Synthesis of 1,3-Difluoroaromatics in One Pot by Addition of Difluorocarbene from Sodium Chlorodifluoroacetate to 1,2-Substituted Cyclobutenes

Article abstract of DOI:10.1021/ol020158j

(Matrix Presented) The synthesis of 1,3-difluoro-2,4-diphenylbenzene has been accomplished in one step from 1,2-diphenylcyclobutene using the environmentally benign difluorocarbene precursor sodium chlorodifluoroacetate. In addition, the preparation of th

Full text of DOI:10.1021/ol020158j

ORGANIC
LETTERS
2002
Vol. 4, No. 22
3871-3873
Synthesis of 1,3-Difluoroaromatics in
One Pot by Addition of Difluorocarbene
from Sodium Chlorodifluoroacetate to
1,2-Substituted Cyclobutenes
Heather M. Morrison, James E. Rainbolt, and Scott B. Lewis*
Department of Chemistry, James Madison UniVersity, MSC 7701,
Harrisonburg, Virginia 22807
lewissb@jmu.edu
Received August 8, 2002
ABSTRACT
The synthesis of 1,3-difluoro-2,4-diphenylbenzene has been accomplished in one step from 1,2-diphenylcyclobutene using the environmentally
benign difluorocarbene precursor sodium chlorodifluoroacetate. In addition, the preparation of the previously unknown compound 1,3-difluoro-
2,4-di-n-propylbenzene has been accomplished in one step from 1,2-di-n-propylcyclobutene using Seyferth’s reagent (Ph−Hg−CF3) and sodium
chlorodifluoroacetate.
Fluorinated organic compounds are a fascinating class of
compounds that continue to grow in importance in society.
They tend to possess markedly different physical, chemical
and electronic properties from those exhibited by compounds
that have no fluorine atoms present.1 In nature, fluorine is
not widely distributed among organic compounds, with only
thirteen fluorine containing natural products having been
isolated and characterized.2 Despite their scarcity in nature,
synthetically prepared organofluorine compounds have found
a wide variety of uses. Fluorinated aromatics, in particular,
have found uses in areas such as antibacterials,3 antiinflam-
matory agents,4 anticonvulsants,5 pesticides6 and liquid
crystals.7
Due to the electronegativity of the fluorine atom and its
directing influence during electrophilic substitution reactions,
it is difficult to obtain a 1,3-difluoroaromatic compound when
starting from benzene. Some years ago, we reported a one-
pot preparation of 1,3-difluoro-2,4-diphenylbenzene (1) in
77% yield from the difluorocarbene addition to 1,2-di-
phenylcyclobutene.8 Recently, only the second paper known
to describe dihalocarbene additions to 1,2-disubstituted cyclo-
butenes showed that both dichloro- and dibromocarbene
(each generated by three sources) do in fact add to 1,2-
diphenylcyclobutene to produce 1,3-dihalo-2,4-diphenyl-
benzenes.9
To date, work involving dihalocarbene additions to cy-
clobutenes has used 1,2-diphenylcyclobutene, while the
difluorocarbene previously used had only been generated by
Seyferth’s method using Ph-Hg-CF3.8,9 Herein, we wish
to report the use of difluorocarbene generated from sodium
chlorodifluoroacetate for the preparation of 1 and difluoro-
carbene generated from two sources (Ph-Hg-CF3 and
(1) Hudlicky, M.; Pavlath, A. E., Eds. Chemistry of Organic Fluorine
Compounds II. A Critical ReView. ACS Monograph 187; American
Chemical Society: Washington, DC, 1995.
(2) O’Hagen, D.; Harper, D. B. J. Fluorine Chem. 1999, 100, 127.
(3) Ziegler, C. B., Jr.; Kuck, N. A.; Strohmeyer, T. W.; Lin, Y. J.
Heterocycl. Chem. 1990, 27, 2077.
(4) Hewitt, C. D.; Silvester, M. J. Aldrichimica Acta 1988, 21, 3.
(5) Bergman, K. J. Clin. Neuropharmacol. 1985, 7, 105.
(6) Szczepanik, M. Prog. Plant Prot. 1998, 28, 385.
(7) Kirsch, P.; Huber, F.; Lenges, M.; Taugerbeck, A. J. Fluorine Chem.
2001, 112, 69.
(8) Lewis, S. B.; Borden, W. T. Tetrahedron Lett. 1994, 35, 1357.
(9) Wagner, R. A.; Weber, J.; Brinker, U. H. Chem. Lett. 2000, 246.
10.1021/ol020158j CCC: $22.00 © 2002 American Chemical Society
Published on Web 10/08/2002

sodium chlorodifluoroacetate) for the preparation of the
previously unknown compound 1,3-difluoro-2,4-di-n-propyl-
benzene (2) from the appropriate 1,2-disubstituted cyclo-
butenes.
Table 1. Yields of 1,3-Difluoroaromatics
yield
entry
source of carbene
1
2
Preparation of 1,2-diphenylcyclobutene (3) was accom-
plished in four steps (39% overall yield) from diphenyl-
acetylene adapting the method of Negishi for preparing
cyclobutenes. The synthesis of 1,2-di-n-propylcyclobutene
(4) was also accomplished in four steps from 4-octyne
following exactly the procedure of Negishi (Scheme 1).10
1
2
Ph-Hg-CF3/NaI/benzene reflux/48 h
NaCClF2CO2/diglyme reflux/60 min
77a
53
60
41
a Reference 8.
with no significant changes observed in upfield signals. The
19F NMR spectrum has features similar to the proton
spectrum: a quartet-like multiplet centered at δ -120.35 and
a triplet-like multiplet at δ -121.43 (relative to CFCl3 at δ
0.00).
Scheme 1a
The most compelling evidence for the structure of 2 comes
from the proton-decoupled 13C NMR spectrum in conjunction
with a DEPT 135 experiment. The two aromatic carbons with
protons attached (δ 127.5 and 110.1), as shown by the DEPT
experiment, are both split into doublets of doublets. The
resonance at δ 127.5 (Cc) shows nearly equal coupling (JCF
) 9.71 and 7.07 Hz) to the two fluorines, indicating it is
meta to both fluorines. The other protonated aromatic carbon
a Reaction conditions: (a) 2EtMgBr/THF/-78 °C; (b) diphenyl-
acetylene or 4-octyne/THF/0 °C; (c) I2/THF/-78 °C. (d) BuLi/
THF/-78 °C.
Compound 4 was then reacted with Ph-Hg-CF3 in refluxing
benzene11 to produce the new compound 2 in 60% yield.
Following this, compounds 3 and 4 were individually
subjected to sodium chlorodifluoroacetate in refluxing di-
glyme (Scheme 2).12 This resulted in the formation of 1 and
2 in 53 and 41% yields, respectively (Table 1).
(Cd) has coupling constants to the two fluorines of JCF
)
22.43 Hz and JCF ) 3.71 Hz. The magnitude of these
coupling constants indicates that this carbon is ortho to one
fluorine and para to the other.13
Similar C-F coupling constant arguments can be made
for the doublets of doublets at δ 124.7 (Cb) and 117.4 (Cf),
which are the carbons holding the propyl groups. The carbon
atoms bonded to the fluorines appear as doublets of doublets
centered at δ 159.8 (JCF ) 243.17 Hz, JCF ) 8.83 Hz) and
δ 159.5 (JCF ) 244.94 Hz, JCF ) 8.83 Hz). The magnitude
of the smaller C-F coupling constant in these carbon
resonances clearly indicates that the two fluorine atoms are
meta to one another.13 Taken together, these data firmly
establish the structure of the previously unknown compound
2.
Scheme 2a
Spectral data collected (1H, 13C, and 19F NMR and GCMS)
of compounds 1 and 2 made from the acetate salt match those
of the compounds made with Ph-Hg-CF3. Attempts to find
an effective but lower boiling solvent for the reaction with
the acetate salt included 1,4-dioxane (bp ) 102 °C), ethylene
glycol diethyl ether (bp ) 121 °C), and dibutyl ether (bp )
142 °C). All of these solvents were regrettably unsuccessful
at initiating the reaction that produces 1,3-difluoroaromatics.
The mechanism originally proposed for this reaction
involved cationic intermediates that did not require any
assistance from the mercury atom of Ph-Hg-CF3.8 The use
of sodium chlorodifluoroacetate to produce 1,3-difluoro-
aromatics clearly indicates that mercury is not involved in
the mechanism that produces these compounds (Figure 1).
While the organomercury compound (Ph-Hg-CF3) was
the first reagent used to produce 1,3-difluoroaromatics in one
step from cyclobutenes, its use has significant drawbacks
a Reaction conditions: (a) Ph-Hg-CF3 or NaCClF2CO2.
The molecular formula of 2 (produced from Ph-Hg-CF3)
was established by high-resolution mass spectrometry (calcd
1
for C12H16F2, 198.1220; found, 198.1225). The H NMR
spectrum indicated the presence of two inequivalent propyl
groups, showing that 2 has no symmetry. This was most
easily detected by the signals for the two benzyl methylenes
[δ 2.65 (t, J ) 7.95 Hz, 2H) and δ 2.58 (t, J ) 7.65 Hz,
2H)]. The other notable feature of the proton spectrum
involved the two aromatic resonances. These appeared as a
quartet-like multiplet centered at δ 6.94 and a triplet-like
multiplet at δ 6.74. A 19F-decoupled 1H spectrum simplified
these two proton signals to a set of doublets (J ) 8.4 Hz),
(10) Negishi, E.; Liu, F.; Choueiry, D.; Mohamud, M. M.; Silveria, A.;
Reeves, M. J. Org. Chem. 1996, 61, 8325.
(11) Seyferth, D.; Hopper, S. P. J. Org. Chem. 1972, 37, 4070.
(12) Csuk, R.; Eversmann, L. Tetrahedron 1998, 54, 6445.
(13) Kalinowski, H.-O.; Berger, S.; Braun, S. Carbon-13 NMR Spec-
troscopy; Wiley and Sons: Chichester, UK, 1984; pp 581-585.
3872
Org. Lett., Vol. 4, No. 22, 2002

to make this class of compounds that are very difficult to
obtain starting from benzene. The ability to prepare these
difluoroaromatics with predictable regiochemistry from a
convenient source that does not require the presence of a
toxic heavy metal organometallic makes this reaction a
powerful tool for synthetic chemists.
Acknowledgment. We thank the Virginia Academy of
Science (Thomas F. and Kate Miller Jeffress Memorial Trust
Fund, J-645), The NSF-REU (CHE-0097448), and The
Department of Chemistry at James Madison University for
financial support, Thomas N. Gallaher for technical help with
NMR experiments, and the Center for Mass Spectrometry
at The University of Nebraska-Lincoln for HRMS.
Figure 1. Proposed mechanism for the formation of 1,3-difluoro-
aromatics from the difluorocarbene addition to substituted cyclo-
butenes.
Supporting Information Available: Experimental pro-
cedure for use of the acetate salt and all spectra for compound
2. This material is available free of charge via the Internet
at http://pubs.acs.org.
not shared by the acetate salt. First, the salt is commercially
available, or easily prepared in one step from the acid.12
Reaction times are reduced to 60 min with the salt compared
with 24-48 h when using Ph-Hg-CF3. The number of
fluorines lost is reduced to one when using the acetate salt
from five when using Ph-Hg-CF3 as the difluorocarbene
precursor.14 Most important of all, no toxic metals are present
with the salt and the only byproducts of the reaction are NaCl
and CO2.
OL020158J
(14) Five fluorine atoms in total are lost when using Ph-Hg-CF3 as
the difluorocarbene source. This is figured on the basis of starting from
CF3CO2H and HgO to initially make (CF3CO2)2Hg. Three fluorines are
lost when the Ph-Hg-CF3 is made, and two more are lost from each
molecule of Ph-Hg-CF3 during the production of the 1,3-difluoroaromatic.
The preparation of 1,3-difluoroaromatics in one step by
the ring expansion of a cyclobutene represents a unique way
Org. Lett., Vol. 4, No. 22, 2002
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