A simple, two-step, site-specific preparation of fluorinated naphthalene and phenanthrene derivatives from fluorobromo-substituted alkenes

Article abstract of DOI:10.1021/jo061305k

(Chemical Equation Presented) A facile two-step procedure for the site-specific preparation of fluorinated naphthalene and phenanthrene derivatives is described. The Sonogashira reaction of bromofluoro-substituted alkenes with terminal alkynes, followed b

Full text of DOI:10.1021/jo061305k

A Simple, Two-Step, Site-Specific Preparation of Fluorinated
Naphthalene and Phenanthrene Derivatives from
Fluorobromo-Substituted Alkenes
Yi Wang, Jianjun Xu, and Donald J. Burton*
Department of Chemistry, UniVersity of Iowa, Iowa City, Iowa 52242
donald-burton@uiowa.edu
ReceiVed June 23, 2006
A facile two-step procedure for the site-specific preparation of fluorinated naphthalene and phenanthrene
derivatives is described. The Sonogashira reaction of bromofluoro-substituted alkenes with terminal alkynes,
followed by base-catalyzed cyclization in refluxing N-methyl-2-pyrrolidinone (NMP), affords the
corresponding fluorinated naphthalene and phenanthrene derivatives in good yields.
Introduction
from being widely employed in the synthesis of fluoroaromat-
ics: hazardous starting materials; intolerance of certain func-
tional groups ortho to the diazonium functional group; and tarry
byproducts from the extensive side reactions of the intermediate
aryl cation.6 It has been reported that Pb(OAc)4 and BF3‚Et2O
can transform aryl silanes into aryl fluoride, either by two steps
or in an one-pot reaction.6,7 Similarly, aryl boronic acids react
with diethanolamine and cesium fluoroxysulfate (CsSO4F) to
form aryl fluorides.8 Other electrophilic fluorinating reagents,
such as N-Fluoro compounds, have been utilized to prepare
fluoroaromatics directly from arenes.9 For example, com-
mercially available SelectFluor has been used to prepare
monofluoronaphthalenes from naphthalene.9 However, there is
poor regioselectivity, and the resultant mixture of 1- and
2-fluoronaphthalenes is difficult to separate. The addition
reaction of fluorinated carbene, :CFX (X ) F, Cl, Br), to indene,
followed by base-induced rearrangement, can also lead to
2-fluoronaphthalene.10 However, this reaction is not practical
for synthetic purposes due to the difficulty obtaining functional
starting materials. Schlosser and co-workers recently reported
Organic compounds in which hydrogen atoms are strategically
replaced by fluorine have attracted increased interest for
applications in the areas of polymer chemistry, medicinal
chemistry, and agricultural chemistry.1 It is proposed that
fluorine modifies the biological activity by altering the physi-
cochemical properties of these compounds.2 Recently, the
fluorination of aromatic compounds, especially the site-specific
fluorination of naphthalenes, has been of interest to us because
of the growing demand of this class of compounds as pharma-
ceutical and agricultural agents and the lack of efficient synthetic
methodologies to these compounds.3
The thermal decomposition of aryl diazonium tetrafluorobo-
rate salts (the Balz-Schiemann reaction) is the most traditional
method for incorporation of fluorine onto the aromatic ring.4
This method has been utilized in the preparation of 2-fluo-
ronaphthalenes.5 However, the following drawbacks prevent it
(1) (a) Organofluorine Chemistry: Principle and Commercial Applica-
tions; Banks, R. E., Smart, B. E., Tatlow, J. C., Eds.; Plenum Press: New
York, 1994. (b) Organofluorine Chemicals and Their Industrial Applica-
tions; Banks, R. E., Ed.; Ellis Harwood Ltd.: Chichester, UK, 1979.
(2) (a) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishman,
S., Eds.; Wiley: New York, 1991. (b) Fluoroorganic Chemistry: Synthetic
Challenges and Biomedical Rewards; Resnati, G., Soloshnok, A., Eds.;
Tetrahedron Symposia in print No. 58, Tetrahedron, 1996; Vol. 52, pp 1-8.
(c) Biomedical Aspects of Fluorine Chemistry; Filler, R., Kobayashi, Y.,
Eds.; Kodasha/Elsevier: New York, 1982. (d) Welch, J. T. Tetrahedron
1987, 43, 3123-3197. (e) McCarthy, J. R.; Huber, E. W.; Le, T.-B.;
Laskovics, F. M.; Matthews, D. P. Tetrahedron 1996, 52, 45-58.
(3) (a) Meio, G. D.; Morgan, J.; Pinhey, J. T. Tetrahedron 1993, 49,
8129-8138. (b) Diorazio, L. J.; Widdowson, D. A.; Clough, J. M.
Tetrahedron 1992, 48, 8073-8088. (c) Tagat, J. R.; McCombie, S. W.;
Nazareno, D.; Boyle, C. D.; Kozlowski, J. A.; Chackalamannil, S.; Josien,
H.; Wang, Y.; Zhou, G. J. Org. Chem. 2002, 67, 1171-1177.
(4) (a) Balz, G.; Schiemann, G. Chem. Ber. 1927, 60, 1186-1190. (b)
Roe, A. Org. React. 1949, 5, 193-228.
(5) Nakata, N. Chem. Ber. 1931, 64, 2059-2069.
(6) Meio, G. D.; Pinhey, J. T. J. Chem. Soc., Chem. Commun. 1990, 15,
1065-1066.
(7) Meio, G. D.; Morgan, J.; Pinhey, J. T. Tetrahedron 1993, 49, 8129-
8138.
(8) Diorazio, L. J.; Widdowson, D. A.; Clough, J. M. Tetrahedron 1992,
48, 8073-8088.
(9) (a) Shamma, T.; Buchholz, H.; Prakash, G. K. S.; Olah, G. A. Isr. J.
Chem. 1999, 39, 207-210. For reviews of SelectFluor, see: (b) Banks, R.
E. J. Fluorine Chem. 1998, 87, 1-17. (c) Lal, G. S.; Pez, G. P.; Syvret, R.
G. Chem. ReV. 1996, 96, 1737-1755.
10.1021/jo061305k CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/23/2006
7780
J. Org. Chem. 2006, 71, 7780-7784

Fluorinated Naphthalene and Phenanthrene DeriVatiVes
TABLE 1. Preparation of 4 by the Coupling Reaction between 2 and Terminal Alkynes
isolated
entry
X
R
time (h)
product
yield (%)
1
2
3
4
5
6
o-Cl
o-Cl
p-MeO
p-MeO
o-(CHdCH)2-m
o-(CHdCH)2-m
n-C5H11
n-C10H21
n-C5H11
Ph
n-C4H9
Ph
36
48
21
45
63
42
4a
4b
4c
4d
4e
4f
92
72
(82)a
(78)a
(89)a
68
a The enyne was not separable from the reduction products; the number in the parentheses is the conversion, which was calculated based on the amount
of 2 in the starting mixture of 2 and 3.
TABLE 2. Cyclization of (E)-Monofluoroenynes 4
a synthetic route to fluoronaphthalenes via fluoroarynes. How-
ever, a regioisomeric mixture was found in their cases.11 Herein,
we wish to report our approach to 3-fluoro-1-substituted
naphthalenes via the cyclization of (E)-monofluoroenynes. A
portion of this research has been reported in a previous
communication.12
entry
X
R
base
time (h) product yield (%)a
Results and Discussion
1
2
3
4
5
6
7
o-Cl
o-Cl
o-Cl
o-Cl
n-C5H11
n-C5H11
n-C5H11
DABCO
DBU
n-Bu3N
6
7
7
5a
5a
5a
5b
93
80
∼8c
94
86
0
Recently, we reported a novel base-catalyzed cyclization of
(E)-monofluoroenynes.12 The preparation of (E)-monofluo-
roenynes is illustrated in Table 1. The kinetic reduction of
mixtures of 1-bromo-1-fluoroalkenes (E/Z ≈ 1:1) afforded a
mixture of 100% (Z)-1-bromo-1-fluoroalkenes and the corre-
sponding reduction products13 (not separable in most cases),
which underwent Sonogashira reaction14 with terminal alkynes
to afford the (E)-monofluoroenynes 4. It was difficult to separate
4 from the reduction products 3 in some cases; therefore, the
mixture of 3 and 4 was utilized at this stage (Table 1, entries
3-5).
The mixture of the (E)-monofluoroenynes (with the corre-
sponding reduction products, if not separable) and 1,4-
diazabicyclo[2,2,2]octane (DABCO) or 1,8-diazabicyclo[5,4,0]-
undec-7-ene (DBU) in refluxing N-methyl-2-pyrrolidinone
(NMP) gave the corresponding cyclized products in good yields
(entries 1, 2, 4, and 5). However, when R is Ph or t-Bu (entries
6 and 7), no reaction was detected in either case. These results
are summarized in Table 2.
n-C10H21 DABCO
6
p-MeO n-C5H11
p-MeO Ph
p-MeO t-Bu
DABCO
DABCO
DABCO
11
43
5
5c
N.R.b
N.R.b
0
a Isolated yield of 5. All products gave satisfactory 19F, H, 13C NMR,
1
GC-MS, and HRMS data. b No reaction. c Determined by 19F NMR.
tively, with 4a in NMP at reflux temperature. The reaction was
smooth and completed within 7 h when DBU was utilized (entry
2), and the desired product was successfully isolated in 80%
yield. However, when n-Bu3N was employed as the base (entry
3), the reaction was very slow. After 7 h, only 1/6 of the starting
4a was consumed, and considerable amount of unidentified side
products was detected by 19F NMR analysis of the reaction
mixture. Therefore, a catalytic amount of an alternative base
(20 mol % DBU) was effective for the cyclization.
Since only (E)-enynes undergo cyclization to give the cyclized
product, to simplify the synthetic route, we investigated the
possibility of utilizing the mixture of (Z)- and (E)-enynes as
the precursors for cyclization. First, E/Z mixtures of 7 (E/Z
≈ 1:1) were prepared in moderate to good yields from the
reaction of 6, CFBr3, and Ph3P in refluxing THF.14 These results
are summarized in Table 3.
Subsequent Sonogashira reaction of the E/Z mixtures of
7a-c with terminal alkynes in Et3N at room temperature
afforded the corresponding enynes, which were used directly
in the next step without purification. Cyclization of the enynes
under normal reaction conditions (0.2 equiv of DBU in refluxing
NMP) occurred smoothly (less than 7.5 h), and the cyclized
compounds 8 were readily isolated in good yields. The yields
in the two steps were based on the amount of (Z)-7 in the E/Z
mixtures. Through this improved route, the kinetic reduction
step was not required. Thus, this modification provided a more
efficient, two-step synthetic route to this class of compounds.
These results are summarized in Table 4.
The use of NMP as the solvent was important in these
reactions. Most reactions could be completed within 10 h in
NMP, compared to 87 h in DMF, presumably due to the
difference of their boiling points. Excess amount of DABCO
(6 equiv) was used as the base, due to sublimation at the reflux
temperature of NMP. A catalytic amount (20 mol %) of
alternative bases, DBU and n-Bu3N, was investigated, respec-
(10) (a) Dolbier, W. R.; Keaffaber, J. J.; Burkholder, C. R.; Koroniak,
H.; Pradhan, J. Tetrahedron 1992, 48, 9649-9660. (b) Nefedov, O. M.;
Volchkov, N. V. J. Fluorine Chem. 1991, 54, 86-86. (c) Parham, W. E.;
Twelves, R. R. J. Org. Chem. 1957, 22, 730-734. (d) Volchkov, N. V.;
Zabolotskikh, A. V.; Ignatenko, A. V.; Nefedov, O. M. Bull. Acad. Sci.
SSSR, DiV. Chem. Sci. (Engl. Transl.) 1990, 39, 1458-1461.
(11) Masson, E.; Schlosser, M. Eur. J. Org. Chem. 2005, 4401-4405.
(12) Xu, J.; Wang, Y.; Burton, D. J. Org. Lett. 2006, 8, 2555-2558.
(13) Xu, J.; Burton, D. J. Org. Lett. 2002, 4, 831-833.
(14) Sonogashira, K.; Tohda, Y.; Hagihara, N. Tetrahedron Lett. 1975,
16, 4467-4470.
J. Org. Chem, Vol. 71, No. 20, 2006 7781

Wang et al.
TABLE 3. Preparation of 1-Bromo-1-fluoroalkenes
SCHEME 1. Cyclization of m-Substituted
1-Aryl-2-fluoroenynes
ratio of
isolated
entry
X
time (h)
Z/Ea
product
yieldb (%)
1
2
3
4-F
4-CF3
3,5-difluoro
6.5
6
6.5
49:51
47:53
44:56
7a
7b
7c
38
81
65
a The ratio was determined by 19F NMR. b Based on the aldehydes.
TABLE 4. Simplified Procedure for the Synthesis of Substituted
3-Fluoronaphthalenes
SCHEME 2. Synthesis of 1,4-Disubstituted
2-Fluoronaphthalene
isolated
entry
X
R
time (h)
product
yielda (%)
SCHEME 3. Synthesis of 4-Fluoro-1-Substituted
Naphthalene
1
2
3
4
5
6
7
8
4-F
4-F
4-CF3
4-CF3
4-CF3
4-CF3
3,5-difluoro
3,5-difluoro
n-C4H9
n-C5H11
n-C4H9
n-C5H11
n-C10H21
PhCH2CH2
n-C4H9
5
7.5
3
2
2
3
2
3
8a
8b
8c
8d
8e
8f
77
77
89
82
74
69
55
66
8g
8h
n-C5H11
a Two steps, based on the (Z)-1-bromo-1-fluoroalkenes.
SCHEME 4. Preparation of 5e
After we demonstrated the success of cyclization of the
o-substituted and p-substituted 1-aryl-2-fluoroenynes in the
presence of base (DBU or DABCO) in NMP, we were prompted
to investigate the reactivity of the meta-substituted 1-aryl-2-
fluoroenyne under similar reaction conditions since the enyne
may give two possible products from two possible cyclization
directions. Reaction of 3-trifluoromethylbenzaldehyde or 3-fluo-
robenzaldehyde, Ph3P, and CFBr3 in THF gave the 1-bromo-
1-fluoroethene 9 or 10 in good yield, respectively. Subsequent
Sonogashira reaction of 9 or 10 with 1-hexyne in MeCN (using
Et3N as base) gave the corresponding enyne, which was used
directly for cyclization without characterization. To our surprise,
a mixture of 11a and 11b, where 11a was predominant, was
obtained after DBU-catalyzed cyclization when the substrate
was CF3-substituted enyne (ratio of 11a:11b was 20:1, deter-
mined by 19F NMR spectrum). In the 1H NMR spectrum of the
mixture, a singlet peak at 8.07 ppm (in the major product)
indicated that 11a was the dominant product. The yield of the
cyclization step was based on (Z)-9 (Scheme 1). This high
regioselectivity was presumably due to steric hindrance of the
CF3 group since the steric bulk of CF3 is comparable to that of
i-Bu.16 However, in the case of cyclization of m-fluoroaryl-
substituted enyne, a mixture of 12a and 12b was formed, where
12b was the major product (12a:12b ) 1:1.5). The assignment
of 12b was based on our observation of a characteristic through-
space coupling17 (5JHF ) 3.6 Hz) between benzylic hydrogens
and fluorine (dR) on the other ring. The formation of 12b as
the major product could be attributed to a weak nonconventional
hydrogen bonding17c,18 between benzylic hydrogens and fluorine
(dR).
Not only trisubstituted fluoroenynes but also tetrasubstituted
analogues could be utilized to prepare fluorinated naphthalenes,
as demonstrated in Scheme 2. The Sonogashira reaction of
1-bromo-1-fluoro-2,2-diphenylethene 13, which was prepared
by the method of Kvicala et al.,19 with 1-hexyne afforded the
corresponding enyne 14. Subsequent cyclization of 14 gave the
fluorinated naphthalene derivative 15 in the presence of 0.2
equiv of DBU in NMP. Therefore, not only 3-fluoro-1-sub-
stituted naphthalenes could be synthesized via this cyclization
(17) (a) Gribble, G. W.; Keavy, D. J.; Branz, S. E.; Kelly, W. J.; Pals,
M. A. Tetrahedron Lett. 1988, 29, 6227-6230. (b) Gribble, G. W.; Kelly,
W. J. Tetrahedron Lett. 1985, 26, 3779-3782. (c) Adcock, W.; Rizvi, S.
Q. A. Aust. J. Chem. 1973, 26, 2659-2663.
(18) For examples of C-F‚‚‚H-C hydrogen bonding, see: (a) Mele,
A.; Vergani, B.; Viani, F.; Meille, S. V.; Farina, A.; Bravo, P. Eur. J. Org.
Chem. 1999, 187-196. (b) Parsch, J.; Engels, W. J. Am. Chem. Soc. 2002,
124, 5664-5672. For reviews, see: (c) Organofluorine Chemistry; Un-
eyama, K., Ed.; Blackwell: Oxford, UK, 2006; pp 173-185. (d) Howard,
J. A. K.; Hoy, V. J.; O’Hagen, D.; Smith, G. T. Tetrahedron 1996, 52,
12613-12622. (e) Dunitz, J. D.; Taylor, R. Chem.sEur. J. 1997, 3, 89-
98.
(15) Vanderhaar, R. W.; Burton, D. J.; Naae, D. G. J. Fluorine Chem.
1971-1972, 1, 381-383.
(16) Organofluorine Compounds: Chemistry and Application; Hiyama,
T., Ed.; Springer: New York, 2000; pp 2-3.
(19) Kvicala, J.; Hrabal, R.; Czernek, J.; Bartosova, I.; Paleta, O.; Pelter,
A. J. Fluorine Chem. 2002, 113, 211-218.
7782 J. Org. Chem., Vol. 71, No. 20, 2006

Fluorinated Naphthalene and Phenanthrene DeriVatiVes
SCHEME 5. Synthesis of Fluorinated Phenanthrenes 19 and 20
SCHEME 6. Synthesis of 1,2-Difluoronaphthalene
methodology, but also 1,4-disubstituted-2-fluoronaphthalene
could be prepared as well in good yield by this methodology.
In addition, via the base-catalyzed cyclization, 4-fluoro-1-
substituted naphthalene derivatives could be prepared, as well,
as illustrated in Scheme 3. The starting E, Z mixture 16 was
prepared according to the published procedure by Rolando and
co-workers.20 Reaction of 16 with 1-hexyne under Sonogashira
conditions afforded the corresponding enynes, which underwent
cyclization to give 4-fluoro-1-substituted 17. The overall yield
(two steps) was based on the amount of the E isomer in the
starting material.
SCHEME 7. Mechanism for the Formation of Naphthalenes
We also extended this novel base-catalyzed cyclization to the
preparation of fluorinated polycyclic aromatic hydrocarbons.
Since there is only one direction for 4e to cyclize, a mixture of
4e (along with reduction product) and DABCO in NMP afforded
the expected fluorinated phenanthrene 5e in 85% yield (based
on 4e) (Scheme 4).
Sonogashira reaction with 1-decyne. Cyclization under similar
reaction conditions afforded the difluorinated naphthalene 23
(Scheme 6).
The structure of 5e was confirmed by its single X-ray
crystallographic structure determination.21 However, no reaction
was observed when 4f was employed as the substrate.
When 2-naphthaldehyde was employed as the substrate, 18
was obtained as an E, Z mixture. Theoretically, the subsequent
cyclization of the enynes, which were prepared by Sonogashira
reaction of 18 with terminal alkynes, would give two possible
products: the fluorinated phenanthrene and/or the anthracene
from two possible cyclization directions, respectively. Surpris-
ingly, the phenanthrene derivative was formed as the sole
product (Scheme 5), based on the fact that there are no singlet
Since the t-Bu- or Ph-substituted enyne did not produce the
desired cyclized product, it suggested that the mechanism might
involve an allene as an intermediate. On the basis of these
experiments and the deuterium experiment reported in the
previous communication, the following mechanism was pro-
posed (Scheme 7).12 First, the base catalyzes the isomerization
of the enyne to the allene,25 which undergoes a 6π cycloaddition
to form a two-ring system. The final product could be formed
either from abstraction of H on C-9 by base followed by
acquisition of H from the proton pool (either from base‚H+ or
trace amount of moisture in the system) or from a [1,7]-H shift
without assistance of the base.26 This proposed mechanism not
only explains the failure of the t-Bu or Ph derivatives due to
the absence of propargyl hydrogen(s) in the enyne but is also
consistent with the results of the deuterium analogue reported
in the previous communication.12
1
peaks at lower field from the 9-H and 10-H in the H NMR
spectrum of either 19 or 20, a characteristic signal of an-
thracene.22
The phenanthrene structure was confirmed by single X-ray
crystallographic structure determination of compound 20.21
The exclusive formation of the fluorinated phenanthrenes
could be rationalized by reported computational studies which
have shown that the total molecular energy of phenanthrene is
lower than that of anthracene, and these molecular energies were
calculated by an ab initio molecular orbital method.23
After the successful cyclization of monofluoroenynes, we
extended the reaction to difluoroenynes. Difluoroenyne 22 was
prepared from (E)-1,2-difluoro-1-iodo-2-phenylethene 21, which
was synthesized by the method reported from this lab,24 via a
Conclusion
A simple and site-specific preparation of 1-fluorosubstituted,
2-fluorosubstituted, 1,2-difluorosubstituted naphthalenes, as well
(22) Spectrometric Identification of Organic Compounds, 5th ed.; Sil-
verstein, R. M., Bassler, G. C., Morrill, T. C., Eds.; John Wiley & Sons:
New York, 1991; p 219.
(23) (a) Gong, X.; Xiao, H. J. Phy. Org. Chem. 1999, 12, 441-446. (b)
Zakrzewski, V. G.; Dolgounitcheva, O.; Ortiz, J. V. J. Chem. Phys. 1996,
105, 8748-8753.
(20) Eddarir, S.; Francesch, C.; Mestdagh, H.; Rolando, C. Bull. Soc.
Chim. Fr. 1997, 134, 741-755.
(21) CCDC 609268 (5e) and CCDC 608645 (20) contain the supple-
mentary crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cambridge Crystal-
lographic Data Centre, 12, Union Road, Cambridge CB2 1EZ, UK.; fax:
+44 1223 336033. Also see the Supporting Information.
(24) Davis, C. R.; Burton, D. J. J. Org. Chem. 1997, 62, 9217-9222.
(25) Allenes in Organic Synthesis; Schuster, H. F., Coppola, G. M., Eds.;
Wiley: New York, 1984.
(26) Nicolaou, K. C.; Vassilikogiannakis, G.; Simonsen, K. B.; Baran,
P. S.; Zhong, Y.; Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. J. Am.
Chem. Soc. 2000, 122, 3071-3079.
J. Org. Chem, Vol. 71, No. 20, 2006 7783

Wang et al.
1-Butyl-3-fluorophenanthrene (5e): Similarly, 187 mg of a
mixture of (E)-1-(2-fluorooct-1-en-3-ynyl)naphthalene 4e and the
corresponding reduced products (containing 0.7 mmol of 4e) and
DABCO (0.48 g, 4.2 mmol) in 3 mL of NMP was refluxed for 5
h. Silica gel column chromatography (hexanes only, Rf ) 0.42)
gave 0.15 g of white solid, 85% yield, mp 57-58 °C. 19F NMR
(CDCl3): δ -114.9 (t, J ) 10.2 Hz, 1 F) ppm. 1H NMR (CDCl3):
δ 8.55 (dm, J ) 7.1 Hz, 1 H), 8.18 (dd, J ) 11.0, 2.5 Hz, 1 H),
7.94 (d, J ) 9.2 Hz, 1 H), 7.89 (dm, J ) 7.0 Hz, 1 H), 7.72 (d, J
) 9.2 Hz, 1 H), 7.64 (td, J ) 6.7, 1.7 Hz, 1 H), 7.60 (td, J ) 7.0,
1.5 Hz, 1 H), 7.21 (dd, J ) 9.2, 2.4 Hz, 1 H), 3.11 (t, J ) 7.8 Hz,
2 H), 1.76 (tt, J ) 7.8, 7.5 Hz, 2 H), 1.48 (sextet, J ) 7.4 Hz, 2
H), 0.99 (t, J ) 7.3 Hz, 3 H) ppm. 13C NMR (CDCl3): δ 161.1 (d,
1JCF ) 244.8 Hz), 142.7 (d, J ) 7.7 Hz), 132.3 (d, J ) 8.4 Hz),
131.9, 130.2 (d, J ) 5.4 Hz), 128.4, 127.0, 126.9, 126.5, 125.7 (d,
J ) 3.0 Hz), 123.1, 122.2, 115.8 (d, J ) 24.4 Hz), 105.6 (d, J )
22.1 Hz), 33.1, 33.0, 22.7, 14.0 ppm. GC-MS m/z (relative
intensity): 254 (M+ + 2, 1), 253 (M+ + 1, 15), 252 (M+, 75), 221
(7), 220 (9), 210 (61), 209 (100), 207 (26), 196 (5), 189 (10), 183
(22), 110 (4), 92 (4). HRMS calcd 252.1314 for C18H17F, found
252.1314.
as fluorinated phenanthrenes from bromofluoro-substituted
alkenes has been developed. This procedure is one of the most
direct methods to incorporate fluorine into naphthalenes and
phenanthrenes. Our work continues to explore the overall scope
of this novel base-catalyzed cyclization.
Experimental Section
The preparation of 4a, 4b, 4c, 5a, 5b, 5c, 7b, 8c, 8f, 22, and 23
has been reported in the previous communication.12
General Procedure for the Preparation of (E)-Monofluo-
roenynes 4: An oven-dried 50 mL round-bottom flask equipped
with a stirring bar was charged with 0.028 g (0.04 mmol) of PdCl2-
(PPh3)2 and 5 mL of Et3N. A mixture of (Z)-1-bromo-1-fluoroalkene
2 and the corresponding reduced products 3 (containing 1 mmol
of 2) was added. The mixture was stirred for 10 min, and the
terminal acetylene (1.5 mmol) was added. Finally, CuI (2 mg, 0.01
mmol) was added, and the reaction mixture was stirred at room
temperature. When the reaction was completed, the mixture was
directly added to a silica gel column and the desired (E)-
monofluoroenyne 4 was obtained.
Simple Two-Step Procedure for the Preparation of 8: A 10
mL round-bottom flask equipped with a stirring bar was charged
with PdCl2 (PPh3)2 (40 mg, 0.057 mmol) and 3 mL of Et3N. A
mixture of (Z)- and (E)-1-bromo-1-fluoroalkene (1.0 mmol) was
added. The mixture was stirred for 10 min, and the terminal alkyne
(1.2 mmol) was added. Then CuI (10 mg, 0.050 mmol) was added,
and the reaction mixture was stirred at room temperature for 48 h.
When the reaction was completed, the mixture was directly poured
onto a silica gel column and the mixture of monofluoroenynes (Z
and E) was obtained, and it was used directly in the next step.
An oven dried 10 mL round-bottom flask equipped with a stirring
bar and a cold water condenser was charged with DBU (0.03 mL,
0.2 mmol) and the mixture of monofluoroenynes (1 mmol) in NMP
(4 mL). Then the mixture was refluxed for about 6 h. When the
reaction was completed, the mixture was cooled to room temper-
ature and poured onto a silica gel column, and the pure product
was obtained.
(E)-2-Fluoro-1-(4-methoxyphenyl)-4-phenylbut-1-en-3-yne (4d)
(not separated from the corresponding reduced products): Similarly,
a mixture of PdCl2(PPh3)2 (0.028 g, 0.04 mmol), Et3N (5 mL),
phenylacetylene (0.153 g, 1.5 mmol), and CuI (2 mg, 0.01 mmol)
was reacted with 474 mg of a mixture of (Z)-1-bromo-1-fluoro-2-
(4-methoxyphenyl)ethene 2 and the corresponding reduced products
3 (containing 1 mmol of 2) at room temperature for 45 h. After
silica gel column chromatography (ethyl acetate:hexanes ) 5:95,
Rf ) 0.31), 0.49 g of a mixture of 4d and the reduced products 3
was obtained as a colorless oil (could not be completely separated);
yield 78%. The weight percentage of 4d is 40%. 19F NMR (CDCl3)
of 4d: δ -106.0 (m, 1 F); (Z)-reduced product: δ -125.4 (dd,
3
2JFH ) 82.7 Hz, JFH(trans) ) 45.9 Hz) ppm; (E)-reduced product:
1
δ -132.7 (dm, J ) 84.2 Hz) ppm. H NMR (CDCl3) of 4d: δ
7.64 (d, J ) 8.9 Hz, 2 H), 7.45 (d, J ) 8.8 Hz, 2 H), 7.33-7.41
(m, 3 H), 6.90 (dm, J ) 9.4 Hz, 2 H) or 6.87 (dm, J ) 8.9 Hz, 2
H), 6.61 (d, 3JHF(cis) ) 16.9 Hz, 1 H) ppm; (Z)-reduced product: δ
7.51-7.55 (m), 7.33-7.41 (m), 6.59 (dd, 2JHF ) 83.1 Hz, 3JHH(cis)
) 5.3 Hz), 5.54 (dd, 3JHF(trans) ) 45.3 Hz, 3JHH(cis) ) 5.4 Hz) ppm;
1-Butyl-3,7-difluoronaphthalene (8a): Colorless oil. 19F NMR
1
(CDCl3): δ -115.9 (m, 1 F), -117.2 (m, 1 F) ppm. H NMR
(CDCl3): δ 7.76 (dd, J ) 9.0, 5.8 Hz, 1 H), 7.61 (dd, J ) 11.1,
2.5 Hz, 1 H), 7.32-7.25 (m, 2 H), 7.15 (dd, J ) 9.6, 2.5 Hz, 1 H),
2.99 (t, J ) 7.8 Hz, 2 H), 1.76-1.69 (m, 2 H), 1.54-1.42 (m, 2
H), 0.98 (t, J ) 7.5 Hz, 3 H) ppm. 13C NMR (CDCl3): δ 160.1
(dd, J ) 242.7, 2.8 Hz), 159.7 (dd, J ) 243.0, 2.8 Hz), 141.7 (dd,
J ) 8.2, 5.8 Hz), 131.5 (dd, J ) 9.4, 1.0 Hz), 130.2 (dd, J ) 8.9,
5.6 Hz), 129.8 (dd, J ) 8.3, 1.0 Hz), 116.9 (d, J ) 6.6 Hz), 116.7
(d, J ) 6.9 Hz), 109.0 (dd, J ) 20.3, 1.0 Hz), 107.8 (dd, J ) 21.4,
1.1 Hz), 32.6 (d, J ) 1.5 Hz), 32.3, 22.8, 13.9 ppm. HRMS calcd
220.1064 for C14H14F2, found 220.1061.
3
3
(E)-reduced product: δ 6.34 (dd, JHF(cis) ) 19.6 Hz, JHH ) 11.3
Hz) ppm. 13C NMR (CDCl3) of the 4d and the reduced products:
δ 159.5, 158.9, 158.7, 148.6 (d, J ) 256.8 Hz), 146.6 (d, JCF
1
)
267.5), 139.6 (d, J ) 228.0 Hz), 132.2, 131.3, 129.9 (d, J ) 7.3
Hz), 129.2, 129.0, 128.3, 128.2, 127.0, 125.0, 124.6 (d, J ) 12.3
Hz), 124.2 (d, J ) 5.0 Hz), 121.5, 121.1, 117.2 (d, J ) 33.2 Hz),
113.9, 113.7 (d, J ) 9.3 Hz), 113.1 (d, J ) 15.8 Hz), 110.1, 97.3,
81.6 (d, J ) 12.4 Hz), 54.5, 54.4 ppm. GC-MS m/z (relative
intensity) of 4d: 254 (M+ + 2, 1), 253 (22), 252 (M+, 100), 237
(27), 236 (13), 220 (19), 219 (46), 209 (73), 207 (53), 189 (32),
183 (26), 181 (9), 163 (7), 157 (5), 126 (10), 110 (7), 104 (10), 91
(9), 81 (6); m/z (relative intensity) of the reduced products: 154
(1), 153 (M+ + 1, 11), 152 (M+, 100), 138 (5), 137 (71), 120 (3),
110 (5), 109 (82), 107 (10), 101 (9), 89 (8), 83 (44), 81 (7), 75 (8),
63 (12), 57 (13).
General Procedure for the Preparation of Substituted 3-Flu-
oronaphthalenes and Derivatives 5: An oven-dried 50 mL round-
bottom flask equipped with a stirring bar, and a cold water
condenser was charged with DABCO (0.34 g, 3.0 mmol) and NMP
(4 mL). (E)-Monofluoroenyne 4 (0.5 mmol) or a mixture of (E)-
monofluoroenyne 4 and the reduced products 3 (containing 0.5
mmol of 4) was added. The mixture was refluxed for 6 h. When
the reaction was completed, the reaction mixture was directly poured
onto a silica gel column and pure product was obtained.
Acknowledgment. Financial support from the National
Science Foundation is acknowledged. We are indebted to Dr.
Dale Swenson for the determination of the X-ray structures.
Supporting Information Available: Experimental procedure
for the synthesis of 4e,f, 7a, 7c, 8b, 8d,e, 8g,h, 9-12, 14, 15, 17-
20 and their characterization by 1H, 19F, and 13C NMR and HRMS;
copies of 1H, 19F, and 13C NMR of compounds 4d-f, 5e, 7c, 8a,b,
8d,e, 8g,h, 9-12, 14, 15, 17, 19, and 20; ORTEP plots of 5e and
20; complete X-ray crystallographic data of compounds 5e and 20
(CIFs). This material is available free of charge via the Internet at
http://pubs.acs.org.
JO061305K
7784 J. Org. Chem., Vol. 71, No. 20, 2006