Copper(I)-catalyzed intramolecular addition of N-chloroamides to double bonds; an efficient synthesis of lactams from unsaturated amides

Article abstract of DOI:10.1055/s-2003-40997

Copper(I) salts catalyse the intramolecular addition of N-chloramides to carbon-carbon double bonds leading to lactams in almost quantitative yield.

Full text of DOI:10.1055/s-2003-40997

1886
PAPER
Copper(I)-Catalyzed Intramolecular Addition of N-Chloroamides to Double
Bonds; an Efficient Synthesis of Lactams from Unsaturated Amides
A
ddition
r
of
N
-Ch
i
loroam
s
ides to
D
ouble
B
A
onds; Synthesis o
n
f
Lactams fr
n
om
U
nsatur
a
e
te
d
A
mides Schulte-Wülwer, Juho Helaja, Richard Göttlich*
Organisch-Chemisches Institut der Westfälischen Wilhelms-Universität Münster, Corrensstr. 40, 48149 Münster, Germany
E-mail: gottlir@uni-muenster.de
Received 14 October 2002
Dedicated to Professor R. W. Hoffmann on the occasion of his 70th birthday.
O
R
N
Cl
Abstract: Copper(I) salts catalyse the intramolecular addition of N-
chloramides to carbon–carbon double bonds leading to lactams in
almost quantitative yield.
R
O
N
Cl
Cu(I)
Key words: catalysis, copper, lactams, radical reactions
A
Lactams are important substructures of a variety of natural
products and pharmacological active compounds.1 One
way to synthesise them is the intramolecular addition of
the NH bond of an amide to a double bond, a process
which is almost thermoneutral and therefore difficult to
perform.2 To circumvent this problem one can utilize the
high energy content of an NCl bond and add N-chloroam-
ides to double bonds. This reaction can be achieved via
free radicals and the approach has been tried by a variety
of groups.3 However, the yield of lactams obtained in
these cyclisations is unsatisfactory. A reason for this is un-
desired side reactions of the carbon radical formed in the
cyclisation.
R
N
C
.
O
B
R
N
Cu(II)
.
O
Scheme 1
We recently reported, that copper(I) salts are efficient cat-
alysts for the radical cyclisation of unsaturated N-chloro-
amines.4 In these reactions the copper salt acts as the
initiator of the radical reaction as well as the scavanger of
the carbon radical formed as intermediate. As copper(II)
chloride oxidises carbon radicals at a diffusion controlled
rate,5 we envisioned, that copper(I) salts should be effi-
cient catalysts for a high yielding cyclisation of unsaturat-
ed N-chloroamides. Undesired reactions of the carbon
radical formed should be minimised. The anticipated cat-
alytic cycle is shown in Scheme 1.
CrO3
SOCl2
O
COOH
81%
91%
COCl
4
3
2
H
N
Cl
BuLi, –78 °C
BuNH2
N
Bu
Bu
87%
then NCS
5a
1a
52%
O
O
Scheme 2
Copper(I) is oxidized by a chloroamide, giving copper(II)
and an amidyl radical A. As the amidyl radical is electro-
philic, it cyclises rapidly B, leading to a carbon radical,
which in turn is quickly oxidised by copper(II) chloride C.
In this last step the catalyst is regenerated and the product,
a 5-chloromethyl-2-pyrrolidinone is formed.
transformed to N-chloroamide 1a by deprotonation and
reaction with NCS.3,7
Upon addition of catalytic amounts of copper(I) chloride
to this chloroamide we obtained lactam 6a in very good
yield (Scheme 3).
To check wether this concept holds true, we synthesised
chloroamide 1a in the following way (Scheme 2).
Bu
N
Cl
Cl
N
The known aldehyde 2 was oxidised under Jones
conditions6 to acid 3. From this the amide 5a was obtained
via the acid chloride 4 in good yield. This amide 5a was
10% CuCl
O
Bu
methanol, 60 ºC
1a
6a
O
96%
Scheme 3
Synthesis 2003, No. 12, Print: 02 09 2003. Web: 07 08 2003.
Art Id.1437-210X,E;2003,0,12,1886,1890,ftx,en;T10902SS.pdf.
DOI: 10.1055/s-2003-40997
© Georg Thieme Verlag Stuttgart · New York

PAPER
Addition of N-Chloroamides to Double Bonds; Synthesis of Lactams from Unsaturated Amides
1887
Amongst various solvents tested for the cyclisation, meth- with copper(II) chloride. Further studies to clarify this un-
anol proved to be most suitable, probably because it dis- usual high diastereomeric ratio are currently being per-
solves the catalyst best. To check the scope of this formed in our group.
reaction, we prepared the amides 5g–i (Scheme 4).8 For
In summary, we have presented a copper(I) chloride catal-
the synthesis of 5g–i, we reacted the acid chloride 4 with
ysed cyclisation of unsaturated N-chloroamides that pro-
different amines whilst 5j was obtained from the known
duces superior yields as compared to the known
cyclisations of chloroamides. We are currently investigat-
ing this reaction in further detail and applying the proce-
dure to natural product synthesis.
acid 79 via the acid chloride. The carbamate 5f was ob-
tained by a straightforward reaction of propylisocyanate
with allylic alcohol.10
H
RNH2
All solvents were purified by distillation and dried, if necessary, pri-
N
R
COCl
or to use. As a standard solvent instead of Et2O in many cases tert-
butyl methyl ether (TBME) was used. The reactions were carried
out in vacuum heat dried glassware under an argon atmosphere.
Products were purified by flash chromatography on silica gel (40–
63 m). NMR spectra were recorded on a Bruker WM 300 and a
Bruker AMX 400 spectrometer in CDCl3 using TMS as internal
standard. Elemental analyses were performed on a CHN-O Rapid
from Foss-Heraeus and a Vario EL III from Elementar Analysen-
systeme.
5g-i
4
O
5g: R = Ph, 82%
5h: R = tert.Bu, 90%
5i: R = Phenylethylamine,
79%
1.) SOCl2
2.) BuNH2
H
N
Bu
COOH
86%
5j
7
O
H
Amides from Acids; General Procedure
OH
O
N
To a solution of the unsaturated acid (0.33 mol) in CH2Cl2 (50 mL),
thionyl chloride (26.2 mL, 0.36 mol) was added slowly at 0 °C. The
mixture was stirred 14 h at r.t., after which the reaction was com-
plete. The so obtained solution of acid chloride was added slowly to
the corresponding amine (1.64 mol) at 0 °C. After stirring the reac-
tion overnight, solvent and excess amine were removed in vacuo
and the remainder taken up in TBME and aq hydrochloric acid (2
M) (150 mL each). The layers were separated and the organic layer
washed again with aq hydrochloric acid (2 M; 150 mL). After dry-
ing (Na2SO4), the solvent was removed in vacuo and the product
was obtained from the residue either by distillation or crystallisa-
tion.
Pr
N C O
+
Pr
73%
5f
O
Scheme 4
The amides 5b–i were transformed to the corresponding
N-chloroamides 1b–i by deprotonation and reaction with
NCS. To our surprise the yields of chloroamides varied
significantly depending on the substrate used (Table 1). In
the reaction of 5g, the chloroamide was formed together
with a mixture of (3,3-dimethyldihydrofuran-2-yli-
dene)phenylamine and 3,3-dimethyl-1-phenylpyrrolidin-
2-one. Due to the electron withdrawing phenyl group in
this substrate, the deprotonated amide seems to be not nu-
cleophilic enough to react efficiently with NCS. Instead
the NCS attacks the double bond forming a chloronium
ion, which in turn is opened by nucleophilic attack of ei-
ther the oxygen or the nitrogen of the deprotonated amide,
leading to the products observed.
N-Butyl-2,2-dimethylpent-4-enoic Acid Amide (5a)
1H NMR (300 MHz, CDCl3): = 0.92 (t, J = 7.2 Hz, 3 H), 1.16 (s,
6 H), 1.34 (m, 2 H), 1.47 (m, 2 H), 2.27 (dt, J = 7.4, 1.2 Hz, 2 H),
3.24 (m, 2 H), 5.05 (m, 2 H), 5.67 (br s, 1 H), 5.74 (m, 1 H).
13C NMR (75 MHz, CDCl3): = 13.7, 20.1, 25.1, 31.7, 39.2, 41.9,
45.2, 117.6, 134.5, 193.4.
Anal. Calcd for C11H21NO: C, 72.08; H, 11.55; N, 7.64. Found: C,
71.75; H, 11.79; N, 7.61.
We next cyclised the chloroamides 1b–i using catalytic
amounts of copper(I) chloride (Table 1).
Propylcarbamic Acid Allyl Ester (5f)
1H NMR (300 MHz, CDCl3): = 0.92 (t, J = 7.2 Hz, 3 H), 1.52 (sx,
J = 7.2 Hz, 2 H), 3.14 (t, J = 6.0 Hz, 2 H), 4.56 (dt, J = 6.0, 3.6 Hz,
2 H), 4.72 (br s, 1 H), 5.24 (m, 2 H), 5.92 (m, 1 H).
As anticipated, mostly good yields of cyclic amides 6b–i
were obtained. Even when a severe steric hindrance is
present, as in the case of 1h, a good yield of lactam 6h
13C NMR (75 MHz, CDCl3): = 11.1, 23.2, 42.9, 65.4, 117.4,
could be isolated. However, 1e and 1f produced lower 133.1, 157.2.
yields of the cyclisation products 6e and 6f, showing the
N-Phenyl-2,2-dimethylpent-4-enoic Acid Amide (5g)
limitations of the reaction. In both cases conformational
effects, disfavouring the conformation required for the cy-
clisation, are present. This result is in accordance with the
observations of other groups performing amidyl-radical
cyclisations.11 This also holds true for the observed dia-
stereomeric ratio (dr, Table 1) in the cyclisation of 1b, 1c
and 1i which is in the range one expects for a relatively
unselective radical cyclisation. Surprisingly, in the case of
the addition to a 1,2-disubstituted double bond (1j to 6j) a
high diastereomeric ratio is observed. This might result
from the quick reaction of the intermediate carbon radical
1H NMR (400 MHz, CDCl3): = 1.29 (s, 6 H), 2.36 (d, J = 8.0Hz,
2 H), 5.17 (m, 2 H), 5.82 (m, 1 H), 7.08 (t, J = 7.2 Hz, 1 H), 7.28 (m,
2 H), 7.39 (s, 1 H), 7.50 (d, J = 7.6 Hz, 2 H).
13C NMR (100 MHz, CDCl3): = 25.2, 42.8, 45.2, 118.4, 120.1,
124.2, 128.9, 134.2, 137.9, 175.4.
Anal. Calcd for C13H17NO: C, 76.81; H, 8.43; N, 6.89. Found: C,
76.58; H, 8.31; N, 6.69.
N-tert-Butyl-2,2-dimethylpent-4-enoic Acid Amide (5h)
1H NMR (300 MHz, CDCl3): = 1.14 (s, 6 H), 1.34 (s, 9 H), 2.24
(dt, J = 7.5, 1.2 Hz, 2 H), 5.06 (m, 2 H), 5.41 (s, 1 H), 5.76 (m, 1 H).
Synthesis 2003, No. 12, 1886–1890 © Thieme Stuttgart · New York

1888
I. A. Schulte-Wülwer et al.
Table 1 Yields of N-Chloroamides and of the Cyclisations
Amide Chloroamide
PAPER
Yield (%)
52
Lactam
Yield (%) (dr)
H
N
Bu
96
Cl
Cl
N
N
O
Bu
Bu
6a
5a
O
1a
1b
1c
O
75
51
91 (4:1)
75 (2:1)
Cl
N
Bu
N
H
N
Cl
O
O
O
Bu
Bu
Bu
Bu
Bu
6b
5b
5c
O
O
O
O
O
H
N
Cl
N
Bu
N
Cl
6c
Cl
43
42
70
34
Cl
N
Bu
N
H
N
Bu
6d
1d
1e
5d
5e
O
H
N
Cl
N
Ac
N
Cl
6e
O
O
64
-
12
Cl
N
Pr
N
H
N
Cl
O
O
O
Pr
Pr
6f
1f
5f
O
O
O
O
O
O
O
H
N
Cl
N
Ph
Ph
5g
5h
1g
1h
47
79
H
N
Cl
N
Cl
N
N
O
6h
61
45
63 (2:1)
Ph
H
N
Cl
N
Cl
Ph
Bu
Ph
Bu
O
O
5i
5j
1i
1j
O
O
6i
76 (10:1)
H
N
Cl
N
Bu
N
Cl
6j
O
O
13C NMR (75 MHz, CDCl3): = 25.3, 28.8, 42.2, 45.4, 50.9, 117.7,
134.6, 176.4.
Anal. Calcd for C15H21NO: C, 77.88; H, 9.15; N, 6.05. Found: C,
77.83; H, 9.24; N, 6.01.
Anal. Calcd for C11H21NO: C, 72.08; H, 11.55; N, 7.64. Found: C,
71.72; H, 11.56; N, 7.52.
(E)-N-Butylhex-4-enoic Acid Amide (5j)
1H NMR (300 MHz, CDCl3): = 0.92 (t, J = 7.2 Hz, 3 H), 1.35 (m,
2 H), 1.48 (m, 2 H), 1.63 (d with fine splitting, J = 4.8 Hz, 3 H), 2.22
(m, 2 H), 2.30 (m, 2 H), 3.23 (q, J = 6.9 Hz, 2 H), 5.45 (m, 2 H),
6.10 (br s, 1 H).
N-Phenylethyl-2,2-dimethylpent-4-enoic Acid Amide (5i)
1H NMR (300 MHz, CDCl3): = 1.16 (s, 6 H), 1.46 (d, J = 6.9 Hz,
3 H), 2.26 (quin, J = 7.2 Hz, 1 H), 5.01 (dt, J = 2.7, 1.2 Hz, 2 H),
5.11 (m, 2 H), 5.70 (m, 1 H), 5.82 (s, 1 H), 7.29 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 21.6, 25.1, 41.8, 45.2, 48.5, 117.9,
126.1, 127.2, 128.6, 134.4, 143.4, 176.1.
13C NMR (75 MHz, CDCl3): = 13.6, 17.6, 19.9, 28.5, 31.6, 36.4,
39.0, 125.9, 129.5, 172.5.
Anal. Calcd for C10H19NO: C, 70.96; H, 11.31; N, 8.27. Found: C,
70.70; H, 11.67; N, 8.21.
Synthesis 2003, No. 12, 1886–1890 © Thieme Stuttgart · New York

PAPER
Addition of N-Chloroamides to Double Bonds; Synthesis of Lactams from Unsaturated Amides
1889
N-Chloroamides; General Procedure
13C NMR (75 MHz, CDCl3): = 15.9, 25.8, 43.6, 43.8, 56.6, 117.8,
To a solution of amide (55 mmol) in anhyd Et2O (200 mL) was add-
ed butyllithium solution (34.5 mL at 1.6 M; 55 mmol) at –78 °C.
The reaction was stirred 30 min at 0 °C and then NCS (8.9 g, 67
mmol) was added. After 2 h stirring at 0 °C, H2O (200 mL) was add-
ed and the layers separated. The aq layer was washed with CH2Cl2
(3 × 50 mL). The combined organic layers were dried (Na2SO4), the
solvent was removed in vacuo and the product isolated from the res-
idue by flash chromatography.
127.6, 128.2, 128.7, 134.0, 139.6, 177.5.
(E)-N-Butyl-N-chlorohex-4-enoic Acid Amide (1j)
1H NMR (400 MHz, CDCl3): = 0.96 (t, J = 7.2 Hz, 3 H), 1.36 (sx,
J = 7.6 Hz, 2 H), 1.67 (m, 5 H), 2.34 (m, 2 H), 2.57 (t, J = 8.4 Hz, 2
H), 3.72 (t, J = 7.2 Hz, 2 H), 5.49 (m, 2 H).
13C NMR (100 MHz, CDCl3): = 13.6, 17.8, 19.3, 27.9, 29.3, 33.6,
52.0, 126.1, 129.4, 172.5.
N-Butyl-N-chloro-2,2-dimethylpent-4-enoic Acid Amide (1a)
1H NMR (300 MHz, CDCl3): = 0.92 (t, J = 7.5Hz, 3 H), 1.25 (s, 6
H), 1.52 (m, 2 H), 3.15 (m, 2 H), 3.72 (m, 2 H), 4.56 (dt, J = 5.4, 1.2
Hz, 2 H), 5.25 (m, 2 H), 5.92 (m, 1 H).
13C NMR (75 MHz, CDCl3): = 13.9, 20.5, 26.3, 26.8, 32.8, 42.3,
46.1, 117.8, 134.3, 177.3.
Cyclisation of N-Chloroamides; General Procedure
To a solution of chloroamide (3 mmol) in MeOH (7 mL) was added
at 60 °C copper(I) chloride (30 mg, 0.3 mmol) and the reaction mix-
ture stirred at this temperature for 36 h. Then TBME and aq ammo-
nia (2 M) (10 mL each) were added, the layers separated and the aq
layer was washed with TBME (3 × 10 mL). After drying the com-
bined organic layers (Na2SO4), the solvent was removed in vacuo.
From the residue the lactams were isolated by flash chromatogra-
phy.
N-Butyl-N-chloro-3-methylpent-4-enoic Acid Amide (1b)
1H NMR (300 MHz, CDCl3): = 0.95 (t, J = 7.2 Hz, 3 H), 1.08 (d,
J = 6.8 Hz, 3 H), 1.34 (m, 2 H), 1.65 (m, 2 H), 2.52 (m, 2 H), 2.75
(m, 1 H), 3.71 (t, J = 7.2 Hz, 2 H), 5.01 (m, 2 H), 5.82 (m, 1 H).
13C NMR (75 MHz, CDCl3): = 13.6, 19.3, 19.6, 29.3, 34.2, 40.1,
52.1, 113.1, 142.7, 176.1.
1-Butyl-5-chloromethyl-3,3-dimethylpyrrolidin-2-one (6a)
1H NMR (300 MHz, CDCl3): = 0.93 (t, J = 7.2 Hz, 3 H), 1.13 (s,
3 H), 1.21 (s, 3 H), 1.33 (m, 2 H), 1.48 (m, 2 H), 1.78 (dd, J = 13.2,
7.3 Hz, 1 H), 2.03 (dd, J = 13.2, 7.8 Hz, 1 H), 2.93 (ddd, J = 13.8,
8.1, 5.3 Hz, 2 H), 3.62 (m, 2 H), 3.83 (m, 1 H).
13C NMR (75 MHz, CDCl3): = 13.7, 20.1, 25.5, 25.8, 29.2, 38.2,
39.9, 40.1, 45.5, 54.5, 179.9.
N-Butyl-N-chloro-2-methylpent-4-enoic Acid Amide (1c)
1H NMR (300 MHz, CDCl3): = 0.96 (t, J = 7.2 Hz, 3 H), 1.16 (d,
J = 6.9 Hz, 3 H), 1.34 (m, 2 H), 1.65 (m, 2 H), 2.15 (m, 2 H), 2.45
(m, 1 H), 3.72 (m, 2 H), 5.05 (m, 2 H), 5.77 (m, 1 H).
13C NMR (75 MHz, CDCl3): = 13.5, 16.8, 19.3, 29.3, 36.1, 37.8,
52.0, 116.6, 135.5, 176.6.
Anal. Calcd for C11H20NOCl: C, 60.68, H, 9.26, N, 6.43. Found: C,
60.80, H, 9.64, N, 6.33.
1-Butyl-5-chloromethyl-4-methylpyrrolidin-2-one (6b)
1H NMR (300 MHz, CDCl3): = 0.94 (t, J = 7.2 Hz, 3 H), 1.16 (t,
J = 7.2 Hz, 3 H), 1.34 (m, 2 H), 1.49 (m, 2 H), 1.99 (dd, J = 17.1,
4.8 Hz, 1 H), 2.35 (m, 1 H), 2.69 (m, 1 H), 2.89 (m, 2 H), 3.62 (m,
2 H), 3.69 (m, 1 H).
N-Butyl-N-chloropent-4-enoic Acid Amide (1d)
1H NMR (400 MHz, CDCl3): = 0.98 (t, J = 7.2 Hz, 3 H), 1.38 (m,
2 H), 1.70 (dt, J = 7.6 Hz, 2 H), 2.43 (m, 2 H), 2.64 (t, J = 7.6 Hz, 2
H), 3.74 (t, J = 7.2 Hz, 2 H), 5.07 (m, 2 H), 5.89 (m, 1 H).
13C NMR (100 MHz, CDCl3): = 13.6, 19.3, 29.3, 31.7, 35.9, 52.0,
115.4, 137.1, 173.2.
13C NMR (75 MHz, CDCl3): = 13.6, 19.9, 20.4, 29.3, 38.2, 40.1,
42.1, 44.3, 65.4, 174.2.
N-Acetyl-N-chloro-3,3-dimethylpent-4-enamine (1e)
1-Butyl-5-chloromethyl-3-methylpyrrolidin-2-one (6c)
1H NMR (300 MHz, CDCl3): = 0.98 (s, 6 H), 2.07 (dt, J = 7.2, 1.2
Hz, 2 H), 2.28 (s, 3 H), 3.59 (s, 2 H), 5.05 (m, 2 H), 5.84 (m, 1 H).
1H NMR (400 MHz, CDCl3): = 0.96 (t, J = 6.8 Hz, 3 H), 1.27 (d,
J = 6.0 Hz, 3 H), 1.35 (m, 2 H), 1.52 (m, 3 H), 2.46 (m, 2 H), 2.97
(m, 1 H), 3.68 (d, J = 4.4 Hz, 2 H), 3.72 (m, 1 H), 3.88 (m, 1 H). 13
NMR (100 MHz, CDCl3): = 13.6, 16.4, 20.0, 29.2, 30.8, 35.7,
40.1, 45.4, 55.7, 177.4. Minor isomer, selected signals: = 16.8,
20.1, 31.5, 35.2, 40.4, 45.5, 56.1.
C
13C NMR (75 MHz, CDCl3): = 22.0, 25.3, 26.9, 36.3, 44.9, 117.7,
134.4, 178.3.
N-Chloro-N-propylcarbamic Acid Allyl Ester (1f)
1H NMR (300 MHz, CDCl3): = 0.87 (t, J = 7.2 Hz, 3 H), 1.65 (sx,
J = 7.2 Hz, 2 H), 3.54 (t, J = 6.9Hz, 2 H), 4.60 (dt, J = 5.7, 1.8 Hz,
2 H), 5.24 (m, 2 H), 5.88 (m, 1 H).
Anal. Calcd for C10H18NOCl: C, 58.96; H, 8.91; N, 6.88. Found: C,
58.71; H, 9.13; N, 6.49.
1-Butyl-5-chloromethylpyrrolidin-2-one (6d)
13C NMR (75 MHz, CDCl3): = 11.2, 20.5, 55.8, 67.7, 118.2,
132.0, 175.7.
1H NMR (400 MHz, CDCl3): = 0.94 (t, J = 7.2 Hz, 3 H), 1.34 (m,
2 H), 1.50 (m, 2 H), 1.99 (m, 2 H), 2.19 (m, 2 H), 2.93 (m, 1 H), 3.63
(d, J = 4.8 Hz, 2 H), 3.64 (m, 1 H), 3.93 (m, 1 H).
N-tert-Butyl-N-chloro-2,2-dimethylpent-4-enoic Acid Amide
(1h)
13C NMR (100 MHz, CDCl3): = 13.7, 20.1, 22.2, 29.4, 29.8, 40.2,
45.5, 57.8, 174.9.
1H NMR (300 MHz, CDCl3): = 1.32 (s, 6 H), 1.43 (s, 9 H), 2.49
(dt, J = 7.5, 1.2 Hz, 2 H), 5.06 (m, 2 H), 5.76 (m, 1 H).
Anal. Calcd for C9H16NOCl: C, 56.99, H, 8.50, N, 7.38. Found: C,
57.26, H, 8.23, N, 7.11.
13C NMR (75 MHz, CDCl3): = 26.3, 29.4, 41.8, 45.1, 64.3, 117.5,
134.7, 181.9.
1-Acetyl-2-chloromethyl-4,4-dimethylpyrrolidine (6e)
This reaction was performed with chloroamide (0.3 mmol). Due to
the low yield a 13C NMR was not obtained.
1H NMR (300 MHz, CDCl3): = 0.89 (s, 6 H), 1.86 (dd, J = 7.8, 3.0
Hz, 2 H), 2.00 (s, 3 H), 3.23 (s, 2 H), 3.73 (dd, J = 10.8, 2,1 Hz, 1
H), 4.05 (dd, J = 10.8, 6.0 Hz, 1 H), 4.33 (m, 1 H).
N-Chloro-N-phenylethyl-2,2-dimethylpent-4-enoic Acid Amide
(1i)
1H NMR (300 MHz, CDCl3): = 1.36 (s, 6 H), 1.57 (d, J = 6.3 Hz,
3 H), 2.53 (m, 2 H), 5.05 (m, 2 H), 5.73 (m, 1 H), 6.13 (q, J = 6.9
Hz, 1 H), 7.32 (m, 5 H).
Synthesis 2003, No. 12, 1886–1890 © Thieme Stuttgart · New York

1890
I. A. Schulte-Wülwer et al.
PAPER
3-Butyl-4-chloromethyloxazolidin-2-one (6f)
Acknowledgement
1H NMR (400 MHz, CDCl3): = 0.97 (t, J = 8.0 Hz, 3 H), 1.66 (m,
2 H), 1.91 (m, 1 H), 3.08 (m, 1 H), 3.46 (m, 1 H), 3.65 (m, 2 H), 4.24
(dd, J = 8.4, 4.4 Hz, 1 H), 4.41 (m, 1 H).
Financial support by the Fonds der Chemischen Industrie by the Al-
fried Krupp von Bohlen und Halbach-Stiftung and the Deutsche
Forschungsgemeinschaft (SFB 424) is gratefully acknowledged.
13C NMR (100 MHz, CDCl3): = 11.1, 20.7, 29.9, 43.9, 55.6, 65.3,
160.2.
References:
1-tert-Butyl-5-chloromethyl-3,3-dimethylpyrrolidin-2-one (6h)
1H NMR (300 MHz, CDCl3): = 1.14 (s, 3 H), 1.22 (s, 3 H), 1.45
(s, 9 H), 1.99 (d, J = 2.7 Hz, 2 H), 3.40 (dd, J = 10.8, 9.6 Hz, 1 H),
3.73 (m, 1 H), 3.88 (m, 1 H).
(1) (a) Dalton, D. R. The Alkaloids; Marcel Dekker: New York,
1979. (b) Gilchrist, T. L. Heterocyclenchemie; VCH:
Weinheim, 1995.
(2) Müller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675.
(3) (a) Kuehne, M. E.; Horne, D. A. J. Org. Chem. 1975, 40,
1278. (b) Lessard, J.; Cote, R.; Mackiewicz, P.; Furstoss, R.;
Waegell, B. J. Org. Chem. 1978, 43, 3750.
(4) (a) Göttlich, R. Synthesis 2000, 1561. (b) Heuger, G.;
Kalsow, S.; Göttlich, R. Eur. J. Org. Chem. 2002, 1848.
(5) (a) Kochi, J. K. Free Radicals; Wiley: New York, 1973.
(b) Kochi, J. K. Acc. Chem. Res. 1974, 7, 351.
(6) Bowden, K.; Heilbron, I.; Jones, E.; Weedon, B. J. Chem.
Soc. 1946, 39.
(7) The NCS used was dried by azeotropic removal of H2O with
toluene and then recrystallised from toluene.
(8) Compounds 5b–f are known, see (4) and: (a) Toshimitsu,
A.; Terao, K.; Uemura, S. J. Org. Chem. 1986, 51, 1724.
(b) Sennyey, G.; Barcelo, G.; Senet, J.-P. Tetrahedron Lett.
1987, 28, 5809.
13C NMR (75 MHz, CDCl3): = 26.8, 28.5, 28.6, 37.0, 40.1, 47.5,
54.2, 56.2, 179.9.
Anal. Calcd for C11H20NOCl: C, 60.68; H, 9.26; N, 6.43. Found: C,
60.69; H, 9.22; N, 6.31.
1-Phenylethyl-5-chloromethyl-3,3-dimethylpyrrolidin-2-one
(6i)
1H NMR (300 MHz, CDCl3): = 1.16 (s, 3 H), 1.28 (s, 3 H), 1.65
(t, J = 7.2 Hz, 3 H), 1.86 (m, 2 H), 3.39 (m, 2 H), 3.48 (m, 1 H), 5.43
(m, 1 H), 7.32 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 18.1, 25.6, 25.9, 38.1, 39.7, 46.6,
46.9, 54.4, 126.7, 127.3, 128.6, 138.8, 179.4. Minor isomer, select-
ed signals: = 25.7, 26.0, 39.0, 49.3, 50.6, 54.3.
Anal. Calcd for C15H20NOCl: C, 67.79; H, 7.58; N, 5.27. Found: C,
67.55; H, 7.86; N, 4.98.
(9) Blenderman, W. G.; Joullie, M. M.; Preti, G. J. Org. Chem.
1983, 48, 3206.
(10) Hanko, R.; Hoppe, D. Angew. Chem. 1981, 93, 115.
(11) (a) Newcomb, M.; Esker, J. L. Tetrahedron Lett. 1991, 32,
1035. (b) Clark, A. J.; Peacock, J. L. Tetrahedron Lett. 1998,
39, 6029.
1-Butyl-5-(1-chloroethyl)pyrrolidin-2-one (6j)
1H NMR (400 MHz, CDCl3): = 0.97 (t, J = 7.6 Hz, 3 H), 1.37 (m,
2 H), 1.55 (d, J = 6.8 Hz, 3 H), 2.07 (m, 2 H), 2.37 (m, 2 H), 2.54
(m, 2 H), 2.96 (m, 1 H), 3.76(m, 2H), 4.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): = 13.6, 18.3, 20.0, 20.5, 29.0, 30.1,
40.0, 57.3, 62.1, 174.9.
Synthesis 2003, No. 12, 1886–1890 © Thieme Stuttgart · New York