Friedel-Crafts reactions of 2,2-difluorocyclopropanecarbonyl chloride: Unexpected ring-opening chemistry

Article abstract of DOI:10.1021/jo200423y

The Friedel-Crafts reactions of 2,2-difluorocyclopropanecarbonyl chloride with various arenes did not lead to the straightforward formation of the expected aryl 2,2-difluorocyclopropyl ketones. Instead the reactions proceeded, to various degrees depending on the reactivity of the arene, via an apparent rearrangement of the initially formed acylium ion to form novel aryl 3-chloro-3,3-difluoropropyl ketones. The ring-opened product was formed exclusively, and therefore the reaction may be synthetically useful when relatively unreactive arene substrates such as benzene, toluene, and p-xylene are used. No conditions were found where ring-intact products could be formed exclusively when using substituted benzenes as substrates, with the very reactive substrate thiophene being most selective in that regard, favoring ring intact product 3 with a selectivity of 98:2. The regioselectivity of ring-opening was examined and compared with other related systems computationally.

Full text of DOI:10.1021/jo200423y

ARTICLE
pubs.acs.org/joc
FriedelꢀCrafts Reactions of 2,2-Difluorocyclopropanecarbonyl
Chloride: Unexpected Ring-Opening Chemistry
William R. Dolbier, Jr.,* Eric Cornett, Henry Martinez, and Wei Xu
Department of Chemistry, University of Florida, Gainesville, Florida 32611-7200, United States
S Supporting Information
b
ABSTRACT: The FriedelꢀCrafts reactions of 2,2-difluorocy-
clopropanecarbonyl chloride with various arenes did not lead to
the straightforward formation of the expected aryl 2,2-difluor-
ocyclopropyl ketones. Instead the reactions proceeded, to
various degrees depending on the reactivity of the arene, via
an apparent rearrangement of the initially formed acylium ion to form novel aryl 3-chloro-3,3-difluoropropyl ketones. The ring-
opened product was formed exclusively, and therefore the reaction may be synthetically useful when relatively unreactive arene
substrates such as benzene, toluene, and p-xylene are used. No conditions were found where ring-intact products could be formed
exclusively when using substituted benzenes as substrates, with the very reactive substrate thiophene being most selective in that
regard, favoring ring intact product 3 with a selectivity of 98:2. The regioselectivity of ring-opening was examined and compared
with other related systems computationally.
Scheme 1. Recent Studies of the Ring-Opening Chemistry of
’ INTRODUCTION
Aryl 2,2-Difluorocyclopropyl Ketones
The chemistry of 2,2-difluorocyclopropyl ketones has become
an area of recent interest to us as a consequence of our discovery
of difluorocarbene reagent TFDA (trimethylsilyl 2-fluorosulfo-
nyl-2,2-difluoroacetate), which facilitated their synthesis.1 Two
studies of reactions of 2,2-difluorocyclopropyl ketones that
resulted in ring-opening were recently published. One was our
study of the MgI2-facilitated reactions of aryl 2,2-difluorocyclo-
propyl ketones with imines,2 which led to products completely
devoid of fluorine, and the second was of their ionic-liquid
facilitated ring-opening by HBr. Examples of each of these
reactions are given in Scheme 1.3
Unfortunately, use of TFDA for the synthesis of unsubstituted
aryl difluorocyclopropyl ketones led only to moderate yields,3
probably due to competing polymerization of their R,β-unsaturated
ketone precursors (Scheme 2). Therefore an alternative synthesis of
the 2,2-difluorocyclopropyl ketones, which involving Friedelꢀ
Crafts acylation of activated aromatics using 2,2-difluorocyclopro-
panecarbonyl chloride, 1, was considered. There were a number of
published examples of successful use of the nonfluorine-containing
cyclopropanecarbonyl chlorides in FriedelꢀCrafts acylations,4 in-
cluding those shown in Scheme 3.5
Scheme 2. TFDA-Facilitated Synthesis of Aryl 2,2-Difluoro-
cyclopropyl Ketones
Since the dichloro analogue 2,2-dichlorocyclopropanecarbonyl
chloride had been used effectively under the usual acylation condi-
tions,6 there was good reason to believe that use of 2,2-difluorocy-
clopropanecarbonyl chloride would lead to similar success.
presence of 1 equiv of benzene in CH2Cl2 at 0 °C, surprisingly
none of the expected aryl 2,2-difluorocyclopropyl ketone was
obtained. Instead, only the ring-opened product 2a was obtained,
’ RESULTS
2,2-Difluorocyclopropanecarbonyl chloride (1) was prepared
from n-butyl 2,2-difluorocyclopropanecarboxylate via base-cata-
lyzed hydrolysis followed by reaction of the carboxylic acid with
thionyl chloride. When 1 was allowed to react with AlCl3 in the
Received: February 24, 2011
Published: April 01, 2011
r
2011 American Chemical Society
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in 50% yield. Compounds of this structure, that is aryl 3-chloro-3,
3-difluorocyclopropyl ketones, have, to our knowledge, not been
previously reported; so this reaction has potential synthetic
importance.
(Scheme 5). The very electron-rich heterocycle thiophene was an
excellent substrate, yielding 86% of a mixture of mostly (98:2) ring-
intact product 3f.
When instead of 1 equiv of aromatic substrate 5 equiv were
used in the reactions, some ring-intact product 3a (20%) was
observed for benzene, and for toluene the ring-intact 3b was now
the major product (90%). Xylene still yielded only ring-opened
product 2d. Overall yields of the reactions were not much
affected by the change from 1 to 5 equiv of aromatic substrate,
nor could this change lead to exclusive formation of the desired
ring-intact products 3 for any of the benzene derivatives. The
results from all of these reactions are summarized in Table 1.
Methylene chloride was in retrospect fortuitously chosen as
the solvent for these FriedelꢀCrafts reactions of acyl chloride 1
in our initial experiments. Other, perhaps equally traditional
solvents for FriedelꢀCrafts reactions were later examined, and
somewhat surprisingly, neither carbon disulfide nor nitroben-
zene proved satisfactory as solvents. No acylation products were
obtained when using either solvent. On the other hand, 1,2-
dichloroethane proved to be an excellent solvent for the reaction,
providing higher overall yields, while giving considerably more
unrearranged, ring-intact products (3) than the analogous reac-
tions in methylene chloride (Scheme 6). It is not clear why this is
so. Mixtures of AlCl3 with both ethylene dichloride and CH2Cl2
(in the absence of 1) slowly darken, with methylene chloride
When toluene, ethylbenzene, or p-xylene were used as the
aromatic substrate, analogous ring-opened products (2b, 2c, and
2d) were again the only products observed, this time in 70%, 78%,
and 78% yields, respectively (Scheme 4). Toluene and ethylbenzene
gave only the para-products, no ortho-products being observed.
That the ortho position was considerably less reactive than the para
was demonstrated by a competition experiment between toluene
and p-xylene. When the reaction was carried out with equal amounts
of each substrate, the only product obtained (2b) derived from
reaction with toluene.
When the highly activated anisole was used as substrate, now
the major product (75%) was 3e, which retained the 2,2-difluoro-
cyclopropane entity, along with 25% of ring-opened product 2e
Scheme 3. Examples of FriedelꢀCrafts Acylation with
Cyclopropanecarbonyl Chlorides
Table 1. FriedelꢀCrafts Reactions of Aromatics with 2,
2-Difluorocyclopropanecarbonyl Chloride in Methylene
Chloridea
ratio of products
equiv of
overall
Scheme 4. Initial FriedelꢀCrafts Reactions of 1
substrate
benzene
substrate
yield (%)
2
3
1
5
1
5
1
1
5
1
5
1
50
55
72
70
78
78
75
52
60
86
2a: 100
2a: 80
2b: 100
2b: 10
2c: 100
2d: 100
2d: 100
2e: 25
2e: 12
2f: 2
3a: 0
benzene
toluene
3a: 20
3b: 0
3b: 90
3c: 0
toluene
ethylbenzene
p-xylene
p-xylene
anisole
3d: 0
3d: 0
3e: 75
3e: 88
3f: 98
anisole
thiophene
a Unless otherwise specified, all reactions were carried out with 6 mmol
of 1, 7.2 mmol of AlCl3 in 20 mL of CH2Cl2 at 0 °C for 2 h.
Scheme 5. FriedelꢀCrafts Reaction of 1 with Anisole and Thiophene
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Scheme 6. Use of 1,2-Dichloroethane As Solvent for FriedelꢀCrafts Acylations of 1
Scheme 7. Relative Energies of Cyclopropyl Acylium Ions versus Their Respective Ring-Opened Ketene Carbocations (in kcal/
mol), As Calculated by the ab Initio HF Method, in CH2Cl2 Environment
Table 2. Computed Ground States of Cyclopropane-Substi-
tuted Carbocations and Their Respective Ring-Opened Ca-
tions (ab initio HF and MP2/6-31G(d)) (kcal/mol)
Scheme 8. Isodesmic Equations Describing the Effect of
Geminal Fluorine and Chlorine Substituents on Cyclopro-
pane Ring Strain (kcal/mol)
Figure 1. Hybrid structure for difluoro acylium ion 4.
unsubstituted and the 2,2-dichlorocyclopropanecarbonyl chlor-
ides gave no evidence of rearrangement to analogous ring-
opened products.4ꢀ6 Why should the 2,2-difluorocyclopropyl
system behave differently? Most likely the results reflect the
difference in the thermodynamics of the hypothetical rearrange-
ments of the respective acylium ion intermediates (4). Insight
into this issue was gained through computation.
The ground states of a series of cyclopropane-substituted
carbocations and their respective ring-opened cations were calcu-
lated in the gas phase at HF and MP2/6-31G(d) levels of theory
using the Gaussian 03 Revision E01 package.7 The stability
provided by the solvent (dichloromethane) was also considered
and calculated by using the Onsager model for both HF and MP2
methods. The results of these calculations are given in Table 2.
appearing to be less stable. Thus the exact nature of the catalyst
may vary somewhat for the two solvents. Neither reaction is
totally homogeneous.
’ DISCUSSION
As indicated above, these results were unexpected because
precedent of FriedelꢀCrafts reactions with both the
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Scheme 9. Proposed Mechanism for Competitive Formation of 2 and 3
structures 4 and 5, as depicted in Figure 1, with the CF2 carbon
bearing significant þ charge (much more so than the CH2 group).
The situation therefore might well behave much like a “bromonium”
ion does, and undergo direct displacement at that carbon, which has
the weaker CꢀC bond, that is at the CF2 carbon.
Scheme 10. Attempted AlCl3-Catalyzed Rearrangement of
2,2-Difluorocyclopropyl Ketone
With this in mind, the trend shown in Table 1 for rearranged
versus rearranged products for the various arene substrates can
nicely be explained by a mechanism in which attack of hybrid
acylium ion 40 by chloride ion competes with its direct acylation
reaction with arene, the former process leading to rearranged
products (2) and the latter to unrearranged products (3). This
mechanism is depicted in Scheme 9. Consistent with this mechanism
is the fact that the most reactive arene substrates, that is, anisole and
thiophene, are the ones whose direct reactions with acylium ion 40
compete effectively with chloride attack of 40. Strongly indicative are
the experiments with five times the amount of benzene and toluene,
which now yielded nonrearranged, ring-intact products. Both of
these observations are consistent with the competitive mechanism
proposed in Scheme 9.
Of course, there is also the possibility that the unrearranged
products 3 might have rearranged to 2 under the reaction condi-
tions. However, this possibility was ruled out by two experiments.
First, allowing the reactions to run for twice as long did not lead
to increased amount of rearranged products. Second, an experi-
ment in which 2,2-difluorocyclopropyl ketone 3b was stirred in
CH2Cl2 at 0 °C with AlCl3 for 2 h, led to no conversion to 2b;
indeed no reaction at all was observed (Scheme 10).
The regiochemistry of the nucleophile-induced ring-opening
of acylium ion 40 is consistent with that which was observed in
our recent study of the solvolysis of 2,2-difluorocyclopropyl-
methyl tosylate (9) (Scheme 11),10 which also resulted only in
formation of products derived from the hypothetical ring-opened
difluoromethyl carbocation 10. A computational examination of
this cyclopropylmethyl cation system, with and without fluorines,
indicates that, in this case, difluoro ring-opened cation 10, in a
solvated environment, is actually more stable, by 12 kcal, than its
respective ring-closed cation 11 (Scheme 12).
Scheme 7 summarizes the HF computational data for the
solvated 2,2-difluoro-, 2,2-dichloro-, and unsubstituted-cyclopro-
pyl acylium ions (4F, 4Cl, and 4H) and their respective possible
rearranged carbocations (5 and 6). The calculations indicate that
in each case, the acylium ions 4 were more stable than either of the
ketene carbocations 5 and 6 that could have been obtained from
rearrangement. In both the fluorine- and the chlorine-substituted
systems, cations 6F and 6Cl were substantially less stable than 5F
and 5Cl, respectively, because of the detrimental inductive effects
of the β-halogen substituents. Fluorinated carbocation 5F is more
stable than chlorinated analogue 5Cl for two reasons. First, R-
fluorines stabilize carbocations whereas R-chlorines do not, and
second because there is a larger release of cyclopropane strain in
the fluorinated case. The substantial (∼12ꢀ13 kcal/mol) impact
of geminal fluorines on the strain of cyclopropanes has long been
recognized and its magnitude confirmed experimentally8 and
computationally.9 However, to our knowledge, there is no com-
parable information available on the thermodynamic effect of
geminal chlorines. Thus we provide the appropriate isodesmic
equation for chlorine inScheme 8, thevaluecalculatedby usingthe
same method used by Wiberg in his computational study of
fluorinated cyclopropanes.9 Our corroborative calculation for the
fluorine system is also included. These calculations confirm that
geminal chlorines do in fact increase the strain of cyclopropane,
but much less so than geminal fluorine substituents.
Thus ketene carbocation 5F, with fluorines at the cationic
carbon, is considerably more stable (relative to the acylium ion)
than either the chlorine-substituted or the unsubstituted, ring-
opened carbocations, 5Cl or 5H. Therefore it would not be
unreasonable to consider the actual “intermediate” in the di-
fluoro case to be best represented as a resonance hybrid (40) of
In stark contrast, the regiochemistry of the above two reac-
tions is different from that observed by us in our study of the
mechanistically similar HBr-induced ring-opening of aryl 2,2-
difluorocyclopropyl ketones (shown above in Scheme 1).3 In a
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Scheme 11. Solvolysis of 2,2-Difluorocyclopropylmethyl
Tosylate
Scheme 14. Relative Energies of Protonated Phenyl and n-
Butyl Cyclopropyl Ketones versus Their Respective Ring-
Opened Enol Carbocations (in kcal/mol), As Calculated by
the ab Initio HF Method, in CH2Cl2 Environment
Scheme 12. Relative Energies of Cyclopropylmethyl Cations
versus Their Respective Ring-Opened Allylcarbinyl Carbo-
cations (in kcal/mol), As Calculated by the ab Initio HF
Method, in CH2Cl2 Environment
than for the acylium ion 4, which is consistent with the results,
although admittedly, it is difficult to argue that the difference
between þ15.6 and þ10.4 kcal/mol (15F compared to 5F)
would be sufficient in and of itself to explain a complete switch
in regiochemistry for the two reactions.
Another factor can also be contributing significantly to the
different regiochemical outcomes. Bromide ion is a much better
nucleophile than chloride ion, and therefore bromide would be a
more “aggressive” nucleophile in an SN2 reaction than would
chloride ion. Thus, all other things being equal, bromide ion
would be more likely than chloride ion to take advantage of
the greater SN2 reactivity of the CH2 group of protonated
ketone 14a. The observed regiochemical dichotomy can be com-
pared with the notoriously variable regiochemical behavior of
unsymmetrical epoxides in their ring-opening reactions with
nucleophiles depending on choice of nucleophile and/or choice
of Lewis or protic acid.
Scheme 13. SN2-like Mechanism for HBr-Induced Ring-
Opening of Ketone 3a
’ CONCLUSIONS
In conclusion, the FriedelꢀCrafts reactions of 2,2-difluorocy-
clopropanecarbonyl chloride (1) with various arenes did not lead to
the straightforward formation of the expected aryl 2,2-difluorocyclo-
propyl ketones (3). Instead the reactions proceeded, to various
degrees depending on the reactivity of the arene, via an apparent
rearrangement of the initially formed acylium ion to form novel aryl
3-chloro-3,3-difluoropropyl ketones (2). The formation of the ring-
opened product 2 was exclusive, and therefore could be synthetically
useful, when relatively unreactive arene substrates such as benzene,
toluene, and p-xylene are used, and when the reactions are run under
dilute conditions with only 1 equiv of arene being used. No
conditions were found where ring-intact products could be formed
exclusively when using substituted benzenes as substrates, with the
very reactive substrate thiophene being most selective in that regard,
favoring ring intact product 3 with a selectivity of 98:2.
typical reaction of this type, when phenyl 2,2-difluorocyclopropyl
ketone, 3a, was allowed to react with HBr in an ionic liquid based
reaction medium, the reaction resulted in the exclusive formation
of 4-bromo-3,3-difluoro-1-phenylbutan-1-one, 13, not the 4-bro-
mo-4,4-difluoro product analogous to 2a (Scheme 13). In this
paper, the regiochemical outcome was rationalized on the basis of
an SN2-like mechanism, where bromide ion preferentially at-
tacked at the more reactive CH2 carbon of the cyclopropane ring,
a mechanism that is remarkably similar to that proposed in
Scheme 7 for the chloride-induced ring-opening of acylium ion
40, but which results in an entirely different regiochemical out-
come! How can one rationalize the observed difference in
regiochemical outcome for these two very similar reactions?
Again, one turns to theory for a possible answer. Calculating
the relative energies of the protonated ketone intermediates, 14a,
fluorinated and nonfluorinated, and the two respective ring-
opened enol carbocations, 15a and 16a, led to predicted more
endothermic energetics for the hypothetical ring-opening of pro-
tonated ketone 14a than for the acylium cation 4 (Scheme 14).
This would be consistent with a more SN2-like process for 14a
’ EXPERIMENTAL SECTION
Materials and Methods. Unless otherwise specified, proton,
fluorine, and carbon NMR spectra were obtained in CDCl3 at 300,
282, and 75.46 MHz, respectively, and chemical shifts are reported in
ppm upfield relative to TMS for proton and carbon, and upfield of
fluorotrichloromethane for fluorine. All aryl 2,2-difluorocyclopropyl
ketones obtained and discussed in this work have been previously
reported and characterized.3
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Experimental Procedures
Preparation of 2,2-difluorocyclopropanecarbonyl Chlor-
ide (1)11
2.68ꢀ2.86 (m, 4H), 3.29 (t, J = 7.8 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H),
7.90 (d, J = 8.1 Hz, 1H); 19F NMR δ ꢀ51.45 (t, J = 12.4 Hz, 2F); 13
C
NMR δ 15.3, 29.1, 32.6, 36.5 (t, J = 25.0 Hz), 128.4, 129.9 (t, J = 291
Hz), 133.8, 134.1, 150.8, 196.2; HRMS (EI) calcd for C12H13OF2Cl
[M]þ 246.0623, found 246.0604. Anal. Calcd for C12H13OF2Cl: C,
58.43; H, 5.31. Found: C, 58.08; H, 5.28.
4-Chloro-1-(2,5-dimethylphenyl)-4,4-difluorobutan-1-one
(2d): liquid, bp 91 °C/10 mmHg, 78% and 75%, respectively, when using
1 or 5 equiv of p-xylene; 1H NMR δ 2.38 (s, 3H), 2.46 (s, 3H), 2.77 (m,
2H), 3.23 (t, J = 7.5 Hz, 2H), 7.20 (m, 2H), 7.48 (br s, 1H); 19F NMR
δ ꢀ51.43 (t, J = 12.4 Hz, 2F); 13C NMR δ 21.0, 21.1, 35.1 (t, J = 2.5 Hz),
36.6 (t, J = 25.4 Hz), 129.4, 129.9 (t, J = 292 Hz), 132.3, 132.8, 135.6,
135.7, 136.7, 200.0; HRMS (EI) calcd for C12H13OF2Cl [M þ H]þ
246.0623, found 246.0616. Anal. Calcd for C12H13OF2Cl: C, 58.43; H,
5.31. Found: C, 58.16; H, 5.32.
4-Chloro-1-(4-methoxyphenyl)-4,4-difluorobutan-1-one (2e):
solid, mp, 40.5ꢀ43 °C, 13% and 9% yield, respectively, when using 1 or
5 equiv of anisole; 1H NMR δ 2.77 (m, 2H), 3.25 (t, J = 7.5 Hz, 2H), 3.88
(s, 3H), 6.95(dm, J= 9 Hz, 2H), 7.96 (dm, J= 9 Hz, 2H); 19FNMRδꢀ51.4
(t, J= 12.4 Hz, 2F); 13CNMRδ32.3, 36.6 (t, J= 18.5 Hz), 55.7, 114.1, 129.4,
130.0 (t, J = 291 Hz), 130.5, 164.1, 195.1; HRMS (EI) calcd for
C11H11O2F2Cl [M þ H]þ 249.0494, found 249.0473. Anal. Calcd for
C11H11O2F2Cl: C, 53.13; H, 4.46. Found: C, 53.50; H, 4.33.
2,2-Difluorocyclopropanecarboxylic acid:12 Potassium hy-
droxide (18.4 g, 3 equiv) was dissolved in 93 mL of water. n-Butyl 2,
2-difluorocyclopropanecarboxylate (19.5 g, 1 equiv)13 was added to the
solution and the mixture heated to reflux and stirred for 10 h. The
solution was cooled to room temperature, after which the volatiles were
removed by rotary evaporation. Water was added to the crude solid
dropwise until it dissolved. Concentrated hydrochloric acid was added
dropwise until the solution reached a pH of 2. The acidic solution then
was extracted with diethyl ether, after which the diethyl ether layer was
then dried with anhydrous MgSO4 and filtered, and the ether solvent was
removed via rotary evaporation to provide 2,2-difluorocyclopropane-
carboxylic acid as a pale yellow solid (9.4 g, 70%).12 The acid was used
without further purification in the next step.
2,2-Difluorocyclopropanecarbonyl chloride (1):11 2,2-Di-
fluorocyclopropanecarboxylic acid (9.0 g) was dissolved in 75 mL of
thionyl chloride under nitrogen. The solution was then heated to 60 °C
and stirred for 6 h, after which the crude reaction mixture was distilled at
atmospheric pressure to provide 2,2-difluorocyclopropanecarbonyl chloride
1 as a transparent, colorless liquid (9.3 g, 90%): bp 106ꢀ107 °C;11 1H
NMR δ 1.98 (m, 1H), 2.27 (m, 1H), 3.02 (m, 1H); 19F NMR δ ꢀ124.6
(dm, J = 149 Hz, 1F), ꢀ138.3 (dm, J = 149 Hz, 1F).
(2,2-Difluorocyclopropyl)(4-methoxyphenyl)methanone
(3e):3 liquid, 39% and 51% yields, respectively, when using 1 or 5 equiv of
anisole; 1H NMR δ 1.68 (m, 1H), 2.30 (m, 1H), 3.36 (m, 1H), 3.72 (s, 3H),
6.96 (m, 2H), 7.54 (m, 2H); 19FNMRδꢀ124.74 (m, 1F), ꢀ140.8 (m, 1F).
4-Chloro-4,4-difluoro-1-(thiophen-2-yl)butan-1-one (2f):
liquid, 2% yield; 1H NMR δ 2.79 (m, 2H), 3.30 (m, 2H), 7.00 (t, J = 4.5
Hz, 1H), 7.16 (dd, J = 5.7 and 1.2 Hz, 1H), 7.21 (dd, J = 3.8 and 1.0 Hz,
1H); 19F NMR δ ꢀ51.5 (t, J = 12.4 Hz).
Typical Procedure for FriedelꢀCrafts Reactions of 2,
2-Difluorocyclopropanecarbonyl Chloride (1). Under nitrogen,
appropriate (1 or 5) equivalents of the aromatic compound were added via
syringe to 20 mL of anhydrous CH2Cl2 at 0 °C.2,2-Difluorocyclopropane-
carbonyl chloride (1) (0.5 mL, 0.84 g, 1 equiv) was added to the solution at
0 °C followed by slow addition of 0.956 g (1.2 equiv) of AlCl3. The mixture
was then stirred under N2 for 2 h at 0 °C. Then, water was slowly added to the
mixture until two distinct layers formed and bubbling ceased. The entire
solution was added to NaHCO3 solution and the products were extracted
with CH2Cl2. The CH2Cl2 layer was then dried with anhydrous MgSO4,
filtered, and then removed via rotary evaporation under reduced pressure,
leaving behind a liquid crude mixture of aromatic compound plus product.
Relative amounts of products 2 and 3 were determined by 19F NMR analysis
of the crude product mixture. Isolation of pure products was accomplished by
column chromatography, using silica gel with hexane as eluent.
(2,2-Difluorocyclopropyl)(thiophen-2-yl)methanone (3f):
solid, mp 47ꢀ49 °C, 84% yield; 1H NMR δ 1.83 (m, 1H), 2.39 (m, 1H),
3.29 (m, 1H), 7.19 (t, J = 4.5 Hz, 1H), 7.72 (dd, J = 5.7 and 1.2 Hz, 1H),
7.82 (dd, J = 3.8 and 1.0 Hz, 1H); 13C NMR δ 16.2 (t, 9 Hz), 30.2 (t, J =
11 Hz), 111.7 (t, J = 289 Hz), 128.7, 133.2, 135.0, 144.4, 183.2; 19F
NMR, δ - 124.6 (dtd J = 149,12.4 and 6.2 Hz, 1F), ꢀ140.9 (ddd, J = 148,
21, and 4.2 Hz, 1F); HRMS (EI) calcd for C8H6OF2S [M þ H]þ
189.0180, found 189.0190. Anal. Calcd for C8H6OF2S: C, 51.06; H,
3.21. Found: C, 50.94; H, 3.11.
4-Chloro-1-phenyl-4,4-difluorobutan-1-one (2a): solid, 54%,
mp 37ꢀ38 °C; 1H NMR δ 2.79 (m, 2H), 3.30 (t, J = 7.2 Hz, 2H), 7.47 (m,
2H), 7.59 (m, 1H), 7.97 (d, J = 8.1 Hz, 2H); 19F NMR δ ꢀ51.4 (t, J = 12.4
Hz, 2F); 13C NMR δ 32.7 (t, JFC = 2.6 Hz), 36.5 (JFC = 25.2 Hz), 128.3,
129.0, 130.0 (JFC = 291 Hz), 133.8, 136.4, 196.5; HRMS (EI) calcd for
C10H9OF2Cl [M þ H]þ 218.0304, found 218.0305. Anal. Calcd for
C10H9OF2Cl: C, 54.94; H, 4.15. Found: C, 55.01; H, 4.08.
’ ASSOCIATED CONTENT
Supporting Information. 1H, 13C, and 19F NMR spectra
S
b
of compounds 2aꢀe and 3f and H and 19F NMR spectra of
1
compounds 1, 2f, 3a, 3b, and 3e. This material is available free of
(2,2-Difluorocyclopropyl)(phenyl)methanone (3a):3 liquid,
obtained in 11% yield when using 5 equiv of benzene; 1H NMR δ 1.80
(m, 1H), 2.42 (m, 1H), 3,38 (m, 1H), 7.46 (m, 2H), 7.60 (m, 1H), 8.02
(m, 2H); 19F NMR δ ꢀ124.72 (m, 1F), ꢀ140.58 (m, 1F).
charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
4-Chloro-1-(4-methylphenyl)-4,4-difluorobutan-1-one (2b):
solid, mp, 61ꢀ63.5 °C, 72% and 7% yield, respectively, when using 1 or 5
equiv of toluene; 1HNMRδ2.43 (s, 3H), 2.79 (m, 2H), 3.29 (m, 2H), 7.28
(m, 2H), 7.88 (m, 2H);19F NMRδꢀ51.4 (t, J= 12.4 Hz, 2F); 13CNMRδ
21.91, 32.6 (t, JFC = 3.0 Hz), 36.6 (t, JFC = 24.7 Hz), 129.4, 129.7, 129.97
(t, JFC =291 Hz), 133.9, 144.7, 196.2; HRMS(EI) calcd forC11H11OF2Cl
[M þ H]þ 233.0539, found 233.0387. Anal. Calcd for C11H11OF2Cl: C,
56.79; H, 4.77. Found: C, 56.88; H, 4.68.
Corresponding Author
*E-mail: wrd@chem.ufl.edu.
’ ACKNOWLEDGMENT
The authors would like to thank the University of Florida High-
Performance Computing Center for providing computing time.
(2,2-Difluorocyclopropyl)(4-methylphenyl)methanone (3b):3
solid, mp 37ꢀ38 °C, 63% yield when using 5 equiv of toluene; 1H NMR δ
1.75 (m, 1H), 2.39 (m, 1H), 2.40 (s, 3H), 3.35 (m, 1H), 7.49 (m, 2H), 7.66
(m, 2H); 19F NMR δ ꢀ124.70 (m, 1F), ꢀ140.70 (m, 1F).
’ REFERENCES
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Cai, X.-H.; Modzelewska, A.; Koroniak, H.; Battiste, M. A.; Chen, Q.-Y.
J. Fluorine Chem. 2004, 125, 459–469.
4-Chloro-1-(4-ethylphenyl)-4,4-difluorobutan-1-one (2c):
liquid, 78%, bp 132 °C/10 mmHg; 1H NMR δ 1.27 (t, J = 7.8 Hz, 3H),
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’ NOTE ADDED AFTER ASAP PUBLICATION
Scheme 7 and related text have been corrected as has an
in-text reference to Scheme 9. The correct version reposted on
April 14, 2011.
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