Dehydrative Ring-Opening of gem-Difluorocyclopropyl Carbinols to Allylic Trifluoromethyl and Difluorohalomethyl Derivatives Promated by Titanium Tetrahalide

Article abstract of DOI:10.1002/ejoc.202000820

We report herein the titanium tetrahalide-promoted dehydrative ring-opening of gem-difluorocyclopropyl carbinols as a novel method for the synthesis of (E)-allylic CF₃, (E)-allylic CF₂Cl, and (E)-allylic CF₂Br compounds. This TiF₄-promoted reaction appears to proceed via a concerted S_N2' mechanism. A control experiment revealed that the TiCl₄-promoted ring-opening initially proceeds by conversion of the gem-difluorocyclopropyl carbinol into a gem-difluorocyclopropyl chloride intermediate.

Full text of DOI:10.1002/ejoc.202000820

Communication
doi.org/10.1002/ejoc.202000820
EurJOC
European Journal of Organic Chemistry
Ring-Opening Reactions
Dehydrative Ring-Opening of gem-Difluorocyclopropyl
Carbinols to Allylic Trifluoromethyl and Difluorohalomethyl
Derivatives Promated by Titanium Tetrahalide
Manickavasakam Ramasamy,[a] Sheng-Chu Kuo,[a,b,c] and Min-Tsang Hsieh*[a,b,c,d]
Abstract: We report herein the titanium tetrahalide-promoted control experiment revealed that the TiCl4-promoted ring-open-
dehydrative ring-opening of gem-difluorocyclopropyl carbinols ing initially proceeds by conversion of the gem-difluorocyclo-
as a novel method for the synthesis of (E)-allylic CF3, (E)-allylic propyl carbinol into a gem-difluorocyclopropyl chloride inter-
CF2Cl, and (E)-allylic CF2Br compounds. This TiF4-promoted reac- mediate.
tion appears to proceed via a concerted SN2′ mechanism. A
similar reaction conditions to those used to prepare 2
(Scheme 1).
Fluorinated molecules have figured prominently in chemistry
due to their unique medicinal properties, structural novelty, and
rich chemistry.[1] Over the past two decades, more than 40 %
of blockbuster drugs have incorporated fluorinated functional
groups.[2] Fluorine substitution is a valuable strategy for en-
hancing target selectivity, drug potency, and achieving a favor-
able physicochemical/pharmacokinetic profile at the lead-to-
candidate optimization stage of drug discovery.[3] Numerous in-
vestigations have cumulated in the development of improved
general methods for the synthesis of fluorinated compounds.
Previously, we developed a practical BF3·OEt2-catalyzed Meyer–
Schuster rearrangement for the preparation of ꢀ-fluoroalkyl-
α,ꢀ-enones,[4] which are versatile compounds for the synthesis
of trifluoroalkyl-containing cyclic compounds.[5] During the
course of our synthetic studies toward trifluoromethyl-substi-
tuted compounds, we observed that treatment of cyclopropyl-
substituted propargylic alcohol 1a with BF3·OEt2 did not afford
the expected rearrangement product, rather, the dehydrative
ring-opening product 2 was obtained instead. Further studies
revealed substitution group-controlled selectivity, as evidenced
by an experiment in which the p-methoxy-substituted com-
pound 1b preferred to rearrange rather than ring-open under
Scheme 1. Reactions of propargylic alcohols with BF3·OEt2.
We then reasoned that an electron-withdrawing group posi-
tioned on the benzene ring would hinder the rearrangement
of the adjacent propargylic alcohol skeleton and facilitate ring-
opening, while BF3·OEt2 would serve as an effective agent to
promote the dehydrative ring-opening of cyclopropyl carbinols
toward the allylic fluoride products. Based on strain energies
calculated by G2 theory, gem-dimethyl substitution lowers the
ring strain of the cyclopropane, whereas gem-difluoro substitu-
tion destabilizes the cyclopropane ring by increasing the strain
energy by 12–14 kcal/mol.[6] The energetic nature of the gem-
difluoro-substituted cyclopropane renders it more reactive to
nucleophilic substitution than an unsubstituted cyclopropane.
Brønsted acids, such as hydrobromic acid and the acetic acid/
p-TSA system,[7] have been documented to promote the ring-
opening of gem-difluorocyclopropyl carbinols towards the ꢀ,ꢀ-
difluorohomoallyl and α,α-difluorohomoallyl derivatives. Xiao et
al. reported that BF3·OEt2 promoted the ring-opening of gem-
difluorocyclopropyl ketones to give ꢀ-trifluoromethyl ketones.[8]
The method is not restricted to BF3·OEt2, as BCl3 and BBr3 both
effectively facilitated the ring-opening of the gem-difluoro-
cyclopropyl ketone. The same group also reported that the
treatment of gem-difluorocyclopropyl ketones with nitriles in
the presence of triflic acid afforded 2-fluoropyrroles.[9] In addi-
[a] M. Ramasamy, Prof. S.-C. Kuo, Prof. M.-T. Hsieh
School of Pharmacy, China Medical University,
Taichung 40402, Taiwan
E-mail: t21917@mail.cmu.edu.tw
http://webap.cmu.edu.tw/TchEportfolio/index_1/t21917
[b] Prof. S.-C. Kuo, Prof. M.-T. Hsieh
Chinese Medicine Research Center, China Medical University,
Taichung 40402, Taiwan
[c] Prof. S.-C. Kuo, Prof. M.-T. Hsieh
Research Center for Chinese Herbal Medicine, China Medical University,
Taichung 40402, Taiwan
[d] Prof. M.-T. Hsieh
Chinese Medicinal Research and Development Center, China Medical
University Hospital, Taiwan
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.202000820.
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[10]
tion, MgI2
strong bases,[11] thiol nucleophiles,[12] and the N- reduced to 0.5 equivalents without significant loss of reaction
pentylpyridinium bromide/triflic acid system[13] showed sub- efficiency or yield (entry 6). The reaction displayed significant
stantial abilities to promote the ring-opening of gem-difluoro- solvent dependence; low yields were obtained with three sol-
cyclopropyl ketones. Recently, the synthesis of 3-fluorofurans vents, namely 1,4-dioxane (entry 8), THF (entry 9), and toluene
from the gem-difluorocyclopropyl ketones was realized with (entry 10). The imide 7 was unexpectedly formed when aceto-
two equivalents of triflic acid.[14]
nitrile was employed as the solvent (entry 11). The formation
of 7 is possibly ascribable to a defluorinative hydrolysis process,
in which the nitrile rather than the fluoride ion is involved in
the initial nucleophilic ring-opening of the gem-difluoromethyl
group to form an unstable intermediate which, in turn, under-
goes facile hydrolysis of its difluoromethyl and nitrile moie-
ties.[18] Therefore, we conclude that the conditions shown in
entry 6 are optimal and were subsequently used in the general
procedure.
With this background in mind, we became interested in the
dehydrative ring-opening of gem-difluorocyclopropyl carbinols
for the synthesis of allylic CF3 compounds.[15] In this communi-
cation, we report the titanium tetrahalide-promoted dehydra-
tive ring-opening of gem-difluorocyclopropyl carbinols for the
synthesis of allylic CF3, allylic CF2Cl,[16] and allylic CF2Br com-
pounds,[7] which are useful fluorine-containing synthetic build-
ing blocks.
The substrate scope and generality of the TiF4-promoted
ring-opening reaction were next examined for gem-difluoro-
cyclopropyl carbinols 4b–l (Table 2). Compounds 4b–f bearing
electron-donating groups, including p-methyl, p-methoxy,
m-methoxy, p-phenoxy, and m-dimethoxy, were amenable to
the optimized reactions and furnished the corresponding
(E)-allylic CF3 compounds 6b–f in moderate-to-good yields (55–
80 %). Electron-withdrawing groups, such as p-chloro, p-bromo,
p-iodo, and p-nitro appeared to retard the reaction and ex-
tended reaction times (≈ 2 h) were required to produce 6g–i.
The reactions of gem-difluorocyclopropyl carbinols substituted
with 3-chloro-4-methoxyphenyl and naphthyl groups pro-
ceeded well to yield 6k (79 %) and 6l (67 %), respectively. The
effect of phenyl substitution at the vicinal position of the gem-
difluoromethylene carbon was then examined. The reactions of
5a and 5b with TiF4 provided the corresponding trifluorinated
compounds 8a and 8b instead of the allylic trifluoromethylated
compounds, suggesting that the benzylic carbon is more elec-
All gem-difluorocyclopropyl carbinols used in the current
study were prepared by the direct reduction of the correspond-
ing gem-difluorocyclopropyl ketones[8] or in four-step sequen-
ces comprising acetal protection of a chalcone followed by
gem-difluorocyclopropanation and acid hydrolysis of the result-
ing 1,3-dioxolane, followed by reduction of the obtained gem-
difluorocyclopropyl chalcone analog[17] (see SI for more details).
At the onset of the study, difluorocyclopropyl carbinol 4a was
used as the model compound. The abilities of BF3·OEt2 and
metal fluorides, including AlF3, TiF4, CuF2, and AgF, to effect the
ring-opening reaction were examined, the results of which are
summarized in Table 1. Carbinol 4a was treated with one equiv-
alent of BF3·OEt2 in 1,2-DCE to give the thermodynamically
more stable (E)-allyl CF3 product 6a in moderate-to-good yields.
1
The (E)-geometry of 6a was determined by the vicinal H NMR
coupling constant of the olefinic moiety, which is typical for
trans-oriented protons. AgF and CuF2, which are mildly Lewis
acidic, did not promote the reaction, and AlF3 appears not to
be the reagent of choice due to the very low yield of 6a ob-
tained. The use of TiF4 proved to be fruitful for producing 6a in
good yield (76 %, entry 5). The reagent loading can also be
Table 2. Reaction scope of the TiF4-promoted dehydrative ring-opening.[a]
Table 1. Optimizing the reaction conditions.[a]
Entry Regent
Solvent/Temp
Time [h]
Yield [%][b]
1
2
3
4
5
6
7
8
BF3·OEt2 (1.0 equiv.) 1,2-DCE/60 °C
0.5
3.0
4.0
4.0
0.5
0.5
2.0
1.0
2.0
2.0
0.5
58
< 5
0
0
AlF3 (1.0 equiv.)
AgF (1.0 equiv.)
CuF2 (1.0 equiv.)
TiF4 (1.0 equiv.)
TiF4 (0.5 equiv.)
TiF4 (0.25 equiv.)
TiF4 (0.5 equiv.)
TiF4 (0.5 equiv.)
TiF4 (0.5 equiv.)
TiF4 (0.5 equiv.)
1,2-DCE/60 °C
1,2-DCE/60 °C
1,2-DCE/60 °C
1,2-DCE/60 °C
1,2-DCE/60 °C
1,2-DCE/60 °C
1,4-dioxane/60 °C
THF/60 °C
76
75
39[c]
26
23
19
9
10
11
Toluene/60 °C
Acetonitrile/40 °C
7 (44 %)[d]
[a] All reactions were performed using alcohol 4a (0.27 mmol) in 1 mL of
anhydrous solvent as indicated above. [b] Yields are for isolated, chromato-
graphically pure products. [c] 4a was recovered in 30 % yield. [d] Imide 7 was
obtained instead of the expected 6a.
[a] Isolated yields after silica gel chromatography. [b] 2 h reaction time is
required for these cases.
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trophilic than the gem-difluoromethylene carbon toward fluor- fied in a reprocessing experiment (eq. 7); 9d was obtained in
ide addition (eq. 1, Scheme 2). Subsequently, TiCl4 and TiBr4, 55 % yield when 12 was heated with TiCl4 (0.5 equiv.).
which are both more Lewis acidic than TiF4, were used to pro-
mote the dehydrative ring-opening reaction. Using slightly
modified reaction temperatures and times, the TiCl4-promoted
reactions of 4a–b, 4g, and 4i smoothly provided the corre-
sponding (E)-allyl CF2Cl compounds 9a–d in good yields (76–
83 %, eq. 2). Similar results were obtained in the TiBr4-mediated
reactions, which smoothly produced the (E)-allyl CF2Br com-
pounds 10a and 10b (eq. 3). In addition, treatment of 5a with
TiCl4 gave the gem-difluorodichloromethane 11 (eq. 4), confirm-
ing again that 5a prefers to be nucleophilically attacked at the
benzylic position.
A plausible mechanism for this chemistry is shown in
Scheme 3. Dehydrative ring-opening of a gem-difluorocyclo-
propyl carbinol can occur via two SN2′-type pathways. In path-
way I, the reaction of the carbinol with TiF4 produces the TiF3-
carbinol complex A, which undergoes fluoride addition and
ring-opening with concurrent elimination of TiOHF3 in a con-
certed fashion. In pathway II, treatment of the carbinol with
TiCl4 gives the TiCl3-carbinol complex B, which quickly rearran-
ges to form the intermediate chloride C; this intermediate then
undergoes an addition/ring-opening/elimination sequence to
yield the allylic CF2Cl product. However, the possibility that the
TiCl4-promoted ring-opening of
a gem-difluorocyclopropyl
carbinol proceeds via a pathway I-like concerted mechanism
still exists.
Scheme 3. The plausible mechanism.
In summary, we established an effective reaction system for
inducing the dehydrative ring-opening of gem-difluorocyclo-
propyl carbinols, leading to the corresponding (E)-allylic CF3,
(E)-allylic CF2Cl, and (E)-allylic CF2Br derivatives in moderate-to-
high yields. The current methodology, which uses readily acces-
sible TiF4, TiBr4, and TiCl4, is operationally simple. We are cur-
rently synthesizing challenging allylic CF3 compounds in our
laboratory by extending these reactions.
Acknowledgments
This research project was funded by Ministry of Science and
Technology, Taiwan (MOST 106-2113-M-039-005) and “Chinese
Medicine Research Center, China Medical University” from The
Featured Areas Research Center Program within the framework
of the Higher Education Sprout Project by the Ministry of Edu-
cation (MOE) in Taiwan (CMRC-CHM-6).
Keywords: Cyclopropanes · Fluorinated compounds · Ring-
opening reactions · Synthetic methods · Titanium
Scheme 2. Ring-opening of gem-difluorocyclopropyl carbinols.
Insight into the ring-opening reaction was gained through
control studies in which reduced amounts of titanium reagents
and mild conditions were used. The reaction of 4i with TiF4
(0.2 equiv.) at ambient temperature led only to 6i and recovery
of starting carbinol, with no trace of a possible intermediate
detected (eq. 5). Apart from (E)-allylic 9d, the TiCl4-promoted
reaction of 4i (eq. 6) afforded chloro compound 12, which is a
possible reaction intermediate. This presumption was then veri-
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Ring-Opening Reactions
M. Ramasamy, S.-C. Kuo,
M.-T. Hsieh* .......................................... 1–5
Dehydrative Ring-Opening of gem-
Difluorocyclopropyl Carbinols to All-
ylic Trifluoromethyl and Difluoro-
halomethyl Derivatives Promated
by Titanium Tetrahalide
An effective approach to (E)-allylic CF3, been developed, based on a titanium
(E)-allylic CF2Cl, (E)-allylic CF2Br deriva- tetrahalide-promoted
dehydrative
tives, 1-chloro-2,2-difluoromethylene, ring-opening of gem-difluorocyclo-
and polyfluorinated compounds has propyl carbinols.
doi.org/10.1002/ejoc.202000820
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