Synthesis of fluorenyl alcohols: Via cooperative palladium/norbornene catalysis

Article abstract of DOI:10.1039/c9ob01085h

Herein, we report a novel catalytic synthesis of substituted 9H-fluoren-9-ols starting from aryl iodides and secondary ortho-bromobenzyl alcohols in the presence of palladium/norbornene as a catalytic system. The present protocol exhibits high functional

Full text of DOI:10.1039/c9ob01085h

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DOI: 10.1039/C9OB01085H
ARTICLE
Synthesis of Fluorenyl Alcohols via Cooperative
Palladium/Norbornene Catalysis
Alessandra Casnati, Marco Fontana, Elena Motti* and Nicola Della Ca’*
Received 00th January 20xx,
Accepted 00th January 20xx
Herein we report a novel catalytic synthesis of substituted 9H-fluoren-9-ols starting from aryl iodides and secondary ortho-
bromobenzyl alcohols in the presence of palladium/norbornene as catalytic system. The present protocol displays high
functional group tolerance, mild reaction conditions and moderate to good yields. This transformation is based on two
sequential pathways: i) the Pd(II)-mediated oxidation of the secondary alcohol to the corresponding ketone and ii) the
Pd(0)/norbornene-catalyzed reaction of the in situ generated ortho-bromoacetophenone with the aryl iodide.
DOI: 10.1039/x0xx00000x
Introduction
The fluorene structural motif is prevalent in many
pharmaceuticals, agrochemicals, and biologically active
compounds.1 Besides, they are widely used in the preparation
of photoluminescent complexes, dyes and polymers,2
optoelectronic
materials,3
and
crystalline
inclusion
compounds.4 Remarkably, 9-hydroxyfluorene derivatives were
recently proposed as precursor for the preparation of new
promising fluorene-derived compounds to be used as
wakefulness enhancing agents in place of Modafinil-based
drugs.1a
Traditionally, the 9-hydroxyfluorene core can be obtained
through various oxidation strategies, such as a photocatalytic
oxidation of the corresponding fluorene moiety by means of
Pd/Bi/Sn-based nanocomposites5 or KMnO4 with a phase
transfer oxidation protocol.6 In both cases, the partial oxidation
to fluorenol is difficult to achieve. Alternatively, 9-substituted-
9H-fluorenol-9-ols may be obtained by reaction of the
corresponding fluorenone with a Grignard type reagent.7
Benzo[b]fluorenols can be synthesized under both thermal
conditions,8 or metal catalysed reactions.9 The synthesis of
benzo[a]fluorenols, bearing a substituent on the 9 position, may
be achieved under catalytic reactions, using for example Ag10 or
Au11 based catalysts (Scheme 1). Lautens and coworkers
reported a straightforward synthesis of fluoren-9-ol derivatives,
based on a palladium/norbornene catalyzed Catellani-type
reaction, from aryl iodides and 2-chloroacetophenones.12 More
recently, Miura has reported a very efficient method to access
9-substituted-9H-fluoren-9-ols starting from 3-arylmethanols
with Iridium-based catalysts.13
Scheme 1. Significative catalytic strategies to 9-substituted-9H-fluoren-9-ol derivatives.
In the framework of the C-H activation, Catellani reactions
represent an outstanding tool for the one-pot ortho and ipso
functionalization of aryl halides14 and ortho-substituted boronic
acids15. In the course of our research aimed at the development
of new palladium/norbornene-based catalytic protocols for the
synthesis of value-added compounds,14e,16 we demonstrated
that heterocycles containing the biaryl unit can be selectively
synthesized by unsymmetrical coupling of an aryl iodide and a
suitably ortho-substituted aryl bromide, followed by an
intramolecular cyclization step.17 In order to achieve this goal it
Department of Chemistry, Life Sciences and Environmental Sustainability and
CIRCC, University of Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. E-
mail: elena.motti@unipr.it, nicola.dellaca@unipr.it
a.Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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is essential to properly choose the two aryl halides, balancing base. Under these conditions, despite the low conversion of the
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their reactivity towards palladium(0) and palladium(II) species. aryl halides (<50%), the fluorenol produDcOt I3: 1a0.w10a3s9/oCb9OtaBi0n1e0d85iHn
It has been ascertained that ortho-substituted aryl iodides 12% yield (Table 1, entry 1) together with the ketone derivative
bearing electron-releasing groups and aryl bromides containing (3%) and the 6H-dibenzopyran (5%).
ortho chelating groups could be the winning combination for
the selective construction of unsymmetrical heterocyclic biaryl
derivatives.14,16
Table 1. Optimization study for the Pd/norbornene catalyzed synthesis of 9H-fluorenols.a
We have previously exploited the reactivity of 2-bromobenzyl
alcohols with aryl iodides under Pd/norbornene catalysis, and
we successfully obtained ortho-biaryl carbaldeydes (Scheme 2a)
and 6H-dibenzopyrans (Scheme 2b) from primary and tertiary
alcohols respectively with good to excellent yields in a one-pot
procedure.17a The chemoselectivity of the reaction was
essentially determined by the alcohol moiety: primary and
tertiary alcohols led selectively to ortho-biaryl aldehydes and
dibenzopyrans, respectively, while secondary alcohols generally
afforded, under similar conditions, mixtures of ortho-biaryl
ketones and dibenzopyrans. In continuation of this work, we
have found that, adding TFP or analogous phosphine ligands to
the reaction mixture, dibenzopyran derivatives were
preferentially obtained from secondary benzyl alcohols
(Scheme 2c).17b Among all the reported examples, the reaction
of 2-iodotoluene and 1-(2-bromophenyl)-phenylmethanol gave
Entry
1
2
3
4
5
6
7
8
Pd cat
Pd(OAc)2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PdI2
PPh3 (mol%)
KI (mol%)
T (°C)
90
90
90
90
90
90
105
80
120
120
Yield (%)b 3a
10
10
10
10
-
15
10
10
10
10
-
-
12
65
77
64
-
49
75
71
66
63
25
50
25
25
25
25
25
25
9
10
PdI2
PdCl2
a
Reaction conditions: 1a (0.34 mmol, 1.05 equiv), 2a (0.32 mmol, 1.0 equiv),
norbornene (0.16 mmol, 0.5 equiv), Pd cat (5 mol%), PPh3, KI, Cs2CO3 (0.7 mmol,
2.2 equiv), in toluene (7 mL) under N2, 24 h. b Determined by NMR analysis.
1-methyl-9-phenyl-9H-fluoren-9-ol
in
11%
yield
as
byproduct.17a Now we report a palladium/norbornene-based
modified protocol for the selective synthesis of substituted 2-
fluorenols from secondary ortho-bromobenzyl alcohols and
ortho-substituted aryl iodides (Scheme 2d).
Surprisingly, PdI2 in place of Pd(OAc)2 gave 65% yield of 3a
(Table 1, entry 2). We found that a moderate addition of KI as
an additive was beneficial to the reaction (Table 1, entry 3).18
Doubling the amount of KI, the yield of 3a slightly decreased to
64% (Table 1, entry 4). No conversion was obtained in the
absence of a ligand (Table 1, entry 4), and among several triaryl
phosphines, PPh3 proved to be the best one, under these
conditions. Moreover, the amount of the phosphine is critical to
the outcome of the reaction and the best results were obtained
with 10 mol% of PPh3. In fact, when PPh3 was increased up to
15 mol% the yield of 3a dropped to 49% (Table 1, entry 6). The
optimal reaction temperature was found to be 90 °C since at
105 °C a similar reaction outcome was observed (Table 1, entry
7), while higher or lower temperatures affected negatively the
fluorenol formation (Table 1, entries 8 and 9). The use of PdCl2
as catalyst gave results comparable to those obtained in the
presence of PdI2 (Table 1, entries 9 and 10).19
Under the optimized reaction conditions (Table 1, entry 3), the
substrate scope was then examined (Scheme 3). First, ortho-
substituted aryliodides were caused to react with 1-(2-
bromophenyl)ethanol (2a). The increased steric hindrance of
the ortho substituent (R1) was well tolerated since the series
Me, Et, i-Pr led respectively to 76, 71, 49% yield of the
corresponding fluorenols
(3a-c). High yield (79%) of
Scheme 2. Reactivity of 2-bromobenzyl alcohols in Catellani-type reactions.
benzo[a]fluorenol 3d was obtained starting from the
commercial 1-iodonaphtalene and substrate 2a. Strongly
electron donating (R1 = OMe, OBn) groups gave satisfactory
yields of the desired fluorenols (57-72%), while the reaction
with 2-iodotrifluoromethylbenzene performed poorly (34%,
3h). Double substituted aryl iodides in ortho and para positions
were successfully converted into the corresponding tricyclic
compounds 3e and 3i with 71 and 75% yield, respectively.
Results and discussion
In the attempt to find appropriate conditions to make the
reaction selective towards fluorenol derivatives, we cause to
react 2-iodotoluene and 1-(2-bromophenyl)ethanol, using
Pd(OAc)2/PPh3 as catalyst, toluene as solvent and Cs2CO3 as a
2 | J. Name., 2012, 00, 1-3
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Differently substituted secondary bromobenzylalcohols were At the beginning, the starting secondary alcohol could easily
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then considered. In particular, electron poor (R4 = F) or electron coordinate to the palladium(II) which DisOI:r1e0s.p10o3n9s/Cib9lOeB0fo10r85itHs
rich (R4 = OMe) bromoaryls were nicely tolerated in this oxidation to the corresponding ketone. After the formation of
transformation leading to synthetically useful yields of 3j (63%), ortho-bromoacetophenone and Pd(0), the aryl iodide
and 3k (54%). The 2-chloro benzylalcohol 2p, bearing a NO2 oxidatively adds to the metal forming the arylpalladium iodide
group in para position to the Cl, readily afforded 3p in 61% yield. I 21
Moreover, more sterically hindered secondary alcohols at the arylpalladium bond of
benzylic position (R3) were converted with high efficacy. In fact, metal and the aryl ring on the same side of the methylene
fluorenols 3l 3m and 3o bearing respectively Et, i-Pr and Ph in bridge of the norbornyl ring. This cis,exo geometry allows a
.
Norbornene readily coordinates and inserts into the
affording intermediate II, displaying the
I
,
that position, were obtained in good to excellent yields. The weak interaction through an η2 coordination mode between the
fused tetracyclic compound 3n was conveniently isolated in palladium atom and a double bond of the aromatic ring, in a sort
65% yield. Curiously, starting from 1-iodo-2-methoxy-4- of pre-organization favouring the ring closure to the
nitrobenzene and 2a, dibenzopyran 4a was obtained in 46% arylalkylpalladacycle III, through C-H activation.22 The resulting
yield in place of the expected fluorenol. Primary alcohols in metallacycle III undergoes oxidative addition by the in situ
place of secondary ones led to very complex reaction mixture, formed ortho-bromoacetophenone, giving the Pd(IV) complex
with large amounts of norbornane-containing organic IV. A Csp2–Csp2 coupling by reductive elimination readily occurs
molecules coming mainly from aryl iodides, and small quantities to generate intermediate
V, containing the biaryl unit. This
of fluorenones in place of fluorenols.
intermediate, due to the steric hindrance around the metal
center, undergoes a C–C cleavage with norbornene deinsertion
yielding complex VI. Palladium is now in proper position to
attack the carbonyl moiety, leading to intermediate VII which,
after protonolysis, affords fluorenol 3 and liberates palladium in
the oxidation state +2. By oxidation of a new alcohol molecule,
ortho-bromoacetophenone is formed and palladium is reduced
to the oxidation state 0, ready to start a new catalytic cycle. As
we have previously observed in other Catellani-type reactions,23
the presence of iodide anions coming from PdI2 and KI exerts a
positive effect to the reaction outcome.
According
to
the
proposed
redox
process,
2-
a
bromoacetophenone is formed at the beginning in
stoichiometric amount and is present in solution in very low
concentration. The palladium(0) species resulting from the
redox process is ready to start the palladium/norbornene cycle
by the oxidative addition of the aryl iodide, leading after a few
Scheme 3. Reaction scope for the Pd/norbornene catalyzed synthesis of fluorenol 3.
The formation of fluorenol
3 usually occurs with the total
conversion of the aryl iodide, while the secondary bromobenzyl
alcohol was often recovered at the end of the reaction (5-25%).
Remarkably, not negligible amounts (see Experimental part for
details) of 2-bromoacetophenones were frequently detected by
GC-MS analysis of the final reaction mixture. The oxidation of
secondary benzyl alcohols to the corresponding ketones can be
readily performed by palladium species.20 According to this
consideration and taking advantage of our deep knowledge on
Pd/norbornene catalyzed reactions involving 2-bromobenzyl
alcohol derivatives and aryl iodides,17a,b a possible rational for
the fluorenol formation is shown in Scheme 4.
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secondary benzyl alcohol and in the presence of an excess of a
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readily oxidizable alcohol, such as 1-DpOhIe: n10y.l1e0t3h9a/Cn9-O1-Bo0l10a8n5Hd
diphenylmethanol (Scheme 5). Fluoren-9-ol 3a was obtained in
high yields (88 and 87%, respectively), comparable with the
amount of acetophenone and diphenylketone, that were
respectively obtained by oxidation of the starting sacrificial
alcohol employed. When we tried the reaction of 2-iodotoluene
and 2-bromoacetophenone in the absence of the alcohol, a very
little amount of fluorenol derivative was instead observed (ca.
12%). Under our optimized reaction conditions, the formation
of fluorenol derivatives from aryl iodides and 2-
bromoacetophenones can be successfully performed in the
presence of a readily oxidizable alcohol, providing a valid
alternative to Lautens’ protocol.25
Scheme 4. Proposed reaction mechanism for the Pd/norbornene catalyzed synthesis of
fluorenol 3.
Scheme 5. Reaction of 1a and 2-bromoacetophenone in the presence of a stoichiometric
amount of a sacrificial secondary alcohol.
steps to the palladacycle, which selectively reacts with o-
bromoacetophenone in spite of the its lower concentration
with respect to those of the starting o-bromobenzyl alcohol.
The electron withdrawing character of the carbonyl substituent
is essential to favor the oxidative addition step (from III to IV).
At the end of the process Pd(II) is released in solution and
another benzyl alcohol molecule can be oxidized to o-
bromoacetophenone.
Thus, this catalytic cycle consists of two complementary
processes (scheme 4): the former starts from a Pd(II) species
and leads to the formation of Pd(0) involving the OH group of
the o-bromobenzyl alcohol; the latter begins with the oxidative
addition of the Pd(0) species by the aryl iodide, and ends up with
the release of the metal in the oxidation state +2. The
combination of the two stoichiometric reactions makes the
entire process catalytic. o-Bromoacetophenone, coming from
the first redox reaction, becomes substrate for the subsequent
palladium-mediated synthesis of the fluorenyl alcohol.
Conclusions
In conclusion, we have developed a catalytic method to obtain
fluorenol derivatives from aryl iodides and secondary 2-
bromobenzylalcohols
in
the
presence
of
the
palladium/norbornene catalytic system. Fluorenols are formed
in fair to good yields making this new Catellani-type
transformation a viable synthetic method complementary to
existing transition-metal catalyzed alternatives. The reaction
proceeds through two independent stoichiometric reactions: 1)
the Pd(II)-mediated oxidation of the secondary alcohol to the
corresponding ketone and 2) the Pd(0)/norbornene-catalyzed
reaction of the in situ generated ortho-bromoacetophenone
with the aryl iodide. Notably, the reaction proceeds well
starting from an aryl iodide and 2-bromoacetophenone in the
presence of a stoichiometric amount of a sacrificial secondary
alcohol.
To the best of our knowledge, this is a rare example of catalytic
process in which two different oxidation states of the same
metal (Pd(0) and Pd(II)) are employed and work synergistically
in two different reactions.24 In our case, we succeeded to
efficiently synchronize two reactions and combine them in a
single process where the “spent” catalyst at the end of a
reaction is regenerated by the other one, and vice versa.
To take advantage from these results, we performed the
reaction under the usual conditions with 2-iodotoluene as
iodide, but using 2-bromoacetophenone in place of the
Experimental
General methods
All chemicals were purchased from commercial sources and
used as received, unless otherwise indicated. Toluene, THF and
all other solvents were dried and stored over molecular sieves
previously activated in oven at 300 °C overnight. Catalytic
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reactions were carried out under nitrogen using standard (d, J = 246.9 Hz), 147.1 (d, J = 6.7 Hz), 133.9 (d, J = 7.8 Hz), 115.9
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Schlenk technique. GC analyses were performed with an Agilent (d, J = 22.8 Hz), 115.3 (d, J = 3.1 Hz), 114.D0O(Id: ,10J.1=02393/.C99HOzB)0,16098.51H,
Technologies 7820A equipped with a FID detector and a 30 m 23.5. 19F NMR (376 MHz, CDCl3) δ -113.49. Anal. Calcd for
capillary column. GC-MS analyses (m/z, relative intensity %) C8H8BrFO: C, 43.87; H, 3.68; Br, 36.48; F, 8.67; O, 7.30. Found: C
were performed with an Agilent Technologies 6890N gas 43.89, H 3.63.
chromatograph coupled to an 5973N mass selective detector 1-(2-Bromo-4-methoxyphenyl)ethanol (2k). Acetyl chloride
(Agilent Technologies) working at 70 eV ionizing voltage. The (1.2 equiv., 6 mmol, 430 μL) is added dropwise to a stirred
conversion of the starting materials has been calculated via GC suspension of 3-bromoanisole (1 equiv., 5 mmol, 630 μL) and
analyses using dodecane as internal standard. NMR spectra AlCl3 (6 mmol, 800 mg) in anhydrous CH2Cl2 (5 mL) at 0°C under
were recorded at 298 K, in CDCl3 on Bruker AV300 and Bruker an N2 atmosphere in a flame dried 25 mL Schlenk tube. The
400 MHz using the solvent as internal standard (7.26 ppm for 1H resulting mixture was stirred at 0 °C for 1 hour and then at room
NMR and 77.00 ppm for 13C NMR). The terms m, s, d, t, q, and temperature for 2 hours. The reaction was then diluted with 10
quint represent multiplet, singlet, doublet, triplet, quadruplet, mL of H2O and 5 mL of 2 N HCl, and extracted with CH2Cl2
and quintuplet, respectively, and the term br means a broad (3×20mL). The combined organics were washed with brine and
signal. MS-ESI analyses were recorded on an Infusion Water dried over MgSO4. The reaction crude was purified by silica-gel
Acquity Ultra Performance LC HO6UPS-823 M instrument column chromatography (hexane/EtOAc 90:10) to afford 1-(2-
(electrospray source, quadrupole analyzer). IR spectra were run bromo-4-methoxyphenyl)ethanone (2’k) as a colorless oil (1.5
on a Nicolet FT-IR 5700 spectrophotometer paired with a mmol, 350 mg, 30%). The spectroscopic data of 2’k were
Diamond Smart Orbit accessory. Melting points were measured consistent with literature values.26 1H NMR (400 MHz, CDCl3) δ
with an Electrothermal apparatus and are uncorrected. 7.51 (d, J = 8.7 Hz, 1H), 7.06 (d, J = 2.5 Hz, 1H), 6.79 (dd, J = 8.7,
Elemental analyses were performed with a Carlo Erba EA 1108- 2.5 Hz, 1H), 3.76 (s, 3H), 2.54 (s, 3H).
Elemental Analyzer.
1-(2-Bromo-4-methoxyphenyl)ethanone 2’k (1.5 mmol, 350
mg) was employed as starting material in the general procedure
B to afford 1-(2-bromo-4-methoxyphenyl)ethanol 2k as a
Preparation of secondary 2-bromobenzylalcohols
1
colorless oil (333 mg, Yield 98%). H NMR (300 MHz, CDCl3) δ
General procedure A: Grignard addition to 2-bromo
benzaldehydes
7.39 (d, J = 8.7 Hz, 1H), 7.00 (d, J = 2.6 Hz, 1H), 6.82 (dd, J = 8.7,
2.5 Hz, 1H), 5.10 (q, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.15 (bs, 1H),
1.38 (d, J = 6.4 Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 158.9, 136.8,
127.2, 121.8, 117.6, 113.8, 68.5, 55.5, 23.7. Anal. Calcd for
C9H11BrO2: C, 46.78; H, 4.80; Br, 34.58; O, 13.85. Found: C 46.84,
H 4.78.
In a flame dried 50 mL Schlenk tube, the required Grignard
reagent (1.1 equiv.) was added dropwise to a solution of
aldehyde (5 mmol, 1.0 equiv.) in anhydrous THF (0.35 M) at 0 °C
under an atmosphere of N2. The resulting mixture was stirred at
0 °C for 30 min and then at rt for 4 hours. The reaction was
quenched with sat. NH4Cl and the organic layer was separated.
The aqueous layer was extracted with EtOAc (3×20mL). The
combined organic layers were washed with brine (3×30mL),
dried over MgSO4, and concentrated under reduced pressure.
The residual was either purified by silica-gel column
chromatography (hexane/EtOAc) or used without further
purification.
1-(2-Bromophenyl)propan-1-ol
(2l).
1-(2-
Bromophenyl)propan-1-ol (2l) was synthesized according to the
general procedure A. The reaction crude was purified by silica-
gel column chromatography (hexane/EtOAc 90:10) to afford 2l
as a colorless oil (467 mg, Yield 51%). 1H NMR (300 MHz, CDCl3)
δ 7.49 (dd, J = 7.9, 1.3 Hz, 2H), 7.30 (td, J = 7.7, 0.9 Hz, 1H), 7.09
(td, J = 7.7, 1.7 Hz, 1H), 4.97 (dd, J = 7.7, 4.7 Hz, 1H), 2.77 (bs,
1H), 1.90 – 1.55 (m, 2H), 0.97 (t, J = 7.4 Hz, 3H). 13C NMR (75
MHz, CDCl3) δ 143.7, 132.6, 128.7, 127.7, 127.5, 122.1, 74.1,
30.6, 10.1. Anal. Calcd for C9H11BrO: C, 50.26; H, 5.15; Br, 37.15;
O, 7.44. Found: C 50.29, H 5.11.
General Procedure B: Reduction of 2-haloketones
Sodium borohydride (2.0 equiv.) was added portionwise to a
solution of the required 2-aloketone (1.0 equiv.) dissolved in
methanol (0.5 M) at 0 °C. The mixture was stirred at 0 °C until
complete conversion was detected by TLC analysis. The mixture
was concentrated under reduced pressure before being diluted
with CH2Cl2, washed with water and brine and then dried over
MgSO4 to afford the product used without further purification.
1-(2-Bromophenyl)-2-methylpropan-1-ol
Bromophenyl)-2-methylpropan-1-ol 2m
(2m).
) was synthesized
1-(2-
(
according to the general procedure A. The reaction crude was
purified by silica-gel column chromatography (hexane/EtOAc
1
90:10) to afford 2m as a yellowish oil (228 mg, Yield 20%). H
NMR (300 MHz, CDCl3) δ 7.50 (td, J = 7.8, 1.5 Hz, 2H), 7.37 – 7.28
(m, 1H), 7.16 – 7.07 (m, 1H), 4.86 (d, J = 5.8 Hz, 1H), 2.15 – 1.96
(m, 1H (bs, OH) and 1H), 0.95 (d, J = 6.8 Hz, 3H), 0.94 (d, J = 6.8
Hz, 3H). 13C NMR (75 MHz, CDCl3) δ 143.0, 132.7, 128.8, 128.4,
127.5, 122.8, 77.6, 34.1, 19.6, 16.9. Anal. Calcd for C10H13BrO: C,
52.42; H, 5.72; Br, 34.88; O, 6.98. Found: C 52.48, H 5.69.
(2-Chloro-5-nitrophenyl)(phenyl)methanol (2p). (2-Chloro-5-
nitrophenyl)(phenyl)methanol (2p) was synthesized according
to the general procedure B. Compound 2p was obtained as dark
yellow oil (301 mg, Yield 76%). 1H NMR (400 MHz, CDCl3) δ 8.61
Synthesis and characterization of 2j, 2k, 2l, 2m, 2p
1-(2-Bromo-5-fluorophenyl)ethanol
fluorophenyl)ethanol (2j) was synthesized according to the
general procedure A without further purification. 2j was
(2j).
1-(2-Bromo-5-
1
obtained as a colorless oil (870 mg, Yield 85%). H NMR (400
MHz, CDCl3) δ 7.41 (dd, J = 8.7, 5.2 Hz, 1H), 7.27 (dd, J = 9.7, 3.1
Hz, 1H), 6.88 – 6.76 (m, 1H), 5.11 (q, J = 6.3 Hz, 1H), 3.00 (bs,
1H), 1.40 (d, J = 6.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.5
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(d, J = 2.7 Hz, 1H), 8.04 (dd, J = 8.7, 2.8 Hz, 1H), 7.45 (d, J = 8.7 chromatography using hexane/ethyl acetate (95:5) plus 1% of
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Hz, 1H), 7.39 – 7.24 (m, 5H), 6.12 (s, 1H), 3.13 (bs, 1H). 13C NMR Et3N as eluent to give 3c (37 mg, 49%)DaOsI:a10w.1h03it9e/Cs9oOliBd0;10m8.5pH.
(101 MHz, CDCl3) δ 146.9, 143.0, 140.8, 139.0, 130.5, 128.8, (hexane) 188.3 – 189.0 °C. 1H NMR (400 MHz, CDCl3) δ 7.58 (d,
128.5, 127.2, 123.4, 122.9, 72.4. Anal. Calcd for C13H10ClNO3: C, J = 7.1 Hz, 1H), 7.52 – 7.47 (m, 1H), 7.45 (d, further splitting, J =
59.22; H, 3.82; Cl, 13.45; N, 5.31; O, 18.20. Found: C 59.26, H 7.3, 1H), 7.38 – 7.22 (m, 4H), 3.81 (dt, J = 13.7, 6.9 Hz, 1H), 2.06
3.80, N 5.37.
(bs, 1H), 1.79 (s, 3H), 1.33 (d, J = 6.9 Hz, 3H), 1.31 (d, J = 6.9 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ 150.8, 147.2, 145.2, 138.9,
138.6, 129.3, 128.8, 128.0, 125.8, 123.0, 119.9, 117.5, 81.2,
28.1, 26.6, 24.5, 24.4. MS (ESI) calcd for C17H17+ (M-OH)+ 221.13,
found 221.23. IR (neat) 3279, 3056, 2978, 1409, 1074, 1067,
769, 756, 740 cm-1. Anal. Calcd for C17H18O: C, 85.67; H, 7.62; O,
6.71. Found: C 85.70, H 7.56.
General procedure for the catalytic synthesis of fluorenols 3
Cesium carbonate (229 mg, 0.70 mmol, 2.2 equiv) is heated at 110 °C
under vacuum in a Schlenk type tube for 1.5 h. After cooling to room
temperature the tube is filled with nitrogen, evacuated and back-
filled with nitrogen three times. A toluene solution (7 ml) of the aryl
iodide (0.34 mmol), aryl bromide (0.32 mmol) and norbornene (15.6
mg, 0.16 mmol) is added to the Schlenk, followed by PdI2 (6.0 mg,
0.016 mmol), PPh3 (8.8 mg, 0.033 mmol) and KI (13.8 mg, 0.08 mmol)
as solids. The reaction flask is stirred under nitrogen at r.t. for 10
minutes and then heated into an oil bath at 90 °C for 24 h. After
cooling to room temperature, the mixture is diluted with ethyl
acetate (50 ml), transferred into a separating funnel and washed
twice with brine (50 ml). The resulting solution is dried over Na2SO4
and the solvent was removed under vacuum. The crude mixture is
purified by flash column chromatography on silica gel using a mixture
of n-hexane/EtOAc.
11-Methyl-11H-benzo[a]fluoren-11-ol (3d). 11-Methyl-11H-
benzo[a]fluoren-11-ol (3d) was obtained following the general
procedure. The crude was purified by flash column
chromatography using hexane/ethyl acetate (95:5) plus 1% of
Et3N as eluent to give 3d (62 mg, 79%) as a light yellow solid;
m.p. (hexane) 176.0 – 177.4 °C. The spectroscopic data of 3d
were consistent with literature values.12 1H NMR (400 MHz,
CDCl3) δ 8.46 (d, J = 8.4 Hz, 1H), 7.95 – 7.85 (m, 2H), 7.78 (d, J =
8.3 Hz, 1H), 7.68 (d, J = 7.4 Hz, 1H), 7.64 – 7.54 (m, 2H), 7.51 –
7.45 (m, 1H), 7.43 – 7.30 (m, 2H), 2.47 (bs, 1H), 1.90 (s, 3H). MS
+
(ESI) calcd for C18H13 (M-OH)+ 229.10, found 229.16. IR (neat)
3205, 3053, 2973, 2925, 1607,1091, 1080, 750, 643 cm-1.
1,3,9-Trimethyl-9H-fluoren-9-ol (3e). 1,3,9-Trimethyl-9H-
fluoren-9-ol (3e) was obtained following the general procedure.
The crude was purified by flash column chromatography using
hexane/ethyl acetate (95:5) plus 1% of Et3N as eluent to give 3e
(51 mg, 71%) as a white solid; m.p. (hexane) 179.7 – 180.8 °C.
1H NMR (400 MHz, CDCl3) δ 7.54 (d, J = 7.2 Hz, 1H), 7.47 (d, J =
7.1 Hz, 1H), 7.35 – 7.26 (m, 2H), 7.25 (s, 1H), 6.87 (s, 1H), 2.52
(s, 3H), 2.37 (s, 3H), 1.97 (bs, 1H), 1.74 (s, 3H). 13C NMR (101
MHz, CDCl3) δ 151.0, 143.8, 139.3, 138.7, 138.6, 135.2, 131.2,
128.7, 127.9, 122.9, 119.8, 118.3, 80.7, 24.7, 21.4, 17.8. MS (ESI)
calcd for C16H15+ (M-OH)+ 207.12, found 207.19. IR (neat) 3271,
2978, 1413, 1097, 760, 751, 743 cm-1. Anal. Calcd for C16H16O:
C, 85.68; H, 7.19; O, 7.13. Found: C 85.73, H 7.18.
Characterization of fluorenols 3
1,9-Dimethyl-9H-fluoren-9-ol (3a). 1,9-Dimethyl-9H-fluoren-9-
ol (3a) was obtained following the general procedure. The crude
was purified by flash column chromatography using
hexane/ethyl acetate (95:5) plus 1% of Et3N as eluent to give 3a
(51 mg, 76%) as a white solid; m.p. (hexane) 176.2 – 177.0 °C.
1H NMR (400 MHz, CDCl3) δ 7.59 (d, J = 7.4 Hz, 1H), 7.51 (d, J =
7.0 Hz, 1H), 7.46 (d, J = 7.4 Hz, 1H), 7.39 – 7.29 (m, 2H), 7.26 (t,
J = 7.5 Hz, 1H), 7.07 (d, J = 7.5 Hz, 1H), 2.60 (s, 3H), 2.21 (bs, 1H),
1.78 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 150.6, 146.6, 139.1,
138.6, 135.5, 130.4, 128.9, 128.8, 128.0, 123.0, 119.9, 117.6,
81.0, 24.6, 17.9. MS (ESI) calcd for C15H13 (M-OH)+ 193.10,
+
found 193.16. IR (neat) 3293, 2972, 1453, 1093, 1075, 765, 758,
741 cm-1. Anal. Calcd for C15H14O: C, 85.68; H, 6.71; O, 7.61.
Found: C 85.72, H 6.70.
1-Methoxy-9-methyl-9H-fluoren-9-ol
(3f).
1-Methoxy-9-
methyl-9H-fluoren-9-ol (3f) was obtained following the general
procedure. The crude was purified by flash column
chromatography using hexane/ethyl acetate (90:10) plus 1% of
Et3N as eluent to give 3f (41 mg, 57%) as a yellow solid; m.p.
(hexane) 98.6 – 100.1 °C. The spectroscopic data of 3f were
consistent with literature values.12 1H NMR (400 MHz, CDCl3) δ
7.67 – 7.62 (m, 1H), 7.62 – 7.56 (m, 1H), 7.42 – 7.32 (m, 3H),
7.31 – 7.27 (m, 1H), 6.85 (d, J = 8.1 Hz, 1H), 3.97 (s, 3H), 2.91 (bs,
1H), 1.89 (s, 3H). MS (ESI) calcd for C15H13O+ (M-OH)+ 209.26,
found 209.22. IR (neat) 3336, 2995, 1602, 1259, 1128, 1075,
750, 582 cm-1.
1-(Benzyloxy)-9-methyl-9H-fluoren-9-ol (3g). 1-(Benzyloxy)-9-
methyl-9H-fluoren-9-ol (3g) was obtained following the general
procedure. The crude was purified by flash column
chromatography using hexane/ethyl acetate (90:10) plus 1% of
Et3N as eluent to give 3g (70 mg, 72%) as a light yellow solid;
m.p. (hexane) 127.6 – 128.8 °C. 1H NMR (400 MHz, CDCl3) δ 7.61
(dd, J = 15.1, 6.5 Hz, 2H), 7.50 (d, J = 7.2 Hz, 2H), 7.43 (t, J = 7.4
Hz, 2H), 7.39 – 7.25 (m, 5H), 6.87 (dd, J = 7.5, 1.0 Hz, 1H), 5.23
1-Ethyl-9-methyl-9H-fluoren-9-ol (3b). 1-Ethyl-9-methyl-9H-
fluoren-9-ol (3b) was obtained following the general procedure.
The crude was purified by flash column chromatography using
hexane/ethyl acetate (95:5) plus 1% of Et3N as eluent to give 3b
(51 mg, 71%) as a white solid; m.p. (hexane) 181.3 – 182.5 °C.
1H NMR (400 MHz, CDCl3) δ 7.61 – 7.56 (m, 1H), 7.53 – 7.48 (m,
1H), 7.46 (d, further splitting, J = 7.4, 1H), 7.37 – 7.27 (m, 3H),
7.15 (d, J = 7.7 Hz, 1H), 3.02 (dq, J = 7.5, 1.7 Hz, 2H), 2.03 (bs,
1H), 1.79 (s, 3H), 1.32 (t, J = 7.6 Hz, 3H). 13C NMR (101 MHz,
CDCl3) δ 150.7, 146.0, 142.0, 139.1, 138.6, 129.1, 128.9, 128.6,
128.0, 123.0, 119.9, 117.5, 81.2, 26.0, 23.9, 15.9. MS (ESI) calcd
for C16H15+ (M-OH)+ 207.12, found 207.20. IR (neat) 3276, 2970,
1431, 1088, 1074, 765, 750, 746 cm-1. Anal. Calcd for C16H16O:
C, 85.68; H, 7.19; O, 7.13. Found: C 85.60, H 7.23.
1-Isopropyl-9-methyl-9H-fluoren-9-ol (3c). 1-Isopropyl-9-
methyl-9H-fluoren-9-ol (3c) was obtained following the general
procedure. The crude was purified by flash column
6 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
(s, 2H), 2.75 (bs, 1H), 1.93 (s, 3H). 13C NMR (101 MHz, CDCl3) δ general procedure. The crude was purified by flash column
View Article Online
155.6, 149.8, 141.0, 138.9, 136.9, 135.8, 130.4, 128.80, 128.77, chromatography using hexane/ethyl aceDtaOtIe: 1(08.150:1395/)Cp9OluBs0110%85oHf
128.2, 128.1, 127.3, 123.2, 120.3, 113.2, 111.6, 80.4, 70.0, 25.6. Et3N as eluent to give 3k (41 mg, 54%) as a dark yellow solid;
MS (ESI) calcd for C21H17O+ (M-OH)+ 285.13, found 285.22. IR m.p. (hexane) 88.3 – 89.6 °C. 1H NMR (400 MHz, CDCl3) δ 7.42 –
(neat) 3280, 3021, 2920, 1612, 1470, 1311, 1211, 1139, 1070, 7.35 (m, J = 7.9, 4.4 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.08 – 7.02
830, 601 cm-1. Anal. Calcd for C21H18O2: C, 83.42; H, 6.00; O, (m, 2H), 6.79 (dd, J = 8.3, 2.4 Hz, 1H), 3.81 (s, 3H), 2.57 (s, 3H),
10.58. Found: C 83.40, H 6.01.
2.17 (bs, 1H), 1.75 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 160.6,
9-Methyl-1-(trifluoromethyl)-9H-fluoren-9-ol (3h). 9-Methyl- 147.4, 142.9, 140.1, 138.9, 135.5, 130.6, 128.7, 123.7, 117.5,
1-(trifluoromethyl)-9H-fluoren-9-ol (3h) was obtained following 113.5, 105.4, 80.5, 55.6, 24.7, 17.9. MS (ESI) calcd for C16H15O+
the general procedure. The conversion of 1-(2- (M-OH)+ 223.11, found 223.14. IR (neat) 3275, 2926, 2385,
bromophenyl)ethanol was 79%. 1-(2-Bromophenyl)ethanone 1608, 1472, 1311, 1215, 1134, 1075, 837, 607 cm-1. Anal. Calcd
was detected by GC-MS analysis (42%). The crude was purified for C16H16O2: C, 79.97; H, 6.71; O, 13.32. Found: C 79.87, H 6.70.
by flash column chromatography using hexane/ethyl acetate 9-Ethyl-1-methyl-9H-fluoren-9-ol (3l). 9-Ethyl-1-methyl-9H-
(95:5) plus 1% of Et3N as eluent to give 3h (29 mg, 34%) as a fluoren-9-ol (3l) was obtained following the general procedure.
white solid; m.p. (hexane) 116.4 – 118.6 °C. The spectroscopic The crude was purified by flash column chromatography using
data of 3h were consistent with literature values.12 1H NMR (400 hexane/ethyl acetate (95:5) plus 1% of Et3N as eluent to give 3l
MHz, CDCl3) δ 7.84 (d, J = 7.1 Hz, 1H), 7.67 – 7.63 (m, 1H), 7.61 (62 mg, 86%) as a white solid; m.p. (hexane) 116.9 – 117.6 °C.
– 7.55 (m, 2H), 7.51 – 7.47 (m, J = 11.9, 4.3 Hz, 1H), 7.42 – 7.36 1H NMR (400 MHz, CDCl3) δ 7.58 – 7.54 (m, 1H), 7.46 – 7.41 (m,
+
(m, 2H), 1.86 (s, 3H), 1.69 (bs, 1H). MS (ESI) calcd for C15H10F3 2H), 7.36 – 7.26 (m, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.04 (d, J = 7.5
(M-OH)+ 247.07, found 247.12. IR (neat) 3334, 2923, 1314, Hz, 1H), 2.53 (s, 3H), 2.45-2.19 (m, 2H), 2.12 (bs, 1H), 0.38 (t, J =
1138, 767 cm-1.
Methyl
(3i). Methyl 9-hydroxy-1,9-dimethyl-9H-fluorene-3-carboxylate 84.9, 30.4, 17.9, 8.4. MS (ESI) calcd for C16H15+ (M-OH)+ 207.12,
7.5 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 148.8, 144.8, 140.2,
9-hydroxy-1,9-dimethyl-9H-fluorene-3-carboxylate 140.0, 135.7, 130.3, 128.9, 128.8, 127.9, 123.1, 119.7, 117.4,
(
3i) was obtained following the general procedure. The crude found 207.24. IR (neat) 3301, 2969, 1454, 1015, 765, 802, 746
was purified by flash column chromatography using cm-1. Anal. Calcd for C16H16O: C, 85.68; H, 7.19; O, 7.13. Found:
hexane/ethyl acetate (85:15) plus 1% of Et3N as eluent to give C 85.60, H 7.21.
3i (64 mg, 75%) as a white solid; m.p. (hexane) 192.3 – 194.5 °C. 9-Isopropyl-1-methyl-9H-fluoren-9-ol (3m). 9-Isopropyl-1-
1H NMR (400 MHz, CDCl3) δ 7.98 (d, J = 0.9 Hz, 1H), 7.66 (dd, J = methyl-9H-fluoren-9-ol
(3m) was obtained following the
1.4, 0.7 Hz, 1H), 7.64 – 7.60 (m, 1H), 7.55 – 7.51 (m, 1H), 7.40 – general procedure. The crude was purified by flash column
7.30 (m, 2H), 3.83 (s, 3H), 2.61 (s, 3H), 2.10 (bs, 1H), 1.76 (s, 3H). chromatography using hexane/ethyl acetate (95:5) plus 1% of
13C NMR (101 MHz, CDCl3) δ 167.3, 151.3, 150.6, 139.5, 137.8, Et3N as eluent to give 3m (48 mg, 68%) as a pale yellow viscous
135.5, 131.9, 130.5, 129.2, 128.6, 123.1, 120.3, 118.7, 80.9, oil. 1H NMR (400 MHz, CDCl3) δ 7.58 (d, J = 7.5 Hz, 1H), 7.53 (d,
+
52.2, 24.7, 17.9. MS (ESI) calcd for C17H15O2 (M-OH)+ 251.11, J = 7.5 Hz, 1H), 7.42 (d, J = 7.4 Hz, 1H), 7.34 (t, J = 7.4 Hz, 1H),
found 251.22. IR (neat) 3381, 2987, 2943, 2385, 1619, 1608, 7.27 – 7.19 (m, 2H), 7.03 (d, J = 7.5 Hz, 1H), 2.84-2.76 (m, 1H),
1479, 1210, 1132, 1098, 833, 603 cm-1. Anal. Calcd for C17H16O3: 2.57 (s, 3H), 2.01 (bs, 1H), 1.31 (d, J = 6.8 Hz, 3H), 0.29 (d, J = 6.9
C, 76.10; H, 6.01; O, 17.89. Found: C 76.04, H 6.03.
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 146.8, 146.7, 140.6, 140.1,
7-Fluoro-1,9-dimethyl-9H-fluoren-9-ol (3j). 7-Fluoro-1,9- 135.0, 130.6, 128.8, 128.6, 127.1, 125.2, 119.7, 117.2, 87.3,
dimethyl-9H-fluoren-9-ol (3j) was obtained following the 34.3, 18.1, 17.7, 17.2. MS (ESI) calcd for C17H17+ (M-OH)+ 221.13,
general procedure. The conversion of 1-(2-bromo-5- found 221.16. IR (neat) 3279, 3051, 2978, 1400, 1067, 761, 752,
fluorophenyl)ethanol
was
complete.
1-(2-Bromo-5- 729 cm-1. Anal. Calcd for C17H18O: C, 85.67; H, 7.61; O, 6.71.
fluorophenyl)ethanone was detected by GC-MS analysis (35%). Found: C 85.60, H 7.57.
The crude was purified by flash column chromatography using 7-Methyl-4,5,6,6a-tetrahydrofluoranthen-6a-ol
hexane/ethyl acetate (95:5) plus 1% of Et3N as eluent to give 3j Methyl-4,5,6,6a-tetrahydrofluoranthen-6a-ol
(3n).
3n
7-
was
(
)
(46 mg, 63%) as a white solid; m.p. (hexane) 159.1 – 160.0 °C. obtained following the general procedure. The crude was
1H NMR (400 MHz, CDCl3) δ 7.52 (dd, J = 8.3, 4.9 Hz, 1H), 7.39 purified by flash column chromatography using hexane/ethyl
(d, J = 7.5 Hz, 1H), 7.27 – 7.19 (m, 2H), 7.08 – 6.99 (m, J = 9.2, acetate (95:5) plus 1% of Et3N as eluent to give 3n (46 mg, 65%)
1
8.3, 2.4 Hz, 2H), 2.58 (s, 3H), 1.86 (bs, 1H), 1.77 (s, 3H). 13C NMR as a viscous transparent oil. H NMR (400 MHz, CDCl3) δ 7.58
(101 MHz, CDCl3) δ 163.2 (d, J = 246.6 Hz), 152.9 (d, J = 7.2 Hz), (dd, J = 7.7, 1.1 Hz, 1H), 7.51 (d, J = 7.7 Hz, 1H), 7.29 – 7.24 (m,
146.4, 138.4, 135.6, 134.5 (d, J = 2.5 Hz), 121.2 (d, J = 8.6 Hz), 1H), 7.13 – 7.05 (m, 2H), 6.95 (t, J = 7.6 Hz, 1H), 4.96 (dd, J =
130.2, 129.1, 117.3, 115.9 (d, J = 23.1 Hz), 110.7 (d, J = 23.0 Hz), 10.4, 5.5 Hz, 1H), 2.94 – 2.78 (m, 2H), 2.57 – 2.47 (m, 1H), 2.29
80.9, 24.7, 17.9. 19F NMR (376 MHz, CDCl3) δ -113.47. MS (ESI) (s, 3H), 2.15 – 1.96 (m, 2H), 1.88 – 1.74 (m, 1H). 13C NMR (101
calcd for C15H12F+ (M-OH)+ 211.09, found 211.14. IR (neat) 3297, MHz, CDCl3) δ 153.2, 135.6, 131.0, 130.75, 130.7, 128.0, 127.9,
2928, 1612, 1466, 1489, 1302, 1120, 806, 601 cm-1. Anal. Calcd 126.6, 123.4, 121.4, 121.3, 120.1, 74.0, 29.4, 28.7, 21.0, 16.0.
+
for C15H13FO: C, 78.93; H, 5.74; F, 8.32; O, 7.01. Found: C 78.85, MS (ESI) calcd for C17H15 (M-OH)+ 219.12, found 219.16. IR
H 5.80.
(neat) 3288, 3033, 2967, 1432, 1232, 1075, 762, 750, 746 cm-1.
6-Methoxy-1,9-dimethyl-9H-fluoren-9-ol (3k). 6-Methoxy-1,9- Anal. Calcd for C17H16O: C, 86.40; H, 6.82; O, 6.77. Found: C
dimethyl-9H-fluoren-9-ol (3k) was obtained following the 86.37, H 6.89.
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 7
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
1-Methyl-9-phenyl-9H-fluoren-9-ol (3o). 1-Methyl-9-phenyl- facilities. We are thankful for the support froVmiewtAhrteicleCOOnlSinTe
DOI: 10.1039/C9OB01085H
9H-fluoren-9-ol (3o) was obtained following the general (European Cooperation in Science and Technology) Action
procedure. The crude was purified by flash column (CA15106) on C–H Activation in Organic Synthesis.
chromatography using hexane/ethyl acetate (95:5) plus 1% of
Et3N as eluent to give 3o (60 mg, 69%) as a white solid; m.p.
(hexane) 137.5 – 138.7 °C. 1H NMR (400 MHz, CDCl3) δ 7.64 (d,
J = 7.5 Hz, 1H), 7.55 (d, J = 7.5 Hz, 1H), 7.39 (dd, J = 8.2, 1.3 Hz,
2H), 7.32 (t, J = 7.5 Hz, 2H), 7.29 – 7.17 (m, 5H), 7.05 (d, J = 7.5
Hz, 1H), 2.28 (bs, 1H), 2.12 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
151.3, 147.4, 142.3, 140.3, 139.2, 136.3, 130.6, 129.5, 129.0,
128.4, 128.3, 127.0, 125.2, 124.5, 120.1, 117.6, 84.2, 18.0. MS
Notes and references
1
(a) D. Dunn, G. Hostetler, M. Iqbal, V.R. Marcy, Y.G. Lin,
B. Jones, L.D. Aimone, J. Gruner, M.A. Ator, E.R. Bacon
and S. Chatterjee, Bioorg. Med. Chem. Lett., 2012, 22
3751; (b) S. Gould and C. Melville, Bioorg. Med. Chem.
Lett., 1995, , 51; (c) S. Gould, N. Tamayo, C. Melville and
,
6
M.C. Cone, J. Am. Chem. Soc., 1994, 116, 2207; (d) S.
Mithani, G. Weeratunga, N. J. Taylor and G. I.
Dmitrienko, J. Am. Chem. Soc., 1994, 116, 2209.
(a) I.O. Koshevoy, C.-L. Lin, A.J. Karttunen, J. Janis, M.
Haukka, S.P. Tunik, P.-T. Chou and T.A. Pakkanen, Chem.
Eur. J., 2011, 17, 11456; (b) T.A.M. Ferenczi, M. Sims and
D.D.C. Bradley, J. Phys.: Condens. Matter, 2008, 20
45220; (c) L. Feng, C. Zhang, H. Bie and Z. Chen, Dyes
Pigm., 2005, 64, 31.
(a) A. Shimizu and Y. Tobe, Angew. Chem., Int. Ed., 2011,
50, 6906; (b) S. Allard, M. Forster, B. Souharce, H. Thiem
and U. Scherf, Angew. Chem., Int. Ed., 2008, 47, 4070;
(c) J. Wang, W. Wan, H. Jiang, Y. Gao, X. Jiang, H. Lin, W.
Zhao and J. Hao, Org. Lett., 2010, 12, 3874; (d) Z. Zeng,
Y. M. Sung, N. Bao, D. Tan, R. Lee, J. L. Zafra, B. S. Lee,
M. Ishida, J. Ding, J. T. López Navarrete, Y. Li, W. Zeng,
D. Kim, K.-W. Huang, R. D. Webster, J. Casado and J. Wu,
J. Am. Chem. Soc., 2012, 134, 14513.
+
(ESI) calcd for C20H15 (M-OH)+ 255.12, found 255.20. IR (neat)
3544, 2922, 2360, 1445, 1066, 765, 746, 693 cm-1. Anal. Calcd
for C20H16O: C, 88.20; H, 5.92; O, 5.87. Found: C 88.18, H 5.97.
1-Methyl-7-nitro-9-phenyl-9H-fluoren-9-ol (3p). 1-Methyl-7-
nitro-9-phenyl-9H-fluoren-9-ol (3p) was obtained following the
general procedure. The conversion of (2-chloro-5-
2
3
,
nitrophenyl)(phenyl)methanol
was
70%.
(2-Chloro-5-
nitrophenyl)(phenyl)methanone was detected by GC-MS
analysis (5%). The crude was purified by flash column
chromatography using hexane/ethyl acetate (90:10) plus 1% of
Et3N as eluent to give 3p (62 mg, 61%) as a white solid; m.p.
(hexane) 199.8 – 202.0 °C. 1H NMR (400 MHz, CDCl3) δ 8.24 (dd,
J = 8.3, 2.0 Hz, 1H), 8.09 (d, J = 2.0 Hz, 1H), 7.75 (d, J = 8.3 Hz,
1H), 7.64 (d, J = 7.5 Hz, 1H), 7.46 – 7.36 (m, 3H), 7.35 – 7.26 (m,
3H), 7.19 (d, J = 7.5 Hz, 1H), 2.55 (bs, 1H), 2.15 (s, 3H). 13C NMR
(101 MHz, CDCl3) δ 152.4, 148.6, 148.0, 145.6, 140.6, 138.0,
137.0, 132.7, 130.1, 128.7, 127.7, 125.2, 125.1, 120.4, 120.2,
119.0, 83.9, 17.9. MS (ESI) calcd for C20H14NO2+ (M-OH)+ 300.10,
found 300.12. IR (neat) 3528, 3462, 2924, 1596, 1508, 1325,
770, 761, 667 cm-1. Anal. Calcd for C20H15NO3: C, 75.70; H, 4.76;
N, 4.41; O, 15.13. Found: C 75.61, H 4.80, N 4.35.
4
5
(a) S.A. Bourne, K. Corin, D.L. Cruickshank, J. Davson, L.R.
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,
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6
7
S. M. Gannon, J. G. Krause, Synthesis, 1987, 10, 915.
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2018, 140, 6818; (b) G. C. Vougioukalakis, M. M.
Roubelakis and M. Orfanopoulos, J. Org. Chem., 2010,
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4-Methoxy-6-methyl-2-nitro-6H-dibenzopyran
(4a).
4-
Methoxy-6-methyl-2-nitro-6H-dibenzopyran (4a) was obtained
following the general procedure at 105 °C. The crude was
purified by flash column chromatography using hexane/ethyl
acetate (80:20) plus 1% of Et3N as eluent to give 4a (40 mg, 46%)
as a dark yellow solid; m.p. (hexane) 172.3 – 174.6 °C. 1H NMR
(400 MHz, CDCl3) δ 8.35 (d, J = 2.3 Hz, 1H), 7.81 – 7.73 (m, J =
11.7, 4.9 Hz, 2H), 7.47 – 7.36 (m, 2H), 7.20 (d, J = 7.5 Hz, 1H),
8
(a) D. Rodrıguez, L. Castedo, D. Domınguez and C. Saa,
Tetrahedron Lett. 1999, 40, 7701; D. Rodrıguez, A.
Navarro, L. Castedo, D. Domınguez, C. Saa, Org. Lett.,
5.51 (q, J = 6.6 Hz, 1H), 4.00 (s, 3H), 1.66 (d, J = 6.6 Hz, 3H). 13
NMR (101 MHz, CDCl3) δ 149.7, 148.2, 142.2, 135.0, 129.4,
C
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+
MS (ESI) calcd for C15H14NO4 (M+H)+ 272.09, found 272.11.
C. Saa and D. Domınguez, Tetrahedron Lett. 2004, 45
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Anal. Calcd for C15H13NO4: C, 66.41; H, 4.83; N, 5.16; O, 23.59.
Found: C 66.47, H 4.80, N 5.28.
4711.
9
Q. Zhao, Q. Hu, L. Wen, M. Wu and Y. Hua, Adv. Synth.
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Conflicts of interest
There are no conflicts to declare.
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13 M. Itoh, K. Hirano, T. Satoh, Y. Shibata, K. Tanaka and M.
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14 For recent reviews on the Catellani Reactions, see: (a) J.
Wang and G. Dong, Chem Rev., 2019, DOI:
10.1021/acs.chemrev.9b00079; (b) H.-G. Cheng, S.
Acknowledgements
We wish to thank the University of Parma and MIUR (Ministry
of Education, University and Research) for financial support,
and CIM (Interdepartmental Measurements Centre) for NMR
8 | J. Name., 2012, 00, 1-3
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Organic & Biomolecular Chemistry
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Journal Name
Chen, R. Chen and Q. Zhou, Angew. Chem. Int. Ed., 2019,
ARTICLE
Delord, T. Dröge, F. Liu and F. Glorius, Chem. Soc. Rev.,
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DOI: 10.1039/C9OB01085H
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25 Head to head comparison of these two protocols (our
protocol vs Lautens protocol in ref 12). Reactions
conditions (e.g. T = 90 °C, base = Cs2CO3) are quite
similar, however the methods differ for: a) amount of
H2O (dry conditions vs 48 equiv); b) amount of
norbornene (0.5 equiv vs 3 equiv); c) palladium source
(PdI2 vs Pd(OAc)2); d) amount of KI (0.25 equiv vs no
iodide anion source); e) use of 2-bromo-benzylalcohols
(1.0 equiv) vs 2-chloro-arylketones (1.5 equiv) as
starting material; f) solvent (Toluene vs DME). Other
minor differences in the amount of Cs2CO3 and in the
aryl iodides : ketones/alcohols stoichiometric ratio are
present.
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20 J. Muzart, Tetrahedron, 2003, 59, 5789.
21 Ortho-substituted aryl iodides are essential to this
transformation as for many other Catellani-type
reactions. The ortho substituent on the aryl iodide is
crucial to direct the reductive elimination (from IV to V,
Scheme 4) towards the aryl-aryl coupling instead of the
aryl-norbornyl one, that would lead to the incorporation
of the norbornane unit. Moreover, the absence of an
ortho substituent would hinder the subsequent
norbornene expulsion step (from
V to VI).
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Inorg. Chim. Acta, 2015, 431, 230; (b) C. Sambiagio, D.
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