Intramolecular aromatic carbenoid insertion of biaryldiazoacetates for the regioselective synthesis of fluorenes

Article abstract of DOI:10.1002/asia.201100142

The rhodium- or copper-catalyzed intramolecular aromatic carbenoid insertion of biaryldiazoacetates offers a convenient route to fluorene carboxylates with high yields. Whereas, thermal conditions provided a mixture of two regioisomeric products when substituted biaryldiazoacetates were employed as substrates. The developed catalytic conditions displayed an excellent level of regioselectivity, presumably owing to steric effects. The insertion mechanism was assumed to be an electrophilic aromatic substitution, which was supported by preliminary mechanistic studies. A chloro-substituted fluorene derivative was efficiently synthesized and utilized as a base-sensitive protecting group of amines.

Full text of DOI:10.1002/asia.201100142

FULL PAPERS
DOI: 10.1002/asia.201100142
Intramolecular Aromatic Carbenoid Insertion of Biaryldiazoacetates for the
Regioselective Synthesis of Fluorenes
Jinho Kim,[a] Youhwa Ohk,[b] Sae Hume Park,[a] Yousung Jung,*[b] and Sukbok Chang*[a]
Dedicated to Professor Eun Lee on the occasion of his retirement and 65th birthday
Abstract: The rhodium- or copper-cata-
lyzed intramolecular aromatic carbe-
noid insertion of biaryldiazoacetates
offers a convenient route to fluorene
carboxylates with high yields. Whereas,
thermal conditions provided a mixture
of two regioisomeric products when
substituted biaryldiazoacetates were
employed as substrates. The developed
catalytic conditions displayed an excel-
lent level of regioselectivity, presuma-
bly owing to steric effects. The inser-
tion mechanism was assumed to be an
electrophilic aromatic substitution,
which was supported by preliminary
mechanistic studies. A chloro-substitut-
ed fluorene derivative was efficiently
synthesized and utilized as a base-sen-
sitive protecting group of amines.
Keywords: biaryldiazoacetates
·
catalysis · fluorenes · regioselec-
tivity · rhodium
Introduction
the other hand, introduction of substituents at the C-9 meth-
ylene bridge of the fluorene unit requires base-mediated
conditions, under which fluorene reacts with electrophiles.[5]
As an alternative approach to synthesize the fluorene
skeleton, an intramolecular aromatic carbenoid insertion
can be regarded as a facile route to form a 5,6-bicyclic ring
system.[6,7] In fact, this strategy was elegantly utilized in the
preparation of (hetero)aromatic bicyclic ring systems, al-
though the reaction efficiency fluctuates depending on the
substrate type and reaction conditions. With regard to this
aspect, the synthesis of fluorenes was previously achieved
with a benzylic carbene intermediate in 1958 by Denney
and Klemchuk,[8] in which 2-phenylphenyldiazomethane was
used as a precursor for the photolytic ring-forming reaction.
Herein, we describe a metal-catalyzed regioselective aro-
matic carbenoid insertion of biaryldiazoacetates to construct
the 5,6-bicyclic ring system of fluorene carboxylates along
Fluorene and its substituted derivatives have been exten-
sively utilized in materials chemistry as dyes and optical
brightening agents,[1] and they are also widely employed in
organic synthesis and peptide chemistry. For instance, 9H-
fluorene-9-carboxylate is a precursor of 9-fluorenylmethy-
loxycarbonyl (Fmoc), which is an easily installable and re-
movable protecting group of amines.[2] Despite this wide-
spread utility of fluorenes, a limited number of preparative
methods have been developed.[3] In this context, it is also a
nontrivial task to prepare unsymmetrically substituted fluo-
rene derivatives with acceptable regioselectivity. Presently,
preparation of substituted fluorenes relies mainly on the
Friedel–Crafts-type reaction with rather low selectivity.[4] On
[a] J. Kim, S. H. Park, Prof. Dr. S. Chang
Molecular-Level Interface Research Center and Department of
Chemistry
À
with a synthetic application of a base-labile Cl Fmoc spe-
cies.[9]
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 305-701 (Republic of Korea)
Fax : (+82)42-350-2810
Results and Discussion
E-mail: sbchang@kaist.ac.kr
[b] Y. Ohk, Prof. Dr. Y. Jung
Graduate School of EEWS (WCU) and Department of Chemistry
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 305-701 (Republic of Korea)
Fax : (+82)42-350-1710
Methyl 2-(biphenyl-2-yl)diazoacetate (1d) was employed as
a model substrate to optimize the cyclization reaction
(Table 1).[10] While the cyclization took place readily at
1008C to afford methyl fluorene-9-carboxylate (2d) in 72%
yield (Table 1, entry 1), no conversion was observed at room
temperature in the absence of metal species (entry 2).
E-mail: ysjn@kaist.ac.kr
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201100142.
2040
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Chem. Asian J. 2011, 6, 2040 – 2047

Table 1. Optimization of the cyclization reaction.
when biaryldiazoacetates bearing electron-deficient substitu-
ents were employed (entries 7–9). In addition, the cycliza-
tion proceeded smoothly in congested substrates, which
have ortho-substituents (entries 10–11). Not only monosub-
stituted fluorenes but also disubstituted derivatives could be
readily obtained in satisfactory yields under the catalytic
conditions (entries 12 and 13). The reaction conditions were
compatible with a broad range of functional groups such as
acetyl, cyano, nitro, and halides.[13] Interestingly, when con-
densed polyaryldiazoacetates were subjected to the optimal
conditions, the annulation took place also efficiently to
afford the corresponding polyaromatic fluorene derivatives
in high yields (entries 14–16).
As it is generally observed that metal-catalyzed protocols
afford notable advantages such as milder conditions and
higher selectivity when compared to the corresponding
metal-free thermal conditions,[14] we decided to compare the
regioselectivity outcomes between these two procedures in
the present cyclization (Table 3). It was observed that while
the thermolytic cyclization took place at high temperatures
over 1008C, the resulting regioselectivity was poor, and only
provided a mixture of two isomers (4 and 5) in a similar
ratio.
Entry[a]
Catalyst
mol%
Solvent
T [oC]
Yield [%][b]
1
2
3
4
none
none
–
–
3
3
toluene
toluene
toluene
toluene
DCE
100
25
25
25
25
25
25
25
25
25
25
72
<1
64
93
98
7
<1
78
80
39
10
A
(tfa)4]
E
5
N
1
6
7
8
9
10
t
5
toluene
toluene
toluene
DCE
Cu
Cu
Cu
N
3
10
11
AlCl3
BF3·Et2O
10
10
DCE
DCE
[a] Reaction conditions: 1d (0.3 mmol) in indicated solvent (1.5 mL).
[b] Yield as determined by 1H NMR (internal standard: 1,1,2,2-tetra-
chloroethane).
Among a range of rhodium species examined, which have
been known to be effective for the decomposition of diazo
compounds, dimeric catalysts [Rh2ACHTUNGTRNENUG(tfa)4] and [Rh2HCATUNGTNER(NUGN OAc)4]
À
(tfa=trifluoroacetic acid) turned out to be most efficient for
the conversion of 1d into 2d (entries 3–5). In particular, an
excellent yield was attained by using 1 mol% of [Rh2
Isomer 4 was formed from the C C bond formation at
the 6’-position of the substituted arene ring, whereas 5 arose
from the reaction at the 2’-position. In sharp contrast, the
metal-mediated ring-closure procedure gave excellent regio-
control, and favored 4 over 5, presumably owing to steric
reasons. For example, a thermolytic reaction of methyl 2-
diazo-2-(3’-methoxybiphenyl-2-yl)acetate (3a) provided an
almost equal mixture of two regioisomeric fluorenes (4a/5a,
49:51) at 1008C, whereas the rhodium- or copper-catalyzed
cyclization proceeded smoothly with an excellent level of se-
lectivity at ambient temperatures (4a/5a, >95:5, entry 1).[15]
It was observed that the regioselectivity varied depending
on the substrate type and metal species employed. For ex-
ample, in the reaction of methyl 2-(3’-methylbiphenyl-2-yl)-
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
CTHUNGTRENNUNG
While Lewis acids such as AlCl3 or BF3·Et2O displayed poor
catalytic activity under the same conditions (entries 10 and
11),[12] Brønsted acids such as trifluoroacetic acid or acetic
acid were ineffective.
To investigate the scope of the catalytic fluorene synthe-
sis, the optimized conditions were next applied to various
biaryldiazoacetates, by altering the electronic and/or steric
environment (Table 2). In general, while the fluorene prod-
ucts were obtained in acceptable yields under both catalytic
conditions, 1 mol% of rhodium catalyst provided higher
yields in general when compared to 3 mol% of the copper
species, however, a full explanation is not clear at this stage.
The difference in the reaction efficiency between rhodium
and copper catalytic conditions was pronounced especially
diazoacetate (3b), it was observed that while [Rh
or Cu(OTf)2 catalysts provided only moderate to poor regio-
selectivity, the use of the [Rh2A(tfa)4] catalyst resulted in sig-
nificantly improved selectivity (4b/5b, 84:16), albeit in
lower yield (entry 2).[6b] When substrates bearing electron-
withdrawing substituents at the meta-position (3c–3 f) were
2ACHTUNGTRENNUNG(OAc)4]
AHCTUNGTRENNUNG
CTHUNGTRENNUNG
employed, the [Rh
(OAc)4] catalyst led to higher product
yields when compared to that of the CuAHCUTNGTRENNUNG
(OTf)2 species,[6g]
but slightly better regioselectivity was achieved with the
latter species (entries 3–6). A similar trend in regioselectivi-
ty was also observed with disubstituted substrates (e.g., 3g,
entry 7). In addition, the reaction conditions were highly
compatible to all functional groups examined.
Abstract in Korean:
To obtain mechanistic clues for the present cyclization re-
action, a series of isotope and scrambling studies were first
performed. When a deuterated substrate [D5]-1d was sub-
jected to the catalytic conditions, a fluorene carboxylate
[D5]-2d was obtained with 98% incorporation of deuterium
at the C-9 position (Scheme 1). In addition, no intermolecu-
lar scrambling of deuterium was detected (Scheme 1), there-
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Y. Jung and S. Chang et al.
FULL PAPERS
Table 2. Metal-catalyzed synthesis of fluorene carboxylates.
Entry[a]
Product
Yield [%][b]
Rh
Entry[a]
Product
Yield [%][b]
Rh
Cu
86
Cu
36
1
92
86
97
9
84
2
3
86
96
10
11
83
72
80
50
4
5
92
83
81
77
12
13
76
77
72
52
6
7
8
62
66
85
61
61
48
14
15
16
97
74
95
80
45
63
[a] Reaction conditions: 1 (0.3 mmol), [Rh2ACHTNUGTRENN(UG OAc)4] (1 mol%) or CuHCATUNGTREN(NUGN OTf)2 (3 mol%) in 1,2-dichloroethane (1.5 mL). [b] Isolated yields.
by suggesting that a hydrogen- transfer step (1,2-hydrogen
shift) takes place in an intramolecular manner during the
course of the reaction.[6g]
As expected, no significant intermolecular kinetic isotope
effects (KIE) were observed in a competition experiment
between substrates 1c and [D5]-1c (Scheme 2).[16,17]
In addition, a kinetic profile study using two substrates,
which have electron-donating and electron-withdrawing sub-
stituents was also carried out. Under the rhodium-catalyzed
conditions, a para-methoxy-substituted biaryldiazoacetate
(1a) was cyclized in a higher initial rate when compared to
a para-nitro-substituted substrate (1i) (68% vs 19% conver-
sion after 5 min, respectively),[17] thus implying that a cation-
ic intermediate, which could be formed by an electrophilic
aromatic attack to an in situ generated metal carbenoid, is
involved as a key species to influence the overall reaction
rate (see the Supporting Information for details)
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Regioselective Synthesis of Fluorenes
ranted.[21] Although the cycloaddition pathway
was previously suggested as an acceptable route
to form of 6,6-bicyclic systems through 3,5-bicy-
clic intermediates starting from 1-diazo-4-phe-
nylbutan-2-one,[19c] the relative instability of pre-
sumed 3,4-bicyclic intermediates that should be
formed in the course of the 5,6-bicyclic fluorene
Table 3. Regioselective synthesis of fluorene derivatives.
Entry[a]
Biaryldiazoacetates Yield [%][b] Ratio
[4:5][c]
thermal:
[Rh2A(OAc)4]: 99 (97)
Cu(OTf)2
99 (96)
49:51
96:4
95:5
1
3a
3b
3c
3d
3e
3 f
3g
G
CHTUNGTRENNUNG
E
:
99 (96)
97
thermal:
[Rh2A
[Rh2A(tfa)4]:
Cu(OTf)2:
46:54
47:53
84:16
64:36
G
CHTUNGTERNN(UNG OAc)4]: 90
2
3
4
5
6
7
R
C
33
82
AHCTUNGTRENNUNG
thermal:
[Rh2A
Cu(OTf)2:
99
61:39
84:16
99:1
N
CHTUNGTERNN(UNG OAc)4]: 94
N
78
thermal :
[Rh2A(tfa)4]:
Cu(OTf)2:
83
73
73
54:46
92:8
95:5
G
CHTUNGTRENNUNG
AHCTUNGTRENNUNG
thermal:
[Rh2A
Cu(OTf)2:
99
60:40
91:9
95:5
N
CHTUNGTERNN(UNG OAc)4]: 93
N
59
Scheme 1. Deuterium-labeling experiments. Incorporation of deuterium=
98%, incorporation of hydrogen=99%.
thermal:
[Rh2A
Cu(OTf)2:
85
67:32
95:5
95:5
N
CHTUNGTERNN(UNG OAc)4]: 70
N
32
thermal:
[Rh2A
Cu(OTf)2:
93
72:28
92:8
94:6
N
CHTUNGTRENNUNG
production, if it follows the rearrangement-involved rearo-
matization pathway, makes this possibility less likely. In con-
trast, the electrophilic aromatic substitution pathway is
strongly endorsed by the experimental observations: lack of
primary KIE and the substituent-depending reaction profile.
In addition, the observed low reactivity in the Lewis acid
catalyzed reaction (Table 1, entries 10 and 11) could also
support this pathway.[20]
[a] Thermolytic conditions: 3 (0.3 mmol) in toluene (1.5 mL) under argon
at 1008C for 1 h; metal-catalyzed conditions: 3 (0.3 mmol), Rh (1 mol%)
or Cu (3 mol%) in 1,2-dichloroethane (1.5 mL) under argon at 258C for
1 h. [b] Yield as determined by 1H NMR (isolated yield in parenthesis).
1
[c] Determined by H NMR integration of crude mixture.
Three possible pathways can be surmised in the aromatic
carbenoid insertion for the fluorene ring formation. The
Although other possibilities, in particular, the cycloaddi-
tion pathway, cannot be completely excluded at the present
stage. The mechanistic proposal of the fluorene ring forma-
tion using rhodium as a catalyst is depicted in Scheme 3. In
the initial step, rhodium(II)-mediated decomposition of biar-
yldiazoacetate 1 generates a rhodium carbenoid species 6,[22]
which will then be readily attacked by aromatic p electrons
to induce a zwitterionic intermediate 7. It has been pro-
posed that the subsequent 1,2-hydrogen shift from an aryl
first possible path is envisioned to proceed through direct
[18]
À
C H activation (s-bond methathesis). The second plausi-
ble one is a rearomatization-involved rearrangement of con-
densed polycycles via equilibrated intermediates between
norcaradiene and cycloheptatriene, which can be produced
from the intramolecular cycloaddition of a metal carbenoid
and a susbtituted arene ring.[19] In addition, an intramolecu-
lar electrophilic aromatic sub-
stitution is another plausible
route, which proceeds via a
zwitterionic intermediate.[20]
Among those possibilities,
the lack of primary KIE sug-
À
gests that the direct C H acti-
vation pathway cannot be war-
Scheme 2. KIE study.
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Y. Jung and S. Chang et al.
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ture (Scheme 4).[18h,27] Figure 1 compares the energy profile
of the carbenoid insertion pathways for a MeO-substituted
biaryldiazoacetate, which takes place through path A or B,
along with the optimized structures at each stationary point.
Herein, path A and B represent presumed reaction routes,
which involve an electrophilic aromatic insertion at the 6’-
and 2’-postion of the substituted arene ring, thus leading to
isomeric products 4a and 5a, respectively. The first step of
the reaction for both paths is to form a metastable metal–
ligand complex (IM1) between the reactant and the rhodium
catalyst. A stable rhodium carbenoid (IM2) is then generat-
ed upon the release of nitrogen in the subsequent step
(TS1), a favorable process that is entropically driven.[28] The
next step is an electrophilic aromatic addition to form a new
À
intramolecular cyclic C C bond (IM3). The subsequent in-
tramolecular hydrogen transfer and release of a rhodium
catalyst occurs concertedly to yield the final product with
the regeneration of the catalyst for the next cycle.
Scheme 3. Proposed mechanism.
carbon to the carbon center takes place upon the rearomati-
zation of the ring system to deliver the desired fluorene
product 2d.
The above-mentioned mechanistic consideration is consis-
tent with the observed H/D scrambling and intermolecular
KIE data in the previous section, and is also similar to an
À
To further understand the catalysis and regioselectivity in
the present metal-catalyzed fluorene synthesis, a density
functional theory (DFT) study was performed by employing
the Q-chem quantum chemistry package.[23] The density
functional theory formalism with B3LYP functional was
used to locate stationary points on the potential energy sur-
faces.[24] The potential energy surfaces were characterized,
whether they are minima or transition states, by computing
the Hessian. Intrinsic reaction coordinate (IRC) calculations
were performed to connect the two stationary geometries
from the transition states.[25] Calculating heavy atoms is
computationally more difficult than for the lighter atoms;
this could be due to a large number of electrons and/or non-
negligible relativistic effects. In the present calculations, we
used the Stuttgart relativistic small core effective core-po-
tential (SRSC-ECP)[26] basis for the rhodium atom to ad-
dress the latter two difficulties, while using 6-31G* all elec-
tron standard basis for all other main group elements. The
SRSC basis for rhodium offers a greater flexibility in the va-
lence shell (6s,5p,3d) compared to LANL2DZ (3s,3p,2d).
analogous rhodium-catalyzed aromatic C H insertion reac-
tion in the literature.[6g] Catalytic reaction measurements for
methyl- and trifluoromethyl-substituted biaryldiazoacetates
were also calculated (see the Supporting Information) to ex-
hibit similar energy profiles when compared to that of the
À
methoxy group, in which cyclic C C bond formation is a re-
gioselective step.[17] As previously calculated, the relative ac-
À
tivation barrier heights for the C C bond formation in paths
A and B, that should be responsible for the observed out-
come of regioselectivity, suggest that the methoxy-substitu-
ent would yield a higher selectivity towards 4, consistent
with the experimental trend. Due to the spatial proximity,
susbtituents at the meta-position make the 2’-position more
À
sterically hindered during the course of the C C bond for-
mation when comapred to the 6’-position, thus favorably
leading to path A over path B. This intrepretation qualita-
tively agrees with the experimental results described above.
Fluorene derivatives obtained by the present study can
have various synthetic utilities.[29] Indeed, a highly interest-
ing example is demonstrated in Scheme 5. Diazoacetate 1e
bearing a chloro substituent was readily prepared in two
steps starting from 9 by Suzuki–Miyaura coupling to form a
biaryl linkage of 10 followed by a diazo-transfer reaction in
91% overall yield.[30]
The [Rh2ACHTUNGTRENNUNG(OAc)4] species was chosen in the present com-
putational approach owing to the high product yields and
the abundance of rhodium carbenoid chemistry in the litera-
The main reaction of the
rhodium-catalyzed cyclization
took place highly efficiently
(tons>1000) in multi-gram
scale to afford methyl 2-
chloro-9-fluorenecarboxylate
(2e) in 87% yield. Reduction
of the ester group of 2e and
then treatment of the resultant
alcohol with triphosgene af-
forded Cl FmocCl 11e,[31]
which was then employed for
À
Scheme 4. Regioselective paths A and B.
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Regioselective Synthesis of Fluorenes
Figure 1. Computed reaction pathways for the [Rh2ACHTNUTRGNE(UNG OAc)4]-catalyzed reaction of MeO-substituted biaryldiazoacetate for two different regioselective
paths A and B. The optimized structures along path A are shown for clarity. (Reaction profiles for the methyl- and trifluoromethyl-substituted biaryldia-
zoacetates are similar and summarized in the Supporting Information.)
Scheme 5. The synthetic pathway for protected aniline. DBU=1,8-diazabicyclo
DIBAL-H=diisobutylaluminum hydride.
ACHTUNGERTN[NUNG 5.4.0]undec-7-ene; p-ABSA=para-acetamido-benzenesulfonyl azide,
the in situ protection of 4-methoxybenzylamine, to provide
carbamate 12e in excellent overall yield (91% over 3 steps).
In a subsequent study, we compared the relative removal
efficiency of protecting groups (X=H and Cl), in which the
former has been most widely used as a facile protecting
group for amines and the latter one was prepared using our
present procedure (Table 4). As 11e bears an electron-with-
drawing chloro substituent, it was anticipated that deprotec-
tion of an amino group protected with 11e would be more
facile than the parent Fmoc group (X=H).[2b,c]
Although the degree of deprotection was not significantly
different between 12d and 12e when piperidine was used as
a deprotecting reagent (Table 4, entries 1–2), deprotection
of the latter compound was readily traced by the color
change during the course of the reaction. This result is sig-
nificant in that a visible deprotection procedure can be
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Y. Jung and S. Chang et al.
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Table 4. Comparison of deprotection between 12d and 12e.
evaporated under reduced pressure and the mixture was poured into
water followed by an extraction with additional CH2Cl2 (30 mL). The
combined organic layers were dried over MgSO4, filtered, evaporated in
vacuo, and the residue was purified by column chromatography on silica
gel to give methyl 2-(biaryl-2-yl)acetates.
General Procedure for the Preparation of Methyl 2-(biaryl-2-
yl)diazoacetates
Methyl 2-(biaryl-2-yl)diazoacetates were synthesized by a diazo-transfer
reaction from methyl 2-(biaryl-2-yl)acetates.[33] Yields were not opti-
mized. Methyl 2-(biaryl-2-yl)acetate (3 mmol) and p-ABSA (6 mmol,
2 equiv) were dissolved in THF (20 mL) under an argon atmosphere in a
dried 100 mL round bottomed flask. After 5 min, DBU (30 mmol,
10 equiv) was added. The reaction mixture was stirred for 12 h at 258C.
The solvent was evaporated, and the residue was dissolved in Et2O
(30 mL) and then washed with an aqueous KOH solution (5%). The
combined organic layers were dried over MgSO4, filtered, evaporated in
vacuo, and the residue was purified by column chromatography on silica
gel give the corresponding methyl 2-(biaryl-2-yl)diazoacetate.
Entry Deprotection Condi-
tions
t [min] Conv
12d [%][a]
Conv
12e [%][a]
1
Piperidine (10%)/
DMF
5
93
98
2
Piperidine (10%)/
DMF
10
99
99(98)[b]
3
4
Pyridine (25%)/DMF
Pyridine (25%)/DMF
30
60
<1
<1
72
99(99)[b]
[a] Conversion was determined based on the 1H NMR integration using
an internal standard (1,1,2,2-tetrachloroethane). [b] NMR yield of depro-
tected 4-methoxy-benzylamine. DMF=N,N-dimethylformamide.
General Procedure for the Synthesis of Fluorene Derivatives, Thermolytic
Conditions
Methyl 2-(biaryl-2-yl)diazoacetate (0.3 mmol) was dissolved in toluene
(1.5 mL) under an argon atmosphere in a dried 10 mL round bottomed
flask. The reaction mixture was stirred for 1 h at 1008C, diluted with
ethyl acetate (10 mL), and evaporated. The residue was purified by
column chromatography on silica gel to give the corresponding methyl
9H-fluorene-9-carboxylate.
À
eventually developed using Cl FmocCl 11e. On the other
hand, a more dramatic difference in the extent of deprotec-
tion was observed when pyridine was used as a deprotecting
reagent. While no conversion was observed for the reaction
of 12d with pyridine, complete deprotection was achieved
with 12e under otherwise identical conditions (entries 3–4).
Transition-Metal-Catalyzed Conditions
A catalyst (Rh: 1 mol%, Cu: 3 mol%) was dissolved in DCE (0.5 mL)
under an argon atmosphere in a dried 10 mL round bottomed flask.
Methyl 2-(biaryl-2-yl)diazoacetate (0.3 mmol, 1 equiv) in DCE (1.0 mL)
was added to the stirred solution. The reaction mixture was stirred for
1 h at 258C, diluted with ethyl acetate (10 mL), and evaporated. The resi-
due was purified by column chromatography on silica gel to give the cor-
responding methyl 9H-fluorene-9-carboxylate.
Conclusions
In summary, we have developed a regioselective and practi-
cal synthetic route to fluorene carboxylates using rhodium
or copper catalysts through the aromatic carbenoid insertion
of biaryldiazoacetates. The reaction is proposed to occur by
an intramolecular electrophilic aromatic substitution path-
way, which is supported by the KIE, scrambling result, and
the substituent effect on the reaction rate. The steric interac-
tion between substituents and metal catalysts becomes a key
factor to achieve high regioselectivity. A synthetic applica-
tion of a chlorine–fluorene derivative as a base-sensitive
protecting group for amines was demonstrated along with
the possibility of developing a visible traceable deprotection
procedure.
Acknowledgements
This research was supported by the Korea Research Foundation (KRF-
2008-C00024, Star Faculty Program) and MIRC (NRF-2010-0001957).
Y.J. acknowledges the support of this research by the WCU program
(R31-2008-000-10055-0) through the NRF.
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Experimental Section
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Received: February 12, 2011
Published online: May 12, 2011
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