Na2S2O4 initiated free radical additions of polyfluoroalkyl halides to 4-pentenamides

Article abstract of DOI:10.1016/j.jfluchem.2007.01.006

The free radical additions of fluorine-containing halides to 4-pentenamides initiated by Na₂S₂O₄ were investigated. Both polyfluoroalkyl iodide and ethyl iododifluoroacetate, gave rise to fluorine-containing γ-butyrolactones as the main products while bromides such as ethyl bromodifluoroacetate gave the addition-reduction product. After steric and stereo effects on reaction yields were studied using various substrates, it was concluded that the reactions of 4-pentenamides and polyfluoroalkyl iodides provide one alternative approach to prepare γ-butyrolactones with fluorinated side chains.

Full text of DOI:10.1016/j.jfluchem.2007.01.006

Journal of Fluorine Chemistry 128 (2007) 540–544
www.elsevier.com/locate/fluor
Na2S2O4 initiated free radical additions of polyfluoroalkyl
halides to 4-pentenamides
Xianjin Yang a,b, Wenjiao Yuan a, Song Gu a, Xueyan Yang a, Fanhua Xiao a,
Quanshen Shen a, Fanhong Wu a,b,
*
a College of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai 200237, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
Received 7 December 2006; received in revised form 14 January 2007; accepted 18 January 2007
Available online 23 January 2007
Abstract
The free radical additions of fluorine-containing halides to 4-pentenamides initiated by Na2S2O4 were investigated. Both polyfluoroalkyl iodide
and ethyl iododifluoroacetate, gave rise to fluorine-containing g-butyrolactones as the main products while bromides such as ethyl bromodi-
fluoroacetate gave the addition–reduction product. After steric and stereo effects on reaction yields were studied using various substrates, it was
concluded that the reactions of 4-pentenamides and polyfluoroalkyl iodides provide one alternative approach to prepare g-butyrolactones with
fluorinated side chains.
# 2007 Elsevier B.V. All rights reserved.
Keywords: 4-Pentenamide; Fluorine-containing halide; Na2S2O4; Free radical addition; g-Butyrolactones with fluorinated side chain
1. Introduction
2. Results and discussion
Introduction of fluorine into lactones or lactams is of great
interest to synthetic chemists due to two facts. First,
fluorination of natural products and drugs has demonstrated
significant improvements of activities and properties. Second,
functionalized lactones or lactams have been found as
substructures in a variety of biologically active natural products
including flavor components, sex attractant pheromones of
different insects, plant-growth regulators, alkaloids, macro-
cyclic antibiotics, and lignanlactones [1,2]. In previous papers,
we reported our results on free radical addition reactions of
fluorine-containing iodide to some pentenoic acid derivatives in
the presence of Na2S2O4 to make fluorine-containing g-
butyrolactones [3–5]. Herein, we extended our research to 4-
pentenamide with an expectation of preparing g-butyrolactams.
Surprisingly, fluorine-containing g-butyrolactones were found
to be the main products. The detailed experimental results and
analysis were described here.
In the presence of Na2S2O4 and sodium bicarbonate, the
reaction 3,3-dimethyl-4-pentenamide (1a) with iodide 2m was
carried out at room temperature in aqueous acetonitrile solution
(CH3CN:H2O = 3:1 (v/v)). The reaction was monitored by GC
until pentenamide 1a was consumed completely, followed by
workup and evaporation. The purification of the reaction
mixture by flash column chromatography afforded a product,
whose spectral data indicated that, rather than expected g-
butyrolactam, it was a fluorine-containing g-butyrolactone 3a.
The same results were obtained when the reactions of other 4-
pentenamides bearing different R groups (1a–1f) with iodides
(2m and 2n). And fluorine-containing g-butyrolactones (3a, 3b,
4a) were obtained in 40–65% yields (Schemes 1 and 2, Table 1,
entries 1–11).
Substituent R1 of 3,3-dimethyl-4-pentenamide played a
significant role on the reaction results. Electron-donating R1
groups (R1 = CH3, C(CH3)3) (Table 1, entries 3–6) led to
smooth addition-lactonization reactions occurred while were
electron-withdrawing R1 groups (R1 = Ph, CH2Ph) resulted in
slow reactions apparently with low yields (Table 1, entries 7–
10). Those results suggested that the conjugated effect or large
steric hindrance slow down the addition and basic hydrolysis of
* Corresponding author at: College of Chemistry and Molecular Engineering,
East China University of Science and Technology, Shanghai 200237, China.
E-mail address: wfh@ecust.edu.cn (F. Wu).
0022-1139/$ – see front matter # 2007 Elsevier B.V. All rights reserved.
doi:10.1016/j.jfluchem.2007.01.006

X. Yang et al. / Journal of Fluorine Chemistry 128 (2007) 540–544
541
Scheme 1.
Scheme 2.
Table 1
(1-benzyl-ethyl)-2-benzyl-4-pentenamide (1g), were allowed
to react with 2m (Scheme 2). The reaction of 1f proceeded
smoothly at room temperature (Table 1, entry 11). In contrast,
1g, did not give any desired product under the same conditions
(Table 1, entry 12).
The reactions of 4-pentenamides with XCF2I
Entry
4-Pentenamide
RFI
Products/yields (%)a
1
2
1a
1a
1b
1b
1c
1c
1d
1d
1e
1e
1f
2m
2n
2m
2n
2m
2n
2m
2n
2m
2n
2m
2m
3a/50%
3b/48%
3a/60%
3b/59%
3a/65%
3b/63%
3a/45%
3b/40%
3a/44%
3b/40%
4a/50%
3
Further study was focused on how halides effect this reaction
(Scheme 3). When ethyl iododifluoroacetate 2o reacted with 1a
or 1b, a small quantity of addition-deiodination product was
observed along with the main product 3c (Table 2, entries 1 and
2). While in case of 1c, 1d, and 1e, no reaction occurred
(Table 2, entries 3–5). In comparison, when ethyl bromodi-
fluoroacetate 2p reacted with 1a, 1b and 1c, only the addition–
reduction product was isolated (Table 2, entries 6–8). No
reaction occurred for 1d and 1e (Table 2, entries 9 and 10).
Referring to the literatures [6,7], we proposed lactonization
mechanism of the reaction as follows (Scheme 4).
4
5
6
7
8
9
10
11
12
b
1g
–
a
Isolated yields.
b
No corresponding products.
Free radical addition to olefin has been extensively studies
while the hydrolysis of the intermediate iodides may undergo
two possible pathways. As we know, the hydrolysis of amide is
difficult to occur under these mild conditions. The first route
was more reasonable than the second. In fact, the reaction of
fluorine-containing halides and 4-pentenamides catalyzed by
N–Ph or N–CH2Ph amide. In addition, low solubility of N–Ph
or N–CH2Ph amide in the aqueous acetonitrile solution might
contribute to low yields as well.
The reaction was also sensitive to 2-position substitution as
well. N-(1-phenyl-ethyl)-2-methyl-4-pentenamide (1f) and N-
Scheme 3.

542
X. Yang et al. / Journal of Fluorine Chemistry 128 (2007) 540–544
Table 2
The reaction of 4-pentenamide with ethyl bromo or iododifluoroacetate
Entry
Amide
X
Compound 3 (%)
Compound 5 (%)a
1
2
1a
1b
1c
1d
1e
1a
1b
1c
1d
1e
I
3c, 50%
3c, 49%
–
5a, minor
5b, minor
–
I
b
3
I
Scheme 5.
4
I
–
–
–
–
–
–
–
–
5
I
–
6
Br
Br
Br
Br
Br
5a, 30%
5b, 22%
5c, 21%
–
Pd(PPh3)4 in anhydrous solution proceeded smoothly to give
fluorine-containing lactone [8] in high yield after dealing with
TEA (Scheme 5, Table 3).
7
8
9
10
–
In conclusion, the free radical addition reactions of fluorine-
containing halides to 4-pentenamides in the presence of
Na2S2O4 were investigated. For fluoroalkyl iodides and ethyl
iododifluoroacetate, the reaction produced fluorine-containing
lactones as the main products instead of fluorine-containing g-
butyrolactams, while only addition–reduction products were
separated when ethyl bromodifluoroacetate was used. Various
a
Isolated yields.
b
(–) indicates no corresponding product is separated.
Scheme 4.

X. Yang et al. / Journal of Fluorine Chemistry 128 (2007) 540–544
543
Table 3
3.2.3. N-t-Butyl-3,3-dimethyl-4-pentenamide (1c)
White solid, mp: 76.4–77.7 8C. 1H NMR (CDCl3) d: 1.12 (s,
6H, 2 ꢀ CH3), 1.31 (s, 9H, 3 ꢀ CH3), 2.10 (s, 2H, CH2), 4.90–
5.10 (m, 2H, CH2), 5.34 (s, 1H, N–H), 5.80–6.00 (m, 1H,
CH). IR (KBr): 3320, 2964, 1643, 1547. EI-MS m/z (%): 183
(31, M+), 168 (30, M+–CH3), 58 (100, C(CH3)3). HRMS calcd.
for C11H21NO: 183.1623, found: 183.1631
The reaction of olefinic amide and fluorine-containing halides catalyzed by
Pd(PPh3)4
Entrya
X
Reaction conditions
Products/yield (%)b
1
2
CF2Cl
rt, 0.5 h
rt, 0.5 h
3a/90%
3b/88%
(CF2)4CF3
a
Reaction conditions: under the protection of N2, the mixture of olefinic
amide (2.5 mmol), XCF2I (10 mmol), Pd(PPh3)4 (0.03 mmol) was stirred for
30 min, then plenty of Et3N was added and stirred for another 30 min.
3.2.4. N-Phenyl-3,3-dimethyl-4-pentenamide (1d) [10]
White solid, mp: 101.2–101.6 8C. 1H NMR (CDCl3) d: 1.19
(s, 6H, 2 ꢀ CH3), 2.36 (s, 2H, CH2), 5.10–5.30 (m, 2H, CH2),
5.90–6.10 (m, 1H, CH), 7.09–7.46 (m, 5H, Ph), but no NH
peak was observed.
b
Isolated yields based on XCF2I.
4-pentenamides were surveyed and it is apparent that steric as
well as electronic effects play the important roles in this
reaction; the corresponding mechanism was suggested though
the reason why the reaction gave no fluorine-containing g-
butyrolactams was still unclear.
3.2.5. N-Benzyl-3,3-dimethyl-4-pentenamide (1e)
Colorless liquid. 1H NMR (CDCl3) d: 1.13 (s, 6H, 2 ꢀ CH3),
2.22 (s, 2H, CH2C O), 4.41 (d, J = 5.6 Hz, 2H, CH2Ph), 4.90–
5.10 (m, 2H, CH2), 5.71–5.81 (s, broad, 1H, N–H), 5.91–6.00
(m, 1H, CH), 7.27–7.32 (m, 5H, Ph). IR (KBr): 3294, 2962,
1642, 1549, 912, 698. EI-MS m/z (%): 217 (15, M+), 202 (11,
M+–CH3), 148 (100), 107 (55), 91 (99). HRMS calcd. for
C14H19NO: 217.1467, found: 217.1475.
3. Experimental
3.1. General experimental procedures
Melting points were measured on a WRS-1B digital melting
point instrument. IR spectra were recorded on a Nicolet FT-IR
20sx IR spectrophotometer. H NMR and 13C NMR spectra
were measured on a Bruker AC500 (500 and 125.8 MHz,
3.2.6. N-(1-Phenyl-ethyl)-2-methyl-4-pentenamide (1f)
25
1
White solid, mp: 77.5–81.0 8C, ½aꢁD ꢂ77.5 (c 0.01,
respectively) spectrometer using TMS as internal standard. 19
F
1
CH3COCH3). H NMR (CDCl3) d: 1.10–1.25 (m, 3H, CH3),
NMR spectra were taken on a Bruker AC500 (470.5 MHz)
spectrometer; chemical shifts are reported as dCFCl3, negative
for upfield shifts. Mass spectra were obtained on a Finnigan
GC–MS 4021 spectrometer. Column chromatography was
performed using silica gel H, particle size 10–40 mm.
1.40–1.50 (m, 3H, CH3), 2.10–2.25 (m, 2H, CH2), 2.30–2.50
(m, 1H, CHC O), 4.90–5.10 (m, 3H, CH2 + CHPh), 5.75–
5.90 (m, 2H, CH + NH), 7.25–7.40 (m, 5H, Ph). IR (KBr):
3299, 2967, 1640, 1546, 916, 699. EI-MS m/z (%): 217 (12,
M+), 202 (4, M+–CH3), 105 (100), 91 (9, CH2Ph), 77 (13, Ph).
HRMS calcd. for C14H19NO: 217.1467, found: 217.1458.
3.2. Preparation of 4-pentenamide derivatives
3.2.7. N-(1-Phenyl-ethyl)-2-benzyl-4-pentenamide (1g)
25
White solid, mp: 91.5–99.6 8C, ½aꢁD ꢂ36.5 (c 0.01,
3,3-Dimethyl-4-pentenyl chloride (130 mmol) was added
drop-wise into a mixture of amine (100 mmol), Et3N
(100 mmol) in 50 mL of solvent at 0 8C, The mixture was
stirred at ambient temperature for 10 h. The reaction mixture
was acidified with aqueous HCl solution and extracted with
ether (3 ꢀ 20 mL). Combined organic layers were neutralized
with aqueous NaOH solution, washed with saturated brine and
dried over anhydrous sodium sulfate. Evaporation of ether
followed by recrystallization afforded the desired product.
1
CH3COCH3). H NMR (CDCl3) d: 1.18–1.39 (m, 3H, CH3),
2.28–2.35 (m, 2H, CH2), 2.47–2.50 (m, 1H, CHCO), 2.77–2.90
(m, 2H, CH2), 5.00–5.20 (m, 3H, CH2 + CHN), 5.20–5.45 (d,
J = 57 Hz, 1H, N–H), 5.60–5.80 (m, 1H, CH), 6.94–7.28 (m,
10H, 2Ph). IR (KBr): 3354 (N–H), 2955, 2877, 1734, 1533,
1235. EI-MS m/z (%): 293 (43, M+), 252 (92), 202 (15, M+–
CH3–Ph), 148 (59, CONHCH(CH3)Ph), 105 (100), 91 (47), 77
(10). HRMS calcd. for C20H23NO: 293.1780, found: 293.1780.
3.3. Na2S2O4 initiated radical addition reaction
of 4-pentenamide and fluorine-containing halides
3.2.1. 3,3-Dimethyl-4-pentenamide (1a) [9]
White solid, mp: 73.1–73.7 8C. 1H NMR (CDCl3) d: 1.10 (s,
6H, 2 ꢀ CH3), 2.25 (s, 2H, CH2), 5.00–5.20 (m, 2H, CH2),
5.50 (s, broad, 2H, NH2), 5.80–6.00 (m, 1H, CH).
Compound 1 (5 mmol) and fluorine-containing halide 2
(6 mmol) were dissolved in a mixture of water (5 mL) and
acetonitrile (15 mL). Sodium dithionite (1.0 g) and sodium
bicarbonate (0.5 g) were added to the solution portion-wise.
The mixture was stirred at ambient temperature. When the
reaction was completed, the mixture was treated with water (ca.
30 mL), and extracted with ether (3 ꢀ 20 mL). The combined
organic layers were washed with saturated brine and dried over
anhydrous sodium sulfate. Evaporation of ether followed by
column chromatography gave the products 3, 4 or 5.
3.2.2. N-Methyl-3,3-dimethyl-4-pentenamide (1b)
Colorless liquid. 1H NMR (CDCl3) d: 1.10 (s, 6H, 2 ꢀ CH3),
2.10 (s, 2H, CH2), 2.60 (s, 3H, N–CH3), 4.80–5.00 (m, 2H,
CH2), 5.80–6.00 (m, 1H, CH), 6.10–6.30 (s, broad, 1H, N–H).
IR (KBr): 3302, 2962, 1647, 1558, 1411, 911. EI-MS m/z (%):
141 (11, M+), 126 (31, M+–CH3), 73 (100), 69 (62), 58 (56), 41
(39). HRMS calcd. for C8H15NO: 141.1154, found: 141.1146.

544
X. Yang et al. / Journal of Fluorine Chemistry 128 (2007) 540–544
3.3.1. 5-(3-Chloro-2,2,3,3-tetrafluoro-propyl)-4,4-
dimethyl-dihydro-furan-2-one (3a) [4]
236 (0.9, M+–CH3), 178 (8, M+–COOEt), 59 (100). HRMS
calcd. for C11H19F2NO3 252.1411, found: 252.1415.
Colorless needles, mp: 55–56 8C. 1H NMR (CDCl3) d: 1.06
(3H, s, CH3), 1.22 (3H, s, CH3), 2.25–2.51 (4H, m, 2 ꢀ CH2),
4.32 (1H, d, J = 8.9 Hz, CH). 19F NMR (CDCl3) d: ꢂ71.2 (2F,
m, ClCF2), ꢂ112.4 (2F, m, CF2CH).
3.3.6. N-Methyl-6-carbamoyl-2,2-difluoro-5,5-dimethyl
heptanedioic acid ethyl ester (5b) [4,5]
Oil. IR: nmax: 3313, 2960, 1766, 1646, 1556, 1087 cmꢂ1. 1H
NMR (CDCl3) d: 1.02 (s, 6H, 2 ꢀ CH3), 1.36 (t, J = 7 Hz, 3H,
CH3), 1.49 (m, 2H, CH2), 2.03–2.13 (m, 4H, 2 ꢀ CH2), 2.79 (d,
J = 4.8 Hz, 3H, N–CH3), 4.33 (q, J = 7 Hz, 2H, OCH2), 5.48 (s,
1H, N–H). 19F NMR (CDCl3) d: ꢂ107.1 (m, 2F, CF2).
3.3.2. 5-(2,2,3,3,4,4,5,5,6,6,7,7,7-Tridecafluoroheptyl)-4,4-
dimethyl-dihydro-furan-2-one (3b) [4]
Colorless needles, mp: 52–53 8C. 1H NMR (CDCl3) d: 1.06
(3H, s, CH3), 1.22 (3H, s, CH3), 2.25–2.51 (4H, m, 2 ꢀ CH2),
4.45 (1H, d, J = 9.2 Hz, CH). 19F NMR (CDCl3) d: ꢂ80.7 (3F,
m, CF3), ꢂ112.6 (2F, m, CF2CH2), ꢂ122.7 (2F, m, CF2),
ꢂ123.8 (2F, m, CF2), ꢂ124.2 (2F, m, CF2), ꢂ127.1 (2F, m,
CF2).
3.3.7. N-t-Butyl-6-carbamoyl-2,2-difluoro-5,5-dimethyl
heptanedioic acid ethyl ester (5c)
Oil. IR: nmax 3333, 2964, 1764, 1647, 1542, 1086 cmꢂ1. 1H
NMR (CDCl3) d: 1.02 (s, 6H, 2 ꢀ CH3), 1.34–1.37 (m, 12H,
3 ꢀ CH3 + CH3), 1.49–1.51 (m, 2H, CH2), 1.95 (s, 2H, CH2),
2.00–2.05 (m, 2H, CH2), 4.35 (q, J = 7 Hz, 2H, OCH2), 5.20–
5.30 (s, broad, 1H, N–H). 19F NMR (CDCl3) d: ꢂ106.4 (m, 2F,
CF2). EI-MS m/z (%): 308 (M+, 0.2), 292 (1), 235(M+–CO2Et,
3), 115 (100), 58 (58). HRMS calcd. for C15H27F2NO3:
307.1959, found: 307.1960.
3.3.3. 5-(3-Chloro-2,2,3,3-tetrafluoro-propyl)-3-methyl-
dihydro-furan-2-one (4a) [4,5]
1
Oil. H NMR (CDCl3) d: 1.34 (3H, d, J = 7.2 Hz, CH3),
2.17–2.42 (3H, m, CH2 + CH), 2.55–2.78 (2H, m, CH2), 4.80–
5.00 (1H, m, CH). 19F NMR (CDCl3) d: ꢂ72.5 (2F, s, ClCF2),
ꢂ113.7 (2F, m, CF2CH).
Acknowledgements
3.3.4. 2,2-Difluoro-3-(3,3-dimethyl-5-oxo-tetrahydro-
furan-2-yl)-propionic acid ethyl ester (3c) [4,5]
Oil. IR: nmax: 2968, 2939, 1781, 1469, 1092 cmꢂ1. 1H NMR
(CDCl3) d: 1.05 (s, 3H, CH3), 1.20 (s, 3H, CH3), 1.37 (t,
J = 7 Hz, 3H, CH3), 2.26–2.49 (m, 4H, CH2 + CH2), 4.31 (d,
J = 10 Hz, 1H, CH), 4.37 (q, J = 7 Hz, 2H, CH2). 19F NMR
(CDCl3) d: ꢂ109.45 to ꢂ108.91 (m, 1F), ꢂ103.00 to ꢂ102.44
(m, 1F). EI-MS m/z (%): 250 (M+, 0.9), 208 (80), 178 (M+–
The authors are indebted to the National Natural Science
Foundation of China and the Shanghai Science and Technology
Committee for the financial support.
References
[1] C. Wang, G.A. Russell, J. Org. Chem. 64 (1999) 2066–2069.
[2] (a) I. Ojima, J.R. McCarthy, J.T. Welch, ACS Symposium Series 639,
American Chemical Society, Washington, DC, 1996;
(b) T. Itoh, K. Kudo, K. Yokota, N. Tanaka, S. Hayase, M. Renou, Eur. J.
Org. Chem. (2004) 406–412.
CO2Et, 4), 167 (91), 163 (100), 113 (M+–CH2CF2CO2Et). 13
C
NMR (125.8 MHz, CDCl3) d: 175.3, 164.0, 115.3 (m), 81.8,
64.0, 44.4, 40.0, 35.6, 25.1, 21.9, 14.5. HRMS calcd. for
C11H16F2O4 250.1017, found: 250.1011.
[3] X.W. Zou, F.H. Wu, Chin. Chem. Lett. 13 (2002) 410–411.
[4] X.W. Zou, F.H. Wu, Y.J. Shen, S. Xu, W.Y. Huang, Tetrahedron 59 (2003)
2555–2560.
3.3.5. 6-Carbamoyl-2,2-difluoro-5,5-dimethyl hexanoic
acid ethyl ester (5a)
[5] F.H. Xiao, F.H. Wu, Y.J. Shen, L.F. Zhou, J. Fluorine Chem. 126 (2005)
63–67.
Oil. IR: nmax: 3404, 3200, 2968, 1760, 1660, 1090 cmꢂ1. 1H
NMR (CDCl3) d: 1.05 (s, 6H, 2 ꢀ CH3), 1.36 (t, 3H, CH3,
J = 7 Hz), 1.53–1.60 (m, 2H, CH2), 2.09–2.20 (m, 4H,
2 ꢀ CH2), 4.34–4.50 (q, 2H, OCH2, J = 7 Hz), 5.30–5.5.0 (s,
broad, 1H, NH), 5.50–5.75 (s, broad, 1H, NH). 19F NMR
(CDCl3) d: ꢂ107.00 (m, 2F, CF2). EI: m/z (%): 252 (0.2, M+),
[6] Y. Ding, J.Y. Li, L.X. Wang, Chin. J. Chem. 9 (1991) 543–546.
[7] W.Y. Huang, L. Lv, Chin. J. Chem. 1 (1990) 68–74.
[8] F.H. Xiao, F.H. Wu, X.Y. Yang, Y.J. Shen, X.M. Shi, J. Fluorine Chem. 126
(2005) 319–323.
[9] N.R. Easton, R.D. Dillard, J. Org. Chem. 27 (1962) 3602–3605.
[10] P. Metz, C. Mues, Tetrahedron 44 (1988) 6841–6854.