Boron-trihalide-promoted regioselective ring-opening reactions of gem-difluorocyclopropyl ketones

Article abstract of DOI:10.1039/c3cc47879c

Boron trihalide-promoted ring-opening reactions of gem-difluorocyclopropyl ketones to give the corresponding β-trifluoromethyl ketones and β-halodifluoromethyl ketones were described. It was found that boron trihalides act as both Lewis acids and nucleophiles and the proximal bond prefers to cleave in this transformation.

Full text of DOI:10.1039/c3cc47879c

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Boron-trihalide-promoted regioselective ring-
opening reactions of gem-difluorocyclopropyl
ketones†
Cite this:DOI: 10.1039/c3cc47879c
Received 14th October 2013,
Accepted 18th November 2013
Tang-Po Yang,‡ Qiang Li,‡ Jin-Hong Lin and Ji-Chang Xiao*
DOI: 10.1039/c3cc47879c
www.rsc.org/chemcomm
Boron trihalide-promoted ring-opening reactions of gem-difluoro-
cyclopropyl ketones to give the corresponding b-trifluoromethyl
ketones and b-halodifluoromethyl ketones were described. It was
found that boron trihalides act as both Lewis acids and nucleophiles
and the proximal bond prefers to cleave in this transformation.
The tremendous advances in fluorinated pharmaceutical chem-
istry and agricultural chemistry during the past few decades
clearly demonstrate the exceptional importance of fluorinated
compounds.1 As one of the important classes of selectively
fluorinated molecules, gem-difluorocyclopropanes have received
much attention due to the unique properties of the gem-
difluorocyclopropyl group.2 Great progress has been made on
the development of new methods for the construction of this
moiety.3 But determined effort is also needed for the studies on
its reactivity, especially on the ring-opening chemistry,4 which
would be expected to be a promising approach for the synthesis
of unique partially fluorinated molecules. As part of our con-
tinuing interest in gem-difluorocyclopropane chemistry,3k,4g,5
herein we describe the regioselective ring-opening reactions of
gem-difluorocyclopropyl ketones leading to b-trifluoromethyl
Scheme 1 The regioselectivity of ring-opening of gem-difluorocyclo-
propyl ketones.
ketones and b-halodifluoromethyl ketones promoted by boron distal bond scission (eqn (1)).4d Soon after this report, they
trihalides. described that gem-difluorocyclopropyl ketones would also
The ring-cleavage of gem-difluorocyclopropyl ketones could undergo distal bond cleavage upon treatment with MgI2 and
be promoted by nucleophiles, bases or acids with different further react with imines to give non-fluorine containing pro-
regiochemical outcomes.4a,b,d,e Strong nucleophiles and strong ducts (eqn (2)).4e Dolbier’s results showed that the distal bond
bases could lead to distal bond scission and proximal bond prefers to cleave in the presence of acids and soft nucleophiles.
scission, respectively, but both of these two routes resulted in Whereas we found that triflic acid favours the proximal bond
complete loss of fluorine.4a,b In acid-mediated reactions, the cleavage with the use of nitriles as the nucleophile and solvent.
regioselectivity was found to be an interesting issue (Scheme 1). The ring-opening of gem-difluorocyclopropyl ketones and the
Dolbier et al. reported that the Brønsted acid-promoted ring- subsequent cyclization with nitriles proceeded smoothly to give
opening reactions proceeded via a SN2-type process involving 2-fluoropyrroles (eqn (3)).4g In this communication, we found that
boron trihalides could act as both Lewis acids and nucleophiles to
Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic
promote ring-opening reactions via proximal bond cleavage to
give b-trifluoromethyl ketones and b-halodifluoromethyl ketones
(eqn (4)).
Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032,
China. E-mail: jchxiao@sioc.ac.cn; Fax: +86-21-6416-6128; Tel: +86-21-5492-5430
† Electronic supplementary information (ESI) available: Experimental procedures
The initial attempt involving the reaction of phenyl gem-
difluorocyclopropyl ketone 1a with boron trifluoride in chloroform
and characterization data for all compounds. See DOI: 10.1039/c3cc47879c
‡ These authors contributed equally to this work.
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Table 1 Optimization of reaction conditionsa
Table
2
Boron-trifluoride-promoted
ring-opening
of
gem-
difluorocyclopropyl ketonesa
Entry MFn
Solvent Temp (1C) 1a/Lewis acidb 2a yieldc (%)
Entry
R
Product, yieldb
1
2
3
4
5
6
7
8
BF3ÁEt2O CHCl3
r.t.
r.t.
r.t.
r.t.
r.t.
r.t.
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/2.0
1.0/1.0
1.0/0.5
41
1
2
3
4
5
6
7
8
Ph (1a)
2a, 95%
2b, 85%
2c, 76%
2d, 84%
2e, 95%
2f, 75%
2g, 93%
2h, 70%
2i, 89%
2j, 77%
2k, 83%
2l, 74%
ZnF2
CuF2
FeF2
FeF3
CHCl3
CHCl3
CHCl3
CHCl3
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
N.R.
21
26
30
70
98
4-CH3C6H4 (1b)
4-CH3OC6H4 (1c)
3-CH3OC6H4 (1d)
4-FC6H4 (1e)
4-ClC6H4 (1f)
4-BrC6H4 (1g)
3-ClC6H4 (1h)
3-BrC6H4 (1i)
4-NO2C6H4 (1j)
Naphthyl (1k)
Cyclohexyl (1l)
BF3ÁEt2O DMSO
BF3ÁEt2O CH3CN r.t.
BF3ÁEt2O THF
BF3ÁEt2O DCM
r.t.
r.t.
9
9
10
11
12
13
14
15
BF3ÁEt2O Toluene r.t.
10
11
12
BF3ÁEt2O DCE
BF3ÁEt2O CHCl3
BF3ÁEt2O CHCl3
BF3ÁEt2O CHCl3
BF3ÁEt2O CHCl3
r.t.
40
60
60
60
a
77
66
Reaction conditions: 1 (0.2 mmol) and BF3ÁEt2O (0.4 mmol) in CHCl3
b
(1 mL) at 60 1C. Isolated yields.
a
The reaction was carried out with 0.2 mmol of 1a in 1 mL of solvent.
b
c
Molar ratio. Determined by 19F NMR with the use of trifluoromethyl
of boron-trichloride-initiated conversion. Under the same reac-
tion conditions as above (entry 13, Table 1), the desired
transformation could proceed but the reaction turned out to
be quite complex as determined by 19F NMR, probably because
boron trichloride showed stronger Lewis acidity than boron
trifluoride so more side reactions occurred at this high tem-
perature (60 1C). Fortunately, the expected conversion pro-
ceeded quite well at room temperature and the scope of
substrates was explored at this temperature (Table 3). It was
found that the reaction could tolerate various functional groups
on the phenyl ring (entries 1–9). The transformation is also
applicable to aliphatic ketones, but the yield was relatively low
(entry 10).
benzene as internal standard.
was successful, even though the yield was quite low (entry 1,
Table 1). Other fluoride-containing Lewis acids were not effec-
tive for this transformation (entries 2–5). Interestingly, the
solvent showed a strong effect on the reaction. Polar solvents
such as DMSO or CH3CN completely suppressed the desired
conversion (entries 6–8). The desired conversion only occurred
in less polar solvents (entries 9–11), and chloroform seemed
to be the most suitable (entry 1 vs. entries 9–11). The screening
of reaction temperature (entries 12–13) and the substrate ratio
of 1a to boron trifluoride (entries 14–15) showed that the
expected product could be obtained almost in quantitative
yield as determined by 19F NMR with the use of trifluoromethyl
benzene as internal standard when the reaction was performed
at 60 1C in the presence of 2 equiv. of boron trifluoride
(entry 13).
The above results suggested that the ring-opening reaction
promoted by stronger Lewis acid required lower temperature.
Indeed, boron-tribromide-initiated reaction proceeded violently
at room temperature and no expected product was detected by
With the optimized reaction conditions in hand (entry 13,
Table 1), we next explored the substrate scope of boron trifluoride-
promoted ring-opening reactions of gem-difluorocyclopropyl
ketones (Table 2). The reaction could tolerate various substi-
tuents on the phenyl ring and resulted in moderate to excellent
yields (entries 1–11). Irrespective of the electronegativity or the
position of substituents on the phenyl ring in substrates, the
reactions proceeded quite well to afford the desired products.
In the case of methoxy substituted substrates (entries 3 and 4),
a longer reaction time was needed (50 h and 56 h, respectively)
in order to obtain reasonable yields, presumably because the
coordination of methoxy to boron trifluoride leads to the
decrease in the reactivity of boron trifluoride. Besides aromatic
ketones, the reaction worked equally well for aliphatic ketones
(entry 12), which means the transformation is applicable to
both aromatic and aliphatic gem-difluorocyclopropyl ketones.
Encouraged by the successful ring-opening reaction pro-
moted by boron trifluoride, we then examined the possibility
Table 3 Boron-trichloride-promoted ring-opening of gem-difluorocyclo-
propyl ketonesa
Entry
R
Product, yieldb
1
2
3
4
5
6
7
8
9
Ph
3a, 63%
3b, 83%
3c, 82%
3d, 77%
3e, 80%
3f, 82%
3g, 83%
3h, 60%
3i, 80%
3j, 49%
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
3-BrC6H4
4-NO2C6H4
Naphthyl
Cyclohexyl
10
a
Reaction conditions: 1 (0.2 mmol) and BCl3 (0.4 mL, 1 M in CH2Cl2) in
b
CHCl3 (1 mL) at room temperature. Isolated yields.
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Table 4 Boron-tribromide-promoted ring-opening of gem-difluorocyclo-
fluorines could stabilize the resulting carbocation. This strategy
represents a new method for the synthesis of b-trifluoromethyl
ketones and b-halodifluoromethyl ketones, which are very
difficult to obtain by other methods. The study on the ring-
opening chemistry of gem-difluorocyclopropyl ketones and the
application of this strategy to the synthesis of other important
fluorinated compounds are currently underway.
propyl ketonesa
Entry
R
Product, yieldb
1
2
3
4
5
6
7
8
9
Ph
4a, 57%
4b, 81%
4c, 48%
4d, 71%
4e, 74%
4f, 58%
4g, 61%
4h, 54%
4i, 57%
4j, 65%
We thank the National Natural Science Foundation (21032006,
21172240), the 973 Program of China (2012CBA01200), and the
Chinese Academy of Sciences.
4-CH3C6H4
4-FC6H4
4-ClC6H4
4-BrC6H4
3-ClC6H4
3-BrC6H4
4-NO2C6H4
Naphthyl
Cyclohexyl
Notes and references
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a
Reaction conditions: 1 (0.2 mmol) and BBr3 (1 mL, 0.4 M in CH2Cl2) in
b
CHCl3 (1 mL) at À78 1C. Isolated yields.
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Scheme 2 Proposed mechanism for the ring-opening reactions.
19F NMR. At À78 1C, the desired transformation could be
observed for a variety of substrates, giving the corresponding
b-bromodifluoromethyl ketones in moderate yields (Table 4).
As for the reaction mechanism, it is reasonable to conceive a
pathway involving partial ring-opening of gem-difluorocyclopropyl
ketones based on previous reports4d–g and the above results
(Scheme 2). The coordination of ketone to boron trihalide occurred
first, leading to the subsequent partial cleavage of the proximal
bond. The resulting carbocation could be stabilized by the fluorines
on the cyclopropane ring.6 The intramolecular nucleophilic
attack of the carbocation by a halogen anion of boron trihalide
resulted in complete ring-cleavage of gem-difluorocyclopropane
to give the intermediate A. Hydrolysis of intermediate A afforded
the final product.
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The distal bond or proximal bond scission depends on the
reaction conditions and nucleophiles. Strong nucleophiles and
weak acids promote the distal bond scission via SN2 by attack-
ing the less hindered carbon of the cyclopropyl group,4d,e while
strong acids promote the proximal bond scission especially in
polar solvents through the generation of a-fluorine stabilized
carbocations (SN1).
In conclusion, we have described ring-opening reactions 5 (a) X.-C. Hang, Q.-Y. Chen and J.-C. Xiao, Eur. J. Org. Chem., 2008,
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of gem-difluorocyclopropyl ketones promoted by boron tri-
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halides to give corresponding b-trifluoromethyl ketones and
2008, 73, 8598–8600; (d) X.-C. Hang, W.-P. Gu, Q.-Y. Chen and J.-C.
b-halodifluoromethyl ketones. Boron trihalides were found to
be able to act as both Lewis acids and nucleophiles. The
proximal bond of gem-difluorocyclopropyl ketones prefers to
cleave in the presence of boron trihalides because the two
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