Synthesis of fluorenes via the palladium-catalyzed 5-exo-dig annulation of o-alkynylbiaryls

Article abstract of DOI:10.1002/adsc.200800765

The direct palladium-catalyzed intramolecular hydro arylation of o-alkynylbiaryls proceeded in a highly stereoselective manner producing fluorenes 2, the products of 5-exo-dig cyclization, in excellent yields. The cascade intermolecular arylation, incorpo

Full text of DOI:10.1002/adsc.200800765

FULL PAPERS
DOI: 10.1002/adsc.200800765
Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig
Annulation of o-Alkynylbiaryls
Natalia Chernyaka and Vladimir Gevorgyana,*
a
Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607-7061, USA
Fax : (+1)-312-355-0836; phone: (+1)-312-355-3579; e-mail: vlad@uic.edu
Received: December 10, 2008; Revised: February 4, 2009; Published online: May 5, 2009
Dedicated to Prof. Armin de Meijere on the occasion of his 70th birthday.
Abstract: The direct palladium-catalyzed intramolec- tron-deficient benzene rings which, in combination
ular hydroarylation of o-alkynylbiaryls proceeded in with a substantial isotope effect observed, strongly
À
a highly stereoselective manner producing fluorenes supports a C H activation mechanism for the key
2, the products of 5-exo-dig cyclization, in excellent annulation step.
yields. The cascade intermolecular arylation, incor-
porated in this transformation, allowed for the effi-
cient synthesis of fully substituted fluorenes 12. Keywords: alkynes; annulations; arylation; C H ac-
These cyclizations proceed more rapidly with elec- tivation; palladium
À
Introduction
hydroarylation of alkynylbiaryls. The palladium-cata-
lyzed version of it was first reported by Fujiwara.[3]
Palladium-catalyzed annulation reactions serve as a The other transition metal-[4,5] and Lewis acid-cata-
powerful tool for the construction of fused polycyclic lyzed[6] versions of this reaction quickly emerged
aromatic and heteroaromatic compounds.[1] Activa- shortly after. Generally, this reaction proceeds via the
ꢀ
tion of the C C triple bond by p-philic metals, fol- Friedel–Crafts-type electrophilic aromatic substitution
lowed by cyclization with the adjacent aromatic ring, pathway and is most efficient with electron-rich aro-
proved efficient for construction of fused five- and matic rings. Thus, as reported by Fꢀrstner, o-alkynyl-
six-membered ring systems.[2] One of the representa- biaryls possessing an electron-rich aryl ring in the
tive examples of this approach is the intramolecular presence of transition metals undergo a facile intra-
Scheme 1.
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Natalia Chernyak and Vladimir Gevorgyan
FULL PAPERS
molecular hydroarylation reaction leading to the ex- this methodology to the cascade arylation of o-alkyn-
clusive or predominant formation of the phenan- ylbiaryls with aryl halides, followed by cyclization into
AHCTUNGTRENNUNG
threne frameworks via a 6-endo-dig carbocyclization the polysubstituted fluorenes (Scheme 1, C).
pathway (Scheme 1, A). In contrast, we have recently
found that employment of the neutral PdACTHNURGTNEUNG(OAc)2/d-i-
Prpf catalytic system triggered the exclusive 5-endo- Results and Discussion
dig cyclization leading to the fluorene derivatives
(Scheme 1, B). We have shown that this reaction is We were intrigued by the palladium-catalyzed intra-
most efficient with electron-neutral and electron-poor molecular hydroarylation of alkynylbiaryls that pro-
arenes.[7] In this paper, we discuss the previously com- ceeds under ligand-free acidic conditions and pro-
municated intramolecular hydroarylation of o-alkyn- duced predominantly 6-exo-dig cyclization products.
ACHTUNGTRENNUNGylbiaryls in more detail, as well as the extension of Initially, it was believed that this reaction proceeds
Table 1. Pd-catalyzed hydroarylation of o-alkynylbiaryls.[a]
#
Product
Time [h]/
Yield
#
Product
Time [h]/
Yield
#
Product
Time [h]/
Yield
[%][b]
[%][b]
[%][b]
1 2a
2 2b
3 2c
2.5/98
3.0/95
1.5/96
7
8
9
2g
2h
2i
4.0/95
1.0/93
0.5/98
13 2m
14 2n
15 2o
5.0/87
1.0/85
1.5/77
4 2d
5 2e
2.0/96
0.5/79
3.0/92
10 2j
11 2k
12 2l
3.0/93
3.0/94
4.0/89
16 2p
17 2q
18 2r
24/47
48/30
6.0/86
6 2f
[a]
Reaction conditions: 0.5 mmol of 1, 0.025 mmol of PdACTHNUTRGENNG(U OAc)2, 0.035 mmol of d-i-Prpf, 1 mL of toluene, 1208C.
Isolated yields.
[b]
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Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig Annulation
FULL PAPERS
[3]
À
via a C H activation path. However, recently an 5, 6, 7, 10, 16), NO2 (entry 12) CO2Me (entries 5 and
electrophilic substitution path for the key annulation 14) and CN (entry 8) were perfectly tolerated under
step of this transformation was unambiguously estab- these reaction conditions. It is worth mentioning that,
lished.[8] We hypothesized that switching from acidic in contrast to the reported intramolecular hydroaryla-
to neutral catalytic conditions may affect the mecha- tions of alkynes,[3–6,8] o-alkynylbiaryls possessing elec-
nism of this reaction. Accordingly, the cyclization of tron-deficient substituents (R2 =F, CF3, CO2Me) un-
o-alkynylbiaryl 1 under the acid-free conditions has derwent the carbocyclization reaction faster compared
been investigated. It was found that biaryl 1a in the to the biaryls bearing electron-neutral aryl rings. Al-
presence of catalytic amounts of PdACTHNUTRGNEUNG
(OAc)2/dppf in though no substituent effect at the alkyne moiety (R1)
toluene at 1208C underwent a facile 5-exo-dig cycliza- on the reaction yield was observed, biaryls bearing
tion to produce the fluorene 2a in 70% yield. Switch- electron-defficient alkynes reacted slightly faster than
ing to a bulkier 1,1’-bis(diisopropylphosphino)ferro- their non-activated analogues (entries 5, 8, 9, and 12).
cene (d-i-Prpf) led to even more efficient cyclization Most importantly, all cyclization reactions of 1a–r pro-
producing fluorene 2a virtually quantitatively ceeded with high cis-stereoselectivity, producing fluo-
(Table 1, entry 1).
renes 2a–r as single geometrical isomers.[9] It was
With these conditions in hand, we explored the found that, contrary to the previous reports on hydro-
generality of this transformation. Thus, a variety of o- arylations under acidic conditions,[3–6,8] cyclizations of
alkynylbiaryls possessing electron-neutral and, most biaryls containing electron-donating groups in the
surprisingly, electron-deficient aryl rings underwent presence of PdACTHNURGTNEUNG(OAc)2/d-i-Prpf proceeded substantial-
smooth 5-exo-dig carbocyclization to produce fluo- ly slower. Thus, the cyclization of o-alkynylbiaryl 1q,
renes 2a–j in good to excellent yields (Table 1). It was possessing methyl groups at the adjacent aromatic
found that a variety of substituents, such as F (entries, ring, was extremely slow, producing fluorene 2q after
48 h in 30% yield only (Table 1, entry 17). Likewise,
annulation of tolyl-substituted alkynylbiaryl 1s pro-
ceeded quite sluggishly. Initially, E-2s, the “normal”
stereoisomer of hydroarylation, was produced in trace
amounts. However, towards completion of the reac-
tion (20 h), increased amounts of Z-2s were produced,
suggesting that E/Z-isomerization under the prolong
heating (Scheme 2).[10]
Towards a better understanding of the mechanism
of this hydroarylation reaction, kinetic isotope effect
studies were performed. The experiments on the cycli-
zation of 3, together with its protio analogue 1b, and
5 revealed a substantial intermolecular (kH/kD =2.6)
and intramolecular (kH/kD =3.5) kinetic isotope effect
(Scheme 3). These data are in the range of the the
isotope effects found in the Pd-catalyzed arylations
[11]
À
proceeding via C H activation pathways. Based on
these observations, we propose the following mecha-
Scheme 2.
nism for this reaction (Scheme 4). According to the
Scheme 3.
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Natalia Chernyak and Vladimir Gevorgyan
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Scheme 4.
path a, upon the ortho-palladation of 1, the intermedi- herein, produces fluorenes with the alternative geom-
ate 8 is produced, which undergoes a migratory inser- etry of the double bond, thus strongly supporting the
tion to the triple bond to give a vinylpalladium spe- cis-cyclization pathway (Table 1, Scheme 4).
cies 9. Protiodepalladation of intermediate 9 produces
Encouraged by the successful hydroarylation of o-
fluorene 2 and regenerates the catalyst. Alternative alkynylbiaryls leading to the fluorene framework, we
pathway (path b) involves the formation of palladium envisioned the cascade intermolecular arylation/annu-
hydride species 10, which upon carbopalladation of lations of o-alkynylbiaryls with aryl halides as an at-
the triple bond produces intermediate 11. Consecutive tractive approach toward densely substituted fluo-
reductive elimination gives the desired fluorenone 2. renes. It should be mentioned that the Pd-catalyzed
However, this pathway is considered to be less likely arylation/annulation approach has been extensively
due to a substantial loss of the deuterium observed in explored by Larock for the synthesis of polycyclic ar-
the cyclization of 3.[12] The Friedel–Crafts-type mecha- omatic compounds.[13] However, the annulation step
nism, which potentially could account for the cycliza- in most of the reported transformations followed the
tion of 1, was ruled out based on both the higher pro- electrophilic path.[14] Consequently, we were eager to
pensity of the electron-deficient biaryls in this hydro- learn whether a possible cascade arylation/annulation
À
arylation reaction and the high values of the obtained reaction of o-alkynylbiaryls would follow the C H ac-
kinetic isotope effects. The observed stereoselectivity tivation reaction path. Accordingly, the transforma-
of reaction also contradicts with the electrophilic tion of different o-alkynylbiaryls 1, in the presence of
mechanism. It should be mentioned that, according to phenyl bromide, was studied under one of the typical
the literature reports,[3–6,8] the Friedel–Crafts cycliza- conditions for Pd-catalyzed arylation reactions.[14,15]
tion of biaryl 1 should proceed in a trans-fashion, re- Thus, cyclization of 1a produced a 58:42 mixture of
sulting in the formation of (Z)-fluorene (Scheme 5). the 5-exo-dig cyclization product 12 and the 6-endo-
However, the hydroarylation reaction, described dig adduct 13 in 90% combined yield (Table 2,
entry 1). Similarly, cyclization of o-alkynylbiaryls 1m,
1t, and 1u produced comparable mixtures of re-
gioisomers 12 and 13 (Table 2, entries 2–4). Notably,
arylation/annulation of alkyl derivative 1v was highly
regioselective, producing fluorene 12 as a sole reac-
tion product in good yield (entry 5). In contrast, cycli-
zation of 1w, possessing an ester functionality at the
alkyne moiety, exhibited reverse regiochemistry[16]
producing phenanthrene 13 selectively, albeit in low
yield (Table 2, entry 6).
Scheme 5.
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Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig Annulation
Table 2. Arylative cyclization of o-alkynylbiaryls.
FULL PAPERS
#
R
Substrate
12:13 Ratio[a]
Combined yield[b] [%]
1
2
3
4
5
6
Ph
1a
1m
1t
1u
1v
1w
58:42
72:28
51:49
53:47
100:0
0:100
90
70
65
60
70
30
p-OMeACHTUNTGRNE(UNG C6H4)
p-CNACHTUNTGRNE(UNG C6H4)
p-COMe
n-Bu
CO2Et
(C6H4)
[a]
[b]
Product ratios determined by GC/MS analysis.
Isolated yields.
Next, we performed an optimization of the reaction much more selective cyclization of 1a into 12a. Ex-
conditions aiming at the development of a selective pectedly, performing reactions in the presence of
cascade arylation/annulation protocol towards 12 Pd(OAc)2/d-i-Prpf led to a more selective reaction. Fi-
AHCTUNGTRENNUNG
(Table 3). Aryl-substituted 1a, which produced nearly nally, use of this catalyst system in the presence of
equal amounts of regioisomeric products (Table 2), DABCO allowed for obtaining 12a as a sole regioiso-
was chosen for optimization studies. It was found that mer in nearly quantitative yield (Table 3).
employment of bidentate phosphine ligands caused
Table 3. Optimization of conditions for arylative cyclization of 1a.
#
[Pd] source
Ligand
Base
Temperature
12a:13a Ratio[a]
Yield of 12a [%][b]
1
2
3
4
5
6
7
8
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
Pd
N
dppp
dppe
KOAc
KOAc
KOAc
KOAc
KOAc
KOAc
Cs2CO3
Et3N
120
120
120
100
100
120
120
120
120
120
120
120
120
100
110
110
110
120
–
–
–
0
0
0
10
12
12
0
45
60
31
20
30
20
70[c]
81
80
95
89[d]
Ph2P
N
dppf
90:10
90:10
95:5
–
d-t-Bupf
d-i-Prpf
d-i-Prpf
d-i-Prpf
d-i-Prpf
d-i-Prpf
d-iPrpf
d-i-Prpf
d-i-Prpf
d-i-Prpf
dppf
99:1
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
9
EtN
EtN
EtN
EtN
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
10
11
12
13
14
15
16
17
18
PdCl2
Pd(dba)2
PdCl2A(CH3CN)2
(OAc)2
(OAc)2
(OAc)2
(OAc)2
(OAc)2
(OAc)2
G
Pd
Pd
Pd
Pd
Bu4NBr
DABCO
DABCO
DABCO
DABCO
DABCO
d-t-Bupf
d-i-Prpf
d-i-Prpf
Pd
Pd
ACHTUNGTRENNUNG
ACHTUNGTRENNUNG
[a]
[b]
[c]
[d]
Product ratios determined by GC/MS analysis.
Yield determined by GC/MS analysis.
Yield after 24 h.
Isolated yield after 6 h.
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Table 4. Arylative cyclization of o-alkynylbiaryls.
#
Substrate
Product
Time
[h]/
#
Substrate
Product
Time
[h]/
Yield
[%]
Yield
[%]
1 1a
12a
12b
6/89
9/86
7
8
1y
1c
12g
12h
10/76
2 1m
4.5/88
3 1x
12c
12d
24/81
12/84
9
1i
12i
12j
6/85
4 1b
10 1z
8/86[c]
5 1o
12e
12f
12/86
12/85
11 1g
12k
12l
8/89[c]
6 1o
12 1m
12/80[c]
[a]
Reaction conditions: 0.5 mmol of 1, 0.025 mmol of PdACTHNUTRGENNG(U OAc)2, 0.035 mmol of d-i-Prpf, 1 mL of toluene, 1208C.
Isolated yields after recrystalization.
Toluene was used as a solvent.
[b]
[c]
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Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig Annulation
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After the efficient conditions for cascade arylation
Although the results in Table 4 indicate faster reac-
of 1 into 12 had been identified, the generality of this tion of biaryls possessing electron-withdrawing sub-
transfromation was examined (Table 4). It was found stituents at the adjacent phenyl ring (entries 1, 7, and
that the cascade arylation/annulation appeared to be 8), we found clarification of this question quite impor-
quite general with respect to both o-alkynylbiaryl and tant and thus set up a competitive reactivity studies
aryl halide used producing fluorenes 12 in high yields. (Figure 1). It was found that, at early stage of the re-
Introduction of electron-withdrawing substituents at action (ca. 25% conversion), MeO-containing 1y re-
either of reactants usually slightly facilitated the reac- acted about 1.5 times slower and CF3-containing 1c
tion (entries 8, 9, 10, and 11), whereas more electron- 1.4 times faster than the unsubstituted substrate 1a
rich substrates reacted somewhat slower (entries 2, 4, (Figure 1). This trend, like that in the hydroarylation
and 7). Pyridine-containing substrate 1o reacted com- reaction (vide supra), strongly contradicts with possi-
parably well producing heteroaryl-substituted fluo- ble electrophilic character of the cyclization step.[3–6,8]
renes 12d,e (entries 5, 6). The reaction was substan- Furthermore, the intermolecular deuterium/hydrogen
tially slower with sterically more hindered 1x, possess- isotope effect studies of the cascade arylation of 1a
ing a methyl group at the ortho-position (entry 3).
and its deuteriated analogue with phenyl bromide re-
vealed a profound isotope effect of 5.2 (Scheme 6).
This value is in a good agreement with the reported
data of the isotope effect in the Pd-catalyzed aryla-
[11]
À
tions proceeding via a C H activation mechanism.
Based on the above-mentioned results, we propose
the following rationale for the Pd-catalyzed cascade
arylation/annulation of o-alkynylbiaryls 1 into fluo-
renes 12 (Scheme 7). ArPdX, upon regioselective car-
bopalladation of triple bond[17] of 1, produces a vinyl-
palladium species 14. The latter, upon a direct[18] or a
ligand-assisted[19] C H activation (15) with subse-
À
Figure 1.
quent loss of HX produces the palladacycle 17. Re-
Scheme 6.
Scheme 7.
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ductive elimination of 17 furnishes the fluorene prod- preference of this catalytic system for 5-exo-dig reac-
uct 12 (Scheme 7, path a). Alternatively, the vinylpal- tion pathway.
ladium species 14 may undergo an elecrophilic aro-
matic substitution (16) to give palladacycle 17. How-
ever, on the basis of the substantial isotope effect Conclusions
values and higher propensity of electron-deficient
arenes towards cyclization (vide supra), this path was In conclusion, we have developed a set of methodolo-
considered to be less likely. Although less plausible, a gies for efficient construction of fluorene framework
triple bond-coordinated[20,21] ArPdX (18) entity may from o-alkynyl biaryls in the presence of Pd
(OAc)2/d-
À
undergo a direct insertion into the C H bond to pro- i-Prpf catalytic system. The intramolecular hydroary-
duce a bis-arylpalladium species 19 (path b). Intramo- lation of o-alkynylbiaryls provides easy access to fluo-
À
lecular migratory insertion of either of the Ar Pd renes with defined geometry. Alternative intermolec-
bonds into the triple bond (20 or 17), followed by re- ular cascade arylation/annulation method allows for
ductive elimination, produces 12.
efficient synthesis of fluorenes, fully substituted at C-
We were intrigued to learn whether the observed 10. It was shown that, regardless of the substitution
exclusive 5-exo-dig annulation for this cascade reac- pattern, these methods proceed exclusively via a 5-
tion is specific for the PdACHTUNRGTNEUNG(OAc)2/d-i-Prpf catalytic exo-dig cyclization motif. Mechanistic studies, includ-
system. In other words, what would happen if, by ing product and hydrogen/deuterium isotope effect
À
design, the vinylpalladium intermediate of type 14 studies, strongly support a C H activation path for
would have a choice to cyclize into 5- and 6-mem- the key annulation step in both transformations.
bered ring? To this end, a bis-biphenyl alkyne 21 was
synthesized. It was reasoned that, upon carbopallada-
tion of the triple bond, a vinylpalladium intermediate
22 would form. It can undergo a C H insertion into
the adjacent phenyl ring to form the pallacycle 23,
Experimental Section
À
NMR spectra were recorded on Bruker Avance DRX-500
which, after reductive elimination, would produce the (500 MHz) or DPX-400 instruments. (+) and (À) represent
positive and negative signals in 13C DEPT-135 experiments.
GC/MS analysis was performed on a Hewlett Packard
Model 6890 GC interfaced to a Hewlett Packard Model
5973 mass selective detector (15 mꢂ0.25 mm capillary
column, HP-5MS). HPLC analysis was performed using a
Gilson 321 pump interfaced with a Gilson Holochrome vari-
able band UV detector tuned for 254 nm. A Chiralcel OD-
H column (250ꢂ4.6 mm) was used for chiral HPLC analysis.
fluorene derivative 24. Alternatively, 22, via a well-
precedented double bond isomerization,[22] may form
À
25, which is set for an insertion into the C H bond of
a distinct aryl ring to produce 26, and, upon reductive
elimination, the phenanthrene derivative 27
(Scheme 8). The experiment showed that, upon stan-
dard reaction conditions, the fluorene 24 was formed
as a single reaction product, thus supporting a strong
Column chromatography was carried out employing Silicy-
Scheme 8.
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Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig Annulation
FULL PAPERS
cle Silia-P Flash silica gel (40–63 mm). Precoated silica gel
plates F-254 were used for thin-layer analytical chromatog-
raphy. Anhydrous solvents were purchased from Aldrich
and stored over calcium hydride. Alkynes and metal cata-
lysts were commercially available and purchased from Al-
drich, Strem Chemicals Inc. or Acros Organics, or synthe-
sized via known literature procedures.
8.07 Hz, 2H), 7.12 (d, J=7.89 Hz, 2H), 2.35 (s, 3H);
13C NMR (126 MHz, CDCl3): d=142.5, 140.3, 138.8, 133.3
(+), 131.3 (+), 130.3 (+), 129.9 (+), 129.5 (+), 129.3 (+),
129.1 (+), 128.7 (+), 128.5, 124.5, 122.4, 122.0, 121.2, 119.5,
93.7, 87.1, 21.5 (+).
3-{[4’-(Trifluoromethyl)biphenyl-2-yl]ethynyl}pyridine
1
(1o): H NMR (500 MHz, CDCl3): d=8.57 (s, 1H), 8.52 (d,
J=5.68 Hz, 1H), 7.67–7.80 (m, 4H), 7.55–7.60 (m, 1H),
7.38–7.50 (m, 3H), 7.21–7.29 (m, 2H); 13C NMR (126 MHz,
CDCl3): d=152.0 (+), 148.7 (+), 144.0, 142.6, 138.1 (+),
133.2 (+), 129.7 (+), 129.5 (+), 129.2 (+), 127.9 (+), 124.9
(+), 123.2, 123.0, 121.0, 91.9, 89.3.
General Procedure Synthesis of o-Alkynylbiaryl
Compounds 1a–z (Table 1)
A round-bottom flask containing a stirring bar was charged
with (Ph3P)2PdCl2 (70.1 mg, 0.1 mmol), arylboronic acid
(2.6 mmol), o-alkynylaryl bromide (2 mmol) and Na2CO3
(424 mg, 4 mmol). The flask was sealed with rubber septum,
evacuated and backfilled with argon. Toluene (10 mL) was
added through the septum via syringe together with EtOH
(5 mL) and water (5 mL). The reaction mixture was placed
into 708C preheated oil bath and heated at this temperature
for 1 to 3 h until judged complete by GC/MS analysis. The
content was cooled down to room temperature, diluted with
10 mL of EtOAc and 10 mL of water and transferred into a
separatory funnel. The organic layer was separated, washed
with water (2ꢂ20 mL), dried over MgSO4. The solvent was
evaporated under reduced pressure and resulting residue
was purified by column chromatography on a silica gel with
hexanes or 20:1 hexanes/DCM system to afford the o-alk-
Pd-Catalyzed Cyclization of o-Alkynylbiaryls;
Representative Procedure
An oven-dried 3-mL Wheaton vial containing a stirring bar
was charged with
1
(0.5 mmol), PdACTHUNGRETNNU(G OAc)2 (5.6 mg,
0.025 mmol) and 1,1’-bis(di-iso-propylphosphino)ferrocene
(146 mg, 0.035 mmol) under an N2 atmosphere. Dry toluene
(1 mL) was added and the reaction vessel was capped with
pressure screw cap. The reaction mixture was heated at
120 8C for 2 h (when judged complete by GC/MS analysis).
The resulting mixture was cooled down to room tempera-
ture and filtered through a short SiO2 plug with the aid of
DCM. The filtrate was concentrated under reduced pressure
and the residue was purified by chromatography on a silica
gel column (20:1 hexanes/DCM) affording the benzylidene-
9H-fluorene.
ACHTUNGTRENNUNGynylbiaryl.
2-[(4-Methylphenyl)ethynyl]-4’-(trifluoromethyl)biphenyl
(1d): 1H NMR (500 MHz, CDCl3): d=7.75–7.83 (m, 2H),
7.71 (s, 2H), 7.67 (d, J=7.52 Hz, 1H), 7.34–7.47 (m, 3H),
7.17–7.23 (m, 2H), 7.12 (s, 2H), 2.35 (s, 3H);13C NMR
(126 MHz, CDCl3): d=144.2, 142.2, 138.6, 132.9 (+), 131.2
(+), 129.7 (+), 129.3 (+), 129.1 (+), 128.5 (+), 127.8 (+),
124.8 (+), 121.9, 120.0, 93.1, 88.0, 21.5 (+).
9-Benzylidene-9H-fluorene (2a):[23] 1H NMR (500 MHz,
CDCl3): d=7.81 (1H, d, J=7.52 Hz), 7.70–7.77 (4H, m),
7.60 (4H, s), 7.48 (3H, t, J=7.43 Hz), 7.38–7.44 (3H, m),
7.30–7.38 (3H, m), 7.08 (1H, dt); 13C NMR (126 MHz,
CDCl3): d=141.27, 139.50, 139.21, 136.92, 136.57 (+), 136.50
(+), 129.28 (+), 128.56 (+), 128.23 (+), 128.04 (+), 127.29
(+), 127.00 (+), 126.68 (+), 124.43 (+), 120.26 (+), 119.73
(+), 119.61 (+).
5-Fluoro-2-methyl-2’-(4-methylphenyl)-ethynylbiphenyl
(1f): 1H NMR (500 MHz, CDCl3): d=7.64 (dd, J=6.60,
1.65 Hz, 1H), 7.33–7.42 (m, 3H), 7.31 (dd, J=7.15, 1.65 Hz,
1H), 7.16 (s, 3H), 7.04–7.11 (m, 3H), 2.38 (s, 3H), 2.33 (s,
3H);13C NMR (126 MHz, CDCl3): d=159.0, 157.1, 138.4,
138.2, 132.8, 132.4 (+), 132.1 (+), 131.3 (+), 130.1 (+), 129.8
(+), 129.7 (+), 129.0 (+), 127.9 (+), 127.6 (+), 123.1, 120.3,
115.3 (+), 115.1 (+), 92.5, 88.1, 21.5 (+), 20.0 (+).
3’,5’-Difluoro-2-[(4-methylphenyl)ethynyl]biphenyl (1g):
1H NMR (500 MHz, CDCl3): d=7.65 (d, J=6.97 Hz, 1H),
7.34–7.44 (m, 3H), 7.27 (s, 2H), 7.20–7.25 (m, 2H), 7.14 (s,
2H), 6.85 (s, 1H), 2.36 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=163.6 (d, J=12.9 Hz), 161.6 (d, J=12.9 Hz),
143.7, 141.2, 138.6, 133.0, 132.8 (d, J=90.6 Hz, +), 131.6
(+), 131.2 (+), 129.2 (+), 128.5 (+), 128.0, 120.9 (d, J=
232.1 Hz), 112.4 (d, J=25.9 Hz, +), 102.7 (t, J=25.4 Hz, +),
93.5, 87.8, 21.5 (+).
9-(4-Methylbenzylidene)-9H-fluorene (2b):[24] 1H NMR
(500 MHz, CDCl3): d=7.80 (d, J=7.34 Hz, 1H), 7.73 (d, J=
7.52 Hz, 2H), 7.68 (s, 2H), 7.51 (s, 2H), 7.36–7.41 (m, 1H),
7.30–7.36 (m, 2H), 7.28 (s, 3H), 7.06–7.12 (m, 1H), 2.45 (s,
3H); 13C NMR (126 MHz, CDCl3): d=141.17, 139.63,
139.08, 138.00, 136.64 (+), 135.99 (+), 133.87 (+), 129.28
(+), 129.23 (+), 128.39 (+), 128.03 (+), 127.54 (+), 126.93
(+), 126.61 (+), 124.38 (+), 120.17 (+), 119.68 (+), 119.55
(+), 21.46 (+).
(9E)-9-Benzylidene-2-(trifluoromethyl)-9H-fluorene (2c):
1H NMR (500 MHz, CDCl3): d=8.03 (1H, s), 7.76–7.83
(3H, m), 7.47–7.52 (2H, m), 7.41–7.46 (1H, m), 7.35–7.39
(1H, m), 7.13–7.18 (1H, m); 13C NMR (126 MHz, CDCl3):
d=142.09, 139.81, 139.69, 137.11, 136.27, 135.42, 129.23,
129.03 (+), 128.82 (+), 128.66 (+), 128.46 (+), 127.81 (+),
125.07 (+), 125.04 (+), 124.53 (+), 120.44 (+), 119.69 (+),
117.32 (+); HR-MS (EI): m/z=322.09712, calcd. for
C21H13F3: 322.09694.
4-[3’,5’-Bis(trifluoromethyl)biphenyl-2-yl]ethynylbenzoni-
1
trile (1h): H NMR (500 MHz, CDCl3): d=8.12 (s, 2H), 7.93
(s, 1H), 7.73 (s, 1H), 7.59 (s, 2H), 7.50–7.56 (m, 1H), 7.48
(s, 3H); 13C NMR (126 MHz, CDCl3): d=142.2, 140.8, 140.4,
133.7 (+), 132.0 (+), 131.8 (+), 131.6 (+), 131.4 (+), 129.8
(+), 129.5 (+), 128.7, 127.4, 124.4, 121.4 (+), 120.7 (+),
118.5 (+), 118.4 (+), 111.9 (+), 92.0, 91.5 (+).
(9E)-9-(4-Methylbenzylidene)-2-(trifluoromethyl)-9H-flu-
orene (2d): 1H NMR (400 MHz, CDCl3): d=8.02 (s, 1H),
7.70–7.85 (m, 4H), 7.63 (d, 1H), 7.51 (d, J=7.89 Hz, 2H),
7.36 (t, J=7.45 Hz, 1H), 7.29 (d, J=7.75 Hz, 2H), 7.16 (t,
J=7.60 Hz, 1H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3):
d=141.94, 139.81, 139.73, 138.55, 137.20, 134.89 (+), 131.75,
129.34 (+), 129.27 (+), 127.74 (+), 124.87 (+), 124.48 (+),
2-(4-Methylphenyl)ethynyl-3’,5’-bis(trifluoromethyl)bi-
1
phenyl (1k): H NMR (500 MHz, CDCl3): d=8.16 (s, 2H),
7.91 (s, 1H), 7.70 (s, 1H), 7.40–7.48 (m, 3H), 7.23 (d, J=
Adv. Synth. Catal. 2009, 351, 1101 – 1114
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1109

Natalia Chernyak and Vladimir Gevorgyan
FULL PAPERS
120.39 (+), 119.64 (+), 117.23 (+), 21.48 (+); HR-MS (EI):
m/z=336.1128, calcd. for C22H15F3: 336.1126.
9-(4-Methylbenzylidene)-1,3-bis(trifluoromethyl)-9H-fluo-
rene (2k): 1H NMR (400 MHz, CDCl3): d=8.22 (s, 1H),
8.16 (s, 1H), 7.90 (s, 1H), 7.78 (d, J=7.60 Hz, 1H), 7.39–
7.48 (m, 3H), 7.32–7.39 (m, 1H), 7.27–7.32 (m, 2H), 7.12 (s,
1H), 2.46 (s, 3H); 13C NMR (101 MHz, CDCl3): d=142.7
(s), 139.2 (s), 138.8 (s), 138.0 (s), 138.0 (s), 137.9 (s), 137.8
(s), 137.2 (s), 133.9 (s), 133.8 (s), 129.5 (s), 128.9 (s), 128.5
(s), 128.2 (s), 124.8 (s), 122.4 (s), 121.8 (s), 119.7 (s), 119.6
(s), 21.5 (s); HR-MS (EI): m/z=404.0998, calcd. for
C23H14F6: 404.1000.
Ethyl
(2E)-(1,3-difluoro-9H-fluoren-9-ylidene)acetate
(2e): 1H NMR (500 MHz, CDCl3): d=8.83 (d, J=7.89 Hz,
1H), 7.61 (d, J=7.34 Hz, 1H), 7.41–7.46 (m, 1H), 7.36–7.40
(m, 1H), 7.16 (dd, J=7.79, 2.11 Hz, 1H), 7.09 (d, J=
4.03 Hz, 1H), 4.35 (q, J=7.15 Hz, 2H), 1.40 (t, J=7.15 Hz,
3H); 13C NMR (126 MHz, CDCl3): d=166.3, 165.4, 163.3,
161.1, 159.1, 144.6, 140.5 (+), 135.8 (+), 130.6 (+), 129.2
(+), 128.8 (+), 120.0 (+), 119.3 (+), 103.4–103.9, 103.2 (+),
60.9 (+), 14.3 (+); HR-MS (EI): m/z=286.0813, calcd. for
C17H22F2O2: 286.0806.
9-(4-Nitrobenzylidene)-9H-fluorene
(2l):[25]
1H NMR
(400 MHz, CDCl3): d=8.32 (s, 2H), 7.66–7.85 (m, 5H), 7.60
(s, 1H), 7.42 (s, 2H), 7.35 (s, 2H), 7.07 (t, J=7.53 Hz, 1H);
13C NMR (101 MHz, CDCl3): d=147.2, 144.0, 141.8, 139.5,
138.9, 138.9, 135.8, 130.2 (+), 129.5 (+), 129.1 (+), 127.3
(+), 127.0 (+), 124.3 (+), 123.9 (+), 120.6 (+), 120.1 (+),
119.8 (+); HR-MS (EI): m/z=300.1025, calcd. for
C20H13NO2: 300.1025.
(9E)-4-Fluoro-1-methyl-9-(4-methylbenzylidene)-9H-fluo-
rene (2f): 1H NMR (500 MHz, CDCl3): d=7.93 (d, J=
7.52 Hz, 1H), 7.83 (s, 1H), 7.40 (s, 3H), 7.29 (s, 3H), 6.92–
7.10 (m, 3H), 2.68 (s, 3H), 2.46 (s, 3H); 13C NMR
(126 MHz, CDCl3): d=158.14 (+), 156.17 (+), 138.45
(+), 138.32 (+), 137.91 (+), 136.72 (+), 134.49 (s, 1C),
133.22 (+), 131.39 (s, 1 C), 131.34 (s, 1 C), 129.91 (s, 1 C),
129.56 (s, 1 C), 129.35 (s, 1 C), 128.95 (s, 1 C), 128.42 (s, 1
C), 126.42 (s, 1 C), 124.39 (s, 1 C), 114.48 (s, 1 C), 114.32 (s,
1 C), 21.81 (s, 1 C), 21.42 (s, 1 C); HR-MS (EI): m/z=
300.1313, calcd. for C22H17F: 300.1314.
(9E)-1,3-Difluoro-9-(4-methylbenzylidene)-9H-fluorene
(2g): 1H NMR (500 MHz, CDCl3): d=7.98 (d, J=2.75 Hz,
1H), 7.67 (d, J=7.52 Hz, 1H), 7.56 (d, J=7.89 Hz, 1H),
7.45 (d, J=7.89 Hz, 2H), 7.32 (dt, J=7.52, 0.92 Hz, 1H),
7.28 (s, 1H), 7.24 (dd, J=7.98, 2.11 Hz, 1H), 7.12 (dd, J=
15.22, 1.10 Hz, 1H), 6.78 (dt, J=11.00, 9.17, 2.20 Hz, 1H),
2.45 (s, 3H); 13C NMR (500 MHz, CDCl3): d=162.8 (dd, J=
248.8, 11.1 Hz), 159.4 (dd, J=253.4, 12.9 Hz), 142.9, 139.6,
138.2, 137.4 (+), 134.0 (+), 133.5 (+), 129.8 (+), 129.3 (+),
129.0 (+), 128.3 (+), 127.8 (+), 124.6 (+), 121.5 (+), 120.1
(+), 10.8 (+), 21.4 (+); HR-MS (EI): m/z=305.1142, calcd.
for C21H14F2: 305.1151.
4-(E)-[1,3-Bis(trifluoromethyl)-9H-fluoren-9-ylidene]me-
thylbenzonitrile (2h): 1H NMR (500 MHz, CDCl3): d=8.1
(d, J=13.9 Hz), 7.9 (s), 7.8 (s), 7.6–7.7 (m), 7.4 (s), 7.0–7.2
(m); 13C NMR (126 MHz, CDCl3): d=143.19, 141.74, 138.55,
138.24, 136.47, 135.92, 134.17, 132.64 (+), 129.53 (+), 129.39
(+), 128.56 (+), 124.81 (+), 122.09 (+), 120.17 (+), 119.84
(+), 118.51 (+), 112.33 (+), 91.16 (+); HR-MS (EI): m/z=
415.0798, calcd. for C23H11F6N: 415.0795.
(9Z)-3-(Trifluoromethyl)-9-[4-(trifluoromethyl)benzyli-
dene]-9H-fluorene (2i): 1H NMR (500 MHz, CDCl3): d=
7.94 (br. s., 1H), 7.82 (d, J=7.34 Hz, 1H), 7.72–7.79 (m,
4H), 7.68 (s, 2H), 7.45–7.51 (m, 2H), 7.38–7.45 (m, 1H),
7.34 (s, 1H); 13C NMR (126 MHz, CDCl3): d=141.9, 140.1,
138.8, 139.4, 138.1, 137.0, 130.6 (+), 129.5 (+), 129.1 (+),
128.1 (+), 127.3, 125.7 (+), 124.4 (+), 123.7 (+), 123.1,
122.9, 121.0 (+) 120.6 (+), 116.7 (+); HR-MS (EI): m/z=
390.0841, calcd. for C22H12F6: 390.0843.
4-(9H-Fluoren-9-ylidenemethyl)phenyl
methyl
ether
(2m):[25] 1H NMR (500 MHz, CDCl3): d=7.79 (d, J=
7.52 Hz, 1H), 7.73 (s, 3H), 7.66 (s, 1H), 7.56 (d, J=8.44 Hz,
2H), 7.29–7.42 (m, 3H), 7.10 (t, J=7.61 Hz, 1H), 7.00 (d,
J=8.80 Hz, 2H), 3.90 (s, 3H); 13C NMR (126 MHz, CDCl3):
d=159.56, 141.11, 139.70, 138.97, 136.64, 135.48, 130.87 (+),
129.12, 128.29 (+), 127.89 (+), 127.34 (+), 126.89 (+),
126.59 (+), 124.19 (+), 120.08 (+), 119.70 (+), 119.53 (+),
113.95 (+), 55.36 (+); HR-MS (EI): m/z=284.1202, calcd.
for C21H16O: 284.1201.
Methyl
(9E)-9-benzylidene-9H-fluorene-2-carboxylate
1
(2n): H NMR (400 MHz, CDCl3): d=8.48 (s, 1H), 8.09 (d,
J=8.04 Hz, 1H), 7.72–7.89 (m, 3H), 7.62 (s, 2H), 7.30–7.56
(m, 3H), 7.15 (s, 1H), 3.98 (s, 3H); 13C NMR (101 MHz,
CDCl3): d=167.3, 143.2, 140.1, 139.5, 137.5, 136.5 (+), 135.6
(+), 129.7 (+), 129.3 (+), 128.8 (+), 128.6 (+), 128.3 (+),
127.8 (+), 125.8, 124.5 (+), 121.7 (+), 120.6 (+), 120.4, 119.3
(+), 52.2 (+); HR-MS (EI): m/z=312.1149, calcd. for
C22H16O2: 312.1150.
3-(9H-Fluoren-9-ylidenemethyl)pyridine (2o): 1H NMR
(500 MHz, CDCl3): d=8.87 (s, 1H), 8.68 (dd, J=4.86,
1.38 Hz, 1H), 8.03 (s, 1H), 7.82 (d, J=7.89 Hz, 1H), 7.78 (d,
J=7.70 Hz, 1H), 7.67 (s, 2H), 7.48 (d, J=7.89 Hz, 1H), 7.43
(dd, J=7.89, 4.95 Hz, 1H), 7.39 (s, 1H), 7.12–7.18 (m, 1H);
13C NMR (126 MHz, CDCl3): d=150.1 (+), 149.4 (+), 142.3,
140.1, 139.2, 137.4, 136.7 (+), 136.4 (+), 132.3, 129.4 (+),
128.1 (+), 125.6, 124.4 (+), 124.3 (+), 123.4 (+), 120.7 (+),
119.8 (+), 117.5 (+); HR-MS (EI): m/z=323.09245, calcd.
for C20H13F3N: 323.09463.
(9E)-2-Fluoro-4-methyl-9-(4-methylbenzylidene)-9H-fluo-
rene (2p): 1H NMR (500 MHz, CDCl3): d=7.80 (d, J=
7.70 Hz, 1H), 7.68 (d, J=7.70 Hz, 1H), 7.61 (s, 1H), 7.48 (d,
J=7.89 Hz, 2H), 7.27–7.35 (m, 4H), 7.05 (s, 1H), 6.88 (s,
1H), 2.69 (s, 3H), 2.45 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=162.1 (d, J=244.1 Hz), 141.5, 138.2, 137.1, 135.5,
134.6, 133.6, 133.1, 129.3 (d, J=8.3 Hz, +), 128.5 (+), 128.1
(+), 125.9, 125.6 (+), 124.1 (+), 122.4 (+), 117.2 (d, J=
22.2 Hz, +), 104.7 (d, J=23.1 Hz, +), 21.4 (+), 21.0 (+);
HR-MS (EI): m/z=305.1142, calcd. for C21H14F2: 305.1151.
(9E)-9-Benzylidene-1,3-difluoro-9H-fluorene
(2j):
1H NMR (500 MHz, CDCl3): d=8.0 (d, J=2.9 Hz), 7.7 (d,
J=7.7 Hz), 7.5 (s), 7.4–7.5 (m), 7.3 (s), 7.2 (s), 7.1 (s), 6.7–
6.8 (m); 13C NMR (126 MHz, CDCl3): d=139.66, 137.31,
137.03, 134.07, 133.14, 133.04, 128.98 (+), 128.58 (+), 128.45
(+), 128.21 (+), 128.15 (+), 127.93 (+), 127.83 (+), 124.67
(+), 120.14 (+), 103.09 (+), 102.88 (+), 102.74 (+), 102.53;
HR-MS (EI): m/z=290.09019, calcd. for C20H12F2:
290.09071.
(9E)-9-Benzylidene-1,4-dimethyl-9H-fluorene
(2q):
1H NMR (500 MHz, CDCl3): d=7.86 (s, 2H), 7.51 (s, 2H),
7.43–7.48 (m, 2H), 7.40 (s, 1H), 7.29 (s, 2H), 7.06 (s, 2H),
6.97 (s, 1H), 2.71 (s, 6H); 13C NMR (126 MHz, CDCl2): d=
141.7, 139.0, 138.2, 137.9, 137.6, 136.5, 131.5 (+), 131.5,
1110
asc.wiley-vch.de
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1101 – 1114

Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig Annulation
FULL PAPERS
130.7, 130.4 (+), 129.0 (+), 128.6 (+), 128.0 (+), 127.6 (+),
125.6 (+), 124.5 (+), 122.8 (+), 22.5 (+), 21.2 (+); HR-MS
(EI): m/z=282.1409, calcd. for C22H18: 282.1410.
129.4 (+), 128.6 (+), 128.3 (+), 128.1 (+), 127.9 (+), 127.0–
127.9 (m), 123.5, 121.6, 92.2, 89.4.
(9Z)-3-Methoxy-9-(4-methoxybenzylidene)-9H-fluorene
(2r): 1H NMR (500 MHz, CDCl3): d=7.77 (d, J=7.15 Hz,
1H), 7.69 (s, 1H), 7.62 (d, J=8.62 Hz, 1H), 7.53 (s, 3H),
7.30–7.40 (m, 2H), 7.24 (s, 1H), 6.99 (d, J=8.80 Hz, 2H),
6.65 (s, 1H), 3.89 (s, 6H); 13C NMR (126 MHz, CDCl3): d=
160.3, 159.4, 142.9, 140.6, 138.7, 135.0, 130.8 (+), 129.6,
129.3, 127.8 (+), 127.0 (+), 125.2 (+), 125.1 (+), 120.1 (+),
119.4 (+), 113.9 (+), 112.7 (+), 104.7 (+), 55.5 (+), 55.4
(+); HR-MS (EI): m/z=314.1308, calcd. for C22H18O2:
314.1307.
Intermollecular Kinetic Isotope Effect Measurements
A mixture of 20 mg of 9-(4-methylbenzylidene)-9H-fluo-
rene-d5 (0.0732 mmol) and 19.64 mg of 9-(4-methylbenzyli-
dene)-9H-fluorene (0.0732 mmol) was placed into an oven-
dry 1-mL Weaton vial, with a stir bar. PdACTHNURTGNENG(U OAc)2 (1.6 mg,
0.0074 mmol) and 1,1’-bis(di-iso-propylphosphino)ferrocene
(3.7 mg, 0.009 mmol) were added under an N2 atmosphere.
Dry toluene ( 292 mL) was added and the reaction vessel
was capped with a pressure screw cap. The reaction mixture
was heated at 1208C. Heating was stopped at 25–30% con-
version of 9-(4-methylbenzylidene)-9H-fluorene as detected
by GC/MS analysis. The mixture was allowed to cool down
to room temperature and filtered through short SiO2 plug
with aid of DCM. The filtrate was collected and solvent was
evaporated under reduced pressure. The resulting mixture
was connected to the high vacuum pump, dried, and ana-
lyzed by 1H NMR without any further purification. The
above experiment was repeated three more times giving the
average of kH/kD =2.6.
Mechanistic Studies
9-(4-Methylbenzylidene)-9H-fluorene-d5 (4):
A
round-
bottom flask containing a stirring bar was charged with
(Ph3P)2PdCl2 (34 mg, 0.05 mmol), phenylboronic acid-d5
(200 mg, 3.2 mmol), 1-bromo-2-[(4-methylphenyl)ethynyl]-
benzene (657 mg, 2.4 mmol) and Na2CO3 (424 mg, 4 mmol).
The flask was sealed with a rubber septum, evacuated and
backfilled with argon. Toluene (4 mL) was added through
the septum via syringe together with EtOH (1 mL) and
water (1 mL). The reaction mixture was placed into 708C
preheated oil bath and heated at this temperature for 2 h
until judged complete by GC/MS analysis. The mixture was
cooled down to room temperature, diluted with 10 mL of
EtOAc and 10 mL of water and transferred into a separato-
ry funnel. The organic layer was separated, washed with
water (2ꢂ10 mL), dried over MgSO4. The solvent was
evaporated under reduced pressure and resulting residue
was purified by column chromatography on a silica gel with
hexanes to afford 9-(4-methylbenzylidene)-9H-fluorene-d5
(99% incorporated deuterium). 1H NMR (500 MHz,
CDCl3): d=7.65 (dd, J=7.70, 0.92 Hz, 1H), 7.41–7.48 (m,
1H), 7.37–7.42 (m, 1H), 7.30–7.36 (m, 1H), 7.23 (s, 2H),
7.10 (d, J=7.89 Hz, 2H), 2.34 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=143.7, 140.4, 138.2, 132.8 (+), 131.2 (+), 129.4
(+), 129.0 (+), 128.3 (+), 127.0 (+), 121.8 , 120.4, 92.4, 88.7,
21.5 (+).
Intramollecular Kinetic Isotope Effect Measurements
An oven-dried 1-mL Wheaton vial containing a stirring bar
was charged with 9-benzylidene-9H-fluorene-d1 (30 mg,
0.117 mmol), PdACTHNUTRGNEUNG(OAc)2 (1.32 mg, 0.006 mmol) and (2.94 mg,
0.007 mmol) under an N2 atmosphere. Dry toluene (240 mL)
was added and the reaction vessel was capped with a pres-
sure screw cap. The reaction mixture was heated at 120 8C.
When the conversion of 9-benzylidene-9H-fluorene-d1 was
detected to be 25–30% (as judged by GC/MS analysis) heat-
ing was stopped. The mixture was cooled down to room
temperature and filtered through short SiO2 plug with the
aid of DCM. The filtrate was concentrated under the re-
duced pressure. The residue was dissolved in 2 mL of
MeOH. A spatula tip of 10% Pd on carbon was added and
the reaction mixture was subjected to the reduction with H2
at atmospheric pressure. The excess of palladium was re-
moved by filtration through celite. The filtrate was concen-
trated under reduced pressure. The resulting residue was
connected to the high vacuum pump, dried and analyzed by
1H NMR without further purification. The above procedure
was repeated two more times, giving the average of kH/kD =
3.5.
9-Benzylidene-9H-fluorene-d1 (6): A round-bottom flask
containing a stirring bar was charged with (Ph3P)2PdCl2
(121 mg, 0.173 mmol), phenylboronic acid-d1 (510 mg,
4.1 mmol),
1-bromo-2-phenylethynylbenzene
(546 mg,
3.5 mmol) and Na2CO3 (424 mg, 4 mmol). The flask was
sealed with a rubber septum, evacuated and backfilled with
argon. Toluene (7 mL) was added through the septum via
syringe together with EtOH (3 mL) and water (3 mL). The
reaction mixture was placed into 708C preheated oil bath
and heated at this temperature for 2 h until judged complet-
ed by GC/MS analysis. The mixture was cooled down to
room temperature, diluted with 10 mL of EtOAc and 10 mL
of water and transferred into a separatory funnel. The or-
ganic layer was separated, washed with water (2ꢂ10 mL),
dried over MgSO4. The solvent was evaporated under re-
duced pressure and resulting residue was purified by column
chromatography on a silica gel with hexanes to afford 9-ben-
zylidene-9H-fluorene-d1 (99% deuterium incorporated).
1H NMR (500 MHz, CDCl3): d=7.64–7.75 (m, 2H), 7.39–
7.53 (m, 5H), 7.23–7.39 (m, 6H); 13C NMR (126 MHz,
CDCl3): d=143.9, 140.5, 132.9 (+), 131.4 (+), 129.5 (+),
General Procedure for Arylative Cyclization of o-
Alkynylbiaryls with Aryl Halides (Table 3)
An oven-dried 1-mL Wheaton vial containing a stirring bar
was charged with
1
(0.5 mmol), PdACTHUNGRETNNU(G OAc)2 (5.6 mg,
0.025 mmol), d-i-Prpf (13 mg, 0.03 mmol), and DABCO
(112 mg, 1 mmol) under an N2 atmosphere. Dry NMP
(1.0 mL) was added followed by the addition of the appro-
priate aryl halide (0.75 mmol) and the reaction vessel was
capped with a pressure screw cap. The reaction mixture was
heated at 1208C until full consumption of starting materials
(as judged by GC/MS analysis). The mixture was cooled
down to room temperature and filtered through a short SiO2
plug with the aid of EtOAc. The filtrate was diluted with
EtOAc and water. The organic layer was separated, washed
Adv. Synth. Catal. 2009, 351, 1101 – 1114
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1111

Natalia Chernyak and Vladimir Gevorgyan
FULL PAPERS
with water (2ꢂ10 mL), dried over Na2SO4. The solvent was
evaporated under reduced pressure, and the resulting crude
material was purified by column chromatography on silica
gel. The resulting fluorene 12, was further purified by re-
crystallization from MeOH.
(d, J=8.07 Hz, 1H), 3.88 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=159.8, 145.5, 143.3, 140.4, 138.9, 135.3, 133.8,
131.5, 130.0 (+), 128.7 (+), 128.2 (+), 127.4 (+), 127.4 (+),
126.3 (+), 126.3 (+), 124.8 (+), 124.7 (+), 119.2 (+), 114.1
(+), 55.3 (+); HR-MS (EI): m/z=360.1514, calcd. for
C27H20O: 360.1513.
9-(Diphenylmethylene)-9H-fluorene (12a):[26] 1H NMR
(500 MHz, CDCl3): d=7.71 (d, J=7.34 Hz, 2H), 7.34–7.50
(m, 7H), 7.25 (s, 2H), 6.94 (t, J=7.52 Hz, 2H), 6.64 (s, 2H);
13C NMR (126 MHz, CDCl3): d=145.50, 142.98, 140.49,
138.70, 134.19, 129.67 (+), 128.82 (+), 128.20 (+), 127.62
(+), 126.41 (+), 124.89 (+), 119.24 (+).
9-{Phenyl[4-(trifluoromethyl)phenyl]methylene}-9H-fluo-
rene (12h): 1H NMR (500 MHz, CDCl3): d=7.67–7.76 (m,
3H), 7.53 (d, J=8.07 Hz, 2H), 7.45 (s, 2H), 7.33–7.40 (m,
2H), 7.22–7.31 (m, 3H), 6.89–7.01 (m, 3H), 6.62 (dd, J=
7.89, 4.22 Hz, 2H); 13C NMR (126 MHz, CDCl3): d=146.6,
143.2, 142.3, 140.8, 140.6, 138.4, 138.1, 135.2 (+), 130.1 (+),
129.6 (+), 129.1, 128.5 (+), 128.1 (+), 127.2 (+), 126.6 (+),
125.9 (+), 125.0 (+), 124.8 (+), 119.5 (+), 119.4 (+); HR-
MS (EI): m/z=398.1282, calcd. for C27H17F3: 398.1285.
9-(Diphenylmethylene)-2-(trifluoromethyl)-9H-fluorene
(12i): 1H NMR (500 MHz, CDCl3): d=7.67–7.76 (m, 3H),
7.53 (d, J=8.07 Hz, 2H), 7.45 (s, 2H), 7.33–7.40 (m, 2H),
7.22–7.31 (m, 3H), 6.89–7.01 (m, 3H), 6.62 (dd, J=7.89,
4.22 Hz, 2H); 13C NMR (126 MHz, CDCl3): d=147.6, 143.2,
143.6, 141.8, 140.6, 139.0, 138.1, 135.2 (+), 131.1 (+), 129.0
(+), 128.8, 128.5 (+), 128.1 (+), 127.2 (+), 126.6 (+), 125.9
(+), 125.0 (+), 124.9 (+), 120.5 (+), 119.4 (+); HR-MS
(EI): m/z=398.1283, calcd. for C27H17F3: 398.1285.
4-[9H-Fluoren-9-ylidene
(phenyl)methyl]phenyl
methyl
1
ether (12b): H NMR (500 MHz, CDCl3): d=7.72 (dd, J=
7.52, 3.12 Hz, 2H), 7.35–7.46 (m, 4H), 7.31 (d, J=8.62 Hz,
2H), 7.21–7.28 (m, 3H), 6.90–7.02 (m, 4H), 6.84 (d, J=
7.89 Hz, 1H), 6.63 (d, J=8.07 Hz, 1H), 3.88 (s, 3H);
13C NMR (126 MHz, CDCl3): d=159.8, 145.5, 143.3, 140.4,
138.9, 135.3, 133.8, 131.5, 130.0 (+), 128.7 (+), 128.2 (+),
127.4 (+), 127.4 (+), 126.3 (+), 126.3 (+), 124.8 (+), 124.7
(+), 119.2 (+), 114.1 (+), 55.3 (+); HR-MS (EI): m/z=
360.1514, calcd. for C27H20O: 360.1512.
4-[9H-Fluoren-9-ylidene
(phenyl)methyl]phenyl
methyl
1
ether (12c): H NMR (500 MHz, CDCl3): d=7.70 (m, 2H),
7.60–7.46 (m, 4H), 7.31 (d, J=8.62 Hz, 2H), 7.21–7.28 (m,
3H), 6.90–7.02 (m, 4H), 6.84 (m, J=7.89 Hz, 1H), 6.63 (d,
J=8.07 Hz, 1H), 2.3 (s, 3H); 13C NMR (126 MHz, CDCl3):
d=159.8, 145.5, 143.3, 140.4, 138.9, 135.3, 133.8, 131.5, 130.0
(+), 128.7 (+), 128.2 (+), 127.4 (+), 127.4 (+), 126.3 (+),
126.3 (+), 124.8 (+), 124.7 (+), 119.2 (+), 114.1 (+), 21.4
(+); HR-MS (EI): m/z=344.1565, calcd. for C27H22:
9-[1,3-Difluoro-9-(4-methylphenylphenyl)methylene]-9H-
1
fluorene (12k): H NMR (500 MHz, CDCl3): d=7.69 (d, J=
7.70 Hz, 1H), 7.40–7.50 (m, 1H), 7.30–7.38 (m, 3H), 7.24–
7.29 (m, 2H), 7.21 (s, 2H), 7.12 (d, J=6.97 Hz, 2H), 6.99 (s,
1H), 6.58–6.64 (m, 1H), 6.43–6.55 (m, 2H), 2.47 (s, 3H);
13C NMR (126 MHz, CDCl3): d=148.5, 145.0, 144.1, 143.2,
142.0, 140.7, 140.1, 139.1, 138.6, 138.3 (+), 130.9 (+), 130.7
(+), 129.5 (+), 128.9, 128.7 (+), 128.5 (+), 128.2 (+), 127.8
(+), 127.6 (+), 127.2 (+), 124.2 (+), 119.7 (+), 102.8 (+),
102.6 (+), 102.4 (+), 21.5 (+); HR-MS (EI): m/z=380.1377,
calcd. for C27H18F2: 380.1380.
344.1568.
9-[Phenyl
1
N
(500 MHz, CDCl3): d=7.72 (m, 2H), 7.35–7.46 (m, 4H),
7.31 (d, J=8.62 Hz, 2H), 7.21–7.28 (m, 3H), 6.90–7.02 (m,
4H), 6.84 (d, J=7.89 Hz, 1H), 6.63 (d, J=8.07 Hz, 1H), 2.3
(s, 3H); 13C NMR (126 MHz, CDCl3): d=159.8, 145.5, 143.3,
140.4, 138.9, 135.3, 133.8, 131.5, 130.0 (+), 128.7 (+), 128.2
(+), 127.4 (+), 127.4 (+), 126.3 (+), 126.3 (+), 124.8 (+),
124.7 (+), 119.2 (+), 114.1 (+), 21.4 (+); HR-MS (EI):
m/z=344.1565, calcd. for C27H22: 344.1568.
4-[9H-Fluoren-9-ylidene(4-trifluoromethyl)phenyl-
AHCTUNGTRENNUNG
(methyl)]phenyl methyl ether (12l): 1H NMR (500 MHz,
CDCl3): d=7.71 (d, J=7.52 Hz, 2H), 7.67 (d, J=8.07 Hz,
2H), 7.50 (d, J=8.07 Hz, 2H), 7.22–7.31 (m, 4H), 6.91–7.01
(m, 4H), 6.81 (d, J=8.07 Hz, 1H), 6.59 (d, J=7.89 Hz, 1H),
3.88 (s, 3H); 13C NMR (126 MHz, CDCl3): d=160.0 , 146.9,
143.2, 140.6, 140.5, 138.6, 138.3, 134.8, 134.6, 131.5 (+), 130.5
(+), 130.3, 127.9 (+), 127.9 (+), 126.5 (+), 126.5 (+), 125.7
(+), 124.8 (+), 124.6 (+), 119.4 (+), 119.3 (+), 114.3 (+),
55.4 (+); HR-MS (EI): m/z=428.1387, calcd. for
C28H119F3O: 428.1387.
3-[9H-Fluoren-9-ylidene
G
(12e):
1H NMR (500 MHz, CDCl3): d=8.67 (s, 2H), 7.64–7.74 (m,
3H), 7.33–7.50 (m, 6H), 7.23–7.31 (m, 2H), 6.91–7.00 (m,
2H), 6.59–6.66 (m, 2H); 13C NMR (126 MHz, CDCl3): d=
150.5 (+), 149.2, 142.2, 141.0, 140.8, 140.7, 138.8, 138.3, 138.2
(+), 137.2, 135.7 (+), 129.8 (+), 129.7 (+), 129.2 (+), 129.0
(+), 128.6 (+), 128.2 (+), 126.7 (+), 126.6 (+), 125.0 (+),
124.6 (+), 123.6 (+), 119.5 (+), 119.4 (+); HR-MS (EI):
m/z=331.1361, calcd. for C25H17N: 331.1357.
4-Chloro-9-[phenylACTHNUTRGNEUNG(p-tolyl)methylene]-9H-fluorene (1j):
1H NMR (500 MHz, CDCl3): d=8.50 (s, 1H), 7.39–7.45 (m,
3H), 7.32–7.38 (m, 2H), 7.18–7.32 (m, 6H), 6.99–7.04 (m,
1H), 6.80–6.89 (m, 1H), 6.67–6.74 (m, 1H), 6.58 (dd, J=
7.98, 0.83 Hz, 1H), 2.45 (s, 3H); 13C NMR (126 MHz,
CDCl3): d=146.9, 143.2, 141.4, 140.0, 139.2, 139.1, 138.5,
136.6, 133.3, 130.8 (s), 130.8 (s), 129.9 (s), 129.8 (s), 129.6
(s), 129.0 (s), 128.9 (s), 128.5, 128.4 (s), 127.5 (s), 126.7 (s),
126.6 (s), 124.5 (s), 123.4 (s), 123.1 (s), 21.5 (s); HR-MS
(EI): m/z=380.1175, calcd. for C27H19Cl: 378.1179.
3-[9H-Fluoren-9-ylidene(3-methylphenyl)methyl] pyridine
(12f): 1H NMR (500 MHz, CDCl3): d=8.68 (s, 2H), 7.54–
7.82 (m, 3H), 7.05–7.46 (m, 7H), 6.96 (s, 2H), 6.64 (s, 2H),
2.37 (s, 3H); 13C NMR (126 MHz, CDCl3): d=150.4 (+),
149.2, 142.2, 141.3, 140.8, 140.6, 138.8, 138.4, 138.2, 137.2,
135.5 (+), 130.2 (+), 130.1 (+), 129.3 (+), 129.0 (+), 128.9
(+), 128.1 (+), 126.8 (+), 126.6 (+), 125.1 (+), 124.6 (+),
123.6 (+), 119.5 (+), 119.3 (+), 21.4 (+); HR-MS (EI):
m/z=345.1517, calcd. for C26H19N: 345.1522.
9-[(2-Phenyl)phenylmethylene]-9H-fluorene
(24):
1H NMR (500 MHz, CDCl3): d=7.77 (d, J=7.15 Hz, 1H),
7.73 (d, J=7.52 Hz, 1H), 7.47–7.56 (m, 2H), 7.41–7.46 (m,
2H), 7.32 (t, J=7.52 Hz, 1H), 7.21–7.27 (m, 2H), 7.08–7.21
(m, 6H), 7.04 (s, 2H), 6.81–6.92 (m, 3H), 6.62 (d, J=
8.07 Hz, 1H), 6.52 (d, J=7.52 Hz, 1H); 13C NMR (126 MHz,
9-(Diphenylmethylene)-2-methoxy-9H-fluorene
(12g):
1H NMR (500 MHz, CDCl3): d=7.72 (dd, J=7.52, 3.12 Hz,
2H), 7.35–7.46 (m, 4H), 7.31 (d, J=8.62 Hz, 2H), 7.21–7.28
(m, 3H), 6.90–7.02 (m, 4H), 6.84 (d, J=7.89 Hz, 1H), 6.63
1112
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ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 2009, 351, 1101 – 1114

Synthesis of Fluorenes via the Palladium-Catalyzed 5-exo-dig Annulation
FULL PAPERS
CDCl3): d=145.9, 142.1, 141.4, 141.3, 141.2, 140.6, 140.4,
139.0, 138.4, 135.3, 130.7 (s), 130.6 (s), 130.5 (s), 128.9 (s),
128.5 (s), 128.4 (s), 128.2 (s), 127.8 (s), 127.8 (s), 127.6 (s),
127.4 (s), 127.2 (s), 126.9 (s), 126.8 (s), 126.4 (s), 125.1 (s),
124.7 (s), 119.4 (s), 119.2 (s); HR-MS (EI): m/z=406.1722,
calcd. for C32H22: 406.1718.
[6] M. Y. Yoon, J. H. Kim, D. S. Choi, U. S. Shin, J. Y. Lee,
C. E. Song, Adv. Synth. Catal. 2007, 349, 1725–1737.
[7] N. Chernyak, V. Gevorgyan, J. Am. Chem. Soc. 2008,
130, 5636–5637.
[8] J. A. Tunge, L. N. Foresee, Organometallics 2005, 24,
6440–6444.
[9] It was assumed that the geometry of all geometrically
pure products was the same as those for 2e,f, the geo-
metries of which were confirmed by NOESY experi-
ments.
[10] It is not clear whether this isomerization occurrs ther-
mally, or it is assisted by Pd. For the Pd-assisted iso-
merizations of alkenes, see, for example: E. Negishi, in:
Handbook of Organopalladium Chemistry for Organic
Synthesis, Vol. 2, (Eds.: E. Negishi, A. de Meijere),
Willey-Interscience, New York, 2002, pp 2783–2788.
[11] For a discussion of kinetic isotope effects in palladium-
Acknowledgements
The financial support of the National Institutes of Health
(GM-64444) and the National Science Foundation (Grant
CHE-0710749) is gratefully acknowledged.
À
catalyzed C H activation processes, see, for example:
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asc.wiley-vch.de
1113

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[21] Although coordination of ArPdX to a triple bond is a
requisite step in numerous transformations, to the best
of our knowledge, there are no reports on employment
of the triple bond as a directing group in the Pd-cata-
À
lyzed C H arylation reactions. For use of other direct-
À
ing groups in C H functionalizations, see, for example:
pyridines: a) K. L. Hull, W. Q. Anani, M. S. Sanford, J
Am. Chem. Soc. 2006, 128, 7134–7135; b) K. L. Hull,
E. L. Lanni, M. S. Sanford, J. Am. Chem. Soc. 2006,
128, 14047–14049; c) T. Y. Thu, W.-Y. Yu, C.-M. Che,
J. Am. Chem. Soc. 2006, 128, 9048–9049; amides: d) S.
Yang, B. Li, X. Wan, Z. Shi, J. Am. Chem. Soc. 2007,
129, 6066–6067; e) A. Lazareva, O. Daugulis, Org. Lett.
2006, 8, 5211–5213; f) D. Shabashov, O. Daugulis, Org.
Indian J. Chem. 1978, 16B, 431.
[25] H. Lund, H. Svith, S. U. Pedersen, K. Daasberg, Elec-
trochim. Acta 2005, 51, 655.
[26] M. Banerjee, S. J. Emond, S. V. Lindeman, R. Rathore
J. Org. Chem. 2007, 72, 8054.
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Adv. Synth. Catal. 2009, 351, 1101 – 1114