Lewis acid-catalyzed atom transfer radical cyclization of unsaturated β-keto amides

Article abstract of DOI:10.1016/j.tet.2003.06.009

The Lewis acid-catalyzed atom transfer radical cyclization reactions of olefinic α-bromo β-keto amides were investigated. It was found Lewis acid Yb(OTf)₃ or Mg(ClO₄)₂ not only promoted the cyclization reactions, but also resulted in excellent trans stereocontrol in the cyclization products. With the catalysis of Lewis acid Yb(OTf) ₃ or Mg(ClO₄)₂ at -78°C in the presence of Et₃B/O₂, the cyclization reactions of C-olefinic β-keto amides provided cyclic ketones, while the cyclization reactions of N-olefinic β-keto amides led to the formation of γ-lactams, which could be converted to 3-aza-bicyclo[3,1,0]hexan-2-ones.

Full text of DOI:10.1016/j.tet.2003.06.009

Tetrahedron 59 (2003) 10465–10475
Lewis acid-catalyzed atom transfer radical cyclization of
unsaturated b-keto amides
*
Dan Yang, Yi-Long Yan, Ka-Lun Law and Nian-Yong Zhu
Department of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong, People’s Republic of China
Received 30 April 2003; accepted 30 June 2003
Abstract—The Lewis acid-catalyzed atom transfer radical cyclization reactions of olefinic a-bromo b-keto amides were investigated. It was
found Lewis acid Yb(OTf)3 or Mg(ClO4)2 not only promoted the cyclization reactions, but also resulted in excellent trans stereocontrol in the
cyclization products. With the catalysis of Lewis acid Yb(OTf)3 or Mg(ClO4)2 at 2788C in the presence of Et3B/O2, the cyclization reactions
of C-olefinic b-keto amides provided cyclic ketones, while the cyclization reactions of N-olefinic b-keto amides led to the formation of
g-lactams, which could be converted to 3-aza-bicyclo[3,1,0]hexan-2-ones.
q 2003 Elsevier Ltd. All rights reserved.
1. Introduction
Lewis acid complexation resulted in excellent stereocontrol
of an atom transfer radical allylation reaction.5a Porter and
co-workers found that Lewis acids such as MgBr2,
Sc(OTf)3, and Yb(OTf)3 could accelerate the intermolecular
atom transfer radical addition of a-bromo oxazolidinones to
alkenes.5b We previously investigated the effect of Lewis
acids on the atom transfer radical mono and tandem
cyclization reactions of unsaturated a-bromo b-keto esters.6
We found that the cyclization reactions catalyzed by Lewis
acid Yb(OTf)3 or Mg(ClO4)2 provided exclusively trans
2,3-disubstituted cyclic ketones, and a highly enantioselec-
tive version (up to 95% ee) of such reactions was developed
by using Lewis acid Mg(ClO4)2 or Yb(OTf)3 combined with
a chiral oxazoline ligand (Eq. (1)).6 These cyclization
reactions required the presence of an a-alkyl substituent
since a-monobromo b-keto esters without an a-alkyl
substituent were unstable during column purification and
upon storage.7,8 In contrast, a-bromo b-keto amides were
found to be rather stable and readily accessible.8 A literature
survey revealed that, while a-halo b-keto esters9 and a-halo
malonates10 had been particularly studied, there was no
report on the atom transfer radical reactions of olefinic
a-bromo b-keto amides. Therefore, we decided to explore
the effect of Lewis acids on the atom transfer radical
cyclization reactions of unsaturated a-bromo b-keto
amides.
Atom transfer radical cyclization reactions are versatile and
powerful tools for the synthesis of cyclic compounds.1
Compared with the reductive reactions using Bu3SnH to
terminate the radicals (Path A, Scheme 1), atom transfer
radical cyclization reactions keep the transfer group (X) in
the products, thereby allowing for further functionalization
(Path B).2
Scheme 1.
In recent years, Lewis acids have been increasingly used to
accelerate radical reactions.3 While Lewis acids such as
lanthanide triflates have shown great promise in reductive
radical addition reactions,4 there are only a few reports
about the effect of Lewis acids on the atom transfer radical
reactions.5 Guindon and co-workers demonstrated that
ð1Þ
Keywords: Lewis acid; radical cyclization; keto amide.
*
Corresponding author; e-mail: yangdan@hku.hk
0040–4020/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2003.06.009

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D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
Two types of unsaturated a-bromo b-keto amides were
investigated. The first type of substrates included C-alkenyl
a-bromo b-keto amides (1a–d), which contain an all carbon
backbone (Scheme 2). The cyclization of this type of
substrates would result in the formation of 2,3-disubstituted
cyclic ketones. The second type of substrates, N-alkenyl
a-bromo b-keto amides (1e–h) in which the olefin tethers
were attached to the nitrogen of the amide group, were
expected to form g-lactams (2-pyrrolidinones) in the
cyclization reactions (Scheme 3).
In this paper, we report that Lewis acids such as Yb(OTf)3
and Mg(ClO4)2 significantly accelerate the atom transfer
radical cyclization reactions of both C- and N-alkenyl
a-bromo b-keto amides.
2. Results and discussion
2.1. Preparation of alkenyl a-bromo b-keto amides
The olefinic tethers of C-alkenyl b-keto amides (1a–d)
were introduced via alkylation of the dianion of N,N-
dimethyl acetoacetamide with various alkenyl bromides
(Scheme 4). N-Alkenyl b-keto amides (1e–h) were
prepared by a transamidation reaction of a b-keto ester
with an unsaturated amine11 (Schemes 5 and 6). All the
b-keto amides (4a–h) were brominated with N-bromo-
succinimide (NBS) in EtOAc in high yield (Schemes 4–6).8
Scheme 2.
2.2. Atom transfer radical cyclization reactions of
C-alkenyl a-bromo b-keto amides 1a–d
In our investigation of Lewis acid-catalyzed atom transfer
radical cyclization of olefinic b-keto esters, Lewis acids
Yb(OTf)3 and Mg(ClO4)2 were found to be the most
efficient catalysts. Therefore, those optimal conditions were
first applied to the cyclization of C-alkenyl a-bromo b-keto
amides 1a–d. All reactions were conducted at 2788C with
Et3B/O2 as the radical initiator (Scheme 2 and Table 1).
Scheme 3.
Scheme 4. Reagents and conditions: (a) NaH, n-BuLi, THF, alkyl bromide, 08C to rt, 50–60% yield; (c) NBS (1.1 equiv.), EtOAc, rt, 70–90% yield.
Scheme 5. Reagents and conditions: (a) amine, DMAP (0.5 equiv.), toluene, reflux, 38–45% yield; (b) NBS (1.1 equiv.), EtOAc, rt, 80–85% yield.
Scheme 6. Reagents and conditions: (a) amine, DMAP (0.5 equiv.), toluene, reflux, 98% yield for 4g, 78% for 4h; (b) NBS (1.1 equiv.), NaH, THF, 41–42%
yield.

D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
10467
Table 1. Lewis acid-catalyzed atom transfer radical cyclization of C-alkenyl substrates 1a–da
Entry
Substrate
Lewis acid (equiv.)
Solvent
Time (h)
Product
Isolated yield (%)
0b
1
–
CH2Cl2
3
2
3
Yb(OTf)3 (0.3)
Mg(ClO4)2 (0.3)
CH2Cl2
CH2Cl2
1
1
74
57
4
5
Yb(OTf)3 (0.3)
Mg(ClO4)2 (0.3)
CH2Cl2
CH2Cl2
2
2
62 (1/1.8)c
78 (1/1.6)c
6
Yb(OTf)3 (0.5)
Et2O
4
40d
7
Mg(ClO4)2 (0.3)
CH2Cl2
4
28d
a
The reactions were carried out with 0.5 mmol (for 1a and 1b) or 0.3 mmol (for 1c and 1d) of substrate at 30 mM concentration in the indicated anhydrous
solvent at 2788C.
Reduction product 4a was isolated in 66% yield and the conversion of 1a was 88%.
Diastereomeric ratios.
Only one diastereomer was isolated. The stereochemistry at the carbon bearing a bromo atom could not be clearly determined from the NOESY experiment
due to peak overlap. The reaction conducted at a higher temperature (2408C) gave a similar result.
b
c
d
Without any Lewis acid, the cyclization reaction of substrate
of 1c under the Yb(OTf)3/Et2O condition only gave a
monocyclization product 2c in 40% yield (entry 6). In the
cyclization of 1d with Mg(ClO4)2 as the catalyst in CH2Cl2,
monocyclization product 2d was obtained in 28% yield
(entry 7). The major side products of these cyclization
reactions were the reduction products 4c and 4d, respect-
ively. The tandem cyclization reactions of 1c and 1d were
also tested at a higher temperature (2408C), but similar
results were obtained as at 2788C. The reason why olefinic
a-bromo b-keto amides failed to give tandem cyclization
products remains unknown.
1a failed to give the desired product 2a, and only reduction
product 4a was isolated in 66% yield with 88% conversion
(entry1). InthepresenceofaLewisacidcatalyst(entries2–7),
cyclization of olefinic b-keto amides 1a–d resulted in the
exclusive formation of the trans cyclization products (the
2-amidegrouptranstothe3-alkylgroup), similartothecaseof
olefinic a-bromo b-keto esters.6a In particular, upon the
addition of 0.3 equiv. of Lewis acid Mg(ClO4)2 or Yb(OTf)3,
cyclization of 1a afforded 2a in 57–74% yield (entries 2 and
3). It is worth pointing out that cyclization product 2a was
formed via a radical process rather than an ionic pathway12
because substrate 1a was stable toward Mg(ClO4)2 or
Yb(OTf)3 in CH2Cl2 at room temperature without the radical
initiator. In the cyclization of substrate 1b, two epimeric
bromides 2b (ratio 1:1.6–1.8) were obtained in 60–80% yield
(entries 4 and 5). These results clearly indicated that the Lewis
acid not only promoted the atom transfer radical cyclization
reactions, but also resulted in excellent trans stereocontrol in
the cyclization products.
The stereochemistry of product 2a was assigned by
comparing the NMR spectral data of 2a and a corresponding
phenylseleno compound reported in literature.13 The 2,3-
trans relationship of the products 2b, 2c and 2d was
determined by the large coupling constant (J¼10–12 Hz)
between the H-2 and H-3. The stereochemistry of the major
isomer of product 2b was confirmed by X-ray crystal-
lographic analysis (Fig. 1).
Tandem cyclization reactions of substrates 1c and 1d were
attempted under the usual conditions. However, no desired
tandem cyclization product was isolated despite of the fact
that analogous b-keto esters underwent tandem radical
cyclization products in moderate yields.6b The cyclization
2.3. Lactam formation via atom transfer radical
cyclization reactions of N-alkenyl a-bromo b-keto
amides 1e–h
g-Lactams (2-pyrrolidinones) are a class of versatile

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D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
Figure 1. X-ray structure of the major isomer of product 2b.
compounds. They not only show various biological
activities, but also are excellent starting materials for the
synthesis of biologically active 5-membered-ring nitrogen
heterocyclic compounds such as (þ)-a-allokainic acid,14
(þ)-a-kainic acid,15 acromelic acid,16 and iso-
cynometrine.17 Consequently, it has stimulated great
interest of organic chemists to develop new methods for
the syntheses of this type of compounds with diverse
structural features.18 The Lewis acid-catalyzed atom
transfer radical cyclization reactions were found to be
useful for the synthesis of g-lactams. In our study, N-alkenyl
a-bromo b-keto amides 1e–h were subjected to the
optimized atom transfer radical cyclization conditions
(Scheme 3), and the results are tabulated in Table 2.
The 2,3-trans relationships of products 2e and 2f were
determined by the coupling constants (J¼6–9 Hz) of the
a-protons according to the literature reports.19,20
3-Aza-2-bicyclo[3.1.0]hexan-2-one derivatives (Fig. 2) are
suitable starting materials for the preparation of cyclopropyl
nucleosides21 and conformationally restricted amino
acids.22 In addition, 3-azabicyclo[3,1,0]hexane unit is also
found in some biologically active compounds such as
trovafloxacin.23 The formation of products 3e and 3f
indicated that atom transfer radical cyclization of N-alkenyl
a-bromo b-keto amides and subsequent intramolecular
cyclopropanation provided a new pathway for the synthesis
of 3-aza-bicyclo[3.1.0]hexan-2-one derivatives.24
The cyclization of substrate 1e with 0.5 equiv. of
Mg(ClO4)2 or Yb(OTf)3 as the catalyst led to the formation
of g-lactam 2e along with a cyclopropanation product 3e in
60–70% total yield, and the ratios of these two products
varied according to the reaction conditions (Table 2, entries
2–4). In contrast, no cyclization product was obtained in the
absence of a Lewis acid (entry 1). The formation of product
3e could be explained by the subsequent intramolecular
cyclopropanation via 1,3-elimination of HBr from product
2e (Scheme 7). Cyclopropanation product 3e could also be
directly obtained from 1e in 43% overall yield by treating
the cyclization reaction mixture with 2 equiv. of NaH
(entry 8).
Spirolactams are useful building blocks for the synthesis of
natural products such as spirostaphylotrichin25 and some
natural alkaloids including sibirine, nitramine, or iso-
nitramine.26 Therefore, the development of new methods
for the synthesis of spirolactams has caught increased
attention of organic chemists. The reported methods include
thermolysis of N-unsaturated b-keto amides27a and enamino
carboxamides,27b and manganese (III) salt promoted radical
cyclization of b-keto carboxamides.27c The cyclization
reactions of substrates 1g and 1h provided spirolactams in
59 and 39% yield, respectively (entries 11 and 12). The
stereochemistries of products 2g and 2h were determined
from NOESY experiment (Fig. 3). Compared with the
reported synthesis of spirolactams,27 the Lewis acid-
catalyzed atom transfer radical cyclization reactions were
conducted under very mild condition at low temperature,
leading to the formation of products with excellent
stereocontrol.
The cyclization of substrate 1f with Lewis acid catalysis
resulted in the formation of g-lactam 2f in 70–80% yield
(Table 2, entries 5–7). Further treatment of product 2f with
NaH in THF gave a cyclopropanation product 3f in 80%
yield (Scheme 8). The cyclopropanation reaction could also
be finished in one pot by treating the cyclization product
mixture with NaH, providing 3f in 60% overall yield
(entry 9).
2.4. Explanation for the stereochemistry
Similar to the trans stereocontrol in the Lewis

D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
Table 2. Lewis acid-catalyzed atom radical cyclization of N-alkenyl substrates 1e–ha
10469
Entry
Substrate
Lewis acid (equiv.)
Solvent
Time (h)
Product
Isolated yield (%)
1
2
3
4
–
CH2Cl2
Et2O
CH2Cl2
CH2Cl2
5
1.5
2
0b
Yb(OTf)3 (0.5)
Yb(OTf)3 (0.5)
Mg(ClO4)2 (0.5)
68 (3/1)c
64 (1/1.6)c
73 (1/1.9)c
2
5
6
7
Yb(OTf)3 (0.3)
Yb(OTf)3 (0.3)
Mg(ClO4)2 (0.5)
Et2O
CH2Cl2
CH2Cl2
2
2
2
79
76
73
8
Yb(OTf)3 (0.5)
Et2O
1
43d
9
Mg(ClO4)2 (0.5)
CH2Cl2
1
60d
10
11
–
Yb(OTf)3 (0.5)
Et2O
Et2O
3
3
0e
59
12
Yb(OTf)3 (0.5)
Et2O
3
39
a
The reactions were carried out at 2788C with 0.4 mmol (for 1e and 1g–h) or 0.5 mmol (for 1f) of substrate at 30 mM concentration in the indicated dry
solvent.
Reductive debromination product 4e was obtained in 72% yield.
Ratios of the two products 2e/3e.
Overall yield of two reactions. After the radical cyclization reaction, the product mixture was treated with 2 equiv. of NaH at 08C for 0.5–2 h.
Reductive debromination product 4g was isolated in 99% yield.
b
c
d
e
acid-catalyzed atom transfer radical cyclization reactions of
(Scheme 9), the two carbonyl groups were locked in the syn
orientation by chelation to a Lewis acid. In transition state
TS1, the steric interaction between the olefinic group and
the locked dicarbonyl group was highly unfavorable.
Therefore, the cyclization proceeded exclusively via
alkenyl a-bromo b-keto esters,6 the excellent stereocontrol
in the cyclization reactions of unsaturated b-keto amides
was rationalized by the chelation effect of the Lewis acids.
As illustrated for the cyclization reaction of substrate 1b
Scheme 7.

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D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
transition state TS2, which resulted in the exclusive
formation of trans product 2b. The trans stereocontrol in
the formation of spirolactam 2h could be similarly
explained (Scheme 10).
Scheme 8.
Figure 2.
3. Conclusion
In summary, Lewis acids such as ytterbium triflates and
magnesium perchlorate significantly accelerated the atom
transfer radical cyclization reactions of two types of olefinic
b-keto amides with excellent stereocontrol. As the cycliza-
tion products were highly functionalized, these reactions
should be very useful in the construction of disubstituted
cyclic ketones, g-lactams, spirolactams, and 3-aza-2-
bicyclo[3.1.0]hexan-2-one derivatives.
4. Experimental
4.1. General methods
Figure 3. NOESY analysis of compounds 2g and 2h. The assignments of
protons were made on the basis of 1H NMR, 13C NMR, DEPT, and
CH-COSY spectra.
All reactions were performed in oven-dried flasks. Air and
Scheme 9. Mechanism of stereocontrol.
Scheme 10.

D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
10471
moisture-sensitive compounds were introduced via syringes
through a rubber septum. THF and Et2O were distilled from
sodium metal-benzophenone ketyl before use. Dichloro-
methane and toluene were distilled over calcium hydride.
Flash column chromatography was performed on E. Merck
silica gel 60 (230–400 mesh ASTM) using ethyl acetate/
n-hexane as eluting solvents.
(MþþH, 2), 211 (Mþ, 8), 142 (11), 129 (100); HRMS (EI)
for C12H21NO2 (Mþ): calcd 211.1572, found 211.1564.
4.1.3. 6-Methyl-3-oxo-undeca-6,10-dienoic acid
dimethylamide (4c). Prepared similarly to 4a. Yield 65%;
a light yellow oil; analytical TLC (silica gel 60), 60%
EtOAc in n-hexane, Rf¼0.24; 1H NMR (300 MHz, CDCl3)
d 14.8 (s, 0.2£1H, enol), 5.87–5.73 (m, 1H), 5.22–5.08 (m,
1H), 5.10 (s, 0.2£1H, enol), 5.03–4.93 (m, 2H), 3.54 (s,
0.8£2H, keto), 2.99 (s, 3H), 2.97 (s, 3H), 2.67 (t, J¼7.3 Hz,
2H), 2.27 (t, J¼7.5 Hz, 2H), 2.08–2.06 (m, 4H), 1.60 (s,
3H); 13C NMR (75 MHz, CDCl3; DEPT) d 204.6 (C), 167.0
(C), 138.8 (CH), 134.0 (C), 124.8 (CH), 114.8 (CH2), 49.6
(CH2), 41.9 (CH2), 38.2 (CH3), 35.7 (CH3), 34.1 (CH2), 33.5
(CH3), 27.6 (CH2), 16.4 (CH3); IR (CH2Cl2) 2929, 1721,
1644 cm21; LRMS for C14H23NO2 (EI, 20 eV) m/z 237
(Mþ, 6), 219 (5), 178 (15), 141 (16), 129 (100); HRMS (EI)
for C14H23NO2 (Mþ): calcd 237.1729, found 237.1731.
Nuclear magnetic resonance spectra were recorded in
deuteriochloroform (CDCl3) unless otherwise indicated,
with tetramethylsilane (TMS) as internal standard at
ambient temperature on a Bruker Avance DPX 300 or 400
Fourier Transform Spectrometer. Infrared absorption spec-
tra were recorded as a solution in CH2Cl2 with a Bio-Rad
FTS 165 Fourier Transform Spectrophotometer. Mass
spectra were recorded with a Finnigan MAT 95 mass
spectrometer for both low resolution and high resolution
mass spectra. Melting points were determined by Axiolab
ZEISS microscope apparatus and were uncorrected. Optical
rotations were recorded on a Perkin–Elmer 343 Polarimeter.
4.1.4. 6,10-Dimethyl-3-oxo-undeca-6,10-dienoic acid
dimethylamide (4d). Prepared similarly as 4a. Yield
63%; a light yellow oil; analytical TLC (silica gel 60),
4.1.1. Preparation of 7-methyl-3-oxo-oct-6-enoic acid
dimethylamide (4a). To a suspension of NaH (60% oil
dispersion, 960 mg, 24 mmol) in THF (50 mL) was added
N,N-dimethyl-3-oxo-butyramide (2.58 g, 20 mmol) slowly
at 08C. After 30 min, n-BuLi (2.4 M in n-hexane, 9 mL,
22 mmol) was added slowly at 08C. 4-Bromo-2-methyl-2-
butene (96%, 2.6 mL, 22 mmol) was added dropwise 0.5 h
later. The reaction was then stirred at room temperature for
4 h. After removal of solvents, the residue was diluted with
water and extracted with ether. The combined extracts were
washed with water, dried over MgSO4, and then concen-
trated. The crude product was purified by flash column
chromatography to give 4a (2.41 g, 12.2 mmol, 61%) as a
light yellow oil. Analytical TLC (silica gel 60), 60% EtOAc
1
60% EtOAc in n-hexane, Rf¼0.24; H NMR (400 MHz,
CDCl3) d 14.8 (s, 0.3£1H, enol), 5.20–5.11 (m, 1H), 5.11
(s, 0.3£1H, enol), 4.70 (s, 1H), 4.66 (s, 1H), 3.54 (s, 0.7£2H,
keto), 3.00–2.97 (4 s, 2£CH3, keto and enol), 2.67 (t,
J¼7.3 Hz, 2H), 2.27 (t, J¼7.6 Hz, 2H), 2.11 (q, J¼7.3 Hz,
2H), 2.04–1.99 (m, 2H), 1.72 (s, 3H), 1.61 (s, 3H); 13C
NMR (75 MHz, CDCl3; DEPT) d 204.6 (C), 167.0 (C),
146.0 (C), 138.8 (C), 125.1 (CH), 110.2 (CH2), 49.7 (CH2),
42.0 (CH2), 38.3 (CH3), 38.0 (CH2), 35.8 (CH3), 33.5 (CH2),
26.5 (CH2), 22.8 (CH3), 16.4 (CH3); IR (CH2Cl2) 3055,
2938, 1721, 1645 cm21; LRMS for C15H25NO2 (EI, 20 eV)
m/z 252 (MþþH, 3), 251 (Mþ, 9), 208 (17), 170 (52), 129
(100); HRMS (EI) for C15H25NO2 (Mþ): calcd 251.1885,
found 251.1896.
1
in n-hexane, Rf¼0.28; H NMR (400 MHz, CDCl3) d 14.8
(s, 0.2£1H, enol), 5.11 (s, 0.2£1H, enol), 5.06 (t, J¼7.1 Hz,
1H), 3.54 (s, 0.8£2H), 2.99 (s, 3H), 2.97 (s, 3H), 2.59 (t,
J¼7.4 Hz, 2H), 2.27 (q, J¼7.2 Hz, 2H), 1.67 (s, 3H), 1.61
(s, 3H); 13C NMR (100 MHz, CDCl3; DEPT) d 204.6 (C),
177.8 (C, enol), 167 (C), 133.1 (C), 122.6 (CH), 86.5 (CH,
enol), 49.6 (CH2), 43.1 (CH2), 38.1 (CH3), 36.2 (CH2, enol),
35.6 (CH3), 25.9 (CH3), 25.3 (CH2, enol), 22.5 (CH2), 17.9
(CH3); IR (CH2Cl2) 2927, 1720, 1645 cm21; LRMS for
C11H19NO2 (EI, 20 eV) m/z 198 (MþþH, 5), 197 (Mþ, 38),
154 (43), 129 (100); HRMS (EI) for C11H19NO2 (Mþ):
calcd 197.1416, found 197.1412.
4.1.5. Preparation of N,N-diallyl-3-oxo-butyramide (4e).
tert-Butyl acetoacetate (6.0 mL, 97%, 35 mmol), diallyl-
amine (5.2 mL, 42 mmol) and DMAP (2.2 g, 18 mmol)
were mixed in toluene (30 mL). The mixture was heated to
reflux for 6 h. After removal of solvent, the residue was
extracted with Et2O. The extract was washed successively
with diluted HCl (2N) and water, and then dried over
MgSO4. After concentration, the crude product was purified
by flash column chromatography to give 4e (2.87 g, 45%) as
a light yellow oil. Analytical TLC (silica gel 60), 20%
EtOAc in n-hexane, Rf¼0.22; 1H NMR (300 MHz, CDCl3)
d 14.65 (s, 0.3£1H, enol), 5.83–5.70 (m, 2H), 5.25–5.13
(m, 4H), 5.06 (s, 0.3£1H), 4.00 (d, J¼5.7 Hz, 2H), 3.85 (d,
J¼4.8 Hz, 2H), 3.53 (s, 0.7£2H, keto), 2.28 (s, 0.7£3H,
keto), 1.94 (s, 0.3£3H, enol); 13C NMR (75 MHz, CDCl3;
DEPT) d 202.8 (C), 175.4 (C, enol), 172.3 (C), 167.0 (C),
132.9 (2£CH), 117.9 (CH2), 117.3 (CH2), 87.4 (CH, enol),
50.1 (CH2), 48.3 (CH2), 30.6 (CH3), 22.3 (CH3); IR
(CH2Cl2) 3056, 2988, 1732, 1651 cm21; LRMS for
C10H15NO2 (EI, 20 eV) m/z 181 (Mþ, 2), 166 (7), 153
(100), 140 (5), 136 (84), 107 (69); HRMS (EI) for
C7H10NO2 (Mþ2C3H5): calcd 140.0711, found 140.0724.
4.1.2. 3-Oxo-dec-7-enoic acid dimethylamide (4b). Pre-
pared similarly to 4a. Yield 50%; a light yellow oil;
analytical TLC (silica gel 60), 50% EtOAc in n-hexane,
1
Rf¼0.30; H NMR (400 MHz, CDCl3) d 14.8 (s, 0.4£1H,
enol), 5.49–5.30 (m, 2H), 5.10 (s, 0.4£1H, enol), 3.53 (s,
0.6£2H, keto), 3.04–2.97 (4 s, 2£CH3, keto and enol), 2.56
(t, J¼7.3 Hz, 1H) 2.18 (t, J¼7.5 Hz, 1H), 2.04–1.95 (m,
4H), 1.70–1.61 (m, 2H), 0.96 (2t, J¼7.5 Hz, 3H); 13C NMR
(100 MHz, CDCl3; DEPT) d 204.9 (C), 178.2 (C), 172.5 (C,
enol), 167.1 (C, enol), 133.4 (CH), 133.2 (CH, enol), 128.6
(CH, enol), 127.8 (CH), 86.5 (CH, enol), 49.6 (CH), 42.5
(CH2), 38.2 (CH3), 35.7 (CH3), 35.6 (CH2), 32.2 (CH2), 32.0
(CH2), 26.7 (CH2), 25.9 (CH2), 25.8 (CH2), 23.6 (CH2), 14.2
(CH3); IR (CH2Cl2) 3669, 3055, 2964, 2948, 1719, 1649,
1589 cm21; LRMS for C12H21NO2 (EI, 20 eV) m/z 212
4.1.6. N-tert-Butyl-N-(3-methyl-but-2-enyl)-3-oxo-butyr-
amide (4f). Prepared similarly as 4e. Yield 38%; a light
yellow oil; analytical TLC (silica gel 60), 40% EtOAc in

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D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
n-hexane, Rf¼0.41; 1H NMR (300 MHz, CDCl3) d 15.21 (s,
0.15£1H, enol), 5.07–5.02 (m, 1H), 5.00 (s, 0.15£1H,
enol), 3.85 (d, J¼5.6 Hz, 2H), 3.46 (s, 0.85£2H, keto), 2.26
(s, 0.85£3H, keto), 1.92 (s, 0.15£3H, enol), 1.73 (s, 3H),
1.62 (s, 3H), 1.45 (s, 9H); 13C NMR (75 MHz, CDCl3;
DEPT) major d 203.7 (C), 167.9 (C), 134.0 (C), 123.1 (CH),
58.0 (C), 53.1 (CH2), 44.5 (CH2), 30.4 (CH3), 29.1
(3£CH3), 25.8 (CH3), 18.2 (CH3); IR (CH2Cl2) 3056,
2975, 1722, 1637 cm21; LRMS for C13H23NO2 (EI, 20 eV)
m/z 226 (MþþH, 4), 225 (Mþ, 20), 169 (21), 168 (100), 126
(34); HRMS (EI) for C13H23NO2 (Mþ): calcd 225.1729,
found 225.1722.
(CH3); IR (CH2Cl2) 2987, 2938, 1746, 1716, 1645 cm21
;
LRMS for C11H18BrNO2 (EI, 20 eV) m/z 276 (Mþ2H, 5),
274 (Mþ2H, 7), 196 (40), 114 (100); HRMS (EI) for
C11H18BrNO2 (Mþ): calcd 275.0521, found 275.0515.
4.2.2. 2-Bromo-3-oxo-dec-7-enoic acid dimethylamide
(1b). Prepared similarly to 1a. Yield 89%; a colorless oil;
analytical TLC (silica gel 60), 50% EtOAc in n-hexane,
Rf¼0.48; 1H NMR (400 MHz, CDCl3) d 5.51–5.44 (m, 1H),
5.39–5.31 (m, 1H), 4.98 (s, 1H), 3.09 (s, 3H), 3.00 (s, 3H),
2.87–2.71 (m, 2H), 2.04–1.69 (m, 4H), 1.69 (m, 2H), 0.96
(t, J¼7.5 Hz, 3H); 13C NMR (100 MHz, CDCl3; DEPT) d
200.5 (C), 165.5 (C), 133.4 (CH), 128.3 (CH), 49.0 (CH),
39.0 (CH2), 38.4 (CH3), 36.6 (CH3), 31.9 (CH2), 25.8 (CH2),
24.1 (CH2), 14.2 (CH3); IR (CH2Cl2) 2964, 2942, 1740,
1714, 1654 cm21; LRMS for C12H20BrNO2 (EI, 20 eV) m/z
210 (Mþ2Br, 100), 165 (14), 129 (44), 113 (13); HRMS
(EI) for C12H20NO2 (Mþ2Br): calcd 210.1494, found
210.1505.
4.1.7. 2-Oxo-cyclopentanecarboxylic acid diallylamide
(4g). Prepared similarly as 4e. Yield 98%; a light yellow oil;
analytical TLC (silica gel 60), 40% EtOAc in n-hexane,
Rf¼0.41; 1H NMR (400 MHz, CDCl3) d 5.90–5.65 (m, 2H),
5.25–5.10 (m, 4H), 4.40– 4.25 (m, 2H), 3.83 (dd, J¼15.5,
2.5 Hz, 1H), 3.69 (dd, J¼15.1, 6.0 Hz, 1H), 3.40 (t,
J¼7.5 Hz, 1H), 2.55–2.45 (m, 1H), 2.32–2.28 (m, 2H),
2.22–2.09 (m, 2H), 1.87–1.79 (m, 1H); 13C NMR
(100 MHz, CDCl3; DEPT) d 212.0 (C), 169.2 (C), 133.5
(CH), 132.9 (CH), 117.1 (CH2), 116.6 (CH2), 52.2 (CH),
49.5 (CH2), 48.4 (CH2), 38.8 (CH2), 27.7 (CH2), 21.22
4.2.3. 2-Bromo-6-methyl-3-oxo-undeca-6,10-dienoic acid
dimethylamide (1c). Prepared similarly to 1a. Yield 84%; a
light yellow oil; analytical TLC (silica gel 60), 30% EtOAc
in n-hexane, Rf¼0.27; 1H NMR (400 MHz, CDCl3) d 5.84–
5.76 (m, 1H), 5.17 (m, 1H), 4.98 (s, 1H), 5.03–4.94 (m, 2H),
3.09 (s, 3H), 3.00 (s, 3H), 2.97– 2.85 (m, 2H), 2.30 (t,
J¼7.7 Hz, 2H), 2.07 (t, J¼3.1 Hz, 4H), 1.61 (s, 3H); 13C
NMR (100 MHz, CDCl3; DEPT) d 200.1 (C), 165.5 (C),
138.8 (CH), 133.9 (C), 125.1 (CH), 114.8 (CH2), 49.0
(CH), 38.5 (CH2), 38.4 (CH3), 36.7 (CH3), 34.1 (CH2), 34.0
(CH2), 27.7 (CH2), 16.4 (CH3); IR (CH2Cl2) 2934, 1736,
1713, 1653 cm21; LRMS for C14H22BrNO2 (EI, 20 eV) m/z
236 (Mþ2Br, 64), 191 (6), 129 (13), 114 (100); HRMS
(EI) for C14H22NO2 (Mþ2Br): calcd 236.1650, found
236.1639.
(CH2); IR (CH2Cl2) 3058, 2981, 2884, 1740, 1637 cm21
;
LRMS for C12H17NO2 (EI, 20 eV) m/z 207 (Mþ, 47), 166
(100); HRMS (EI) for C12H17NO2 (Mþ): calcd 207.1259,
found 207.1262.
4.1.8. 2-Oxo-cyclohexanecarboxylic acid diallylamide
(4h). Prepared similarly as 4e. Yield 78%; a yellow oil;
analytical TLC (silica gel 60), 30% EtOAc in n-hexane,
Rf¼0.25; 1H NMR (300 MHz, CDCl3) d 5.84–5.71 (m, 2H),
5.30–5.15 (m, 4H), 4.34–4.26 (m, 1H), 3.88–3.81 (m, 1H),
3.76–3.73 (m, 1H), 3.70–3.69 (m, 1H), 3.51 (ddd, J¼10.0,
5.1, 1.2 Hz, 1H), 2.60–2.53 (m, 1H), 2.37–2.19 (m, 2H),
2.08–1.96 (m, 3H), 1.88–1.79 (m, 1H), 1.71–1.62 (m, 1H);
13C NMR (75.5 MHz, CDCl3; DEPT) d 207.5 (C), 169.6
(C), 133.3 (CH), 132.8 (CH), 117.0 (CH2), 116.5 (CH2),
54.3 (CH), 49.1 (CH2), 48.0 (CH2), 41.8 (CH2), 30.3 (CH2),
26.8 (CH2), 23.4 (CH2); IR (CH2Cl2) 3086, 2949, 1711,
1651 cm21; LRMS for C13H19NO2 (EI, 20 eV) m/z 221
(Mþ, 100), 206 (10), 193 (25), 180 (33); HRMS (EI) for
C13H19NO2 (Mþ): calcd 221.1415, found 221.1416.
4.2.4. 2-Bromo-6,10-dimethyl-3-oxo-undeca-6,10-
dienoic acid dimethylamide (1d). Prepared similarly to
1a. Yield 63%; a light yellow oil; analytical TLC (silica gel
60), 50% EtOAc in n-hexane, Rf¼0.56; 1H NMR (400 MHz,
CDCl3) d 5.16 (t, J¼6.7 Hz, 1H), 4.97 (s, 1H), 4.70 (d,
J¼0.7 Hz, 1H), 4.66 (d, J¼0.7 Hz, 1H), 3.09 (s, 3H), 3.00
(s, 3H), 2.84–2.98 (m, 2H), 2.30 (t, J¼7.6 Hz, 2H), 2.12 (q,
J¼7.0 Hz, 2H), 2.02 (t, J¼7.5 Hz, 2H), 1.72 (s, 3H), 1.62 (s,
3H); 13C NMR (75 MHz, CDCl3; DEPT) d 200.1 (C), 165.5
(C), 145.9 (C), 137.7 (C), 125.3 (CH), 110.2 (CH2), 49.0
(CH), 38.5 (CH3), 38.4 (CH2), 37.9 (CH2), 36.6 (CH3), 34.0
(CH2), 26.5 (CH2), 22.7 (CH3), 16.3 (CH3); IR (CH2Cl2)
2939, 1741, 1715, 1651 cm21; LRMS for C15H24BrNO2
(EI, 20 eV) m/z 330 (Mþ2H, 15), 328 (Mþ2H, 19), 250
(35), 121 (17), 114 (100); HRMS (EI) for C15H23BrNO2
(Mþ2H): calcd 328.0912, found 328.0907.
4.2. Typical procedure for the a-bromination of olefinic
b-keto amides
4.2.1. Preparation of 2-bromo-7-methyl-3-oxo-oct-6-
enoic acid dimethylamide (1a). To a stirred solution of
4a (1.00 g, 5.06 mmol) in EtOAc (30 mL) was added solid
N-bromosuccinimide (0.99 g, 5.60 mmol) at room tempera-
ture. The reaction completed in around 1 h. The reaction
mixture was diluted with Et2O, then washed with water and
dried over MgSO4. After concentration, the crude product
was purified by flash column chromatography to give 1a
(1.01 g, 72%). A light yellow oil; analytical TLC (silica gel
60), 70% EtOAc in n-hexane, Rf¼0.56; 1H NMR (300 MHz,
CDCl3) d 5.08 (t, J¼7.1 Hz, 1H), 4.98 (s, 1H), 3.07 (s, 3H),
3.00 (s, 3H), 2.83 (m, 2H), 2.25 (q, J¼7.2 Hz, 2H), 1.68 (s,
3H), 1.62 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) d
200.1 (C), 165.5 (C), 133.5 (C), 122.6 (CH), 49.2 (CH), 39.8
(CH2), 38.4 (CH3), 36.7 (CH3), 26.0 (CH3), 23.1 (CH2), 18.0
4.2.5. N,N-Diallyl-2-bromo-3-oxo-butyramide (1e). Pre-
pared similarly to 1a. Yield 78%; a light yellow oil;
analytical TLC (silica gel 60), 30% EtOAc in n-hexane,
Rf¼0.39; 1H NMR (300 MHz, CDCl3) d 5.91–5.70 (m, 2H),
5.32–5.16 (m, 4H), 4.88 (s, 1H), 4.20–3.82 (m, 4H), 2.47
(s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) d 198.1 (C),
165.8 (C), 132.5 (CH), 132.1 (CH), 118.3 (CH2), 117.9
(CH2), 50.3 (CH2), 48.9 (CH2), 48.6 (CH), 27.4 (CH3); IR
(CH2Cl2) 3063, 2988, 1748, 1716, 1656 cm21; LRMS for
C10H14BrNO2 (EI, 20 eV) m/z 261 (Mþ, 100), 259 (Mþ, 72),

D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
10473
180 (31), 153 (77), 136 (67); HRMS (EI) for C10H14BrNO2
(Mþ): calcd 259.0208, found 259.0216.
gel 60), 50% EtOAc in n-hexane, Rf¼0.50; 1H NMR
(300 MHz, CDCl3) d 3.77 (d, J¼9.9 Hz, 1H), 3.24 (s, 3H),
3.02 (s, 3H), 2.86 (dt, J¼7.0, 10.7 Hz, 1H), 2.50–2.34 (m,
2H), 2.32–2.22 (m, 1H), 1.95 (dt, J¼8.9, 11.1 Hz, 1H), 1.83
(s, 3H), 1.66 (s, 3H); 13C NMR (75 MHz, CDCl3; DEPT) d
213.1 (C), 169.1 (C), 73.7 (C), 56.9 (CH), 52.9 (CH), 39.2
(CH2), 38.1 (CH3), 36.5 (CH3), 34.8 (CH3), 33.0 (CH3), 24.9
4.2.6. 2-Bromo-N-tert-butyl-N-(3-methyl-but-2-enyl)-3-
oxo-butyramide (1f). Prepared similarly to 1a. Yield
82%; a light yellow oil; analytical TLC (silica gel 60),
1
30% EtOAc in n-hexane, Rf¼0.48; H NMR (300 MHz,
CDCl3) d 5.14–5.09 (m, 1H), 4.84 (s, 1H), 3.99 (d,
J¼5.6 Hz, 2H), 2.43 (s, 3H), 1.76 (s, 3H), 1.67 (s, 3H),
1.44 (s, 9H); 13C NMR (75 MHz, CDCl3; DEPT) major d
198.3 (C), 166.4 (C), 135.2 (C), 122.8 (CH), 59.0 (C), 52.0
(CH), 44.5 (CH2), 28.8 (3£CH3), 27.4 (CH3), 25.9 (CH3),
18.3 (CH3); IR (CH2Cl2) 3063, 2978, 1743, 1715,
1647 cm21; LRMS for C13H22BrNO2 (EI, 20 eV) m/z 305
(Mþ, 6), 303 (Mþ, 6), 223 (11), 208 (15), 140 (100); HRMS
(EI) for C13H22BrNO2 (Mþ): calcd 303.0834, found
303.0834.
(CH2); IR (CH2Cl2) 2976, 2938, 1773, 1744, 1651 cm21
;
LRMS for C11H18BrNO2 (EI, 20 eV) m/z 277 (Mþ, 4), 275
(Mþ, 3), 196 (100), 167 (70), 154 (65); HRMS (EI) for
C11H18BrNO2 (Mþ): calcd 275.0521, found 275.0515.
4.2.10. 2-(1-Bromo-propyl)-6-oxo-cyclohexanecarb-
oxylic acid dimethylamide (2b) (the minor isomer of
product 2b). A white solid, mp 128–1298C (Et2O);
analytical TLC (silica gel 60), 50% EtOAc in n-hexane,
1
Rf¼0.26; H NMR (400 MHz, CDCl3) d 4.04 (ddd, J¼2.1,
4.4, 9.6 Hz, 1H), 3.88 (d, J¼11.1 Hz, 1H), 3.04 (s, 3H), 2.99
(s, 3H), 2.56–2.49 (m, 2H), 2.36–2.28 (m, 1H), 2.16–2.10
(m, 1H), 2.05–1.93 (m, 2H), 1.90–1.83 (m, 1H), 1.81–1.72
(m, 2H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3; DEPT) d 206.7 (C), 168.9 (C), 66.1 (CH), 59.2
(CH), 46.2 (CH), 41.7 (CH2), 37.7 (CH3), 36.2 (CH3), 31.1
(CH2), 24.0 (CH2), 24.0 (CH2), 13.3 (CH3); IR (CH2Cl2)
2971, 2940, 1712, 1647cm21; LRMS for C12H20BrNO2 (EI,
20 eV) m/z 291 (Mþ, 7), 289 (Mþ, 7), 210 (100), 209 (18),
129 (78); HRMS (EI) for C12H20BrNO2 (Mþ): calcd
289.0677, found 289.0667.
4.2.7. 1-Bromo-2-oxo-cyclopentanecarboxylic acid
diallylamide (1g). Yield 43%; a light yellow oil; analytical
1
TLC (silica gel 60), 40% EtOAc in n-hexane, Rf¼0.59; H
NMR (400 MHz, CDCl3) d 5.81–5.74 (m, 2H), 5.22–5.13
(m, 4H), 4.31–4.15 (m, 2H), 4.07–3.96 (m, 2H), 2.96 (ddd,
J¼14.3, 7.2, 7.1 Hz, 1H), 2.51–2.33 (m, 3H), 2.19–2.08
(m, 1H), 2.07–1.96 (m, 1H); 13C NMR (100 MHz, CDCl3;
DEPT) d 206.4 (C), 162.3 (C), 133.3 (CH), 131.8 (CH),
118.2 (CH2), 117.2 (CH2), 61.6 (C), 51.0 (CH2), 48.1 (CH2),
39.2 (CH2), 34.9 (CH2), 18.6 (CH2); IR (CH2Cl2) 3055,
2988, 2306, 1743, 1637 cm21; LRMS (EI, 20 eV) for
C12H16NO2Br, m/z 287 (Mþ, 16), 285 (Mþ, 18), 232 (50),
206 (68), 192 (100); HRMS (EI) for C12H16NO2 (Mþ2Br):
calcd 206.1181, found 206.1180.
4.2.11. 2-(1-Bromo-propyl)-6-oxo-cyclohexanecarb-
oxylic acid dimethylamide (2b) (the major isomer of
product 2b). A white solid, mp 125–1268C (Et2O);
analytical TLC (silica gel 60), 50% EtOAc in n-hexane,
1
4.2.8. 1-Bromo-2-oxo-cyclohexanecarboxylic acid
diallylamide (1h). Yield 42%; a light yellow oil; analytical
Rf¼0.20; H NMR (400 MHz, CDCl3) d 4.06 (dt, J¼3.1,
10.4 Hz, 1H), 3.84 (d, J¼10.0 Hz, 1H), 3.06 (s, 3H), 3.02 (s,
3H), 2.86–2.80 (m, 1H), 2.60–2.50 (m, 1H), 2.31–2.22 (m,
1H), 2.07–1.96 (m, 2H), 1.88–1.72 (m, 3H), 1.69–1.54 (m,
1H), 1.03 (t, J¼7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3;
DEPT) d 207.2 (C), 169.7 (C), 67.3 (CH), 56.6 (CH), 46.2
(CH), 41.0 (CH2), 38.0 (CH3), 36.4 (CH3), 30.4 (CH2), 28.9
(CH2), 23.0 (CH2), 13.8 (CH3); IR (CH2Cl2) 2971, 2940,
1712, 1647 cm21; LRMS for C12H20BrNO2 (EI, 20 eV) m/z
291 (Mþ, 4), 289 (Mþ, 4), 210 (100), 192 (14), 129 (41);
HRMS (EI) for C12H20BrNO2 (Mþ): calcd 289.0677, found
289.0669.
1
TLC (silica gel 60), 30% EtOAc in n-hexane, Rf¼0.38; H
NMR (400 MHz, CDCl3) d 5.82–5.61 (m, 2H), 5.22–5.12
(m, 4H), 4.17 (dd, J¼15.2, 4.3 Hz, 1H), 4.03 (dd, J¼16.7,
4.9 Hz, 1H), 3.81–3.74 (m, 2H), 3.11–3.05 (m, 1H), 2.86–
2.80 (m, 1H), 2.50–2.43 (m, 1H), 2.24–2.17 (m, 1H), 2.05–
1.94 (m, 2H), 1.87–1.79 (m, 2H); 13C NMR (100 MHz,
CDCl3; DEPT) d 206.1 (C), 165.6 (C), 133.6 (CH), 131.9
(CH), 118.8 (CH2), 117.9 (CH2), 69.0 (C), 50.8 (CH2), 48.6
(CH2), 44.8 (CH2), 40.9 (CH2), 29.2 (CH2), 24.4 (CH2); IR
(CH2Cl2) 3055, 2987, 2953, 2254, 1726, 1714, 1651 cm21
;
LRMS (EI, 20 eV) for C13H18NO2Br, m/z 301 (Mþ, 22) 299
(Mþ, 22), 260 (46), 258 (49), 220 (100), 192 (89); HRMS
(EI) for C13H18NO2Br (Mþ): calcd 299.0521, found
299.0511.
4.2.12. 3-Bromo-2-but-3-enyl-3-methyl-6-oxo-cyclo-
hexanecarboxylic acid dimethylamide (2c). A light
yellow oil; analytical TLC (silica gel 60), 50% EtOAc in
n-hexane, Rf¼0.27; H NMR (400 MHz, CDCl3) d 5.82–
1
4.2.9. Typical procedure for Lewis acid-catalyzed atom
transfer radical cyclization reactions of olefinic b-keto
amides (Table 1, entry 2). To a stirred solution of 1a
(138.1 mg, 0.5 mmol) in dry CH2Cl2 (10 mL) was added
Yb(OTf)3 (93 mg, 0.15 mmol) at room temperature. Then
the mixture was cooled to 2788C. Half an hour later, Et3B
(1 M in hexane, 1.5 mL, 1.5 mmol) and O2 gas (5.0 mL)
were added via syringe. The reaction mixture was stirred at
2788C and was followed by TLC. The reaction completed
after 1 h. The mixture was filtered through a thin pad of
silica gel and then concentrated. The crude product was
purified by flash column chromatography to give 2a
(102 mg, 74%) as a light yellow oil. Analytical TLC (silica
5.72 (m, 1H), 5.03–4.93 (m, 2H), 3.72 (d, J¼10.8 Hz, 1H),
3.03 (s, 3H), 3.02 (s, 3H), 2.95–2.86 (m, 1H), 2.51 (ddd,
J¼2.1, 5.2, 16.1 Hz, 1H), 2.38 (ddd, J¼2.1, 6.6, 14.7 Hz,
1H), 2.28–2.16 (m, 2H), 2.14–2.01 (m, 2H), 1.92 (s, 3H),
1.91–1.82 (m, 1H), 1.21–1.13 (m, 1H); 13C NMR
(100 MHz, CDCl3; DEPT, CH COSY) d 205.8 (C), 169.2
(C), 138.5 (CH), 115.2 (CH2), 75.0 (C), 59.1 (CH), 50.6
(CH), 42.2 (CH2), 39.1 (CH2), 38.0 (CH3), 36.3 (CH3), 34.2
(CH2), 33.4 (CH2), 32.7 (CH3); IR (CH2Cl2) 2936, 1712,
1678, 1641 cm21; LRMS for C14H22BrNO2 (EI, 20 eV) m/z
236 (Mþ2Br, 22), 235 (Mþ2HBr, 36), 207 (40), 191 (39),
162 (41), 121 (100); HRMS (EI) for C14H22NO2 (Mþ2Br):
calcd 236.1651, found 236.1646.

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D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
4.2.13. 3-Bromo-3-methyl-2-(3-methyl-but-3-enyl)-6-
oxo-cyclohexanecarboxylic acid dimethylamide (2d). A
light yellow oil; analytical TLC (silica gel 60), 50% EtOAc
gel 60), 40% EtOAc in n-hexane, Rf¼0.35; 1H NMR
(400 MHz, CDCl3) d 5.71–5.58 (m, 1H), 5.20–5.12 (m,
2H), 3.90–3.74 (m, 2H), 3.66 (dd, J¼14.6, 7.5 Hz, 1H),
3.37–3.31 (m, 1H), 3.25–3.19 (m, 1H), 3.11–3.06 (m, 1H),
2.95–2.86 (m, 1H), 2.48–2.16 (m, 4H), 2.00–1.89 (m, 2H);
13C NMR (100 MHz, CDCl3; DEPT) d 216.2 (C), 171.9 (C),
132.0 (CH), 118.8 (CH2), 62.3 (C), 49.8 (CH2), 45.8 (CH2),
40.4 (CH), 37.6 (CH2), 32.5 (CH2), 28.3 (CH2), 19.8 (CH2);
IR (CH2Cl2) 3055, 2987, 2306, 1739, 1686 cm21; LRMS
(EI, 20 eV) for C12H16NO2Br, m/z 287 (Mþ, 47), 285 (Mþ,
40), 230 (52); 192 (100); HRMS (EI) for C12H16NO2 Br
(Mþ): calcd 285.0365, found 285.0350.
1
in n-hexane, Rf¼0.36; H NMR (400 MHz, CDCl3) d 4.69
(s, 1H), 4.66 (s, 1H), 3.74 (d, J¼10.8 Hz, 1H), 3.03 (s, 3H),
3.02 (s, 3H), 2.91 (m, 1H), 2.52 (ddd, J¼2.1, 5.2, 16.6 Hz,
1H), 2.38 (ddd, J¼2.1, 6.6, 14.7 Hz, 1H), 2.24–1.87 (m,
5H), 1.92 (s, 3H), 1.70 (s, 3H), 1.24–1.14 (m, 1H); 13C
NMR (100 MHz, CDCl3; DEPT) d 205.8 (C), 169.2 (C),
145.9 (C), 110.3 (CH2), 75.0 (C), 59.1 (CH), 51.0 (CH), 42.3
(CH2), 39.2 (CH2), 38.1 (CH3), 37.5 (CH2), 36.3 (CH3), 33.3
(CH2), 32.6 (CH3), 22.8 (CH3); IR (CH2Cl2) 2938, 1714,
1647 cm21; LRMS for C15H24BrNO2 (EI, 20 eV) m/z 250
(Mþ2Br, 100), 221 (45), 205 (59), 189 (68), 121 (93);
HRMS (EI) for C15H24NO2 (Mþ2Br): calcd 250.1807,
found 250.1809.
4.2.18. 2-Allyl-4-bromomethyl-2-aza-spiro[4.5]decane-
1,6-dione (2h). A light yellow oil; analytical TLC (silica
gel 60), 30% EtOAc in n-hexane, Rf¼0.34; 1H NMR
(400 MHz, CDCl3) d 5.77–5.64 (m, 1H), 5.24–5.16 (m,
2H), 3.88 (dd, J¼6.1, 1.3 Hz, 2H), 3.39–3.56 (m, 3H),
3.29–3.22 (m, 1H), 3.15–3.04 (m, 2H), 2.52–2.45 (m, 1H),
2.35–2.28 (m, 1H), 2.15–2.05 (m, 2H), 1.60–1.43 (m, 3H);
13C NMR (100 MHz, CDCl3; DEPT) d 206.9 (C), 171.5 (C),
131.6 (CH), 118.6 (CH2), 61.8 (C), 48.6 (CH2), 45.6 (CH2),
40.2 (CH2), 38.7 (CH), 31.4 (CH2), 30.7 (CH2), 26.8 (CH2),
20.5 (CH2); IR (CH2Cl2) 3055, 2986, 2950, 1709,
1686 cm21; LRMS (EI, 20 eV) for C13H18NO2 Br m/z 301
(Mþ, 24), 299 (Mþ, 26), 220 (67); 192 (100); HRMS
(EI) for C13H18NO2 Br (Mþ): calcd 299.0521, found
299.0518.
4.2.14. 3-Acetyl-1-allyl-4-bromomethyl-pyrrolidin-2-one
(2e). A light yellow oil; analytical TLC (silica gel 60), 40%
EtOAc in n-hexane, Rf¼0.31; 1H NMR (400 MHz, CDCl3)
d 12.00 (s, 0.02£1H, enol), 5.76–5.63 (m, 1H), 5.25–5.18
(m, 2H), 3.89 (d, J¼6.1 Hz, 2H), 3.54 (d, J¼7.0 Hz,
0.98£1H, keto), 3.52–3.41 (m, 3H), 3.33–3.28 (m, 1H),
3.16 (dd, J¼6.2, 8.9 Hz, 1H), 2.48 (s, 3H); 13C NMR
(100 MHz, CDCl3; DEPT) d 202.7 (C), 168.3 (C), 131.8
(CH), 119.0 (CH2), 60.7 (CH), 49.4 (CH2), 45.9 (CH2), 37.7
(CH2), 36.5 (CH), 32.6 (CH3); IR (CH2Cl2) 3055, 2986,
1716, 1691, 1645 cm21; LRMS for C10H14BrNO2 (EI,
20 eV) m/z 261 (Mþ, 34), 259 (Mþ, 37), 218 (25), 216 (27),
180 (100); HRMS (EI) for C10H14BrNO2 (Mþ): calcd
259.0208, found 259.0198.
4.3. Typical procedure for cyclopropanation reaction of
atom transfer radical cyclization product
4.2.15. 1-Acetyl-3-allyl-3-aza-bicyclo[3.1.0]hexan-2-one
(3e). A light yellow oil; analytical TLC (silica gel 60),
4.3.1. Preparation of 2-allyl-4-bromomethyl-2-aza-
spiro[4.5]decane-1,6-dione (3f) from 2f. To a stirred of
solution of cyclization product 2f (152 mg, 0.5 mmol) in dry
THF (20 mL) at 08C was added NaH (60% oil dispersion,
24 mg, 0.6 mmol). The mixture was stirred at 08C for 1 h.
After removal of THF, the residue was extracted with
Et2O. The organic extract was washed with water then dried
over MgSO4. After concentration, the crude product was
purified by flash column chromatography to give 3f (89 mg,
80%). A light yellow oil; analytical TLC (silica gel 60),
1
40% EtOAc in n-hexane, Rf¼0.20; H NMR (400 MHz,
CDCl3) d 5.77–5.64 (m, 1H), 5.30–5.15 (m, 2H), 3.90–
3.77 (m, 2H), 3.50 (dd, J¼5.9, 10.5 Hz, 1H), 3.23 (d,
J¼10.5 Hz, 1H), 2.58 (s, 3H), 2.44–2.39 (m, 1H), 1.94 (dd,
J¼3.9, 8.0 Hz, 1H), 1.12 (dd, J¼4.0, 5.3 Hz, 1H); 13C NMR
(100 MHz, CDCl3; DEPT) d 203.7 (C), 171.2 (C), 132.5
(CH), 118.7 (CH2), 47.1 (CH2), 45.4 (CH2), 39.5 (C), 29.9
(CH3), 25.4 (CH), 24.8 (CH2); IR (CH2Cl2) 3056, 2923,
1711, 1691, 1645 cm21; LRMS for C10H13NO2 (EI, 20 eV)
m/z 180 (MþþH, 14), 179 (Mþ, 100), 178 (Mþ2H, 20), 164
(52); HRMS (EI) for C10H13NO2 (Mþ): calcd 179.0946,
found 179.0944.
1
30% EtOAc in n-hexane, Rf¼0.42; H NMR (300 MHz,
CDCl3) d 3.52 (dd, J¼6.6, 10.9 Hz, 1H), 3.23 (d,
J¼10.9 Hz, 1H), 2.49 (s, 3H), 2.15 (d, J¼6.6 Hz, 1H),
1.38 (s, 9H), 1.21 (s, 3H), 1.07 (s, 3H); 13C NMR (75 MHz,
CDCl3; DEPT) d 203.9 (C), 169.6 (C), 54.6 (C), 52.2 (C),
42.9 (CH2), 32.2 (C), 30.9 (CH), 28.5 (CH3), 27.9 (3£CH3),
21.1 (CH3), 15.4 (CH3); IR (CH2Cl2) 2985, 1673,
1666 cm21; LRMS for C13H21NO2 (EI, 20 eV) m/z 223
(Mþ, 24), 209 (13), 208 (100), 138 (31); HRMS (EI) for
C13H21NO2 (Mþ): calcd 223.1572, found 223.1572.
4.2.16. 3-Acetyl-4-(1-bromo-1-methyl-ethyl)-1-tert-
butyl-pyrrolidin-2-one (2f). A light yellow oil; analytical
1
TLC (silica gel 60), 30% EtOAc in n-hexane, Rf¼0.50; H
NMR (300 MHz, CDCl3) d 3.71 (d, J¼7.7 Hz, 1H), 3.58 (t,
J¼9.5 Hz, 1H), 3.43–3.35 (m, 1H), 2.93–2.85 (m, 1H),
2.48 (s, 3H), 1.72 (s, 3H), 1.59 (s, 3H), 1.40 (s, 9H); 13C
NMR (75 MHz, CDCl3; DEPT) d 204.1 (C), 168.6 (C), 70.2
(C), 61.6 (CH), 55.2 (C), 47.7 (CH2), 44.1 (CH), 33.2 (CH3),
32.4 (CH3), 31.1 (CH3), 27.9 (3£CH3); IR (CH2Cl2) 2980,
1717, 1680, 1627 cm21; LRMS for C13H22BrNO2 (EI,
20 eV) m/z 305 (Mþ, 16), 303 (Mþ, 17), 290 (61), 288 (62),
208 (100); HRMS (EI) for C13H22BrNO2 (Mþ): calcd
303.0834, found 303.0823.
Acknowledgements
This work was supported by The University of Hong Kong
and Hong Kong Research Grants Council. D. Y. acknowl-
edges the Bristol–Myers Squibb Foundation for an
Unrestricted Grant in Synthetic Organic Chemistry and
the Croucher Foundation for a Croucher Senior Research
Fellowship Award.
4.2.17. 2-Allyl-4-bromomethyl-2-aza-spiro[4.4]nonane-
1,6-dione (2g). A light yellow oil; analytical TLC (silica

D. Yang et al. / Tetrahedron 59 (2003) 10465–10475
14. Parsons, A. F. Tetrahedron 1996, 52, 4149–4174.
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