Copper-catalyzed cyclization of N-allylhalodifluoroacetamides: An efficient synthesis of α,α-difluorinated γ-lactams

Full text of DOI:10.1021/jo001187f

J . Org. Chem. 2001, 66, 315-319
315
and Newcomb,6 there are two rotamers in the amide
substrate; one is suitable for the cyclization and the other
is not. When the exchange rate of two rotamers is low
and there is a side reaction pathway from the radical
intermediate, one rotamer successfully gives the product,
whereas the other forms byproducts or does not react at
all. Thus, we have achieved facile cyclization of N-
alkoxycarbonyl or N-tosyl N-allyltrichloroacetamides at
room temperature, using the CuCl(bipy) catalyst and
introduction of Ts, Cbz, and other electron-withdrawing
substituents to the amide nitrogen.3b,d
Cop p er -Ca ta lyzed Cycliza tion of
N-Allylh a lod iflu or oa ceta m id es: An
Efficien t Syn th esis of r,r-Diflu or in a ted
γ-La cta m s
Hideo Nagashima,* Yoshimi Isono, and
Sho-ichi Iwamatsu
Institute of Advanced Material Study and
Graduate School of Engineering Sciences, Kyushu
University, Kasuga, Fukuoka 816-8580, J apan
As an application of this system, we were interested
in cyclization of N-allylhalodifluoroacetamide derivatives.
Since the difluoromethylene group biologically resembles
ether-oxygen, potential biological activity of R,R-difluori-
nated γ-lactams has received considerable attention.7
However, activation of a carbon-halogen bond in fluori-
nated halocarbons such as CF3C-X or ROCOCF2-X is
difficult to achieve compared with that in chlorinated
homologues. In fact, addition of CF3C-X or ROCOCF2-X
to olefins works well only when X ) I, and reactions of
the corresponding easily available fluorinated starting
materials, CF3C-X or ROCOCF2-X (X ) F, Cl, Br), are
difficult to accomplish.8,9 Other examples showing that
polyfluorinated halocarbons are difficult to activate are
seen in atom transfer radical cyclizations of allyl iodoac-
etate, monofluoroiodoacetate, and difluoroiodoacetate; the
former two compounds give the corresponding lactones
in moderate yields,10 whereas no reaction takes place
with allyl difluoroiodoacetate.10 Difficulty in achieving the
cyclization of N-allylhalodifluoroacetamides is also ex-
pected because of the high rotational barrier of polyflu-
orinated amides. For example, the energy barrier re-
quired for amide rotation of CF3CONR2 is higher than
the corresponding trichlorinated analogue by 4 kcal/mol.11
The energy barrier of the amide rotation of the fluori-
nated amide XCF2CONR2 is expected to be higher than
the corresponding chlorinated amides; this could be a
factor in the lower yield of the product in the cyclization
of N-alkyl-N-allylhalodifluoroacetamide derivatives.
In this paper, we report that cyclization of N-allylha-
lodifluoroacetamides was actually accomplished using the
reactive catalyst, CuX(bipy), and by introduction of tosyl
group to the amide nitrogen as shown in Scheme 1.
Although the rate of the reaction is slower than the
cyclization of N-allyl-N-tosyltrichloroacetamides, the re-
action offers a novel and effective synthetic method for
R,R-difluoro-γ-lactams in good yields.
nagasima@cm.kyushu-u.ac.jp
Received August 4, 2000
In tr od u ction
Numerous investigations in the past 20 years have
made radical cyclization an important synthetic protocol
to produce carbo- or heterocyclic compounds.1 Reductive
and atom-transfer radical cyclization of ω-haloolefins are
one of the well studied examples, and many reactions
including facile access to synthetically useful cyclic
skeletons have been reported.1 As reported earlier,
certain transition metal complexes efficiently catalyzed
cyclization of N-allyltrichloroacetamides to R,R,γ-trichlo-
rinated γ-lactams.2-5 We found that important factors in
facilitating the cyclization were appropriate choice of a
transition metal catalyst such as CuCl(bipy) (bipy )
bipyridine) and introduction of electron-withdrawing
substituents to the nitrogen atom of the amide. These
factors contribute to increasing the rate of homolytic
cleavage of a carbon-chlorine bond in the substrate at
the initiation of the cyclization.3 There is another impor-
tant role of electron-withdrawing groups on the amide
nitrogen: substantial decrease of the energy barrier of
amide rotation.5b As pointed out by Stork, Ikeda, Curran,
(1) For recent extensive reviews on radical cyclization: (a) Giese,
B.; Kopping, B.; Go¨bel, T.; Dickhaut, J .; Thoma, G.; Kulicke, K. J . Org.
React. 1996, 48, 301. (b) Giese, B. Radicals in Organic Synthesis:
Formation of Carbon-Carbon Bonds; Pergamon: New York, 1986. (c)
Curran, D. P.; Porter, N. A.; Giese, B. Stereochemistry of Radical
Reaction; VCH: Weinheim, 1996. (d) Curran, D. P. In Comprehensive
Organic Synthesis; Trost, B. M.; Fleming, I., Eds.; Pergamon: Oxford,
1991; vol. 4, p 715.
(2) For a review of transition metal-catalyzed radical cyclization:
Iqbal, J .; Bhatia, B.; Nayyar, N. K. Chem. Rev. 1994, 94, 519.
(3) (a) Nagashima, H.; Wakamatsu, H.; Itoh, K. J . Chem. Soc., Chem.
Commun. 1984, 652. (b) Nagashima, H.; Ozaki, N.; Seki, K.; Ishii, M.;
Itoh, K. J . Org. Chem. 1989, 54, 4497. (c) Nagashima, H.; Ozaki, N.;
Ishii, M.; Seki, K.; Washiyama, M.; Itoh, K. J . Org. Chem. 1993, 58,
464. (d) Nagashima, H.; Wakamatsu, H.; Ozaki, N.; Ishii, T.; Watanabe,
M.; Tajima, T.; Itoh, K. J . Org. Chem. 1992, 57, 1682. (e) Nagashima,
H.; Itoh, K. J . Synth. Org. J pn, 1995, 53, 298.
(4) Other transition metal catalyzed cyclizations of N-allylhaloac-
etamides: (a) Baldovini, N.; Bertrand, M. P.; Carrie`re, A.; Nouguier,
R.; Plancher, J . M. J . Org. Chem. 1996, 61, 3205. (b) Clark, A. J .; Filik,
R. P.; Haddleton, D. M.; Radigue, A.; Sanders, C. J .; Thomas, G. H.;
Smith, M. E. J . Org. Chem. 1999, 64, 8954. (c) Ghelfi, F.; Bellesia, F.;
Forti, L.; Ghirardini, G.; Grandi, R.; Libertini, E.; Montemaggi, M. C.;
Pagnoni, U. M.; Pinetti, A.; De Buyck, L.; Parsons, A. F. Tetrahedron
1999, 55, 5839. (d) Gilbert, B. C.; Kalz, W.; Lindsay, C. I.; McGrail, P.
T.; Parsons, A. F.; Whittaker, D. T. E. J . Chem. Soc., Perkin Trans. 1,
2000, 1187 and references therein.
(5) For an efficient synthetic route to highly substituted lactams and
mesembrane alkaloid skeletons which had not been successfully
achieved by conventional methods, see: (a) Iwamatsu, S.; Kondo, H.;
Matsubara, K.; Nagashima, H. Tetrahedron 1999, 55, 1687. (b)
Iwamatsu, S.; Matsubara, K.; Nagashima, H. J . Org. Chem. 1999, 64,
9625.
(6) (a) Stork, G.; Mah, R. Heterocycles 1989, 28, 723. (b) Sato, T.;
Wada, Y.; Nishimoto, M.; Ishibashi, H.; Ikeda, M. J . Chem. Soc., Perkin
Trans. 1 1989, 879. (c) Curran, D. P.; Tamine, J . J . Org. Chem. 1991,
56, 2746. (d) Musa, O. M.; Horner, J . H.; Newcomb, M. J . Org. Chem.
1999, 64, 1022.
(7) Welch, J . T. Tetrahedron 1987, 43, 3123.
(8) (a) Walling, C. Org. React. 1963, 13, 91. (b) Sellers, S. F. In
Chemistry of Organic Fluorine Compounds II; Hudlicky´, M.; Pavlath,
A. E., Eds.; ACS Monograph 187, American Chemical Society: Wash-
ington, DC, 1995; p 747.
(9) Recent excellent work on cyclization reactivity of fluorinated
alkyl radicals: Rong, X. X.; Pan, H.-Q.; Dolbier, W. R., J r.; Smart, B.
E. J . Am. Chem. Soc. 1994, 116, 4521. Dolbier, W. R., J r.; Rong, X. X.
Tetrahedron Lett. 1996, 37, 5321. Dolbier, W. R., J r.; Rong, X. X.;
Bartberger, M. D.; Koroniak, H.; Smart, B. E.; Yang, Z.-Y. J . Chem.
Soc., Perkin Trans. 2 1998, 219.
(10) Barth, F.; O-Yang, C. Tetrahedron Lett. 1990, 31, 1121.
(11) Stewart, W. E.; Siddall, T. H., III. Chem. Rev. 1970, 70, 517.
10.1021/jo001187f CCC: $20.00 © 2001 American Chemical Society
Published on Web 12/01/2000

316 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
Sch em e 1
panediamine), Pd(PPh3)4, or RuCl2(PPh3)3, whereas de-
crease of the product yields was observed with CuOTf-
(bipy). In sharp contrast, N-allyldifluoroiodoacetamide 3c
is photosensitive, and a small amount of the cyclization
product 5c was detectable when a THF solution of 3c
was stirred in fluorescent light at room temperature for
12 h.12 The reaction was accelerated in the presence of a
catalytic amount of either PPh3 (20 - 40 mol %) or Pd-
(PPh3)4 (10 mol %) as shown in Scheme 2. For example,
3c was cyclized to 5c with the aid of PPh3 (40 mol %) or
Pd(PPh3)4 (5 mol %) in THF in the fluorescent light at
room temperature; the product was obtained in moderate
to good yields after 12 h. No reaction catalyzed by PPh3
or Pd(PPh3)4 occurred in the dark. Some amounts (5-
20%) of reduction product, N-allyl-N-tosyldifluoroaceta-
mide, were formed as a byproduct. Cyclization reaction
of 3a , 3b, or 3c with 10 mol % of Pd(PPh3)4 in THF in
fluorescent light at room temperature for15 h afforded
the corresponding lactam in 98, 34, and 94% yield,
respectively. The low yield formation of 5b can be
explained by the high amide rotational barrier as de-
scribed above. Thus, facile cyclization of 3a -c in fluo-
rescent light with the aid of PPh3 or Pd(PPh3)4 is an
attractive method for preparation of fluorinated γ-lac-
tams under mild conditions, though there are drawbacks
in that access of N-allyl-N-tosyldifluoroiodoacetamides is
not as easy as synthesis of 2a -c, and high photosensitiv-
ity of 3a -c leads to their decomposition to give a mixture
of products even during storage in a refrigerator.
Ta ble 1. Cycliza tion of N-Su bstitu ted
N-Allylh a lod iflu or oa ceta m id esa
cat. temp time
yield
(%)
entry amide
X
Z
(%)
(°C)
(h)
product
1
2
3
4
5
6
7
2a
2b
2c
3a
3b
3c
3c
Br allyl 30
80
80
80
80
80
80
40
15
4a
4b
4c
5a
5b
5c
5c
81
58
84
92
34
69
69
Br Bn
Br Ts
I
I
I
I
30
30
15
15
15
15
15
15
allyl 10
Bn
Ts
Ts
10
10
10
a
To avoid the halogen exchange of both the starting material
and the product, CuX, of which X group (X ) Cl, Br, I) was the
same as that in the starting material, was used.
Resu lts a n d Discu ssion
A series of N-allylhalodifluoroacetamide derivatives
was synthesized and subjected to cyclization in the
presence of a catalytic amount of CuX(bipyridine) in
dichloroethane. The results are summarized in Table 1.
The N-allylbromodifluoroacetamides, 2a -c, were suc-
cessfully cyclized to the corresponding γ-lactams, 4a -c,
with 30 mol % of CuBr(bipy) at 80 °C for 15 h. Cyclization
of the difluoroiodoacetamides, 3a -c, in the presence of
CuI(bipy) proceeded smoothly even with lower concentra-
tion of the catalyst (∼10 mol %) or at lower temperature
(40 °C) as shown in entries 6-9. Attempts to cyclize
N-allyl-N-benzylchlorodifluoroacetamide (1b) and N-allyl-
N-tosylchlorodifluoroaceamide (1c) resulted in complete
recovery of the starting materials under the same condi-
tions. Thus, the reactivity of these halodifluoroacetamides
decreased in the order, halogen ) I > Br . Cl.
Table 2 summarizes the cyclization of various N-allyl-
N-tosylbromodifluoroacetamides. The substrates derived
from primary allylic amines generally gave the product
in good yields. In contrast, a bromodifluoroacetamide
from 2-cyclohexenylamine afforded a substantial amount
of intractable products when 30 mol % of the catalyst was
used. Using 100 mol % of CuCl(bipy), the corresponding
cyclization products were available in moderate yields.
As shown in entries 1 and 5, the reaction was sometimes
accompanied by dehydrobromination reaction as a side
reaction.
The N-allyl and N-tosyl derivatives, 2a , 3a , 2c, and
3c, underwent the cyclization to give the product in good
to high yields. In contrast, the N-benzyl analogues, 2b
and 3b, gave the corresponding lactams in lower yields
as shown in entries 2 and 5. This is attributed to the
amide rotation effect reported earlier. Variable temper-
ature 1H NMR spectra of 2b and 2c in toluene-d8 showed
that the coalescence temperature of the peak due to the
methylene protons adjacent to the olefinic bond was 70
°C for 2b, whereas it was at -90 °C for 2c as shown in
Figure 1. We reported that the coalescence temperature
of the peak due to the methylene protons adjacent to the
olefinic bond was 20 °C for N-allyl-N-benzyltrichloroac-
etamide, whereas no coalescence occurred even at -105
°C for N-allyl-N-tosyltrichloroacetamides.5b Thus, it is
apparent that the rotational barrier of the fluorinated
amides, 2b or 2c, is higher than the corresponding
trichlorinated amides. Introduction of N-tosyl group
essentially helps to lower the rotational barriers of the
fluorinated amides leading to facile access of the rotamer
favorable for the cyclization. This results in high yield
formation of the N-tosylated R,R-difluoro-γ-lactams.
For cyclization of N-allylbromodifluoroacetamides, ad-
dition of the copper catalyst is crucial. In fact, screening
of the catalyst for cyclization of 2a -c revealed that no
reaction occurred with CuCl(N,N,N′,N′-tetramethylpro-
In summary, we found that efficient cyclization of
N-allylhalodifluoroacetamides was achieved by catalysis
of CuX(bipy). Introduction of N-tosyl group is effective
to raise product yields. Radical cyclization to synthesize
fluorinated carbo- and heterocyclic compounds has re-
cently received considerable attention from organic chem-
ists; however, only a few successful examples have been
reported.9,10,13-16 As the closest examples to the fluori-
(12) Photochemical or palladium-catalyzed intermolecular addition
of difluoroiodocarbonyl compounds to olefins: Yang, Z.-Y.; Burton, D.
J . J . Org. Chem. 1991, 56, 5125. Qiu, Z.-M.; Burton, D. J . J . Org. Chem.
1995, 60, 5570.
(13) Yamamoto, T.; Ishibuchi, S.; Ishizuka, T.; Haratake, M.;
Kunieda, T. J . Org. Chem. 1993, 58, 1997.
(14) Efficient access to R,R-difluorinated γ-lactones via radical
cyclization of allyl siloxy acetals has recently been reported by Itoh
and co-workers: Itoh, T.; Sakabe, K.; Kudo, K.; Ohara, H.; Takagi, Y.;
Kihara, H.; Zagatti, P.; Renou, M. J . Org. Chem. 1999, 64, 252.
(15) (a) Uneyama, K.; Yanagiguchi, T.; Asai, H. Tetrahedron Lett.
1997, 38, 7763. (b) Uneyama, K.; Asai, H. Chem. Lett. 1995, 1123.
(16) Radical cyclization of other R,R-difluoro and â,â-difluoro radi-
cals: (a) Cavicchio, G.; Marchetti, V.; Arnone, A.; Bravo, P.; Viani, F.
Tetrahedron 1991, 47, 9439. (b) Arnone, A.; Bravo, P.; Cavicchio, G.;
Frigerio, M.; Viani, F. Tetrahedron 1992, 48, 8523. (c) Arnone, A.;
Bravo, P.; Frigerio, M.; Viani, F.; Cavicchio, G.; Crucianelli, M. J . Org.
Chem. 1994, 59, 3459. (d) Buttle, L. A.; Motherwell, W. B. Tetrahedron
Lett. 1994, 35, 3995. (e) Morikawa, T.; Kodama, Y.; Uchida, J .; Takano,
M.; Washio, Y.; Taguchi, T. Tetrahedron 1992, 48, 8915. (f) Okano, T.;
Ishihara, H.; Takakura, N.; Tsuge, H.; Eguchi, S.; Kimoto, H. J . Org.
Chem. 1997, 62, 7192.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 317
F igu r e 1. Variable temperature NMR spectra of 2b (left) and 2c (right).
Ta ble 2. Cycliza tion of Va r iou s
Sch em e 2
N-Allyl-N-tosylbr om od iflu or oa ceta m id esa
nated γ-lactam synthesis presented in this paper, prepa-
ration of R,R-difluorinated lactones or lactams was
investigated by several groups.10,13,14,15b Atom transfer
radical cyclization of allyl halodifluoroacetates or N-
allylhalodifluoroacetamides did not work well;10,14 the
only exception is cyclization of certain bromodifluoroac-
etates having a carbon-carbon double bond in the
molecule which reportedly afforded a macrocyclic R,R-
difluorolactone.13 Elegant cyclization of N-allylbromodi-
fluoroacetamide promoted by phenylseleno radicals at
room temperature was reported by Uneyama and co-
workers;15a however, one drawback is that a stoichiomet-
ric amount of phenylseleno group is required, and yield
of the product is not very high in the cyclization of
N-allyl-N-benzylbromodifluoroacetamide compared with
the corresponding N,N-diallyl homologue due to the high
energy barrier of amide rotation. Thus, the reaction
described in this paper is a rare synthetic method for R,R-
difluorinated γ-lactams by cyclization of easily available
N-allylbromodifluoroacetamides and is valuable as a
a
novel successful example of direct radical cyclization of
All of the reactions were carried out in dichloroethane at 80
b
°C for 15 h. Diastereomer ratio.
R,R,R-halodifluoro carbonyl compounds.

318 J . Org. Chem., Vol. 66, No. 1, 2001
Notes
(CH2Cl2) 1713 cm-1; FAB-MS m/z 416 [MH+]; FAB-HRMS calcd
for C12H12NO3IF2S+H 415.9629, found 415.9623.
Exp er im en ta l Section
Gen er a l. All manipulations were performed under an argon
atmosphere unless otherwise noted. Cuprous chloride (CuCl) was
prepared from CuCl2 hydrate17 and stored under a dry argon
atmosphere. Purification of 2,2′-bipyridine was made by subli-
mation. Solvents were distilled under an inert atmosphere in
the presence of drying reagents. The solvent used for the
cyclization was degassed by three freeze-pump-thaw cycles just
prior to use. Difluoroiodoacetyl chloride was prepared by the
procedure in the literature.12 Column chromatography was
carried out using silica gel (Merck No. 1.07734.9025 or Wakogel
FC-40). Thin-layer chromatography was carried out with silica
gel 60 F254 (Merck). Typical experimental procedures including
analytical and spectroscopic data are described below. Other
data are summarized in the Supporting Information in detail.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Alk yl-N-
a llylh a lod iflu or oa ceta m id es (a lk yl ) a llyl, ben zyl). In a
typical example, to a solution of N,N-diallylamine (0.5 mL, 394
mg, 4.1 mmol) containing triethylamine (0.68 mL, 493 mg, 4.9
mmol) in ether (10 mL) was added dropwise bromodifluoroacetyl
chloride (970 mg, 5.0 mmol), and the mixture was stirred at room
temperature for 5 h. The reaction was quenched by adding
aqueous NH4Cl and then extracted with ether. The combined
organic layers were washed with brine, dried over MgSO4,
filtered, and concentrated. The residue was purified by column
chromatography by eluting with 15% ether in hexane to give
N,N-diallylbromodifluoroacetamide (2a ) as a colorless oil (840
mg, 83%).
Gen er a l P r oced u r e for th e Cop p er -Ca ta lyzed Cycliza -
tion . In a typical example, CuBr (12.8 mg, 0.09 mmol) and
N-allyl-N-tosylbromodifluoroacetamide (2c) (110 mg, 0.3 mmol)
were measured into a flask, and the atmosphere was replaced
by argon. Degassed dichloroethane (1.2 mL) was added, and the
mixture was allowed to warm at 80 °C. Then, a dichloroethane
solution of bipyridine (0.3 M, 0.3 mL, 0.09 mmol) was added.
After heating at this temperature for 15 h, the mixture was
cooled to room temperature and transferred to the head of a
short pad of a silica gel column and eluted with ether. The eluent
was concentrated, and the residue was purified by column
chromatography (eluent; 25% ether in hexane) to afford the
lactam 5c as a colorless solid (92 mg, 84%).
N-Ben zyl-â-br om om eth yl-r,r-d iflu or o-γ-la cta m (4b): 58%
yield; colorless oil; 1H NMR (CDCl3) δ 7.41-7.31 (m, 3H), 7.28-
7.23 (m, 2H), 4.54 (s, 2H), 3.64 (dd, J ) 10, 5 Hz, 1H), 3.51 (ddd,
J ) 10, 8, 2 Hz, 1H), 3.33 (t, J ) 10 Hz, 1H), 3.10 (ddd, J ) 10,
7, 3 Hz, 1H), 3.03-2.87 (m, 1H); 13C NMR (CDCl3) δ 162.73 (t,
J ) 30 Hz), 134.16, 129.11, 128.42, 128.34, 116.68 (dd, J ) 256,
251 Hz), 47.45, 46.74 (d, J ) 6 Hz), 42.38 (dd, J ) 22, 20 Hz),
25.79 (d, J ) 11 Hz); 19F NMR (CDCl3) δ 65.50 (ddd; J ) 271,
14, 2 Hz, 1F), 56.95 (dd, J ) 271, 15 Hz, 1F); IR (CH2Cl2) 1734
cm-1; EI-MS m/z 305 [M+ + 2], 303 [M+]; HRMS calcd for C12H12
-
BrF2NO 303.0070, found 303.0070; Anal. Calcd for C12H12BrF2-
NO: C, 47.39; H, 3.98; N, 4.61. Found: C,47.29; H, 4.05; N, 4.57.
N-Ben zyl-r,r-d iflu or o-â-iod om eth yl-γ-la cta m (5b): 34%
yield; colorless oil; 1H NMR (CDCl3) δ 7.40-7.33 (m, 3H), 7.27-
7.23 (m, 2H), 4.55 (d, J ) 15 Hz, 1H), 4.52 (d, J ) 15 Hz, 1H),
3.49 (t, J ) 10 Hz, 1H, NCH2), 3.40 (dd, J ) 11, 5 Hz, 1H), 3.07
(t, J ) 11 Hz, 1H), 3.02-2.98 (m, 1H), 2.95-2.83 (m, 1H); 13C
NMR (CDCl3) δ 162.97 (dd, J ) 31, 30 Hz), 134.17, 129.07,
128.36, 128.27, 116.53 (dd, J ) 257, 251 Hz), 48.57 (d, J ) 6
Hz), 47.37, 43.01 (dd, J ) 22, 21 Hz), -4.40 (d, J ) 10 Hz); 19F
NMR (CDCl3) δ 51.75 (dd, J ) 269, 14 Hz, 1F), 44.15 (dd, J )
269, 16 Hz, 1F); IR (CH2Cl2) 1733 cm-1; FAB-MS m/z 352 [MH+];
FAB-HRMS calcd for C12H12F2INO+H 352.0010, found 352.0014.
N,N-Dia llylbr om od iflu or oa ceta m id e (2a ): 83% yield; col-
orless oil; 1H NMR (CDCl3) δ 5.83-5.72 (m, 2H), 5.31-5.19 (m,
4H), 4.09 (d, J ) 6 Hz, 2H), 4.01 (d, J ) 6 Hz, 2H); 13C NMR
(CDCl3) δ 159.09 (t, J ) 27 Hz), 131.70, 130.78, 119.10, 118.44,
110.80 (t, J ) 315 Hz), 50.08 (t, J ) 4 Hz), 48.47; 19F NMR
(CDCl3) δ 107.47; IR (CH2Cl2) 1685 cm-1; EI-MS m/z 255 [M+
+
2], 253 [M+]; HRMS calcd for C8H10NOBrF2 252.9914, found
252.9913.
N,N-Dia llyld iflu or oiod oa ceta m id e (3a ): 89% yield; color-
less oil; 1H NMR (CDCl3) δ 5.85-5.73 (m, 2H), 5.31-5.19 (m,
4H), 4.07 (d, J ) 6 Hz, 2H), 3.99 (d, J ) 6 Hz, 2H); 13C NMR
(CDCl3) δ 159.96 (t, J ) 24 Hz), 131.56, 130.79, 119.09, 118.41,
90.19 (t, J ) 323 Hz), 50.66 (t, J ) 4 Hz), 48.61; 19F NMR (CDCl3)
δ 111.22; IR (CH2Cl2) 1680 cm-1; FAB-MS m/z 302 [MH+]; FAB-
HRMS calcd for C8H10NOF2I+H 301.9853, found 301.9862.
Gen er a l P r oced u r e for th e P r ep a r a tion of N-Allyl-N-
tosylh a lod iflu or oa ceta m id es. A solution of N-allyltosylamide
(115 mg, 0.54 mmol) in THF (2 mL) was treated with n-BuLi
(1.6 M in hexane, 0.35 mL) at -78 °C. After 10 min, bromodi-
fluoroacetyl chloride (0.70 mL, 126 mg, 0.65 mmol) was added,
and the mixture was kept at this temperature for 30 min with
stirring. The mixture was quenched with aq NH4Cl and then
extracted with ether. The combined organic layers were washed
with cold aq NaHCO3 and brine, dried over MgSO4, filtered, and
concentrated. The residue was purified by column chromatog-
raphy at -78 °C (eluent; 15% ether in hexane) to give N-allyl-
N-tosylbromodifluoroacetamide (2c) as a white solid (187 mg,
94%).
Anal. Calcd for
C12H12F2INO: C, 41.05; H, 3.44; N, 3.99.
Found: C, 40.77; H, 3.69; N, 4.09.
N-Tosyl-â-br om om eth yl-r,r-d iflu or o-γ-la cta m (4c): 84%
1
yield; colorless solid; mp. 168-169 °C; H NMR (CDCl3) δ 7.96
(d, J ) 8 Hz, 2H), 7.39 (d, J ) 8 Hz, 2H), 4.22 (dd, J ) 11, 8 Hz,
1H), 3.64-3.56 (m, 2H), 3.34 (t, J ) 11 Hz, 1H), 3.07-2.91 (m,
1H), 2.47 (s, 3H); 13C NMR (CDCl3) δ 160.38 (t, J ) 32 Hz),
146.62, 133.53, 130.14, 128.34, 115.15 (dd, J ) 261, 255 Hz),
46.68 (d, J ) 5 Hz), 42.32 (dd, J ) 22, 20 Hz), 24.35 (d, J ) 9
Hz), 21.80; 19F NMR (CDCl3) δ 52.21 (dd, J ) 272, 13 Hz, 1F),
43.27 (dd, J ) 272, 17 Hz, 1F); IR (CH2Cl2) 1771 cm-1; FAB-MS
m/z 370 [MH+ + 2], 368 [MH+]; FAB-HRMS calcd for C12H12
BrF2NO3S+H 367.9768, found 367.9770. Anal. Calcd for C12H12
-
-
BrF2NO3S: C, 39.14; H, 3.29; N, 3.80. Found: C, 39.36; H, 3.21;
N, 3.73.
N-Tosyl-r,r-d iflu or o-â-iod om eth yl-γ-la cta m (5c): 69%
1
yield; colorless solid; mp 160-161 °C; H NMR (CDCl3) δ 7.95
(d, J ) 8 Hz, 2H), 7.39 (d, J ) 8 Hz, 2H), 4.22 (dd, J ) 10, 8 Hz,
1H), 3.47 (dd, J ) 10, 8 Hz, 1H), 3.36 (dd, J ) 10, 5 Hz, 1H),
3.06 (t, J ) 10 Hz, 1H), 2.96-2.85 (m, 1H), 2.47 (s, 3H); 13C
NMR (CDCl3) δ 160.64 (dd, J ) 33, 32 Hz), 146.59, 133.50,
130.12, 128.28, 114.99 (dd, J ) 254, 252 Hz), 48.52 (d, J ) 6
Hz), 42.95 (dd, J ) 22, 21 Hz), 21.77, -6.60 (d, J ) 8 Hz); 19F
NMR (CDCl3) δ 50.93 (dd, J ) 271, 12 Hz, 1F), 43.23 (dd, J )
271, 17 Hz, 1F); IR (CH2Cl2) 1770 cm-1; FAB-MS m/z 416 [MH+];
N-Allyl-N-tosylbr om od iflu or oa ceta m id e (2c): 94% yield;
1
colorless solid; mp 47.5-48.5 °C; H NMR (CDCl3) δ 7.92 (d, J
) 8 Hz, 2H), 7.34 (d, J ) 8 Hz, 2H), 5.90 (ddt, J ) 17, 11, 5 Hz,
1H), 5.39 (d, J ) 17 Hz, 1H), 5.35 (d, J ) 11 Hz, 1H), 4.70-4.66
(m, 2H), 2.45 (s, 3H); 13C NMR (CDCl3) δ 157.75 (t, J ) 29 Hz),
145.90, 134.25, 131.94, 129.47, 129.41, 119.52, 109.80 (t, J )
317 Hz), 49.47 (t, J ) 3 Hz), 21.72; 19F NMR (CDCl3) δ 105.33;
IR (CH2Cl2) 1718 cm-1; FAB-MS m/z 370 [MH++2], 368 [MH+];
FAB-HRMS calcd for C12H12NO3BrF2S+H 367.9768, found
367.9767.
FAB-HRMS calcd for
C12H12F2INO3S+H 415.9629, found
415.9630; Anal. Calcd for C12H12 F2INO3S: C, 34.71; H, 2.91;
N, 3.37. Found: C, 34.86; H, 2.91; N, 3.34.
P h otoch em ica l Cycliza tion of 3c w ith th e Aid of P d -
(P P h 3)4. In a typical example, a THF solution of 3c (0.05 mmol,
20.8 mg, in 1 mL of THF) was treated with a catalytic amount
of Pd(PPh3)4, prepared from Pd2(dibenzylideneacetone)3‚CHCl3
(1.3 mg, 0.00125 mmol) and PPh3 (2.6 mg, 0.01 mmol) in THF
(1 mL) at room temperature, in fluorescent light for 16 h.
Metallic components were removed by passing the resulting
reaction mixture through a short column of silica gel by eluting
with ether. After concentration of the eluents, purification of the
residue by medium-pressure liquid chromatography (silica, by
eluting with 40% ether in hexane) gave 5c as a colorless solid
N-Allyl-N-tosyld iflu or oiod oa ceta m id e (3c): 62% yield;
1
colorless solid; mp 56-58 °C; H NMR (CDCl3) δ 7.92 (d, J ) 8
Hz, 2H), 7.34 (d, J ) 8 Hz, 2H), 5.90 (ddt, J ) 17, 11, 5 Hz, 1H),
5.41 (d, J ) 17 Hz, 1H), 5.36 (d, J ) 11 Hz, 1H), 4.66 (d, J ) 5
Hz, 2H), 2.46 (s, 3H); 13C NMR (CDCl3) δ 158.40 (t, J ) 26 Hz),
145.84, 134.25, 131.87, 129.47, 129.41, 119.50, 88.87 (t, J ) 325
Hz), 49.98 (t, J ) 3 Hz), 21.77; 19F NMR (CDCl3) δ 111.22; IR
(17) Keller, R. N.; Wycoff, H. D. Inorg. Synth. 1946, 2, 1.

Notes
J . Org. Chem., Vol. 66, No. 1, 2001 319
in 87% yield (18 mg). As described in the text, no reaction took
place without exposure to fluorescent light. Similar results were
obtainable when PPh3 was used as the catalyst, but yield of the
product was lower.
Su p p or tin g In for m a tion Ava ila ble: List of other spec-
troscopic data except those described in the Experimental
1
Section. Copies of H and 13C NMR spectra of all compounds
lacking elemental analysis [2a -c, 3a -c, 6, 7, 9, 10, 12, 13
(the minor isomer), 14 (the minor isomer)]. This material is
available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t . This work was support by
Grants-In-Aid for Scientific Research (Nos. 10125230
and 10450343) from J apan Society for the Promotion
of Science.
J O001187F