives.
Chem. Asian J. 2018, 13, 143−157. (b) Carreras, J.; Popowski, Y.;
Caballero, A.; Amir, E.; Perez, P. J. Catalytic Functionalization of C-H
Bonds of Azulene by Carbene/Nitrene Incorporation. J. Org. Chem.
(28) (a) Ghazvini Zadeh, E. H.; Tang, S.; Woodward, A. W.; Liu, T.;
Bondar, M. V.; Belfield, K. D. Chromophoric materials derived from a
natural azulene: syntheses, halochromism and one-photon and two-
photon microlithography. J. Mater. Chem. C 2015, 3, 8495−8503.
́
(b) Webster, S. J.; Lopez-Alled, C. M.; Liang, X. X.; McMullin, C. L.;
̈
Kociok-Kohn, G.; Lyall, C. L.; James, T. D.; Wenk, J.; Cameron, P. J.;
Lewis, S. E. Azulenes with aryl substituents bearing pentafluor-
osulfanyl groups: synthesis, spectroscopic and halochromic properties.
New J. Chem. 2019, 43, 992−1000. (c) Tang, T.; Lin, T. T.; Erden, F.;
Wang, F.; He, C. B. Configuration-dependent optical properties and
acid susceptibility of azulene compounds. J. Mater. Chem. C 2018, 6,
5153−5160. (d) Gai, L. Z.; Chen, J. Z.; Zhao, Y.; Mack, J.; Lu, H.;
Shen, Z. Synthesis and properties of azulene-functionalized BODIPYs.
RSC Adv. 2016, 6, 32124−32129. (e) Murai, M.; Takami, K.;
Takeshima, H.; Takai, K. Iridium-Catalyzed Dehydrogenative
Silylation of Azulenes Based on Regioselective C-H Bond Activation.
Org. Lett. 2015, 17, 1798−1801. (f) Murai, M.; Ku, S. Y.; Treat, N.
D.; Robb, M. J.; Chabinyc, M. L.; Hawker, C. J. Modulating structure
and properties in organic chromophores: influence of azulene as a
building block. Chem. Sci. 2014, 5, 3753−3760. (g) Koch, M.;
Blacque, O.; Venkatesan, K. Impact of 2,6-connectivity in azulene:
́
2018, 83, 11125−11132. (c) Szekely, A.; Peter, A.; Aradi, K.; Tolnai,
G. L.; Novak, Z. Gold-Catalyzed Direct Alkynylation of Azulenes. Org.
Lett. 2017, 19, 954−957. (d) Cowper, P.; Jin, Y.; Turton, M. D.;
̈
Kociok-Kohn, G.; Lewis, S. E. Azulenesulfonium Salts: Accessible,
Stable, and Versatile Reagents for Cross-Coupling. Angew. Chem., Int.
Ed. 2016, 55, 2564−2568. (e) Murai, M.; Yanagawa, M.; Nakamura,
M.; Takai, K. Palladium-Catalyzed Direct Arylation of Azulene Based
on Regioselective C-H Bond Activation. Asian J. Org. Chem. 2016, 5,
629−635. (f) Park, S.; Yong, W. S.; Kim, S.; Lee, P. H.
Diastereoselective N-Sulfonylaminoalkenylation of Azulenes from
Terminal Alkynes and Azides via N-Sulfonyl-1,2,3-triazoles. Org.
Lett. 2014, 16, 4468−4471.
L
https://dx.doi.org/10.1021/acs.joc.0c01412
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
pubs.acs.org/joc
Article
optical properties and stimuli responsive behavior. J. Mater. Chem. C
2013, 1, 7400−7408.
Radical Framework Reconstruction. J. Am. Chem. Soc. 2020, 142,
104−108.
(29) (a) Shoji, T.; Sugiyama, S.; Kobayashi, Y.; Yamazaki, A.; Ariga,
Y.; Katoh, R.; Wakui, H.; Yasunami, M.; Ito, S. Direct synthesis of 2-
arylazulenes by [8+2] cycloaddition of 2H-cyclohepta[b]furan-2-ones
with silyl enol ethers. Chem. Commun. 2020, 56, 1485−1488.
(b) Ohtsu, K.; Hayami, R.; Sagawa, T.; Tsukada, S.; Yamamoto, K.;
Gunji, T. Syntheses and properties of linear π-conjugated molecules
composed of 1-azaazulene and azulene. Tetrahedron 2019, 75,
No. 130658. (c) Gao, H. L.; Yang, X. D.; Xin, H. S.; Gao, T. Z.;
Gong, H. G.; Gao, X. K. Design, Synthesis and Properties of 2/6-Aryl
Substituted Azulene Derivatives. Chin. J. Org. Chem. 2018, 38, 2680−
2692. (d) Amir, E.; Murai, M.; Amir, R. J.; Cowart, J. S.; Chabinyc, M.
L.; Hawker, C. J. Conjugated oligomers incorporating azulene
building blocks - seven- vs. five-membered ring connectivity. Chem.
Sci. 2014, 5, 4483−4489. (e) Koch, M.; Blacque, O.; Venkatesan, K.
Syntheses and Tunable Emission Properties of 2-Alkynyl Azulenes.
Org. Lett. 2012, 14, 1580−1583. (f) Amir, E.; Amir, R. J.; Campos, L.
M.; Hawker, C. J. Stimuli-Responsive Azulene-Based Conjugated
Oligomers with Polyaniline-like Properties. J. Am. Chem. Soc. 2011,
133, 10046−10049.
(43) Leivers, M.; Tam, I.; Groves, K.; Leung, D.; Xie, Y. L.; Breslow,
R. A forbidden rearrangement. Org. Lett. 2003, 5, 3407−3409.
(44) Birch, A. J.; Chamberlain, K. Tricarbonyl[(2,3,4,5-η)-2,4-
cyclohexadien-1-one]iron and tricarbonyl[(1,2,3,4,5-η)-2-methoxy-
2,4-cyclohexadien-1-yl]iron(1+) hexafluorophosphate(1−) from ani-
sole. Org. Synth. 1977, 57, No. 107.
(45) Treibs, W.; Neupert, H. J.; Hiebsch, J. Uber bicyclische und
polycyclische Azulene. 37. Synthesen und Eigenschaften von Azulen-
aldehyden. Chem. Ber. 1959, 92, 141−154.
(46) Lash, T. D.; El-Beck, J. A.; Ferrence, G. M. Syntheses and
reactivity of meso-unsubstituted azuliporphyrins derived from 6-tert-
butyl- and 6-phenylazulene. J. Org. Chem. 2007, 72, 8402−8415.
(47) Narita, M.; Murafuji, T.; Yamashita, S.; Fujinaga, M.; Hiyama,
K.; Oka, Y.; Tani, F.; Kamijo, S.; Ishiguro, K. Synthesis of 2-
Iodoazulenes by the Iododeboronation of Azulen-2-ylboronic Acid
Pinacol Esters with Copper(I) Iodide. J. Org. Chem. 2018, 83, 1298−
1303.
(48) Ito, S.; Terazono, T.; Kubo, T.; Okujima, T.; Morita, N.;
Murafuji, T.; Sugihara, Y.; Fujimori, K.; Kawakami, J.; Tajiri, A.
Efficient preparation of 2-azulenylboronate and Miyaura-Suzuki cross-
coupling reaction with aryl bromides for easy access to poly(2-
azulenyl)benzenes. Tetrahedron 2004, 60, 5357−5366.
(30) Grellmann, K. H.; Heilbronner, E.; Seiler, P.; Weller, A. Proton
dissociation of azulenium cations in excited state. J. Am. Chem. Soc.
1968, 90, 4238−4242.
(49) Crombie, A. L.; Kane, J. L.; Shea, K. M.; Danheiser, R. L. Ring
expansion-annulation strategy for the synthesis of substituted azulenes
and oligoazulenes. 2. Synthesis of azulenyl halides, sulfonates, and
azulenylmetal compounds and their application in transition-metal-
mediated coupling reactions. J. Org. Chem. 2004, 69, 8652−8667.
(50) Ho, T. I.; Ku, C. K.; Liu, R. S. H. Preparation of 1-arylazulenes
through regioselective photoarylation of azulene with aryl iodides.
Tetrahedron Lett. 2001, 42, 715−717.
(31) (a) Jaouen, G.; Vessieres, A.; Top, S.; Ismail, A. A.; Butler, I. S.
Metal-carbonyl fragments as a new class of markers in molecular-
biology. J. Am. Chem. Soc. 1985, 107, 4778−4780. (b) Lam, Z. Y.;
Kong, K. V.; Olivo, M.; Leong, W. K. Vibrational spectroscopy of
metal carbonyls for bio-imaging and -sensing. Analyst 2016, 141,
1569−1586.
(32) Franck-Neumann, M.; Heitz, M. P.; Martina, D. A simple
method of freeing organic-ligands from their iron carbonyl-complexes.
Tetrahedron Lett. 1983, 24, 1615−1616.
(33) Holmes, J. D.; Pettit, R. Synthesis and Properties of
Homotropone. J. Am. Chem. Soc. 1963, 85, 2531−2532.
(34) Shvo, Y.; Hazum, E. Simple Method for Disengagement of
Organic Ligands from Iron Complexes. J. Chem. Soc., Chem. Commun.
1974, 336−337.
(35) Thompson, D. J. Reaction of tricarbonylcyclohexadieneiron
complexes with cupric chloride. J. Organomet. Chem. 1976, 108, 381−
383.
̈
(36) Knolker, H. J.; Goesmann, H.; Klauss, R. Transition metal
complexes in organic synthesis, part 48. A novel method for the
demetalation of tricarbonyliron-diene complexes by a photolytically
induced ligand exchange reaction with acetonitrile. Angew. Chem., Int.
Ed. 1999, 38, 702−705.
́
(37) Bergh, A.; Graden, H.; Pera, N. P.; Olsson, T.; Nilsson, U. J.;
Kann, N. Carbohydrate functionalization using cationic iron carbonyl
complexes. Carbohydr. Res. 2008, 343, 1808−1813.
̈
(38) (a) Krahl, M. P.; Kataeva, O.; Schmidt, A. W.; Knolker, H. J.
Iron-Mediated Total Synthesis of 2,7-Dioxygenated Carbazole
Alkaloids. Eur. J. Org. Chem. 2013, 2013, 59−64. (b) Pearson, A. J.;
Kole, S. L.; Yoon, J. Stereocontrolled Double Functionalization of
(Cyclohexadiene)-Iron and (Cycloheptadiene)Iron Complexes Via
Oxidative Cyclization Techniques. Organometallics 1986, 5, 2075−
2081.
(39) Song, J. F.; Hansen, H. J. An improved and simplified synthesis
of 4-styrylazulenes. Helv. Chim. Acta 1999, 82, 309−314.
(40) Kurokawa, S. Reaction of 3-(2-substituted ethenyl)guaiazulenes
with alkenes. Nippon Kagaku Kaishi 1997, 365−372.
(41) (a) Gong, J.; Sun, P.; Jiang, N.; Riccio, R.; Lauro, G.; Bifulco,
G.; Li, T. J.; Gerwick, W. H.; Zhang, W. New Steroids with a
Rearranged Skeleton as (h)P300 Inhibitors from the Sponge
Theonella swinhoei. Org. Lett. 2014, 16, 2224−2227. (b) Li, J.;
Tang, H.; Kurtan, T.; Mandi, A.; Zhuang, C. L.; Su, L.; Zheng, G. L.;
Zhang, W. Swinhoeisterols from the South China Sea Sponge
Theonella swinhoei. J. Nat. Prod. 2018, 81, 1645−1650.
(42) Duecker, F. L.; Heinze, R. C.; Heretsch, P. Synthesis of
Swinhoeisterol A, Dankasterone A and B, and Periconiastone A by
M
https://dx.doi.org/10.1021/acs.joc.0c01412
J. Org. Chem. XXXX, XXX, XXX−XXX