Synthesis of fluorinated imines by addition of fluoroalkyl radicals to conjugated imines

Article abstract of DOI:10.1055/s-0029-1218755

A novel preparation of β-perfluoroalkyl imine derivatives, useful as synthetic building blocks, was achieved by a route involving addition of electrophilic fluoroalkyl radicals to α,β-unsaturated imines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218755

PAPER
1999
Synthesis of Fluorinated Imines by Addition of Fluoroalkyl Radicals to
Conjugated Imines
Radical Fluoroalkylati
a
s
gate
d
Imi
a
nes fumi Ueda,a Eri Iwasada,a Hideto Miyabe,b Okiko Miyata,*a Takeaki Naito*a
a
Kobe Pharmaceutical University, Motoyamakita, Higashinada, Kobe 658-8558, Japan
School of Pharmacy, Hyogo University of Health Sciences, Minatojima, Chuo-ku, Kobe 650-8530, Japan
b
Fax +81(78)4417554; fax +81(78)4417642; E-mail: miyata@kobepharma-u.ac.jp; E-mail: taknaito@kobepharma-u.ac.jp
Received 22 February 2010; revised 12 March 2010
regioselectively at the position b to the imino group. For
the successful completion of the radical addition reaction,
a smaller excess of the perfluoroalkyl iodide is required as
a radical precursor than is the case with simple nucleo-
philic alkyl iodides, for which large excesses of the
reagent are needed.7
Abstract: A novel preparation of b-perfluoroalkyl imine deriva-
tives, useful as synthetic building blocks, was achieved by a route
involving addition of electrophilic fluoroalkyl radicals to a,b-unsat-
urated imines.
Key words: imines, fluoro compounds, addition reactions, radical
reactions, fluoroalkylimines
To our knowledge, there have been no reports on addition
reactions of electrophilic perfluoroalkyl radicals to elec-
tron-deficient a,b-unsaturated aldehyde or imine deriva-
tives. We therefore investigated the reactions of
electrophilic fluoroalkyl radicals with a variety of a,b-un-
saturated imines, a task that appeared to be a highly chal-
lenging. We have already developed very efficient radical
additions of both nucleophilic7 and moderately electro-
philic carbon radicals to glyoxylic oxime ether.8 We re-
cently also reported that dual-activated C–C multiple
bonds in which the terminal carbon atoms are substituted
with an ester and an imino group can be efficiently em-
ployed as excellent substrates for a synthetically useful
domino reaction involving the addition of either a nucleo-
philic alkyl or a thiyl radical.9
Because of their chemical and thermal stability and their
unique properties arising from the presence of fluorine at-
oms, fluorinated organic compounds have a wide range of
applications, particularly in drug development and crop
protection.1 Indeed, many new pharmaceuticals incorpo-
rate one or more fluorine atoms.2 The bulkiness and elec-
tronegativity of drugs can be adjusted by the introduction
of a variety of perfluoroalkyl groups into the original drug
structures. The modification of drugs by fluorination is of
considerable interest because fluorination can result in en-
hanced selectivity in binding, elevated lipophilicity, and
improved metabolic stability in the resulting analogues.2
However, the range of efficient methods for the synthesis
of fluorinated organic compounds is still limited.3 In this
context, we were interested in developing new and effi-
cient methods for synthesizing fluorinated building
blocks from readily available starting materials.
Among the hitherto known radical reactions, we selected
a triethylborane-mediated radical reaction under environ-
mentally benign conditions involving an iodine atom-
transfer process10 using readily available fluoroalkyl io-
dides as a source of radicals and a,b-unsaturated imines as
the substrates.
Because fluoroalkyl radicals are electrophilic, they react
more easily with electron-rich olefins than do electron-
deficient olefins.4 Additionally, p-sufficient aromatic
compounds, including benzene itself, react with fluoro-
alkyl radicals to afford substituted arenes in the same
manner as the electrophilic substitution of arenes.5 In con-
trast, addition reactions of fluoroalkyl radical with elec-
tron-deficient olefins, such as conjugated esters, amides,
or nitriles are relatively unusual.6
We first examined the radical addition reaction between
perfluoropropyl iodide and the oxime ether 1 (Table 1).
Perfluoropropyl iodide (5 equiv) and triethylborane (5
equiv) were added to a solution of oxime ether 17a in
dichloromethane at room temperature, and then the solu-
tion was stirred at the same temperature for one hour to
give the b-addition products. A 2:1 mixture of the two iso-
meric oxime ethers (E)-2a and (Z)-2a was obtained in
65% yield and subsequently separated (entry 1). Fortu-
nately, the ethyl radical-addition product 2c,7b derived
from triethylborane, and the a-addition product were not
detected under these conditions. In our previous study on
nucleophilic alkyl radical addition to the same substrate 1,
many equivalents of the alkyl iodide were required for
successful reaction, as shown in entry 2.9a,c
Here, we report a new synthesis of b-perfluoroalkyl imine
derivatives by means of radical addition to a,b-unsaturat-
ed imines. This route to b-perfluoroalkyl imines involves
the triethylborane-mediated addition of perfluoroalkyl
radicals to a,b-unsaturated imines to give fluorinated
imines directly, although highly electrophilic perfluoro-
alkyl radicals would appear to be unlikely to add to elec-
tron-deficient olefins. The radical addition takes place
To evaluate the scope of this perfluoroalkyl radical addi-
tion reaction, we next examined the effects of substituents
on the substrates, and we found that the corresponding
aldehyde 3 was inert under our radical conditions
SYNTHESIS 2010, No. 12, pp 1999–2004
Advanced online publication: 23.04.2010
DOI: 10.1055/s-0029-1218755; Art ID: F03710SS
© Georg Thieme Verlag Stuttgart · New York
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M. Ueda et al.
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moderate yields of the respective adducts 8a and 8b
(Table 3; entries 1 and 2). It is noteworthy that the reac-
tion of the N,N-diphenylhydrazone 7a11 proceeded rapidly
within only 5 minutes, and longer reaction times reduced
the yield of this reaction. Addition of a catalytic amount
of tetrakis(triphenylphosphine)palladium [Pd(PPh3)4] is
known to accelerate triethylborane- and triethylalumi-
num-mediated fluoroalkylation reactions.4b,12 Unfortu-
nately, in our case, addition of Pd(PPh3)4 did not shorten
the reaction time, nor did it improve the yield of product
8b (entry 3). The reaction failed with both the oxime 7c13
and the N-benzoylhydrazone 7d,14 and unidentifiable
products were obtained in both cases. The amounts of tri-
ethylborane and perfluoropropyl iodide were also exam-
ined for the reaction of the oxime ether 4a (entries 4–6).
Good chemical yields were obtained, even when the
amount of perfluoropropyl iodide was reduced to two
equivalents (entries 5 and 6). Other radical initiators such
as diethylzinc, triethylaluminum, or diethylaluminum
chloride were quite inefficient, and starting materials were
recovered in all the reactions.
Table 1 Radical Addition Reactions of the a,b-Unsaturated Oxime
Ether 1
α
RI, Et3B (5 equiv)
CH2Cl2, r.t.
NOBn
NOBn
EtO2C
EtO2C
β
1
R
2a R = CF2CF2CF3
2b R = i-Pr
2c R = Et
Entry RI
Time (h) Product Yield (%)
1
2
CF3CF2CF2I (5 equiv)
1.0
0.5
2a
2b
65
60
i-PrI (30 equiv)
(Scheme 1). However, the methyl- and phenyl-substituted
oxime ethers 4a and 4b, respectively, were effective as
substrates in the perfluoroalkyl radical addition reaction,
and gave moderate yields of the corresponding adducts 5a
and 5b (Table 2; entries 1 and 2). However, when the ter-
minal olefin 4c was used as a substrate (entry 3), the de-
sired adduct 5c could not be isolated from the resulting
complex mixture, which included polymerization prod-
ucts. In contrast, the phenylsulfanyl-substituted oxime
ether 4d gave a complex mixture of products from which
the a-addition product 6 was isolated in low yield (entry
4). The reversed regioselectivity of this reaction may be
explained by the resonance effect of the phenylsulfanyl
group, which increases the electron density at the a-posi-
tion.
Table 3 Perfluoroalkyl Radical Addition to a,b-Unsaturated Imine
Derivatives 4–7
CF3CF2CF2I, Et3B
NR
CF2CF2CF3
NR
CH2Cl2, r.t.
4a R = OBn
7a R = NPh2
7b R = NMeBz
7c R = OH
5a R = OBn
8a R = NPh2
7d R = NHBz
8b R = NMeBz
CF3CF2CF2I (5 equiv), Et3B (5 equiv)
O
EtO2C
complex mixture
Entry Substratea Et3B
CF3CF3CF2I Time
Product Yield
(%)
CH2Cl2, r.t.
3
Scheme 1 Attempted addition of perfluoroalkyl radicals to alde-
hyde 3
1
7a
7b
7b
4a
4a
4a
5 equiv
5 equiv
5 equiv
5 equiv
5 equiv
2 equiv
5 equiv
5 equiv
5 equiv
5 equiv
2 equiv
2 equiv
5 min
1 h
8a
8b
8b
5a
5a
5a
49
65
69
67
64
64
2
Table 2 Addition Reactions of Perfluoroalkyl Radicals with a,b-
Unsaturated Oxime Ethers 4a–d
3b
4
1 h
1 h
α
CF3CF2CF2I (5 equiv)
Et3B (5 equiv)
NOBn
5a R = Me
NOBn
R
R
β
5
1 h
4a R = Me
4b R = Ph
4c R = H
CH2Cl2, r.t.
CF2CF2CF3
5b R = Ph
5c R = H
6
1 h
+
4d R = SPh
a The reactions of oxime 7c and of N-benzoylhydrazone 7d gave un-
identifiable products.
CF2CF2CF3
NOBn
PhS
b Pd(PPh3)4 (0.05 equiv) was added.
6
Entry
Substrate
R
Time
1 h
Product Yield (%)
The reaction of the N-benzoyl-N-methylhydrazone-
substituted ester 9 worked well to afford the b-adduct 10
in 58% yield (Scheme 2).
1
2
3
4
4a
4b
4c
4d
Me
Ph
H
5a
5b
–
67
1 h
50 (11)a
15 min
1 h
–
CF3CF2CF2I (5 equiv)
Et3B (5 equiv)
NNMeBz
NNMeBz
EtO2C
EtO2C
SPh
6
15
CH2Cl2, r.t.
9
CF2CF2CF3
10 (58%)
a Yield of recovered oxime ether 4b.
Scheme 2 Perfluoroalkyl radical addition to hydrazone 9
Next, we turned our attention to examining the effects of
the oxime ether group by using other imino groups
(Table 3). The N,N-diphenylhydrazone 7a and the N-ben-
zoyl-N-methyhydrazone 7b reacted efficiently to give
In contrast to nucleophilic alkyl radical addition reactions
of a,b-unsaturated imines, which require many equiva-
Synthesis 2010, No. 12, 1999–2004 © Thieme Stuttgart · New York

PAPER
Radical Fluoroalkylation of Conjugated Imines
2001
lents of the alkyl iodide as a radical precursor,9a,c it is
worth emphasizing that a few equivalents of perfluoropro-
pyl iodide (two or five) were sufficient to achieve success-
ful radical addition reactions (compare entries 1 and 2 in
Table 1 and entry 6 in Table 3). The efficient addition of
the perfluoroalkyl radical can explained as follows. In the
initial step, the iodine atom-transfer process from an ethyl
radical to a perfluoroalkyl radical is less effective owing
to the low stability of the perfluoroalkyl radical. However,
the less-stable but electrophilic perfluoroalkyl radical is
more reactive than the nucleophilic ethyl radical in react-
ing at the b-position of a conjugated imine derivative car-
rying an additional heteroatom (X = O or N) that renders
the position moderately nucleophilic. The reaction may
involve the transition state A and the boryl enamine inter-
mediate B (Scheme 3).
Addition of a Perfluoropropyl Radical to Oxime Ether (E)-1
(Table 1, Entry 1)
Perfluoropropyl iodide (317 mg, 1.07 mmol) and a 1.00 M soln of
Et3B in hexane (1.07 mL, 1.07 mmol) were added to a soln of (E)-
1
5a (50 mg, 0.21 mmol) in CH2Cl2 (5 mL) under N2 at r.t., and the
mixture was stirred at r.t. for 1 h. The mixture was then diluted with
sat. aq NaHCO3 (15 mL) and extracted with CHCl3 (3 × 15 mL).
The organic phase was dried (MgSO4) and concentrated under re-
duced pressure to give a crude product that was purified by prepar-
ative TLC (benzene) to give (E)- and (Z)-2a.
Ethyl 2-{(2E)-2-[(Benzyloxy)imino]ethyl}-3,3,4,4,5,5,5-hepta-
fluoropentanoate [(E)-2a)]
Colorless oil; yield: 38.3 mg (44%).
IR (CHCl3): 2987, 2938, 1744, 1454, 1239, 1187 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.45 (t, J = 4.5 Hz, 1 H, iminoic
H), 7.37–7.28 (m, 5 H, ArH), 5.03 (s, 2 H, CH2Ph), 4.14 (dq,
J = 10.5, 7.0 Hz, 1 H, OCH2Me), 4.08 (dq, J = 10.5, 7.0 Hz, 1 H,
OCH2Me), 3.59–2.49 (m, 1 H, 2-H), 2.91 (ddd, J = 16.0, 11.5, 4.5
Hz, 1 H, 1¢-H), 2.68 (br dt, J = 16.0, 4.5 Hz, 1 H, 1¢-H), 1.23 (t,
J = 7.0 Hz, 3 H, OCH2Me).
O2
Et3B
Et
+
CF3CF2CF2I
•
13C NMR (125 MHz, CDCl3): d = 166.3 (d, J = 7.5 Hz, CO), 145.6
(iminoic C), 137.4 (Ar), 128.4 (Ar), 128.2 (Ar), 128.0 (Ar), 117.6
(qt, J = 286.5, 33.0 Hz, CF2CF2CF3), 115.5 (tt, J = 258.5, 31.5 Hz,
CF2CF2CF3), 109.0 (t-sext, J = 264.5, 37.0 Hz, CF2CF2CF3), 76.1
(CH2Ph), 62.1, 45.1 (t, J = 21.5 Hz, 2-C), 25.7, 13.9.
HRMS (EI): m/z [M+] calcd for C16H16F7NO3: 403.1018; found:
403.1021.
+
EtI
CF3CF2CHF2 •
NXR2
CF2CF2CF3
R1
NXR2
R1
R1 = Me, Ph, CO2Et
XR2 = OBn, NPh2, NMeBz
BEt2
N
R1
R1
N
R2
XR2
Et3B
X
Ethyl 2-{(2Z)-2-[(Benzyloxy)imino]ethyl}-3,3,4,4,5,5,5-hepta-
fluoropentanoate [(Z)-2a)]
Colorless oil; yield: 18.0 mg (21%).
CF2CF2CF3
CF3CF2CF2
A
B
IR (CHCl3): 2939, 1744, 1455, 1235, 1127 cm–1.
Scheme 3 Possible reaction pathway
1H NMR (500 MHz, CDCl3): d = 7.38–7.29 (m, 5 H, ArH), 6.71 (t,
J = 5.0 Hz, 1 H, iminoic H), 5.13 (s, 2 H, CH2Ph), 4.21 (dq,
J = 10.5, 7.0 Hz, 1 H, OCH2Me), 4.19 (dq, J = 10.5, 7.0 Hz, 1 H,
OCH2Me), 3.49 (br m, 1 H, 2-H), 2.94 (br dt, J = 15.5, 5.0 Hz, 1 H,
1¢-H), 2.90 (ddd, J = 15.5, 10.0, 5.0 Hz, 1 H, 1¢-H), 1.25 (t, J = 7.0
Hz, 3 H, OCH2Me).
13C NMR (125 MHz, CDCl3): d = 166.5 (d, J = 8.0 Hz, CO), 145.7
(iminoic C), 137.4 (Ar), 128.5 (Ar), 128.1 (Ar), 128.0 (Ar), 117.6
(qt, J = 286.5, 34.0 Hz, CF2CF2CF3), 115.3 (tt, J = 260.0, 32.0 Hz,
CF2CF2CF3), 109.0 (t-sext, J = 264.0, 37.5 Hz, CF2CF2CF3), 76.3
(CH2Ph), 62.3, 44.9 (t, J = 21.5 Hz, 2-C), 22.3, 13.9.
Finally, we investigated the reaction of the methyl-substi-
tuted oxime ether 4a with five equivalents of ethyl bro-
modifluoroacetate as a reaction that involves a different
electrophilic radical,15 and we succeeded in preparing the
fluoroalkylated ester 11 in moderate yield (Scheme 4).
NOBn
BrF2CCO2Et (5 equiv)
Et3B (5 equiv)
NOBn
CF2CO2Et
11 (40%)
CH2Cl2, r.t.
4a
HRMS (EI): m/z [M+] calcd for C16H16F7NO3: 403.1018; found:
Scheme 4 Difluoroacetate radical addition to oxime ether 4a
403.1021.
Addition of an Isopropyl Radical to Oxime Ether (E)-1 (Table
1; Entry 2)
In conclusion, we have developed a new and efficient
method for the practical synthesis of b-perfluoroalkyl
imine derivatives by regioselective addition of a perfluo-
roalkyl radicals to a,b-unsaturated imines. The resulting
addition products are versatile building blocks for the syn-
thesis of fluorinated organic compounds.
i-PrI (1.02 g, 6.00 mmol) and a 1.01 M soln of Et3B in hexane (0.99
mL, 1.00 mmol) were added to a soln of (E)-1 (46.6 mg, 0.20 mmol)
in CH2Cl2 (5 mL) under N2 at r.t., and the mixture was stirred at r.t.
for 0.5 h. The mixture was then diluted with sat. aq NaHCO3 (15
mL) and extracted with CHCl3 (3 × 15 mL). The organic phase was
dried (MgSO4) and concentrated under reduced pressure. The crude
product was purified by preparative TLC (hexane–EtOAc, 5:1) to
give 2b as a colorless oil consisting of a 2:1 mixture of the E- and
Z-isomers; yield: 33.2 mg (60%).
1H and 13C NMR spectra were recorded on a Varian Unity 500 at
500 MHz and at 125 MHz, respectively. IR spectra were recorded
using a Perkin-Elmer 1600 FTIR spectrometer. EI mass spectra
were recorded on a Hitachi M-4100 mass spectrometer. Preparative
TLC separations were carried out on precoated silica gel plates
(Merck 60F254).
Addition of Perfluoropropyl Radical to the Conjugated Oxime
Ether 4a; Typical Procedure
Perfluoropropyl iodide (422 mg, 1.43 mmol) and a 1.00 M soln of
Et3B in hexane (1.43 mL, 1.43 mmol) were added to a soln of (E)-
4a (50.0 mg, 0.29 mmol) in CH2Cl2 (6.5 mL) under N2 at r.t., and
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2002
M. Ueda et al.
PAPER
the mixture was stirred at r.t. for 1 h. The mixture was then diluted
with sat. aq NaHCO3 (20 mL) and extracted with CHCl3 (3 × 20
mL). The organic phase was dried (MgSO4) and concentrated under
reduced pressure. The crude product was purified by preparative
TLC (hexane–EtOAc, 2:1) to give (E)-5a and (Z)-5a.
H, CH2Ph), 3.70–3.59 (m, 1 H, 3-H), 3.13 (br dt, J = 16.0, 5.0 Hz, 1
H, 2-H), 2.94 (dq, J = 16.0, 5.0 Hz, 1 H, 2-H).
13C NMR (125 MHz, CDCl3): d = 147.3 (iminoic C), 137.7 (Ar),
133.2 (br d, J = 5.5 Hz, Ar), 129.3 (Ar), 128.8 (Ar), 128.6 (Ar),
128.4 (Ar), 128.0 (Ar), 127.9 (Ar), 117.7 (qt, J = 286.0, 34.0 Hz,
CF2CF2CF3), 117.1 (tt, J = 256.0, 30.0 Hz, CF2CF2CF3), 109.4 (t-
sext, J = 264.0, 37.5 Hz, CF2CF2CF3), 76.1 (CH2Ph), 45.0 (t,
J = 21.0 Hz, 3-C), 25.2 (2-C).
(1E)-4,4,5,5,6,6,6-Heptafluoro-3-methylhexanal O-Benzyl-
oxime [(E)-5a]
Colorless oil; yield: 33.9 mg (34%).
IR (CHCl3): 2934, 1455, 1231 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.43 (t, J = 6.5 Hz, 1 H, iminoic
H), 7.36–7.28 (m, 5 H, ArH), 5.08 (s, 2 H, CH2Ph), 2.62 (br dt,
J = 15.0, 6.5 Hz, 1 H, 2-H), 2.62–2.50 (m, 1 H, 3-H), 2.28 (ddd,
J = 15.0, 9.0, 6.5 Hz, 1 H, 2-H), 1.14 (d, J = 6.5 Hz, 3 H, Me).
HRMS (EI): m/z [M+] calcd for C19H16F7NO: 407.1120; found:
407.1137.
(1E)-3,3,4,4,5,5,5-Heptafluoro-2-[(phenylsulfanyl)methyl]pen-
tanal O-Benzyloxime [(E)-6]
Colorless oil; yield: 8.6 mg (10%) from 4d (50.0 mg, 0.19 mmol).
13C NMR (125 MHz, CDCl3): d = 147.5 (iminoic C), 137.5 (Ar),
128.5 (Ar), 128.3 (Ar), 128.0 (Ar), 118.1 (tt, J = 255.0, 30.5 Hz,
CF2CF2CF3), 117.8 (qt, J = 286.0, 34.0 Hz, CF2CF2CF3), 109.8 (t-
sext, J = 264.0, 37.0 Hz, CF2CF2CF3), 75.9 (CH2Ph), 34.5 (t,
J = 21.5 Hz, 3-C), 29.2, 12.2.
HRMS (EI): m/z [M+] calcd for C14H14F7NO: 345.0964; found:
345.0975.
IR (CHCl3): 2934, 1584, 1482, 1228 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.22 (m, 11 H, ArH + imi-
noic H), 5.13 (s, 2 H, CH2Ph), 3.41 (dd, J = 13.5, 3.5 Hz, 1 H, 1¢-H),
3.36–3.24 (m, 1 H, 2-H), 3.09 (dd, J = 13.5, 11.0 Hz, 1 H, 1¢-H).
13C NMR (125 MHz, CDCl3): d = 143.1 (d, J = 4.0 Hz, iminoic C),
137.2 (Ar), 133.7 (Ar), 131.2 (Ar), 129.3 (Ar), 128.4 (Ar), 128.2
(Ar), 128.0 (Ar), 127.4 (Ar), 117.5 (qt, J = 286.5, 33.5 Hz,
CF2CF2CF3), 116.3 (tt, J = 258.0, 31.0 Hz, CF2CF2CF3), 109.1 (t-
sext, J = 263.5, 37.0 Hz, CF2CF2CF3), 76.5 (CH2Ph), 43.6 (t,
J = 21.5 Hz, 2-C), 30.3 (1¢-C).
(1Z)-4,4,5,5,6,6,6-Heptafluoro-3-methylhexanalO-Benzyloxime
[(Z)-5a]
Colorless oil; yield: 32.1 mg (33%).
IR (CHCl3): 2935, 1455, 1232 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.29 (m, 5 H, ArH), 6.72 (br
t, J = 5.5 Hz, 1 H, iminoic H), 5.13 (s, 2 H, CH2Ph), 2.71 (br dt,
J = 15.5, 5.5 Hz, 1 H, 2-H), 2.64–2.52 (m, 1 H, 3-H), 2.54 (ddd,
J = 15.0, 9.0, 5.5 Hz, 1 H, 2-H), 1.16 (br d, J = 6.5 Hz, 3 H, Me).
HRMS (EI): m/z [M+] calcd for C19H16F7NOS: 439.0841; found:
439.0851.
(1Z)-3,3,4,4,5,5,5-Heptafluoro-2-[(phenylsulfanyl)methyl]pen-
tanal O-Benzyloxime [(Z)-6]
Colorless oil; yield: 3.7 mg (5%) from 4d (50.0 mg, 0.19 mmol).
13C NMR (125 MHz, CDCl3): d = 147.9 (iminoic C), 137.7 (Ar),
128.4 (Ar), 128.0 (Ar), 127.9 (Ar), 118.1 (tt, J = 254.5, 31.0 Hz,
CF2CF2CF3), 117.8 (qt, J = 286.5, 34.0 Hz, CF2CF2CF3), 109.7 (t-
sext, J = 264.0, 37.5 Hz, CF2CF2CF3), 76.1 (CH2Ph), 34.3 (t,
J = 21.0 Hz, 3-C), 25.7, 12.7.
HRMS (EI): m/z [M+] calcd for C14H14F7NO: 345.0964; found:
345.0974.
IR (CHCl3): 2932, 1584, 1482, 1228 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.40–7.20 (m, 10 H, ArH), 6.66
(d, J = 8.0 Hz, 1 H, iminoic H), 5.11 (s, 2 H, CH2Ph), 4.35–4.22 (m,
1 H, 2-H), 3.42 (dd, J = 14.0, 4.0 Hz, 1 H, 1¢-H), 2.99 (dd, J = 14.0,
10.0 Hz, 1 H, 1¢-H).
HRMS (EI): m/z [M+] calcd for C19H16F7NOS: 439.0841; found:
439.0852.
(1E)-4,4,5,5,6,6,6-Heptafluoro-3-phenylhexanalO-Benzyloxime
[(E)-5b]
Colorless oil; yield: 20.3 mg (24%) from 4b (50.0 mg, 0.21 mmol).
IR (CHCl3): 2931, 2859, 1497, 1456, 1227 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.34–7.21 (m, 10 H, ArH), 7.16 (t,
J = 5.5 Hz, 1 H, iminoic H), 4.97 (s, 2 H, CH2Ph), 3.69–3.58 (m, 1
H, 3-H), 2.98 (br ddd, J = 15.5, 5.5, 4.0 Hz, 1 H, 2-H), 2.80 (dq,
J = 15.0, 5.5 Hz, 1 H, 2-H).
13C NMR (125 MHz, CDCl3): d = 147.0 (iminoic C), 137.4 (Ar),
132.9 (br d, J = 5.5 Hz, Ar), 129.4 (Ar), 128.7 (Ar), 128.5 (Ar),
128.4 (Ar), 128.1 (Ar), 127.8 (Ar), 117.7 (qt, J = 286.5, 34.0 Hz,
CF2CF2CF3), 117.1 (tt, J = 255.0, 32.5 Hz, CF2CF2CF3), 109.4 (t-
sext, J = 264.5, 37.0 Hz, CF2CF2CF3), 75.8 (CH2Ph), 45.8 (t,
J = 21.0 Hz, 3-C), 28.9 (br t, J = 3.5 Hz, 2-C).
Addition of Perfluoropropyl Radical to Conjugated Imines 7a;
Typical Procedure
Perfluoropropyl iodide (313 mg, 1.06 mmol) and a 1.00 M soln of
Et3B in hexane (1.06 mL, 1.06 mmol) were added to a soln of 7a11
(50.0 mg, 0.21 mmol) in CH2Cl2 (5 mL) under N2 at r.t., and the
mixture was stirred at r.t. for 5 min. The mixture was then diluted
with sat. aq NaHCO3 sat. aq NaHCO3 (15 mL) and extracted with
CHCl3 (3 × 15 mL). The organic phase was dried (MgSO4) and con-
centrated under reduced pressure. The crude product was purified
by preparative TLC (hexane–EtOAc, 30:1) to afford 8a.
Other conjugated oxime ethers 7b–d, 9, and 4a were also subjected
to the radical reaction under similar conditions for 1 h; in the cases
of 7c and 7d, unidentified products (30.5 mg in for 7c; 9.9 mg for
7d) were obtained as white solids.
HRMS (EI): m/z [M+] calcd for C19H16F7NO: 407.1120; found:
407.1132.
(2-(4,4,5,5,6,6,6-Heptafluoro-3-methylhexylidene)-1,1-diphe-
nylhydrazine (8a)
Pale yellow oil; yield: 41.8 mg (49%).
IR (neat): 2932, 2857, 1597, 1497, 1217 cm–1.
(1Z)-4,4,5,5,6,6,6-Heptafluoro-3-phenylhexanalO-Benzyloxime
[(Z)-5b]
Colorless oil; yield: 22.4 mg (26%) from 4b (50.0 mg, 0.21 mmol).
IR (CHCl3): 2934, 2875, 1497, 1456, 1235 cm–1.
1H NMR (500 MHz, CDCl3): d = 7.38–7.29 (m, 8 H, ArH), 7.24–
7.20 (m, 2 H, ArH), 6.43 (t, J = 5.0 Hz, 1 H, iminoic H), 5.08 (s, 2
1H NMR (500 MHz, CDCl3): d = 7.38 (br t, J = 8.0 Hz, 4 H, ArH),
7.15 (br tt, J = 8.0, 1.0 Hz, 2 H, ArH), 7.08 (br d, J = 8.0 Hz, 4 H,
ArH), 6.44 (br t, J = 5.0 Hz, 1 H, iminoic H), 2.71 (br dt, J = 15.0,
5.0 Hz, 1 H, 2-H), 2.70–2.58 (m, 1 H, 3-H), 2.34 (ddd, J = 15.0, 9.5,
5.0 Hz, 1 H, 2-H), 1.17 (br d, J = 6.5 Hz, 3 H, Me).
Synthesis 2010, No. 12, 1999–2004 © Thieme Stuttgart · New York

PAPER
Radical Fluoroalkylation of Conjugated Imines
2003
13C NMR (125 MHz, CDCl3): d = 143.9 (iminoic C), 134.6 (Ar),
129.8 (Ar), 124.2 (Ar), 122.3 (Ar), 118.4 (tt, J = 254.0, 30.5 Hz,
CF2CF2CF3), 117.9 (qt, J = 286.5, 34.5 Hz, CF2CF2CF3), 109.8 (t-
sext, J = 264.0, 37.5 Hz, CF2CF2CF3), 34.8 (t, J = 21.0 Hz, 3-C),
31.9 (2-C), 12.3 (br t, J = 2.0 Hz, Me).
HRMS (EI): m/z [M+] calcd for C19H17F7N2O: 406.1280; found:
406.1298.
13C NMR (125 MHz, CDCl3): d = 163.8 (t, J = 33.0 Hz, CO), 163.8
(t, J = 33.0 Hz, CO), 148.5 (iminoic C), 148.1 (iminoic C), 137.8
(Ar), 137.5 (Ar), 128.4 (Ar), 128.2 (Ar), 128.0 (Ar), 127.9 (Ar),
127.9 (Ar), 117.1 (t, J = 253.0 Hz, CF2), 76.0 (CH2Ph), 75.8
(CH2Ph), 62.9 (OCH2Me), 36.1 (t, J = 22.0 Hz, 3-C), 35.9 (t,
J = 22.0 Hz, 3-C), 29.3 (t, J = 4.0 Hz, 4-C), 25.8 (t, J = 4.0 Hz, 4-
C), 14.0 (OCH2Me), 14.0 (OCH2Me), 12.8 (t, J = 4.5 Hz, 3-Me),
12.4 (t, J = 4.5 Hz, 3-Me). Some of the carbon peaks could not be
clearly assigned because of overlapping and weak signals.
N¢-[(1E)-4,4,5,5,6,6,6-Heptafluoro-3-methylhexylidene]-N-
methylbenzohydrazide (8b)
HRMS (EI): m/z [M+] calcd for C15H19F2NO3: 299.1333; found:
Pale yellow oil; yield: 59.8 mg (65%) from 7b (50.0 mg, 0.25
mmol).
299.1326.
IR (neat): 2954, 1666, 1472, 1227 cm–1.
Acknowledgment
1H NMR (500 MHz, CDCl3): d = 7.58 (br d, J = 7.5 Hz, 2 H, ArH),
7.42 (br tt, J = 7.5, 1.5 Hz, 1 H, ArH), 7.36 (br t, J = 7.5 Hz, 2 H,
ArH), 7.08 (br t, J = 4.5 Hz, 1 H, iminoic H), 3.41 (s, 3 H, NMe),
2.70 (br dt, J = 16.0, 4.5 Hz, 1 H, 2¢-H), 2.68–2.55 (m, 1 H, 3¢-H),
2.31 (ddd, J = 16.0, 9.0, 4.5 Hz, 1 H, 2¢-H), 1.06 (br d, J = 7.0 Hz,
3 H, Me).
13C NMR (125 MHz, CDCl3): d = 171.2 (CO), 138.1 (iminoic C),
135.3 (Ar), 130.1 (Ar), 129.3 (Ar), 127.4 (Ar), 118.3 (tt, J = 255.0,
30.5 Hz, CF2CF2CF3), 117.8 (qt, J = 286.5, 34.0 Hz, CF2CF2CF3),
109.7 (t-sext, J = 265.0, 37.0 Hz, CF2CF2CF3), 34.0 (t, J = 21.0 Hz,
3¢-C), 32.2, 28.5, 12.6.
This work was supported in part by Grants-in-Aid for Scientific Re-
search (B) (T.N.), for Young Scientists (B) (M.U.), and for Scienti-
fic Research (C) (H.M. and O.M.) from the Ministry of Education,
Culture, Sports, Science and Technology of Japan and by the Sci-
ence Research Promotion Fund of the Japan Private School Promo-
tion.
References
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372.1064.
Fluoroorganic Chemistry: Synthesis, Reactivity,
Ethyl 2-{2-[Benzoyl(methyl)hydrazono]ethyl}-3,3,4,4,5,5,5-
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1.10 (t, J = 7.0 Hz, 3 H, OCH2Me).
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2.0 Hz, CO), 136.6 (iminoic C), 134.9 (Ar), 130.3 (Ar), 129.4 (Ar),
127.4 (Ar), 117.6 (qt, J = 286.0, 33.5 Hz, CF2CF2CF3), 115.6 (tt,
J = 258.5, 32.0 Hz, CF2CF2CF3), 109.0 (t-sext, J = 263.5, 37.5 Hz,
CF2CF2CF3), 62.0, 44.6 (t, J = 21.0 Hz, 3¢-C), 28.2 (br t, J = 4.0 Hz,
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430.1136.
Ethyl (5E/Z)-5-[(Benzyloxy)imino]-2,2-difluoro-3-methylpen-
tanoate (11)
Colorless oil; E/Z = 6:5; yield: 25.7 mg (40%) from 4a (37.5 mg,
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J = 6.5 Hz, 15/11 H, 3-Me (Z)], 1.03 [d, J = 7.0 Hz, 18/11 H, 3-Me
(E)].
Synthesis 2010, No. 12, 1999–2004 © Thieme Stuttgart · New York

2004
M. Ueda et al.
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Synthesis 2010, No. 12, 1999–2004 © Thieme Stuttgart · New York