Bergman cyclization of fluorinated benzo-fused enediynes to naphthalene derivatives: Syntheses and structures

Article abstract of DOI:10.1002/ejoc.201001747

Fluorinated naphthalene derivatives were prepared by Bergman cyclization of fluorinated benzo-fused enediynes. This route provides access to the aromatic target compounds in a two-step procedure from commercially available precursors, via a Sonogashira cross-coupling and a subsequent, thermally initiated Bergman cyclization. Crystal structures of six fluorinated benzo-enediynes and three fluorinated naphthalene derivatives display significant diversity in their molecular structures and in the crystal packing arrangements. The rather subtle structural change from di- to tetrafluorobenzo-enediynes, as well as the variation in the terminal acetylene subunit led to different non-covalent interactions in the solid state that ultimately govern their crystal structures. Fluorinated naphthalene derivatives were obtained from a series of di- and tetrafluorinated benzo-fused enediyne precursors, readily available by Sonogashira cross-coupling. The crystal structures of six fluorinated benzo-enediynes and of three fluorinated naphthalenes show how acombination of non-covalent arene-(fluoro)arene interactions, hydrogen bonding and crystal packing effects impact the molecular structures in the solid state and, ultimately, lead to very different packing arrangements.

Full text of DOI:10.1002/ejoc.201001747

FULL PAPER
DOI: 10.1002/ejoc.201001747
Bergman Cyclization of Fluorinated Benzo-Fused Enediynes to Naphthalene
Derivatives: Syntheses and Structures
Christopher M. Kane,[a] Tiffany B. Meyers,[a] Xin Yu,[b] Michael Gerken,*[b] and
Markus Etzkorn*[a]
Keywords: Cyclization / Alkynes / Alkenes / Fluorine
Fluorinated naphthalene derivatives were prepared by
Bergman cyclization of fluorinated benzo-fused enediynes.
This route provides access to the aromatic target compounds
thalene derivatives display significant diversity in their mo-
lecular structures and in the crystal packing arrangements.
The rather subtle structural change from di- to tetrafluo-
in a two-step procedure from commercially available precur- robenzo-enediynes, as well as the variation in the terminal
sors, via a Sonogashira cross-coupling and a subsequent,
thermally initiated Bergman cyclization. Crystal structures of
six fluorinated benzo-enediynes and three fluorinated naph-
acetylene subunit led to different non-covalent interactions
in the solid state that ultimately govern their crystal struc-
tures.
In our research on fluorinated molecular tweezers,[13] we
are currently investigating the 6,7-dimethyl derivatives of di-
and tetrafluoronaphthalene as building blocks for fluori-
nated glycoluril-derived molecular tweezers with extended
pincer sidewalls. Although the synthesis of 1,2,3,4-tetra-
fluoro-6,7-dimethylnaphthalene has been previously re-
ported by several groups,[1c,14] a large scale preparation is
not a trivial task; it either relies on starting materials that
are difficult to obtain and/or involve harsh reaction condi-
tions that are sometimes difficult to reproduce, i.e., a flash
vacuum pyrolysis.[15] The Bergman cyclization[16] has not
yet been applied for the synthesis of fluorinated naphtha-
lenes, hence, the feasibility of such a synthetic approach to
these target compounds was studied. We wish to report our
results on the synthesis and Bergman cyclization of a series
of di- and tetrafluoro-benzo-enediyne precursors. Further-
more, we will demonstrate how various non-covalent inter-
actions in six fluorinated benzo-enediynes and selected
naphthalene derivatives lead to vastly different packing ar-
rangements in the solid state and, as a consequence, differ-
ences in their molecular structures.
Introduction
The synthesis of polyfluoroaromatic compounds[1] has
not only triggered the investigation of non-covalent arene-
(per)fluoroarene interactions but also provided a structural
motif for crystal engineering applications[2] and novel or-
ganic electronic materials.[3] More recently, polyfluoroarom-
atic compounds have been investigated in carbon-fluorine
bond activation processes,[4] potentially providing suitable
substrates for the preparation of low-fluorinated building
blocks in medicinal chemistry.[5] Many synthetic techniques
have been developed for the preparation of polyfluoroar-
enes. Thus, highly fluorinated naphthalenes or derivatives
thereof have become available along various routes, e.g., di-
rect fluorination of naphthalene with subsequent rearomati-
zation,[1c,6] electrochemical fluorination of suitable naph-
thalene derivatives,[1c,7] the conversion of perchloronaph-
thalene to the perfluoro derivative by the HALEX pro-
cess,[1c,8] nucleophilic aromatic substitution of perfluo-
ronaphthalene,[1c,9] electrophilic modifications of perfluo-
ronaphthalene under superacidic conditions,[1c,10] through
tetrafluorobenzyne chemistry,[1c,11] or by a recent approach
of trapping 1,4-dilithio-1,3-dienes with hexafluorobenzene
to yield tetrafluoronaphthalene derivatives.[12]
Results and Discussion
[a] Department of Chemistry,
Synthesis and spectroscopic characterization of enediynes:
Two series of di- and tetrafluorinated benzo-enediynes with
variations in the “terminal” acetylene unit were obtained
by Sonogashira cross-coupling (Table 1). Only compound
7f was previously reported in the literature: it was obtained
through a copper-assisted nucleophilic substitution reaction
and has been characterized by elemental analysis, MS, UV/
Vis and 19F NMR spectroscopy.[17] The coupling reactions
of dibromoarene 1 and diiodo precursor 2 with the alkyne
The University of North Carolina at Charlotte,
9201 University City Blvd., Charlotte, NC 28223, USA
Fax: +1-704-6873151
E-mail: metzkorn@uncc.edu
[b] Department of Chemistry and Biochemistry,
University of Lethbridge,
4401 University Drive, Lethbridge, AB T1K 3M4, Canada
Fax: +1-403-3292057
E-mail: michael.gerken@uleth.ca
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001747.
Eur. J. Org. Chem. 2011, 2969–2980
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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FULL PAPER
Table 1. Synthesis of fluorinated benzo-enediynes.
The homo-coupling of alkyne 3 to the corresponding diyne,
though observed, did only diminish the yields of the alcohol
derivatives 6d,e (7d,e). The eight benzo-enediynes 6a–f and
7a–f were isolated by column chromatography, and all com-
pounds, with the exception of the two oily products 6b and
7b, were further purified by recrystallization and obtained
as colorless or slightly beige crystals, typically as long need-
les.
1
The H, 13C, and 19F NMR spectroscopic data of the
fluorinated benzo-enediynes 6 and 7 in CDCl3 solutions re-
flect the C2v symmetry of the di- and tetrafluorobenzo-en-
ediyne subunit in solution. The H NMR spectra of 6a–f
show apparent triplets for the arene units, and the expected
signals for the groups in the terminal acetylene position;
compounds 7a–f display only the latter. The 13C{1H} NMR
spectra contain coupling information to 19F for all aromatic
carbon atoms. The 19F NMR spectra show apparent triplets
for 6a–f and the expected AAЈXXЈ multiplet patterns for
the tetrafluoro derivatives 7a–f.
Entry
Arene
Alkyne
Enediyne
Yield [%]
1[a]
2[a]
3[a]
4[a]
5[a]
6[a]
7
8
9
10
11
12
1
1
1
1
1
1
2
2
2
2
2
2
3a
3b
3c
3d
3e
3f
3a
3b
3c
3d
3e
3f
6a
6b
6c
6d
6e
6f
7a
7b
7c
7d
7e
7f
82
71
1
78
62[b]
55[b]
84
88
75
85
67[b]
60[b]
89
The UV/Vis spectra of compounds 6a–e and the tetra-
fluoro derivatives 7a–e display the same electronic transi-
[a] PPh3 added. [b] Significant amount of the homocoupling prod- tions (see Figures S7 and S8 in the Supporting Infor-
uct observed.
mation), showing a strong absorption at 230 nm with a
shoulder or an additional peak at shorter wavelengths, two
derivatives 3a–f were optimized along typical protocols[18] transitions at 260 and 270 nm, as well as a broad absorption
and delivered the target compounds in moderate to good with poorly resolved vibrational fine-structure at approxi-
yields. The reaction was monitored by 19F NMR spec- mately 300 nm. The UV/Vis spectra of both diphenylethynyl
troscopy and the intermediate mono-coupling products 4 derivatives 6f and 7f (see Figures S7 and S8 in the Support-
(5) were typically not isolated, but identified by 19F NMR ing Information) are nearly identical with that of the non-
spectroscopy (see Table S1 in the Supporting Information). fluorinated parent compound, 1,2-bis(phenylethynyl)ben-
Table 2. Crystallographic and selected structural data for fluorinated benzo-enediynes, 6d, 6f, 7a, 7d, 7e, and 7f.
6e
6f
7a
7d
7e
7f
Empirical formula
Formula weight
Temperature [K]
Color
C16H16F2O2
278.29
153
C22H12F2
314.32
153
C12H6F4
226.17
153
C12H6F4O2
258.17
153
C16H14F4O2
314.27
153
C22H10F4
350.30
153
colorless
colorless
colorless
pale yellow
colorless
colorless
Crystal size [mm3]
Crystal system, space
group
0.37ϫ0.24ϫ0.18 0.52ϫ0.21ϫ0.13
0.74ϫ0.35ϫ0.23 0.40ϫ0.24ϫ0.16 0.45ϫ0.26ϫ0.22 0.37ϫ0.34ϫ0.18
¯
monoclinic, P21/n triclinic P1
monoclinic, P21/n monoclinic, P21/c monoclinic, P21/n monoclinic, P21/n
a [Å]
b [Å]
c [Å]
α [°]
10.5054(9)
34.005(3)
38.611(3)
90
96.7930(10)
90
13696(2)
36
1.215
0.0588
0.1171
0.1385
0.1652
0.55/–0.52
10.8565(8)
11.6626(9)
14.0043(11)
82.1400(10)
75.6010(10)
69.9130(10)
1610.4(2)
4
1.296
0.0376
0.0533
0.0943
4.8440(14)
15.649(5)
13.196(4)
90
90.645(3)
90
1000.2(5)
4
1.502
0.0605
0.0784
0.1967
0.2119
0.35/–0.31
13.2228(13)
4.7997(5)
17.8967(18)
90
109.9190(10)
90
1067.87(19)
4
1.606
0.0299
0.0348
0.0830
0.0864
8.1949(8)
16.3693(16)
11.2676(11)
90
100.5770(10)
90
1485.8(3)
4
1.405
0.0334
0.0406
0.0971
0.0910
5.8800(4)
26.2507(18)
10.6188(7)
90
99.2450(10)
90
1617.76(19)
4
1.438
0.0365
0.0414
0.0978
0.1014
β [°]
γ [°]
Volume [Å3]
Z
ρcalcd [mgm–3]
[a]
R1[a] [IϾ2σ(I)]
R1 (all)
[b]
wR2[b] [IϾ2σ(I)]
wR2 (all)
0.1035
0.20/–0.19
Largest diff. peak/
0.25/–0.19
0.28/–0.17
0.27/–0.19
hole [eÅ–3]
[c]
d1 [Å]
2.785(3) to
2.899(3)
3.665(3) to
4.211(3)
2.8446(18)/
2.8519(18)
3.9871(19)/
3.9967(19)
2.921(3)
4.281(4)
1.4(4)
2.9192(16)
4.2298(17)
3.69(16)
2.8153(16)
3.6822(16)
3.04(13)
2.8909(17)
4.1491(18)
4.26(16)
[c]
d2 [Å]
|φ|[d] [°]
0.1(3) to 2.4(3)
1.72(17)/4.78(16)
[a] R1 is defined as Σ||Fo| – |Fc||/Σ|Fo|. [b] wR2 is defined as [Σ[w(Fo – Fc ) ]/Σw(Fo2)2]1/2. [c] The distances d1 and d2 are defined in Table 1. [d]
The dihedral angle φ is defined as the angle between the four acetylenic carbon atoms.
2
2 2
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Cyclization of Fluorinated Benzo-Fused Enediynes
zene,[19] prominently displaying an intense transition at
275 nm and a broad, poorly defined peak between 285 and
340 nm, reflecting the larger, conjugated π-electron system.
Altogether, the UV/Vis spectra are mostly determined by
the extended (benzo)enediyne substructure and show no
pronounced effect of the fluorine substituents.[20]
Crystal structures of enediynes: Single crystals suitable for
X-ray structure determination were grown of six fluorinated
benzo-enediyne derivatives. The molecular structures dis-
play variations in the distances between the alkyne sp-car-
bon atoms (d1, d2), the dihedral angle (φ), and for deriva-
tives 6f and 7f in the orientation of the two phenyl substitu-
ents (Table 2). The packing is governed by a variety of inter-
actions. In the presence of hydroxy groups, hydrogen bond-
ing is dominant (6d,e; 7d,e). More interestingly, non-cova-
lent interactions involving the fluoroarene moieties are ob-
served. Compared to benzene, which has an electron-rich
Scheme 1. 1,2-Bis(phenylethynyl)benzene derivatives 8 and fluori-
nated dehydroannulenes 9, 10 with known crystal structures.
C6 core, hexafluorobenzene exhibits the opposite polariza- the solid state, 7a forms slightly undulating layers along the
tion with a negatively polarized periphery and a positively (103) plane. The molecules are arranged in alternating di-
polarized C6 core.
rections in the layers (Figure 1, b). The packing within these
Such interactions have been discussed in the literature in layers is governed by attractive alternating molecular di-
terms of arene-arene interactions (edge-to-face, face-to- poles and close packing. The closest Cmethyl···F contacts
face) among fluoro aromatics and between fluoroaromatics within the layers are 3.154 Å. The layers are stacked on top
and non-fluorinated aromatics.[2,21] In complex molecular of each other so that the electron-rich alkyne groups are on
systems, deviations from such idealized interactions are ob- top of the tetrafluorobenzene subunit with Calkyne···Carene
served (vide infra). In addition to arene-arene interactions, distances of 3.305, 3.305, 3.434, and 3.461 Å, which are
interactions involving overall molecular dipole moments are close to the sum of the van-der-Waals radii (3.40 Å)[25] (see
important and the alkyne groups have also to be consid- Figures S9 in the Supporting Information). In addition,
δ+
ered.
Fδ–···Carene distances with 3.032 Å are present between
Despite the importance of the structural enediyne motif tetrafluorobenzene subunits of different layers which is
in the context of Bergman cyclization reactions, the Cam- shorter than the sum of the van-der-Waals radii (3.17 Å).[25]
bridge Data base[22] reveals only five closely related, non-
The alcohol 7d (Figure 2, a) shows the expected bond
fluorinated benzo-enediyne crystal structures amongst the lengths and angles of a slightly less planar carbon frame-
listed data, i.e., the chromium complex of the non-fluori- work with a torsional angle φ of 3.69(16)°. The two oxygen
nated parent compound 8a and the four derivatives 8b–d.[23] atoms of the hydroxy groups participate in intermolecular
Conversely, crystal structures of fluorinated benzo-enediyne hydrogen-bonding forming sheets along the (100) plane
derivatives have so far only been reported for two groups, with a thickness of the unit cell (Figure 2, b). The fluorine
i.e., the dehydroannulenes 9 and 10 (Scheme 1).[24]
atoms are located on the outside of these sheets, while the
Compound 7a (Figure 1, a) crystallizes in the monoclinic H-bonded network with the hydroxy groups are in its cen-
space group P21/n and the carbon and fluorine framework ter. Within the sheets, hydrogen bonds link two molecules
is nearly planar with typical bond lengths and angles. In in a V shape. These V-shaped “dimers” are stacked along
Figure 1. (a) Thermal ellipsoid plot of compound 7a, (b) view of one layer in the (103) plane. Thermal ellipsoids are drawn at the 50%
probability level.
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Figure 2. (a) Thermal ellipsoid plot of 7d, (b) view of contacts of a sheet with one molecule of a second sheet. Thermal ellipsoids are
drawn at the 50% probability level.
the b axis. The forces in between the V-shaped stacks are strong intramolecular hydrogen bonding which effectively
hydrogen bonds. Along the c-axis, the second dimension of causes the hydroxy-substituted groups on the triple bonds
the layer is formed by V-shaped stacks alternating their di- to bend toward each other, depressing the substituent
rections, being also connected by hydrogen bonding. The angles along the triple bond (171.54, 175.87; 171.96,
interactions between sheets are edge-to-face interactions of 178.59°). The dihedral angle φ of 3.04(13)° is in the interme-
δ+
the tetrafluorobenzene subunit with Fδ–···Carene contacts diate range of the investigated fluorobenzo-enediynes. Inter-
of 2.931 Å as shown in Figure 2 (b).
molecular hydrogen bonding between two molecules, which
The tetramethyl-substituted alcohol 7e shows signifi- are related by crystallographic symmetry, result in dimer
cantly shortened distances between the alkyne carbon formation (Figure 3, a). Within the unit cell the molecules
atoms (d1 and d2). These short distances are a result of are stacked in alternating directions, exhibiting π-stacking
Figure 3. (a) Thermal ellipsoid plot of the hydrogen-bridged dimers in the crystal structure of compound 7e, (b) view of the stacking
arrangement of the dimers. Thermal ellipsoids are drawn at the 50% probability level.
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Cyclization of Fluorinated Benzo-Fused Enediynes
(plane···aryl distances: 3.384 Å). In addition, the laterally
adjacent molecules are also oriented in the opposite direc-
tions according to their attractive molecular dipole mo-
ments.
Single crystals were also obtained of diol 6e with 36 mo-
lecules in the unit cell and nine crystallographically inde-
pendent molecules. In contrast to 7e only three of the nine
crystallographically independent molecules exhibit intramo-
lecular hydrogen-bonding. Intermolecular hydrogen-bond-
ing connects molecules in sheets of two-molecule thickness.
As in 7e, the hydrogen-bonded network is located in the
center of these sheets. The three molecules that show intra-
molecular hydrogen bonding, display d1 and d2 distances
of 2.785(3)–2.790(3) and 3.665(3)–3.695(3) Å, respectively,
which are significantly shorter than those without intramo-
lecular hydrogen bonding [distances d1 of 2.839(3)–
2.899(3) Å, distances d2 of 3.989(3)–4.221(3) Å]. Such
shortening of the distances between the acetylenic carbon
atoms as a consequence of intramolecular hydrogen bonds
is in agreement with the structure of 7e (vide supra). The
values for the dihedral angle φ cover also a considerable
range of 0.1(3)° to 2.4(3)°. In addition to hydrogen bond-
ing, π-stacking is observed along the a axis (see Figures S10
in the Supporting Information).
Crystals suitable for X-ray crystallography were obtained
for both diphenyl derivatives 6f and 7f. Since both com-
pounds have an extended π-system, they are expected to be
nearly planar. While 7f deviates slightly from planarity,
mainly as a consequence of the steric crowding of the
Figure 4. (a) Thermal ellipsoid plot of 7f, (b) view of the herring-
bone pattern with edge-to-face arene interaction. Thermal ellip-
soids are drawn at the 50% probability level.
phenyl groups, the phenyl groups of 6f were found to be dent molecules in the unit cell. The molecular structures of
twisted significantly out of the expected planar molecular each of these are significantly different from that of 7f. The
arrangement. Surprisingly, the d1 and d2 distances in 6f and distance between the two terminal acetylenic carbon atoms
7f are not the largest among the enediynes in this study, is smaller than in 7f, and as a consequence the phenyl sub-
despite of the steric crowding of the phenyl substituents. stituents are significantly rotated out of the difluorobenzene
The shorter alkyne distances are likely a consequence of plane (I/II: 21.59°, I/III: 23.13°; IV/V: 45.42°, IV/VI:
packing in the solid state, and structures in solution are 18.73°). At first sight, the packing arrangement of 6f seems
likely to display longer d1 and d2 distances.
similar to that of 7f as it also adopts a herring-bone struc-
Compound 7f (Figure 4, a) with its distinct delocalized ture. The bands along the [10–1] direction have, however, a
π-system displays the largest dihedral angle φ amongst the width of one molecule and different intermolecular interac-
tetrafluoro derivatives. While one phenyl group (II) is nearly tions are present. The adjacent bands are linked via edge-
coplanar with the tetrafluoroarene moiety (I) with 1.68° be- to-face arene interactions with the molecules of adjacent
tween the two planes, the second phenyl group (III) displays bands having the opposite orientation. The distances be-
a larger twist with an angle of 8.39° out of the tetrafluo- tween hydrogen atoms of the difluoroarene and the plane
roarene plane (I) between the arene planes I and III (Fig- of the phenyl groups are 2.560 (II/IV) and 2.600 Å (I/VI).
ure 4, a).
Due to the marked twisting of the phenyl groups, the cor-
The packing arrangement in the crystal lattice of 7f is a ners of zig-zag layers are more rounded. In contrast to 7f,
herring bone structure. Bands with a width of two mole- the difluoro arene unit in 6f is involved in edge-to-face in-
cules extend along the [10–1] direction. The tetrafluoroar- teractions with the phenyl groups. Perpendicular Cphenyl
–
ene groups are in the center of the bands while the phenyl H···F contacts of 2.576 and 2.619 Å link the enediyne mole-
groups are on its periphery. Adjacent bands are perpendicu- cules to two neighbours that are parallel to each other but
lar to each other exhibiting edge-to-face arene interactions with opposite orientation. In addition to the edge-to-face
of the phenyl groups (arene-centroid···arene-H distance: contacts, attracting opposite dipole moments seems to gov-
2.809 Å, Figure 4, b), resulting in a zig-zag structure. These ern the crystal structure (Figure 5).
zig-zag structures are stacked into the third dimension by
Bergman cyclization: The Bergman cyclization is a well
π-stacking.
established synthetic route to aromatic moieties and numer-
Different to tetrafluorobenzo-enediyne 7f, the less fluori- ous reports provide experimental and theoretical details for
nated derivative 6f crystallizes in the triclinic system with the thermally, photochemically or metal-activated cycliza-
space group P1 showing two crystallographically indepen- tion of enediyne precursors.[16] Nevertheless, the reaction
¯
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propyl-terminated substrates 6b and 7b proceed more
slowly to yield rather complex, product-containing mixtures
(GC/MS) (Table 3). The enediynes 6c, 6e, 7c and 7e with
bulky alkyne termini did – expectedly – not yield any naph-
thalene products and showed only marginal conversion to
other, unidentified products or complete conversion to
complex product mixtures (NMR, GC/MS). In either case,
we could neither isolate products forming through alterna-
tive cyclization pathways, such as the Schmittel cyclization,
nor find unequivocal spectroscopic evidence for any of the
latter. Although the short terminal alkyne distance d2 of 7e
in the solid state might suggest a facile Bergman cyclization,
we want to emphasize that the corresponding structure in
solution will most likely differ and, furthermore, that steric
hindrance of two bulky substituents in the adjacent 6- and
7-position of the naphthalene 12f prevents the cyclization.
Although this latter argument certainly applies to enediyne
precursors 6c and 7c it is quite noteworthy that Zaleski et
al. demonstrated the feasibility of a Bergman cyclization for
Figure 5. Thermal ellipsoid plot of 6f; thermal ellipsoids are drawn
at the 50% probability level.
has not yet been applied to fluorinated benzo-enediyne pre- an isopropyl-terminated benzo-enediyne substructure in a
cursors, although a few reports by Alabugin et al. provide porphyrin derivative, though at low conversion rates.[30]
calculated data on the ortho-effect of fluorine substituents Conversely, the diphenyl substrates 6f and 7f displayed only
on the Bergman cyclization[26] of selected substrates, includ- 5–10% conversion to complex mixtures that did not reveal
ing fluoro-diethynylbenzene.[27] Furthermore, the cycliza- the desired naphthalene target compounds. This observa-
tion of tetrafluoro-o-diethynyl benzene to the correspond- tion is in accordance with an earlier report on the Bergman
ing p-benzyne intermediate was discussed in the context of cyclization of the non-fluorinated parent compound, o-bis-
a rehybridization model, establishing a mechanistic rela- (phenylethynyl)benzene, yielding only small amounts of the
tionship between the Bergman cyclization and the Cope re- corresponding naphthalene products with a 2,3-, 2,4- and
arrangement.[27]
4,4-diphenyl substitution pattern.[31]
An initial comparison of the thermal reactivities of the
ten crystalline fluorinated benzo-enediynes 6a, 6c–f, 7a, and
7c–f by differential scanning calorimetry (DSC) is rather
inconclusive: All compounds display a sharp endothermic
peak for the melting transition at temperatures below
130 °C, but differ in their behaviour at higher temperatures.
Only compounds 6c, 6d, 6f, 7c and 7d display exothermic
peaks, whereas all other derivatives show endothermic
events. A possible explanation for compounds 6d and 6f is
that only diols can complete the naphthalene formation as
the corresponding p-benzyne intermediate abstracts two hy-
drogen atoms from the hydroxy groups.
Table 3. Fluorinated naphthalene derivatives from benzo-enediyne
precursors by Bergman cyclization.
The cyclization reactions were carried out safely in a
Biotage Initiator microwave reactor on a 100-mg scale, as
reaction temperature and pressure were continuously moni-
tored throughout each run. Typically, ortho-dichloroben-
zene was employed as a solvent, although the diol sub-
strates (6c, 6d, 7c, 7d) required a co-solvent (ethanol). As a
hydrogen atom source 1,4-cyclohexadiene was used in a
100-fold excess, typically leading to pressures between 10–
12 atm within the reaction vial at the target temperature.
As discussed in a previous communication on a microwave-
assisted Bergman cyclization,[28] and as now accepted for
microwave-assisted reactions in general,[29] no “special
microwave effects” could be observed.
M. p.
[°C][a]
DSC onset temp. Conv.
[°C][b] [%][c]
Product (yield)
[%][d]
6a
50–52
oil
116–118
102–103
oil
146 (endothermic) 50
140 (endothermic) 90
11a (85)
11b[e]
11d (87)
12a (90)
12b[e]
6b
6d[f]
7a
157 (exothermic)
100
124 (endothermic) 30
118 (endothermic) 70
7b
7d[f]
117–118
185 (exothermic)
100
12d (82)
[a] Uncorrected melting points. [b] DSC data were determined in
an aluminium pan without addition of a hydrogen atom donor;
DSC onset temperatures for 6c, 6e, 6f, 7c, 7e and 7f are reported
in the experimental section; see also Table S2 and S3. [c] To avoid
an increase in tarry materials the reactions were not always driven
to completion. [d] The reported yields refer to isolated products
and are based on the converted starting materials. [e] The naphtha-
lene derivatives could not be purified from these reaction mixtures,
though GC/MS and NMR spectra of the crude products clearly
demonstrated their formation. [f] Ethanol was required as a co-
The methyl- and hydroxymethyl-substituted benzo-en-
ediynes 6a, 6d, 7a and 7d delivered the corresponding fluo-
rinated naphthalene target compounds 11a, 11d, 12a and
12d in good yields, whereas the sterically more demanding solvent.
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Cyclization of Fluorinated Benzo-Fused Enediynes
Thus, we were successful in isolating the fluoronaphtha- vation barriers. On a small scale these reactions can be car-
lenes 11a, 11d, 12a, and 12d as colorless solids after column ried out safely within a microwave reaction chamber,
chromatography. Their NMR spectroscopic data show - de- whereas a large scale preparation would require the use of
spite the structural change – a close relationship to their an autoclave to allow for the generated high pressures.
precursors, i.e., the characteristic di- and tetrafluorobenzo
Crystal structures of fluorinated naphthalenes: Single
subunit, the resonances of the substituents in the 6- and 7- crystals of fluoronaphthalenes 12a and 12d were grown
position, and new signals associated with the annulated ar- from acetonitrile and benzene, respectively. Surprisingly, we
ene unit.
also obtained the crystal structure of the derived acetonide
Attempts to convert the enediynes 6 and 7 photochemi- 13 from one crystallization batch, most certainly due to a
cally under various conditions (solvents: 2-propanol, hex- contaminated solvent (acetone, traces of acid). A control
anes; experimental set-up/light source: Rayonet reactor or experiment under standard acetalization conditions (ace-
immersion well/300 nm; concentration: 6ϫ10–6 m; reaction tone, p-toluenesulfonic acid) confirmed the facile formation
times: hours to days) were unsuccessful.[32]
of the naphthodioxepane derivative 13. The crystallo-
In summary, the preparation of fluorinated naphthalene graphic data for 12a, 12d, and 13 are summarized in
derivatives from the corresponding benzo-enediyne precur- Table 4. The structures (Figure 6) show typical bond
sors via a thermal Bergman cyclization approach is feasible lengths and angles. Compounds 12a and 12d display planar
and shows no unusual restrictions other than high acti- carbon-fluorine frameworks; in diol 12d one of the oxygen
Table 4. Crystallographic data for fluorinated naphthalenes, 12a, 12d, and 13.
12a
12d
13
Empirical formula
Formula weight
C12H8F4
228.18
C12H8F4O2
260.18
C15H12F4O2
300.25
temperature [K]
153
153
153
colorless
0.23ϫ0.15ϫ0.15
triclinic, P1
6.7557(10)
9.3248(14)
10.4622(15)
78.269(2)
75.853(2)
87.920(2)
625.67(16)
2
1.594
0.0458
0.0852
0.0974
0.1143
0.24/–0.22
Color
colorless
0.22ϫ0.18ϫ0.12
triclinic, P1
colorless
0.22ϫ0.11ϫ0.09
monoclinic, P21
4.6752(6)
8.4448(11)
13.0623(16)
90
93.352(2)
90
514.83(11)
2
1.678
0.0402
0.0590
0.0846
0.0925
0.33/–0.23
Crystal size [mm3]
¯
¯
Crystal system, space group
a [Å]
b [Å]
c [Å]
7.2598(11)
8.0642(12)
9.3905(14)
95.050(2)
110.040(2)
106.800(2)
483.62(13)
2
1.567
0.0396
0.0697
0.1022
α [°]
β [°]
γ [°]
Volume [Å3]
Z
ρcalcd [mgm–3]
[a]
R1[a] [IϾ2σ(I)]
R1 (all)
[b]
wR2[b] [IϾ2σ(I)]
wR2 (all)
0.1186
0.28/–0.17
Largest diff. peak/hole [eÅ–3]
2
2 2
[a] R1 is defined as Σ||Fo| – |Fc||/Σ|Fo|. [b] wR2 is defined as [Σ[w(Fo – Fc ) ]/Σw(Fo2)2]1/2
.
Figure 6. Thermal ellipsoid plots of (a) dimethyl naphthalene 12a, (b) diol 12d, and (c) ketal 13; thermal ellipsoids are drawn at the 50%
probability level.
Eur. J. Org. Chem. 2011, 2969–2980
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C. M. Kane, T. B. Meyers, X. Yu, M. Gerken, M. Etzkorn
FULL PAPER
ter. Mass spectra, using electrospray ionization, were obtained on
a PerSpective Biosystems: Mariner Biospectrometry Workstation
model, using Mariner Instrument Control Panel v. 4.0.0.0 software
and Data Explorer, version 4.0.0.1 software for data analysis. Di-
rect insertion mass spectra were obtained on a Thermo Finnigan
GCQ Plus MS instrument. GC–MS data were obtained on an Ag-
ilent Technologies 6850 network GC System, using Agilent MSD
Chemstation and GC–MS Data Analysis Software. NMR spectra
were measured on a 300 MHz Joel 300 ECX or 500 MHz Joel ECA
500 instrument. All spectra were recorded at 298 K and the chemi-
atoms is located out of plane. The packing diagram of diol
12d reveals intermolecular hydrogen-bonding and π-stack-
ing interactions resulting in sheets along the (001) plane
(see Figure S11 in the Supporting Information). Similar to
7d, the hydroxy groups are located at the center of these
sheets, while the tetrafluoro arene moieties point to the
outside. Interactions between the sheets are mainly
δ+
Fδ–···Carene of 2.999 Å, which is smaller than the sum of
the van der Waals radii (3.17 Å).[25] The fluoronaphthalene
12a, with the absence of hydrogen-bonding, forms a layered cal shifts are reported in ppm, assigning tetramethylsilane [δ(TMS)
= 0.00 ppm] as 1H and 13C reference and CFCl3 [δ(CFCl3) =
structure, where fluoronaphthalene molecules are of dif-
0.00 ppm] as 19F reference. Signal assignments are based on homo-
ferent layers are placed above each other with opposite ori-
and heteronuclear 2D NMR experiments and on comparison with
entation based on attracting opposite molecular dipole mo-
analogous compounds when applicable. Signals indicated with *,
ments with Cfluoroareneδ–···Carene distances of 3.372 Å and
**, etc. are mutually interchangeable. The signal structure is indi-
a distance between the molecular planes of 3.355 Å. The
cated with the usual abbreviations for singlet (s), doublet (d), mul-
δ+
packing within the layers also seems to be governed by mo-
tiplets are quoted over the entire signal range or as centered mul-
lecular dipole moments and close packing. Such a layered
tiplet. If a multiplet has an apparent triplet structure it is quoted
structure with the fluoroarene moiety located on top of the
non-fluorinated arene moiety has also been observed in the
crystal structure of unsubstituted tetrafluoronaphtha-
lene.[21a,33]
The characteristic structural feature in compound 13 is
the prominent non-planar, twist-like conformation of the
dioxepane subunit. The crystal packing of ketal 13 displays
a π-stacked arrangement in which pairs of molecules inter-
act through their fluorinated and non-fluorinated arene
moieties, respectively (3.381 Å plane distance). Further-
more, the fluoroarene subunits show additional π-stacking
with a larger plane distance (3.435 Å).
as tapp. Elemental analysis was carried out by Atlantic Microlab,
Inc.
X-ray Crystallography: Collection and Reduction of X-ray Data: X-
ray diffraction data were collected using a Bruker SMART APEX
II diffractometer equipped with an APEX II 4 K charge-coupled
device (CCD) area detector (by use of the program APEX2)[34] and
a sealed-tube X-ray source (graphite-monochromated Mo-Kα radi-
ation, λ = 0.71073 Å). A complete sphere of data was collected to
better than 0.8 Å resolution. Processing was carried out by using
the program SAINT,[35] which applied Lorentz and polarization
corrections to three-dimensionally integrated diffraction spots. The
program, SADABS,[36] was used for the scaling of diffraction data,
the application of a decay correction and an empirical absorption
correction based on redundant reflections.
Solution and Refinement of the Structure: All calculations were per-
formed using the SHELXTL Plus package[37] for structure determi-
nation, refinement and molecular graphics. The XPREP pro-
gram[37] was used to confirm the unit cell dimensions and the crys-
Conclusions
In summary, we have achieved the synthesis of twelve
fluorinated benzo-enediynes and determined the crystal
structures of six. Despite rather subtle changes (difluoro- tal lattice. A solution was obtained using direct methods. Successive
difference Fourier syntheses revealed all atoms. The final refine-
ment was obtained by introducing a weighting factor and aniso-
tropic thermal parameters for all non-hydrogen atoms.
vs. tetrafluoro derivatives) in the arene unit and some modi-
fications in the terminal acetylene unit, the molecular struc-
tures display variations in the enediyne substructure (d2,
orientation of phenyl substituents) and significantly dif-
ferent arrangements in the crystal lattice. These effects were
explained by non-covalent arene-arene interactions and hy-
drogen bonding, dipole–dipole interactions, as well as pack-
ing effects. Furthermore, we obtained fluorinated naphtha-
lene derivatives by a thermally initiated Bergman cycliza-
tion, thus circumventing the rather laborious preparation of
suitable precursors. Crystal structures of three naphthalene
derivatives complemented the analytical data.
General Procedure for Cross-Coupling of Aryl Halides with Alkynes:
To a degassed solution of the dihaloarene 1 (2) [750 mg, 1 equiv.] in
toluene [15 mL] and diisopropylamine [4.5 mL], CuI [0.083 equiv.],
alkyne 3 [2.2 equiv.] and the catalyst Pd(PPh3)4 [0.075 equiv.] were
added. In case of the difluoroarene precursor 1 an additional
amount of triphenylphosphane [half of the mass of the catalyst]
was dissolved with the reaction mixture. The yellow reaction mix-
ture was heated [85 °C] under nitrogen atmosphere overnight. Once
the reaction was complete or upon no further conversion (19F
NMR spectroscopy, Table S1), the solvent/base was removed in
vacuo, and the crude residue was worked up further as described
for each case below.
Experimental Section
1,2-Difluoro-4,5-bis(prop-1-ynyl)benzene (6a): The resulting residue
was taken up in cyclohexane, filtered through neutral alumina, con-
centrated, and then purified by column chromatography (silica gel,
Materials and Instrumentation: Starting materials and reagents were
used as purchased. All solvents were purified and dried along stan-
dard procedures. All reactions were carried out under Ar atmo-
sphere. Melting points are uncorrected and were determined in un-
sealed capillary tubes on a MEL-TEMP® Electrothermal appara-
tus. Infrared spectra were recorded on KBr pellets on a Thermo-
Matteson Satellite 3000 FTIR spectrophotometer. UV/Vis spectra
were recorded on a Varian Cary 300 Bio UV/Vis spectrophotome-
cylcohexane, Rf = 0.27). A light yellow solid was isolated (430 mg,
1
82%), m.p. 50–52 °C. H NMR (300 MHz, CDCl3): δ = 7.14 (tapp
,
2 H, ArH), 2.09 (s, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
δ = 149.4 (dd, JCF = 252.2; JCF = 15.2 Hz, C1,2), 123.3 (m, C3,6),
1
2
120.6 (m, C4,5), 90.4 (CCCH3), 77.0 (CCCH3), 4.7 (CH3) ppm. 19F
NMR (283 MHz, CDCl3): δ = –137.5 (tapp) ppm. IR (KBr): ν =
˜
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Cyclization of Fluorinated Benzo-Fused Enediynes
3055, 2923, 2852 (ArH), 2234, 2050 (Csp–Csp), 1749, 1589 (C=C),
1495, 1407, 1335, 1266, 1237, 1188, 1142, 892, 878, 794, 671 . UV/
876, 742, 710, 695 cm–1. UV/Vis (MeCN): λmax (ε) = 221 (25,283),
231 (33,919), 258 (11,005), 271 (9,830), 294 (744), 306 (566) nm
Vis (MeCN): λmax (ε) = 220 (30,723), 230 (43,926), 255 (13,656), (m–1 cm–1). MS (EI, 70 eV): m/z (%) = 222 (21) [M·+], 204 (16), 191
268 (12,734), 295 (1,042), 308 (5,918) nm (m–1 ) cm–1. MS (EI, (7), 177 (10), 176 (56), 175 (100), 165 (10), 164 (27), 163 (11), 162
70 eV): m/z (%) = 191 (13) [M·+ + 1], 190 (100) [M·+], 189 (26), 188
(7), 157 (13), 156 (15), 155 (6), 151 (23), 150 (6), 149 (6), 145 (12),
(71), 187 (8), 175 (7) [M·+ – CH3], 170 (18), 169 (13), 168 (6), 164 144 (6), 143 (15), 125 (11), 123 (7), 99 (6), 87 (6), 75 (8), 74 (6), 63
(11), 162 (5), 151 (8) [M·+ – CCCH3], 94 (13), 83 (6), 82 (6), 75 (6), (6). C12H8F2O2 (222.19): calcd. C 64.87, H 3.63; found C 64.76, H
74 (6). C12H8F2 (190.19): calcd. C 75.78, H 4.24; found C 75.81, H
.22.
3.59.
4-[4,5-Difluoro-2-(3-hydroxy-3-methylbut-1-yn-1-yl)phenyl]-2-meth-
1,2-Difluoro-4,5-bis(pent-1-ynyl)benzene (6b): The resulting residue
ylbut-3-yn-2-ol (6e): The residue was taken up with ethyl ether and
was taken up in hexanes, filtered through neutral alumina, and con- filtered through neutral alumina. The solvent was evaporated in
centrated. Purification by column chromatography (silica gel, hex-
vacuo and purification by column chromatography (silica gel, cy-
clohexane/EtOAc, [2:1], Rf = 0.21) furnished an off- white solid
(422 mg, 55%), m.p. 66–68 °C. DSC-onset temperature: 150 °C (en-
dothermic). 1H NMR (300 MHz, CDCl3): δ = 7.19 (tapp, 2 H,
ArH), 2.58 (s, 2 H, OH), 1.62 (s, 12 H, CH3) ppm. 13C NMR
anes, Rf = 0.30), yielded an orange oil (482 mg, 71%). 1H NMR
3
(300 MHz, CDCl3): δ = 7.15 (tapp, 2 H, ArH), 2.42 (t, JCH2-CH2
=
=
3
7.0 Hz, 4 H, CH2), 1.64 (m, 4 H, CH2), 1.07 (t, JCH3-CH2
7.35 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 149.4
(dd, JCF = 252.2; JCF = 15.2 Hz, C1,2), 123.5 (m, C4,5), 120.5 (m,
(75 MHz, CDCl3): δ = 151.5 (dd, JCF = 253.6; JCF = 15.1 Hz,
1
2
1
2
C3,6), 94.8 [CC(CH2)2CH3], 78.2 [CC(CH2)2CH3], 22.1 (CH2), 21.6 C4,5), 122.8 (m, C3,6), 120.1 (m, C1,2), 98.8 [CCC(CH3)2OH], 79.3
(CH2), 13.6 (CH3) ppm. 19F NMR (283 MHz, CDCl3): δ = –137.8 [CCC(CH3)2OH], 65.8 [CCC(CH3)2OH], 31.4 (CH3) ppm. 19F
(tapp) ppm. IR (KBr): ν = 2964 (ArH), 2934, 2874, 2229 (C –C ), NMR (283 MHz, CDCl3): δ = –136.0 (tapp) ppm. IR (KBr): ν =
˜
˜
sp
sp
1587 (C=C), 1498, 1413, 1317, 1187, 1147, 880, 799, 769 cm–1. UV/
3239 (OH), 2982, 2934 (ArH), 2223 (Csp–Csp), 1586 (C=C), 1500,
Vis (MeCN): λmax (ε) = 222 (26,023), 232 (38,717), 258 (12,551), 1411, 1362, 1226, 1151, 914, 872, 700 cm–1. UV/Vis (MeCN): λmax
272 (11,551), 298 (2,545), 310 (2,351) nm (m–1 cm–1). MS (EI, (ε) = 221 (28,740), 231 (41,848), 258 (12,345), 271(11,221), 295
70 eV): m/z (%) = 247 (17) [M·+ + 1], 246 (100) [M·+], 217 (15)
[M·+ – CH2CH3], 215 (8), 214 (11), 203 (25), 202 (45), 201 (78),
199 (5), 197 (23), 196 (7), 190 (7), 189 (24), 188 (29), 188 (29), 187
(454), 307 (312) nm (m–1 cm–1). MS (EI, 70 eV): m/z (%) = 278 (7)
[M·+], 246 (15), 245 (94), 230 (23), 228 (6), 227 (9), 225 (7), 217
(25), 215 (5), 214 (5), 207 (5), 203 (12), 202 (47), 201 (69), 198 (5),
(7), 186 (5), 184 (5), 183 (33), 177 (20), 175 (11), 170 (5), 168 (5), 197 (30), 189 (6), 188 (13), 183 (19), 181 (5), 177 (15), 175 (10), 164
164 (11), 162 (5), 151 (12). C16H16F2 (246.29): calcd. C 78.02, H
6.54; found C 78.09, H 6.49.
(5), 162 (5), 151 (14), 124 (8), 59 (7), 43 (100). C16H16F2O2 (278.29):
calcd. C 69.05, H 5.79; found C 68.96, H 5.82.
1,2-Difluoro-4,5-bis(3-methylbut-1-ynyl)benzene (6c): The residue 1,2-Difluoro-4,5-bis(2-phenylethynyl)benzene (6f): The resulting res-
was taken up in hexanes and filtered through neutral alumina. Af-
ter concentration, column chromatography (silica gel, hexanes, Rf
= 0.31) yielded a light orange solid (530 mg, 78%), m.p. 37–39 °C.
idue was taken up in hexanes and filtered through neutral alumina.
The solution was concentrated and purified by column chromatog-
raphy (silica gel, hexanes, Rf = 0.23) to yield a yellow to orange
1
DSC-onset temperature: 90 °C (exothermic). H NMR (300 MHz,
solid (727 mg, 84 %), m.p. 80–82 °C. DSC-onset temperature:
1
CDCl3): δ = 7.15 (tapp, 2 H, ArH), 2.82 (m, 2 H, CH), 1.28 (d, 232 °C (exothermic). H NMR (300 MHz, CDCl3): δ = 7.55 (m, 4
1JCH3-CH = 7.00 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3):
H, ArH), 7.36 (m, 8 H, HPh3Ј,5Ј, HPh4Ј, ArH) ppm. 13C NMR
1
2
1
2
δ = 149.2 (dd, JCF = 252.5; JCF = 15.0 Hz, C1,2), 123.3 (m, C4,5),
120.2 (m, C3,6), 100.1 [CCCH(CH3)2], 77.0 [CCCH(CH3)2], 22.9
(CH), 21.3 (CH3) ppm. 19F NMR (283 MHz, CDCl3): δ = –137.8
(125 MHz, CDCl3): δ = 149.6 (dd, JCF = 254.4, JCF = 15.6 Hz,
C1,2), 131.7 (CPh2Ј,6Ј), 128.8 (CPh4Ј), 128.4 (CPh3Ј,5Ј), 123.0 (m, C3,6),
122.7 (CPh1Ј), 120.4 (m, C4,5), 94.2 (CC–Ph), 86.4 (CC–Ph) ppm.
(tapp) ppm. IR (KBr): ν = 2976 (ArH), 2229 (C –C ), 1755, 1579
19F NMR (283 MHz, CDCl3): δ = –135.9 (tapp) ppm. IR (KBr): ν
˜
˜
sp
sp
(C=C), 1495, 1465, 1412, 1304, 1231, 1199, 1130, 1076, 888, 846, = 3057 (C–H), 2923, 2853, 2202 (Csp–Csp), 1965, 1586 (C=C), 1503,
773, 667 cm–1. UV/Vis (MeCN): λmax (ε) = 223 (33,180), 232 1354, 1230, 1183, 1069, 877, 754, 688 cm–1. UV/Vis (MeCN): λmax
(50,247), 259 (15,102), 272 (13,989), 398 (1,469), 310 (1,330) nm (ε) = 220 (26,979), 271 (46,536), 310 (22,262) nm (m–1 cm–1). UV/
(m–1 cm–1). MS (EI, 70 eV): m/z (%) = 245 (17) [M·+ + 1], 246 (100)
Vis iPrOH): λmax (ε): 221 (23,867), 270 (44,567), 311 (21,583) nm
[M·+], 231 (6) [M·+ – CH3], 217 (6), 216 {36) [M·+ – 2(CH3)]}, 215 (m–1 cm–1). MS (EI, 70 eV): m/z (%) = 315 (23) [M·+ + 1], 314 (100)
(28), 214 (27), 212 (7), 211 (13), 204 (6), 203 (42) [M·+ –CH- [M·+], 313 (18), 312 (55), 310 (10), 294 (10), 292 (19), 157 (5), 156
(CH3)2], 202 (27), 201 (93), 197 (8), 196 (8), 194 (6), 191 (6), 189
(13), 147 (5), 146 (5). C22H12F2 (314.33): calcd. C 84.06, H 3.85;
(17), 188 (33), 184 (8), 183 (58), 177 (13), 175 (8), 170 (7), 165 (6), found C 84.02, H 3.82.
164 (8), 151 (12), 107 (7), 94 (8). C16H16F2 (246.29): calcd. C 78.02,
1,2,3,4-Tetrafluoro-5,6-bis(propyn-1-yl)benzene (7a): The resulting
residue was taken up in cyclohexane, filtered through neutral alu-
H 6.54; found C 78.00, H 6.57.
3-[4,5-Difluoro-2-(3-hydroxyprop-1-yn-1-yl)phenyl]prop-2-yn-1-ol mina, and concentrated. Recrystallization with methanol afforded
(6d): The resulting residue was taken up with ethyl ether, filtered
through neutral alumina and purified by column chromatography
(silica gel, cyclohexane/EtOAc,[2:1], Rf = 0.39). Concentration of
the eluate and recrystallization with methanol, afforded a colorless
solid (379 mg, 62 %), m.p. 116–118 °C. 1H NMR (300 MHz,
a white crystalline material (371 mg, 88%), m.p. 102–104 °C. 1H
NMR (300 MHz, CDCl3): δ = 2.06 (s, 6 H, CH3) ppm. 13C NMR
1
(75 MHz, CDCl3): δ = 148.3 (dm, JCF = 247.9 Hz, C2,3), 140.3
1
(dm, JCF = 248.5 Hz, C1,4), 111.9 (m, C5,6), 97.8 (CCCH3), 69.6
(CCCH3), 4.9 (CH3) ppm. 19F NMR (283 MHz, CDCl3): δ =
CDCl3): δ = 7.21 (tapp, 2 H, ArH), 4.52 (s, 4 H, CH2) ppm. 13C –136.9 (m, 2 F), –156.4 (m, 2 F) ppm. IR (KBr): ν = 2922 (C–H),
˜
1
2
NMR (125 MHz, CDCl3): δ = 149.9 (dd, JCF = 254.9; JCF
=
2245 (Csp–Csp), 1634 (C=C), 1501, 1475, 1376, 1261, 1175, 1077,
15.0 Hz, C4,5), 122.5 (m, C3,6), 120.1 (m, C1,2), 92.4 (CCCH2OH), 1054, 1010 cm–1. UV/Vis (MeCN): λmax (ε): 227 (45,940), 259
82.7 (CCCH2OH), 51.6 (CH2) ppm. 19F NMR (283 MHz, CDCl3): (16,517), 270 (16,418), 302 (2,148) nm (m–1 cm–1). UV/Vis iPrOH):
δ = –135.4 (tapp) ppm. IR (KBr): ν = 3356 (OH), 2919 (ArH), 2232
(Csp–Csp), 1588 (C=C), 1497, 1411, 1331, 1230, 1187, 1012, 959,
λmax (ε) = 228 (57,663), 260 (20,748), 271 (20,939), 305 (2,679) nm
(m–1 cm–1). MS (EI, 70 eV): m/z (%) = 227 (13) [M·+ + 1], 226 (100)
˜
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C. M. Kane, T. B. Meyers, X. Yu, M. Gerken, M. Etzkorn
FULL PAPER
[M·+], 225 (13), 224 (35), 211 (8) [M·+ – CH3], 207 (10), 206 (39),
(62), 192 (13), 191 (9), 187 (31), 186 (6), 182 (7), 180 (10), 179 (6),
162 (16), 161 (14), 151 (41), 150 (5), 149 (12), 147 (6), 129 (10), 123
205 (12), 204 (8), 200 (15), 198 (6), 187 (15) [M·+ – CC(CH3)], 186
(5), 175 (19), 174 (5), 123 (5), 112 (5), 99 (7), 75 (6), 74 (6), 51 (5). (11), 111 (6), 105 (6), 99 (13), 98 (5), 93 (7), 81 (5), 75 (6).
C12H6F4 (226.17): calcd. C 63.73, H 2.67; found C 63.80, H 2.62.
C12H6F4O2 (258.17): calcd. C 55.83, H 2.34; found C 55.78, H 2.29.
2-Methyl-4-[2,3,4,5-tetrafluoro-6-(3-hydroxy-3-methylbut-1-ynyl)-
phenyl]but-3-yn-2-ol (7e): The residue was taken up with ethyl ether,
filtered through neutral alumina and concentrated in vacuo. After
chromatography (silica gel, cyclohexane/EtOAc, 2:1, Rf = 0.14) a
beige solid (352 mg, 60%) was obtained, m.p. 122–124 °C. DSC-
onset temperature: 205 °C (endothermic). 1H NMR (300 MHz,
CDCl3): δ = 2.77 (s, 2 H, OH), 1.65 (s, 12 H, CH3) ppm. 13C NMR
1,2,3.4-Tetrafluoro-5,6-bis(pent-1-ynyl)benzene (7b): The residue
was taken up in hexanes and filtered through neutral alumina.
Upon concentration and column chromatography (silica gel, hex-
anes, Rf = 0.37) the product was obtained as a light yellow oil
3
(395 mg, 75%). 1H NMR (300 MHz, CDCl3): δ = 2.48 (t, JCH2-
3
= 7.0 Hz, 4 H, CH2), 1.67 (m, 4 H, CH2), 1.09 (t, JCH3-CH2
=
CH2
7.4 Hz, 6 H, CH3) ppm. 13C NMR (75 MHz, CDCl3): δ = 148.1
1
(125 MHz, CDCl3): δ = 147.6 (dm, JCF = 243.6 Hz, C3,4), 140.6
(dm, JCF = 248.5 Hz, C2,3), 140.3 (dm, JCF = 249.3 Hz, C1,4),
112.1 (m, C5,6), 102.1 [CC(CH2)2CH3], 70.6 [CC(CH2)2CH3], 21.9
(CH2), 21.8 (CH2), 13.3 (CH3) ppm. 19F NMR (283 MHz, CDCl3):
1
1
1
(dm, JCF = 251.4 Hz, C2,5), 111.2 (m, C5,6), 105.4 [CCC(CH3)2-
OH], 71.8 [CCC(CH3)2OH], 65.7 [CCC(CH3)2OH], 31.0 (CH3)
ppm. 19F NMR (283 MHz, CDCl3): δ = –135.6 (m, 2 F), –154.7
δ = –136.9 (m, 2 F), –156.7 (m, 2 F) ppm. IR (KBr): ν = 2968 (C–
˜
(m, 2 F) ppm. IR (KBr): ν = 3307 (OH), 2150 (C –C ), 1503
˜
H), 2937, 2238 (Csp–Csp), 1631, 1605 (C=C), 1504, 1477, 1064, 999,
749 cm–1. UV/Vis (MeCN): λmax (ε) = 221 (27,166), 229 (37,952),
262 (13,276), 273 (13,081), 295 (1,978), 305 (1,992) nm (m–1 cm–1).
MS (EI, 70 eV): m/z (%) = 283 (28) [M·+ + 1], 282 (100) [M·+], 253
(25), 252 (9), 251 (12), 250 (11), 240 (15), 239 (70), 238 (72), 237
(86), 235 (7), 234 (10), 233 (49), 232 (19), 227 (6), 226 (12), 225
(39), 224 (40), 222 (5), 193 (11), 189 (8), 188 (17), 187 (29), 186 (6),
184 (8), 183 (16), 175 (9), 174 (8), 170 (9), 53 (6), 41 (10). C16H14F4
(282.28): calcd. C 68.08, H 5.00; found C 68.11, H 4.97.
sp
sp
(C=C), 1491, 1009 cm–1. UV/Vis iPrOH): λmax (ε): 229 (49,555),
262 (16,710), 274 (16,554), 305 (2,543) nm (m–1 cm–1). UV/Vis
(MeCN): λmax (ε) = 228 (48,431), 260 (16,685), 272 (16,278), 306
(2,621) nm (m–1 cm–1). MS (EI, 70 eV): m/z (%) = 314 (4) [M·+], 299
(7), 295 (5), 282 (17), 281 (100), 279 (5), 266 (17), 263 (7), 254 (5),
253 (29), 251 (5), 243 (5), 241 (12), 239 (9), 238 (37), 237 (46), 233
(23), 232 (7), 225 (5), 224 (10), 222 (5), 220 (6), 219 (38), 217 (5),
214 (5), 213 (23), 211 (14), 206 (8), 204 (6), 201 (8), 200 (6), 199
(8), 198 (28), 197 (8), 193 (11), 188 (12), 187 (27), 183 (8), 147 (9),
129 (9), 123 (8), 99 (7), 59 (7), 58 (7). C16H14F4O2 (314.27): calcd.
C 61.15, H 4.49; found C 61.05, H 4.53.
1,2,3,4-Tetrafluoro-5,6-bis(3-methylbut-1-ynyl) (7c): The residue
was taken up in hexanes, filtered through neutral alumina and con-
centrated. Purification by column chromatography (silica gel, hex-
anes, Rf = 0.34) afforded a colorless solid upon recrystallization
from methanol (447 mg, 85%), m.p. 73–76 °C. DSC-onset tempera-
1,2,3,4-Tetrafluoro-5,6-bis(2-phenylethynyl)benzene (7f): Analytical
data as in ref.[16] The resulting residue was taken up in hexanes and
filtered through neutral alumina. The solution was concentrated
and then purified by chromatography (silica gel, hexanes, Rf =
0.24). After recrystallization from methanol the colorless product
(582 mg, 89 %) was obtained, m.p. 109–110 °C. DSC-onset tem-
1
ture: 114 °C (exothermic). H NMR (300 MHz, CDCl3): δ = 2.86
3
(m, 2 H, CH), 1.30 (d, JCH3-CH = 7.0 Hz, 6 H, CH3) ppm. 13C
1
NMR (75 MHz, CDCl3): δ = 147.9 (dm, JCF = 249.9 Hz, C2,3),
1
140.3 (dm, JCF = 257.2 Hz, C1,4), 112.0 (m, C5,6), 107.3
1
perature: 282 °C (endothermic). H NMR (300 MHz, CDCl3): δ =
[CCCH(CH3)2], 77.3 [CCCH(CH3)2], 22.8 (CH3), 21.7 (CH) ppm.
7.59 (m, 4 H, HPh 2Ј,5Ј), 7.39 (m, 6 H, HPh3Ј,5Ј, HPh4Ј) ppm. 13C
19F NMR (283 MHz, CDCl3): δ = –136.8 (m, 2 F), –156.7 (m, 2
1
NMR (75 MHz, CDCl3): δ = 147.9 (dm, JCF = 250.0 Hz, C2,3),
F) ppm. IR (KBr): ν = 2977 (C–H), 2935, 2875, 2233 (C –C ),
˜
sp
sp
1
140.8 (dm, JCF = 262.3 Hz, C1,4), 131.9 (Ph2Ј,6Ј), 129.5 (Ph4Ј),
1626 (C=C), 1486, 1308, 1103, 1087, 996, 894, 880, 748 cm–1. UV/
Vis (MeCN): λmax (ε) = 219 (28,921), 229 (39,704), 261 (14,037),
273 (13,710), 295 (2,217), 305 (2,322) nm (m–1 cm–1). MS (EI,
70 eV): m/z (%) = 283 (17) [M·+ + 1], 282 (100) [M·+], 267 (19), 253
(11), 252 (54), 251 (26), 250 (19), 248 (6), 247 (17), 240 (8), 239
(56), 238 (93), 233 (19), 232 (20), 230 (6), 227 (9), 225 (13), 224
(21), 220 (12), 219 (75), 213 (6), 211 (11), 202 (5), 201 (25), 200
(10), 199 (6), 198 (6), 193 (5), 189 (8), 188 (11), 187 (18), 175 (6),
170 (9), 125 (5), 112 (7). C16H14F4 (282.28): calcd. C 68.08, H 5.00;
found C 68.13, H 4.96.
128.6 (Ph2Ј,5Ј), 122.1 (Ph1Ј), 111.6 (C5Ј,6Ј), 100.8 (CC-Ph), 79.1 (CC-
Ph) ppm. 19F NMR (283 MHz, CDCl3): δ = –135.2 (m, 2 F), –154.8
(m, 2 F) ppm. IR (KBr): ν = 3056 (ArH), 2215 (C –C ), 1506
˜
sp
sp
(C=C), 1497, 1472, 1097, 1067, 1025, 752 cm–1. UV/Vis (iPrOH):
λmax (ε) = 222 (9,895), 271 (21,355), 313 (10,291) nm (m–1 cm–1).
UV/Vis (MeCN): λmax (ε): 221 (18,670), 270 (32,229), 311 (17,925)
nm (m–1 cm–1). MS (EI, 70 eV): m/z (%) = 351 (23[M·+ + 1]), 350
(100) [M·+], 349 (16), 348 (36), 331 (9), 330 (34), 329 (5), 328 (11),
324 (6), 310 (5), 299 (6), 175 (7), 174 (8), 165 (12), 164 (5), 162 (5),
149 (11). C22H10F4 (350.31): calcd. C 75.43, H 2.88; found C 75.41,
H 2.90.
3-[2,3,4,5-Tetrafluoro-6-(3-hydroxyprop-1-ynyl)phenyl]prop-2-yn-1-
ol (7d): The residue was taken up in ethyl ether, filtered through
neutral alumina and purified by chromatography (silica gel, cyclo-
hexane/EtOAc, [2:1], Rf = 0.07). A light brown solid (320 mg, 67%)
General Procedure. Bergman Cyclization: A solution of the en-
ediyne precursor [100 mg or 100 μL] in ortho-dichlorobenzene
[1 mL] and 1,4-cyclohexadiene [1 mL] was heated to 250 °C in a
microwave reactor (Biotage Initiator) for 4 h. The sample was con-
centrated and the naphthalene derivative purified by column
chromatography.
1
was isolated, m.p. 117–118 °C. H NMR (300 MHz, CDCl3): δ =
3
3
4.56 (d, JCH2-OH = 4.7 Hz, 4 H, CH2), 2.50 (t, JOH-CH2 = 5.3 Hz,
2 H, OH) ppm. 13C NMR (125 MHz, CDCl3): δ = 147.8 (dm, 1JCF
= 243.5 Hz, C2,3), 140.8 (dm, JCF = 253.1 Hz, C1,4), 111.0 (C5,6),
1
99.0 (CCCH2OH), 75.4 (CCCH2OH), 51.5 (CH2) ppm. 19F NMR
2,3-Difluoro-6,7-dimethylnaphthalene (11a): After chromatography
(silica gel, pentanes, Rf = 0.49) a white solid (42 mg, 85%) was
(283 MHz, CDCl3): δ = –135.2 (m, 2 F, F2,3), –154.0 (m, 2 F, F1,4
)
1
ppm. IR (KBr): ν = 3260 (OH), 2239 (C –C ), 1506 (C=C), 1448,
obtained, m.p. 150.8–153.9 °C. H NMR (300 MHz, CDCl3): δ =
˜
sp
sp
1052, 1041, 1003 cm–1. UV/Vis iPrOH): λmax (ε): 228 (30197), 261
7.49 (s, 2 H, ArH), 7.42 (tapp, 2 H, ArH), 2.40 (s, 6 H, CH3) ppm.
1
2
(10495), 273 (10304), 306 (1715), nm (m–1 cm–1). UV/Vis (MeCN): 13C NMR (75 MHz, CDCl3): δ = 149.6 (dd, JCF = 240.4, JCF
=
λmax (ε) = 227 (35,326), 260 (12,607), 272 (12,282), 306 (2,179) nm
(m–1 cm–1). MS (EI, 70 eV): m/z (%) = 258 (5) [M·+], 240 (13), 213
(8), 212 (60), 211 (100), 200 (15), 199 (11), 198 (7), 194 (8), 193
17.7 Hz, C2,3), 136.1 (C1,4), 129.0 (m, C7,6), 126.8 (C5,8), 112.6 (m,
C4a,8a), 20.2 (CH3) ppm. 19F NMR (283 MHz, CDCl3): δ = –139.6
(m) ppm. IR (KBr): ν = 2931 (C–H), 1505 (C=C), 1370, 1257,
˜
2978
www.eurjoc.org
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2011, 2969–2980

Cyclization of Fluorinated Benzo-Fused Enediynes
1142, 1023, 890, 754 cm–1. MS (EI, 70 eV): m/z (%) = 193 (15), 192
301 (9), 300 (49), 286 (7), 285 (42), 243 (11), 242 (77), 241 (26), 215
(91) [M·+], 191 (29), 189 (8), 188 (11), 178 (17), 177 (100), 175 (7), (7), 214 (53), 213 (100), 212 (9), 211 (19), 200 (6), 195 (19), 193
171 (9), 170 (13), 165 (5), 164 (16), 151 (31), 96 (6), 94 (8). C12H10F2
(192.20): calcd. C 74.99, H 5.24; found C 74.89, H 5.22.
(20), 187 (41), 164 (6), 142 (5). C15H12F4O2 (300.25): calcd. C 60.00,
H 4.03; found C 59.89, H 4.08.
CCDC-783290 (for 6e), -783291 (for 6f), -783292 (for 7a), -783293
(for 7d), -783294 (for 7e), -783295 (for 7f), -783296 (for 12a),
-783297 (for 12d), and -783298 (for 13) contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge from The Cambridge Crystallographic Data Centre
via www.ccdc.cam.ac.uk/data_request/cif.
[6,7-Difluoro-3-(hydroxymethyl)naphthalen-2-yl]methanol (11d): Af-
ter chromatography (neutral alumina, cyclohexane/EtOAc, 4:1, Rf
= 0.09) a light brown solid (87 mg, 87%) was obtained, m.p. 172.5–
176.3 °C. 1H NMR (300 MHz, CDCl3): δ = 7.58 (s, 2 H, ArH),
7.56 (tapp, 2 H, ArH), 5.01 (s, 4 H, CH2), 2.20 (s, br., 2 H, OH)
ppm. 13C NMR (125 MHz, CDCl3): δ = 150.40 (1JCF = 241.2, 2JCF
= 16.8 Hz, C6,7), 137.79 (C5,8), 129.43 (C3,2), 125.89 (C1,4), 113.55
(C4a,8a), 73.39 (CH2) ppm. 19F NMR (283 MHz, CDCl3): δ =
Supporting Information (see footnote on the first page of this arti-
cle): 19F NMR spectroscopic data of compounds 4 and 5 (Table
S1), DSC data for compounds 6 and 7 (Tables S2 and S3), colour
versions of Figures 1, 2, 3, 4, 5, and 6 (Figure S1–S6), UV/Vis spec-
tra of compounds 6 and 7 (Figures S7 and S8), view of yne-ene
interactions in 7a (Figure S9), packing diagram of 6e (Figure S10),
packing diagram of 12d (Figure S11).
–137.1 (tapp, 2 F) ppm. IR (KBr): ν = 3201 (br., OH), 2918 (C–H),
˜
1720, 1620, 1516, 1474, 1357, 1263, 1209, 1167, 1046, 900,
754 cm–1. C12H10F2O2 (224.20): calcd. C 64.28, H 4.50; found C
64.32, H 4.47.
1,2,3,4-Tetrafluoro-6,7-dimethylnaphthalene (12a): The residue was
purified by chromatography (silica gel, pentanes, Rf = 0.36), to fur-
nish a colorless solid (27 mg, 90%), m.p. 88–90 °C. 1H NMR
(300 MHz, CDCl3): δ = 7.71 (s, 2 H, ArH), 2.39 (s, 6 H, CH3) ppm.
Acknowledgments
1
13C NMR (125 MHz, CDCl3): δ = 141.6 (dm, JCF = 244.7 Hz,
The authors thank the University of North Carolina at Charlotte
and the Natural Science and Engineering Research Council of
Canada for financial support (to M. E. and M. G., respectively).
C. M. K. was generously supported by a Thomas D. Walsh Gradu-
ate Student Research Fellowship.
1
C5,8), 137.7 (C1,4), 137.1 (dm, JCF = 254.9 Hz, C6,7), 119.4 (C2,3),
118.4 (m, C4a,8a), 20.4 (CH3) ppm. 19F NMR (283 MHz, CDCl3):
δ = –152.2 (m, 2 F), –161.7 (m, 2 F) ppm. IR (KBr): ν = 2953,
˜
2924 (ArH), 1626 (C=C), 1506, 1476, 1431, 1347, 1258, 1149, 1022,
969, 867, 788, 677 cm–1. MS (EI, 70 eV): m/z (%) = 229 (12), 228
(93) [M·+], 227 (17), 214 (12), 213 (100), 209 (7), 207 (9), 206 (11),
200 (13), 193 (12), 188 (12), 187 (30), 151 (10). C12H8F4 (228.18):
calcd. C 63.16, H 3.53; found C 63.22, H 3.48.
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[5,6,7,8-Tetrafluoro-3-(hydroxymethyl)naphthalene-2-yl]methanol
(12d): Purification by column chromatography (neutral alumina,
cyclohexane/EtOAc, 4:1, Rf = 0.12) afforded a light yellow solid
1
(82 mg, 82%), m.p. 131–132 °C. H NMR (300 MHz, CDCl3): δ =
8.06 (s, 2 H, ArH), 4.94 (s, 4 H, CH2), 2.18 (s, 2 H, OH) ppm. 13C
NMR (125 MHz, CDCl3): δ = 141.8 (1JCF = 254 Hz, C6,7), 139.7
(C1,4), 137.6 (C5,8, 1JCF = 254 Hz), 119.1 (C2,3), 118.7 (tapp, C4a,8a),
62.8 (CH2) ppm. 19F NMR (283 MHz, CDCl3): δ = –150.48 (m, 2
F), –158.67 (m, 2 F) ppm. IR (KBr): ν = 3318 (OH), 2897 (ArH),
˜
1670 (C=C), 1629 (C=C), 1469, 1371, 1129, 1045, 985, 879, 713,
669 cm–1. MS (EI, 70 eV): m/z (%) = 260 (24) [M·+], 243 (14), 242
(98), 241 (77), 229 (5), 224 (6), 223 (5), 215 (5), 214 (35), 213 (100),
212 (8), 211 (12), 201 (9), 200 (14), 199 (7), 195 (17), 193 (18), 188
(5), 187 (47), 169 (8), 164 (6), 163 (5), 161 (5), 151 (24), 149 (5),
121 (8), 106 (8). C12H8F4O2 (260.18): calcd. C 55.39, H 3.10; found
C 55.33, H 3.08.
7,8,9,10-Tetrafluoro-3,3-dimethyl-1H,3H,5H-naphtho[2,3-e][1,3]-
dioxepine (13): A solution of precursor 12d (100 mg, 0.38 mmol)
and a catalytic amount of p-toluenesulfonic acid was stirred in ace-
tone (5 mL) in the presence of molecular sieves (4 Å). After com-
plete conversion the mixture was quenched with water, extracted
with dichloromethane, neutralized with hydrogen carbonate solu-
tion and dried (Na2SO4). After removal of the solvent the slightly
beige crude product was obtained. Recrystallization from hexanes
and a trace amount of benzene furnished the colorless product
1
(108 mg, 95%), m.p. 142–144 °C. H NMR (300 MHz, CDCl3): δ
= 7.66 (s, 2 H, H6,11), 4.94 (s, 4 H, H1,5), 1.47 (s, 6 H, CH3) ppm.
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13C NMR (125 MHz, CDCl3): δ = 141.9 (1JCF = 252.5 Hz, C7,10),
138.8 (C6,11), 137.7 (C8,9 1JCF = 240.5 Hz), 118.5 (C6a,10a), 117.0
,
(C5a,11a), 102.6 (C3), 64.8 (C1,5), 23.7 (CH3) ppm. 19F NMR
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ν = 3000, 2935 (ArH), 1670, 1626, 1515, 1467, 1380, 1335, 1214,
˜
1156, 1081, 1037, 979, 872, 670 cm–1. MS (EI, 70 eV): m/z (%) =
Eur. J. Org. Chem. 2011, 2969–2980
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
2979

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Received: December 31, 2010
Published Online: April 19, 2011
2980
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Eur. J. Org. Chem. 2011, 2969–2980