Divergent rearrangements of cyclopropyl-substituted fluoroepoxides involving c-f bond cleavage and formation

Article abstract of DOI:10.1021/ol403644n

Unprecedented divergent rearrangements of cyclopropyl-substituted fluoroepoxides are reported. In the presence of a catalytic amount of benzoic acid, cyclopropyl-substituted fluoroepoxides efficiently undergo 1,5-fluorine migration. However, when the fluo

Full text of DOI:10.1021/ol403644n

Letter
pubs.acs.org/OrgLett
Divergent Rearrangements of Cyclopropyl-Substituted
Fluoroepoxides Involving C−F Bond Cleavage and Formation
Tao Luo, Rui Zhang, Wei Zhang, Xiao Shen, Teruo Umemoto, and Jinbo Hu*
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Ling-Ling
Road, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: Unprecedented divergent rearrangements of cyclopropyl-substituted fluoroepoxides are reported. In the presence
of a catalytic amount of benzoic acid, cyclopropyl-substituted fluoroepoxides efficiently undergo 1,5-fluorine migration. However,
when the fluoroepoxides are heated with K2CO3 at 60 °C, 1,2-fluorine migration occurs. The 1,5-fluorine migration is believed to
proceed via a carbocation intermediate, while the 1,2-fluorine migration may involve a tight ion pair intermediate or proceed via a
concerted process.
branch of synthetic organic chemistry. In this context, one
would envision that a process that combines C−F bond
cleavage and C−F bond formation within one molecule could
become a new intriguing protocol for the synthesis of
organofluorine compounds (Scheme 1, eq (c)).
he carbon−fluorine bond is the strongest single bond that
Tcarbon can form, and therefore, the activation and/or
functionalization of C−F bonds are challenging tasks that have
drawn much attention during the past three decades.1 In
general, the currently known C−F bond activation/function-
alization processes often lose the fluorine atom as waste
(Scheme 1, eq (a)).2 On the other hand, despite their rarity in
nature,3 organofluorine compounds play very important roles in
pharmaceuticals, agrochemicals, and advanced materials.4 As a
result, selective C−F bond formation has become one of the
most desirable reactions in modern organic chemistry (Scheme
1, eq (b)).5,6 Therefore, the fusion of C−F bond activation/
functionalization and C−F bond formation may create a new
Fluorine migration reactions typically involve C−F bond
cleavage and C−F bond formation within one molecule
without adding external fluorinating agent(s). However, reports
on fluorine migration are scarce,7 and most of these reported
methods require harsh reaction conditions7a−d and/or specific
substrates.7e,f Recently, we synthesized fluoroepoxides and
transformed them to α-fluorinated ketones in one pot.8 In this
process, we used external fluorinating agents such as TiF4 or
Py·10HF to facilitate the formal 1,2-fluorine migration reaction.
To realize a real fluorine migration reaction without adding
external fluorinating agents, we conducted extensive screening
of reaction conditions (Supporting Information, Tables 1−4)
and structural optimization of substrates (Supporting Informa-
tion, Table 5). Eventually, we realized a real fluorine migration
reaction with cyclopropyl-substituted fluoroepoxides. Remark-
ably, these fluoroepoxides can selectively undergo regioselective
1,2- or 1,5-fluorine migration by changing the acidity of the
reaction system (Scheme 1, eq (d)). Although the rearrange-
ment from epoxides to carbonyl compounds has appeared in
the literature,9 to the best of our knowledge, the selective 1,2-
and 1,5-divergent rearrangements of epoxides have never been
reported.10
Scheme 1. Reactions Involving C−F Bond
At the onset of our investigation, we successfully synthesized
cyclopropyl-substituted fluoroepoxides from fluorosulfoximines
and ketones using an improved procedure.11 The crude
fluoroepoxide 1a (as a mixture of four diastereomers)12 was
directly used to optimize reaction conditions of rearrangements
Received: December 17, 2013
Published: January 14, 2014
© 2014 American Chemical Society
888
dx.doi.org/10.1021/ol403644n | Org. Lett. 2014, 16, 888−891

Organic Letters
Letter
owing to the instability of 1a during the purification process.8
The results are summarized in Table 1. The fluoroepoxide 1a
70% (Table 1, entry 3). However, the reaction became less
efficient when we changed the reaction parameters such as
catalyst loading (Table 1, entries 4 and 5), temperature (Table
1, entry 6), reaction time (Table 1, entry 7), and concentration
(Table 1, entry 8). To our surprise, 1a was also able to undergo
a thermal rearrangement even in the absence of an acid catalyst
(P[1,5]:P[1,2] = 78:22) (Table 1, entry 9). When we changed the
solvent to CH3CN, the regioselectivity of the reaction was also
Table 1. Survey of Reaction Conditions of the Divergent
a
Rearrangements
changed, with the major product being P[1,2] (P[1,5]:P[1,2]
=
48:52, yield of P[1,2] = 27%) (Table 1, entry 10). When
triethylamine was added (2.0 equiv) to the reaction system, the
product ratio (P[1,5]:P[1,2]) was remarkably improved to 5:95,
and the yield of P[1,2] increased to 54% (Table 1, entry 11). It
seems that K2CO3 was a better additive than NEt3 (P[1,5]:P[1,2]
= 3:97, yield (P[1,2]) = 60%) (Table 1, entry 12). Decreasing
the reaction temperature to 60 °C could make the thermal
rearrangement more efficient (P[1,5]:P[1,2] = 1:99, yield (P[1,2]) =
65%) (Table 1, entry 13). However, further lowering the
reaction temperature to 50 °C resulted in an incomplete
reaction (Table 1, entry 14). Finally, we chose the reaction
conditions of entry 3 in Table 1 as standard for 1,5-fluorine
migration reaction, and those of entry 13 in Table 1 were
selected as standard for 1,2-fluorine migration reaction.
With optimized reaction conditions in hand, we next
examined the substrate scope of 1,5-fluorine migration reaction.
The results are summarized in Scheme 2.13 All isolated yields of
products (2a−h) refer to the overall yields for two steps
starting from ketones. The PhCOOH-catalyzed 1,5-fluorine
migration was amenable to structurally diverse cyclopropyl-
substituted fluoroepoxides. When R1 was changed from phenyl
(2a) to 1-naphthyl (2b), 2-naphthyl (2c), or 4-tert-butylphenyl
(2d), the reaction showed good efficiency (46−64% yields) and
excellent regioselectivity (P[1,5]:P[1,2] ≥ 90:10). However, when
R1 = styryl (2e), the 1,5-migration became less efficient (34%
c
temp
P
/
yield
(%)
[1,5]b
entry
additive
Null
solvent
(°C)
time
P[1,2]
1
2
CH3CN
CH3CN
rt
0.5 h
NR
ND
PhCOOH (5
mol %)
rt
15 min
69:31
95:5
93:7
93:7
90:10
92:8
91:9
3
4
5
6
7
PhCOOH (5
mol %)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
rt
15 min
15 min
15 min
15 min
3 h
70
62
55
41
62
64
PhCOOH (10
mol %)
rt
PhCOOH (20
mol %)
rt
PhCOOH (5
mol %)
0 °C
rt
PhCOOH (5
mol %)
d
8
PhCOOH (5
mol %)
rt
15 min
9
Null
Null
DCE
80 °C
80 °C
80 °C
2h
78:22
48:52
5:95
ND
27
yield) due to the decreased regioselectivity (P[1,5]:P[1,2]
=
10
11
CH3CN
CH3CN
4 h
4 h
73:27). When R1 was an alkyl group (2f), the reaction was still
effective (yield of P[1,5] = 49%; P[1,5]:P[1,2] = 85:15). When we
changed R2 from methyl to ethyl (2g), the reaction exhibited
slightly increased regioselectivity (P[1,5]:P[1,2] = 96:4) and
decreased efficiency (39% yield). Furthermore, when R3 = ethyl
group (2h), the efficiency of the reaction was only moderate
(34% yield; P[1,5]:P[1,2] = 87:13).
NEt3
(2.0 equiv)
54
12
K2CO3
(2.0 equiv)
CH3CN
CH3CN
CH3CN
80 °C
60 °C
50 °C
4 h
3:97
1:99
2:98
60
13 K2CO3 (2.0
equiv)
12 h
12 h
65
e
14
K2CO3
(2.0 equiv)
34
a
Next, we examined the substrate scope of the 1,2-fluorine
migration reaction. The results are summarized in Scheme 3.14
Compared to 1,5-fluorine migration, the thermal 1,2-fluorine
migration exhibited higher regioselectivity and efficiency in the
cases of all cyclopropyl-substituted fluoroepoxides that we
investigated. When R1 = phenyl (3a), 1-naphthyl (3b), 2-
naphthyl (3c), styryl (3e), or alkyl (3f) group, the reaction
proceeded smoothly to give 1,2-migration products in 51−74%
yields and with excellent regioselectivity (P[1,2]:P[1,5] ≥ 98:2).
When R2 = ethyl (3h), the product yield was moderate (47%
yield) but with high regioselectivity (P[1,2]:P[1,5] = 98:2).
To gain more insight into these unusual 1,5- and 1,2-
divergent rearrangements of cyclopropyl-substituted fluoroep-
oxides, we carried out several experiments to probe the reaction
mechanism. As shown in Scheme 4, P[1,5] (2a) and P[1,2] (3a)
were not able to transform between each other under the
aforementioned reaction conditions (Scheme 4, eqs a and b),
which suggests that the formations of P[1,5] (2a) and P[1,2] (3a)
should proceed through two different pathways. When we
added water (1 mL) into the thermal rearrangement reaction
system, we isolated two major products 3a (16%) and 4a
General reaction conditions: crude 1a (0.2 mmol) was dissolved in
solvent (3 mL) and stirred with additives under N2 atmosphere at the
b
indicated temperature for the indicated time. The value of
c
(P[1,5]:P[1,2]) was detected by 19FNMR. Yield was of the major
product (two steps’ total yield, calculated from ketones) and detected
d
by 19F NMR using PhS(NTs)(O)CFH2 as internal standard. Using
e
CH2Cl2 (6 mL) as solvent. There were 31% fluoroepoxides
unreacted. NR = no reaction. ND = not determined. DCE = 1,2-
dichloroethane.
showed good stability in CH3CN solution when no additive
was added (Table 1, entry 1). However, an acid dramatically
promoted the rearrangement reaction, and all of the four
diastereomers of 1a can readily undergo the rearrangement.
When benzoic acid (5 mol %) was added as a catalyst, the crude
1a was consumed completely within 15 min and was mainly
converted to 1,5-fluorine migration product (the ratio of 1,5-
and 1,2-migration products P[1,5]:P[1,2] = 69:31) (Table 1, entry
2). It seems that dichloromethane (DCM) was a better solvent
for the 1,5-fluorine migration, and the ratio (P[1,5]:P[1,2]
)
increased to 95:5, with the yield of P[1,5] being improved to
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Organic Letters
Letter
Scheme 2. PhCOOH-Catalyzed 1,5-Fluorine Migration with
Cyclopropyl-Substituted Fluoroepoxides
Scheme 3. Thermal 1,2-Fluorine Migration with
Cyclopropyl-Substituted Fluoroepoxides
a
a
a
General conditions: a crude fluoroepoxide12 (0.2 mmol) was
dissolved in CH3CN (3 mL) and stirred with K2CO3 (55 mg, 0.4
mmol) at 60 °C for 12 h. Yields refer to isolated P[1,2] (two steps’ total
yields caclulated from ketones).
Scheme 4. Probing the Reaction Mechanism19
a
General conditions: a crude fluoroepoxide12 (0.2 mmol) and
PhCOOH (1.2 mg, 0.01 mmol, 5 mol %) were dissolved in CH2Cl2
(3 mL) and stirred at room temperature for 15 min. Yields refer to
b
isolated P[1,5] (two steps’ total yield, caculated from ketones). The
c
elimination byproduct 6a was also isolated. PhCOOH (2.4 mg, 0.02
mmol, 10 mol %).
(57%) (Scheme 4, eq c). The formation of 4a suggests that
water could compete with fluoride ion to capture the reaction
intermediate, and therefore, the formation of the P[1,5] (2a)
might involve a carbocation intermediate. The fact that 5a15
was not formed during the reaction indicates that the formation
of P[1,2] (3a) might proceed via a tight ion pair intermediate16
or through a concerted process.7e,f,17,18
Based on these experimental results, we propose a reaction
mechanism for these novel 1,5- and 1,2-divergent rearrange-
ments (Scheme 5). When 1a is treated with an acid, it mainly
undergoes 1,5-fluorine migration to give P[1,5] (2a). The acid
activates the epoxide to form a carbocation intermediate A.
Owing to the high ring strain of cyclopropyl group, A
undergoes ring-opening to form carbocation B. Intermediate
B could either be captured by a fluoride ion to give P[1,5] (2a)
or eliminate a proton to afford 6a. On the other hand, when 1a
is heated with a base at 60 °C, it mainly undergoes 1,2-fluorine
migration to form P[1,2] (3a). The 1,2-migration may involve a
tight ion pair intermediate or pass through a concerted
mechanism,20 and in this process, the addition of a base
presumably inhibits the acid-catalyzed 1,5-migration.
migration. On the other hand, when treated with K2CO3 at
60 °C in acetonitrile, fluoroepoxides undergo an efficient 1,2-
fluorine migration. The 1,5-fluorine migration is believed to
proceed via a carbocation intermediate, while the 1,2-fluorine
migration may involve a tight ion pair intermediate or proceed
through a concerted process. These interesting transformations,
combining the C−F bond cleavage and formation within one
molecule without adding external fluorinating agent(s), provide
a proof of concept for the efficient fluorine migration under
mild reaction conditions. These results promise to trigger
further development of more practically useful fluorine
migration reactions. Further exploration in this direction is
currently underway in our laboratory.
In summary, we have reported the first 1,5- and 1,2-divergent
rearrangements of the cyclopropyl-substituted fluoroepoxides.
In the presence of a catalytic amount of benzoic acid, the
cyclopropyl-substituted fluoroepoxides undergo 1,5-fluorine
890
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Organic Letters
Letter
(c) Babudri, F.; Farinola, G. M.; Naso, F.; Ragni, R. Chem. Commum.
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Scheme 5. Proposed Reaction Mechanism for the 1,5-and
1,2-Divergent Rearrangements
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H. J. Org. Chem. 2000, 65, 8032. (c) van Alem, K.; Belder, G.; Lodder,
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(11) The preparative method for cyclopropyl-substituted fluoroep-
oxide 1a is an improved version of the one reported in ref 8. The
experimental details are described in the Supporting Information.
(12) A crude fluoroepoxide contains four diastereomers, and the ratio
was determined by 19F NMR (see the Supporting Information).
(13) Based on the NOE experiment of 2d, the configuration of the
newly formed double bond in P[1,5] is assigned as the E-configuration.
For details, see the Supporting Information.
(14) P[1,2] is a pair of diastereomers. The dr for the product is
detected by 19F NMR, which is shown in the Supporting Information.
(15) We synthesized 5a through another route, and 5a showed good
stability under the reaction conditions as shown in eq (c) of Scheme 4.
For details, see the Supporting Information.
(16) The thermal rearrangement of cloroepoxides passed through a
tight ion pair mechanism: McDonald, R. N.; Steppel, R. N. J. Am.
Chem. Soc. 1970, 92, 5664.
(17) It was reported that the fluorine migrations pass through a
bridged, three-membered-ring transition state in the gas-phase
reaction: (a) Shaler, T. A.; Morton, T. H. J. Am. Chem. Soc. 1994,
116, 9222. (b) Nguyen, V.; Cheng, X.; Morton, T. H. J. Am. Chem. Soc.
1992, 114, 7127. (c) Shaler, T. A.; Morton, T. H. J. Am. Chem. Soc.
1991, 113, 6771. (d) Shaler, T. A.; Morton, T. H. J. Am. Chem. Soc.
1989, 111, 6868.
(18) It was reported that the bridged fluoronium ion was unstable in
solution reaction: (a) Olah, G. A.; Prakash, G. K. S.; Rasul, G. Proc.
Natl. Acad. Sci. U.S.A. 2013, 110, 8427. (b) Olah, G. A.; Prakash, G. K.
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ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and characterization data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
■
S
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: jinbohu@sioc.ac.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Support of our work by the National Basic Research Program
of China (2012CB215500 and 2012CB821600), the National
Natural Science Foundation of China (21372246), Shanghai
QMX program (13QH1402400), and the Chinese Academy of
Sciences is gratefully acknowledged. T.U. thanks the Chinese
Academy of Sciences for sponsoring his work at SIOC as a CAS
Visiting Professor.
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(20) We thank one of the reviewers for raising a point that it is also
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