Palladium-catalyzed carbonylation of homoallylic amine derivatives in the presence of a copper co-catalyst

Article abstract of DOI:10.1246/bcsj.76.1251

γ-Lactams were synthesized from N-tosylhomoallylamines by a carbonylation reaction catalyzed by palladium and copper salts under the normal pressure of CO and O₂ at room temperature. Monocarbonylation proceeded by the use of [PdCl₂(C

Full text of DOI:10.1246/bcsj.76.1251

Ó 2003 The Chemical Society of Japan
Bull. Chem. Soc. Jpn., 76, 1251–1256 (2003) 1251
Palladium-Catalyzed Carbonylation of Homoallylic Amine Derivatives
in the Presence of a Copper Co-catalyst
ꢀ
ꢀ
Takanori Mizutani, Yutaka Ukaji, and Katsuhiko Inomata
Department of Chemical Science, Graduate School of Natural Science and Technology, Kanazawa University,
Kakuma, Kanazawa, Ishikawa 920-1192
(Received December 9, 2002)
ꢀ-Lactams were synthesized from N-tosylhomoallylamines by a carbonylation reaction catalyzed by palladium and
copper salts under the normal pressure of CO and O2 at room temperature. Monocarbonylation proceeded by the use of
[PdCl2(CH3CN)2] and CuCl2 to afford 3-methyl-2-pyrrolidones, while the use of PdCl2 and CuCl switched the reaction
from monocarbonylation to dicarbonylation to produce alkyl 2-oxopyrrolidine-3-acetate in good yields, respectively.
The transition-metal catalyzed carbonylation of alkenes
with CO is a useful method for the preparation of homologated
carbonyl compounds.1 Especially, the intramolecular carbony-
lation of unsaturated alcohols and amines is an attractive way
to produce heterocyclic compounds that are often difficult to
prepare by other methods. Concerning the cyclization of ole-
finic amines, the intramolecular monocarbonylation of allyl-
amine in the presence of Co2(CO)8 was reported to give a mix-
ture of 3-methyl-2-pyrrolidone and 2-piperidone.2 Utilizing a
rhodium catalyst instead of a cobalt catalyst, 2-pyrrolidone
was selectively obtained.3 The hydrocarbonylation of 3-buten-
amides catalyzed by rhodium gave 3,4-dihydro-2(1H)-pyridi-
none or 4-methyl-3-pyrrolin-2-one derivatives, depending on
the reaction conditions.4 The intramolecular cyclocarbonyla-
tion of 2-aminostyrenes or 2-allylanilines in the presence of
palladium catalysts produced the corresponding five, six, or se-
ven-membered ring lactams.5 Furthermore, the rhodium-cata-
lyzed tandem cyclohydrocarbonylation/CO insertion of ꢁ-imi-
no alkynes under CO and H2 gave 2-oxo-3-pyrroline-4-
carbaldehyde, regarded as intra- and intermolecular dicarbony-
lation products.6 However, these reactions were conducted un-
der drastic conditions, such as high pressure and high
temperature. The development of the intramolecular carbony-
lation of unsaturated amines under mild conditions is still re-
garded as being a challenging problem for the synthesis of lac-
tams, which have biological activity7 and are versatile
synthetic intermediates for nitrogen-containing chemicals.8
We recently reported on selective mono- and bis(alkoxycarbo-
nylation) reactions of terminal olefins catalyzed by palladium
salts in the presence of copper salts under the normal pressure
of CO and O2 at room temperature. Furthermore, ꢀ-butyrolac-
tones were prepared from homoallylic alcohols under similar
conditions.9;10 When the homoallylamine derivatives were
subjected to the carbonylation reaction, the formation of one
carbon homologated 2-pyrrolidones was anticipated. Herein,
we describe selective mono- and dicarbonylation reactions of
N-tosylhomoallylamines catalyzed by palladium in the pre-
sence of CuCl2 or CuCl under remarkably mild conditions to
afford 3-methyl-1-tosyl-2-pyrrolidones or methyl 2-oxo-1-to-
sylpyrrolidine-3-acetate, respectively.
Results and Discussion
First, a carbonylation reaction of homoallylamine deriva-
tives was carried out in the presence of a 0.05 molar amount
of [PdCl2(CH3CN)2] and 1.5 molar amounts of CuCl2 under
a CO and O2 [ca. 1/1, v/v, 1 atm (¼ 1:0 ꢁ 105 Pa)] atmosphere
in MeOH (2a) and THF (1/1, v/v) at room temperature
(Scheme 1).9b In the reaction of N-benzoyl and N-benzyloxy-
carbonyl substituted homoallylamines, intramolecularly carbo-
nylated products were not formed, but only intermolecularly
monocarbonylated esters were obtained. To the contrary, N-
tosylhomoallylamine 1A afforded ꢀ-lactam, 3-methyl-1-to-
syl-2-pyrrolidone (3A) in 52% yield accompanied by intermo-
lecularly carbonylated esters, methyl 4-(N-tosylamino)-2-me-
thylbutanoate (4Aa) and methyl 5-(N-tosylamino)pentanoate
(5Aa) (Table 1, Entry 1). In the case of N-trifluoromethylsul-
fonylhomoallylamine, only intermolecularly monocarbonyla-
ted esters were again obtained. In order to suppress intermo-
lecular carbonylation, the influence of alcohols was examined.
i
t
When EtOH (2b), PrOH (2c), and BuOH (2d) were used in-
stead of MeOH (2a), the intramolecular carbonylation pro-
ceeded more selectively (Entries 2–4). Utilizing 3-ethyl-3-
pentanol (2e), ꢀ-lactam 3A was selectively obtained in 86%
yield (Entry 5). Furthermore, PhOH (2f) was found to be ef-
fective for selective intramolecular carbonylation to afford 3A
in 88% yield (Entry 6). Even in the absence of alcohols, the
Scheme 1.

1252 Bull. Chem. Soc. Jpn., 76, No. 6 (2003)
Carbonylation of Homoallylic Amine Derivatives
Table 1. Monocarbonylation of Homoallylamine Deriva-
tives 1 Using CuCl2 as a Co-catalyst
Table 2. Dicarbonylation of Homoallylamine Derivatives 1
Using CuCl as a Co-catalyst
Entry
R1
H
R2
H
1
R3OH
2
t/h 3/% 4/% 5/%
Entry
R1
H
R2
H
1
Co-solvent t/h 6/%
7/%
1
2
3
4
5
6
7
8
9
A
MeOH
EtOH
a
b
c
d
e
f
17 52
19 73
19 80
19 82
21 86
6
6
2
9
9
10
14
1
2
3
4
5
A
—
48 69
46 84a)
17
—
THF
THF
THF
THF
iPrOH
tBuOH
Et3COH
PhOH
—
Ph
Ph(CH2)3
H
H
B
C
D
42 82b) < 13c)
—
—
—
—
—
—
—
—
—
—
65 70b)
72 85
trace
trace
trace
—
—
—
—
—
—
–(CH2)5–
37 88
a) Monocarbonylated ꢀ-lactam 3A was also obtained (6%). b)
The ratios of diastereomers were ca. 1/1. c) Contaminated
with small amounts of unknown substrates that could not be
separated.
47 57a)
39 86b)
38 79b)
27 86b)
74 75b)
17 78
Ph
H
H
B
Et3COH
PhOH
e
f
e
f
e
f
10 Ph(CH2)3
11
12
13
C Et3COH
PhOH
D Et3COH
PhOH
< 6c)
—
was transferred to palladium chloride to generate complex
11, in which olefin can coordinate to the palladium metal.
Successive carbopalladation to internal olefin gave the cy-
clized intermediate 12. In a reaction using copper(b) chloride,
protonation by HCl generated from 8 and R3OH furnished
monocarbonylated lactam 3. On the other hand, second carbo-
nylation proceeded via 13, generated from 12 by a carbonyl
transfer from 9, formed by using CuCl, followed by reductive
elimination to give dicarbonylated lactam 6. Palladium(b) is
regenerated by a reaction with O2 and copper salt.12;13
As described above, a novel synthetic method for the con-
struction of ꢀ-lactam by the carbonylation of homoallylic
amine derivatives was realized by utilizing palladium and cop-
per salts under remarkably mild conditions. Depending on the
kinds of used copper salts, mono- and dicarbonylation could be
controlled to give a different type of ꢀ-lactams chemoselec-
tively.
–(CH2)5–
162 88
a) The starting compound 1A was recovered (21%). b) The
ratios of diastereomers were ca. 1/1. c) Contaminated with
small amounts of unknown substrates that could not be sepa-
rated.
reaction proceeded, but was rather sluggish (Entry 7).
Under the optimized conditions, the intramolecular mono-
carbonylation of several homoallylic N-tosylamines was car-
ried out in the presence of 3-ethyl-3-pentanol (2e) or PhOH
(2f). In the reactions of monosubstituted homoallylic amines
1B,C, a ca. 1/1 mixture of diastereomers was produced (En-
tries 8–11). In all cases including disubstituted homoallylic
amine 1D, the corresponding ꢀ-lactams 3 were obtained in
good yields (Entries 8–13).
Next, the intra- and intermolecular dicarbonylation reaction
was investigated in the presence of a 0.05 molar amount of
PdCl2 and 1.5 molar amounts of CuCl under a CO and O2
(1/1, v/v, 1 atm) atmosphere in MeOH at room temperature
(Scheme 2).9b In the reaction of 1A, intra- and intermolecular-
ly dicarbonylated lactam 6A and intermolecularly bis(alkoxy-
carbonyl)ated diesters 7A were obtained (Table 2, Entry 1).
By the addition of THF as a co-solvent, intra- and intermole-
cular dicarbonylation proceeded selectively to afford ꢀ-lactam
6A bearing a methoxycarbonylmethyl side chain in 84% yield
accompanied by monocarbonylated ꢀ-lactam 3A (6%)
(Entry 2). The dicarbonylation of 1B–D was also carried
out in MeOH/THF to give the corresponding ꢀ-lactams, meth-
yl 5-substituted 2-oxo-1-tosylpyrrolidine-3-acetate 6B–D in
good yields (Entries 3–5).
Experimental
All of the melting points were determined with a micro melting
apparatus (Yanagimoto-Seisakusho) and were uncorrected. The
1H NMR spectra were recorded on a JEOL Lambda 400 spectro-
meter with tetramethylsilane as an internal standard. The IR spec-
tra were measured with a JASCO FT/IR-230 spectrometer. The
MS spectra were measured with a Hitachi M-80, or a JMS-
SX102A mass spectrometer. The specific optical rotations were
recorded on a JASCO DIP-370 spectrometer. THF was freshly
distilled from sodium diphenylketyl. All other solvents were dis-
tilled and stored over drying agents. Thin-layer chromatography
(TLC), column chromatography, and HPLC were performed on
Merck’s silica gel 60 PF254 (Art. 7749), Cica-Merck’s silica gel
60 (No. 9385-5B), and JAIGL-SIL (s-043-15), respectively.
N-(3-Butenyl)-p-toluenesulfonamide (1A):16 To a mixture of
4-amino-1-butene17 (177 mg, 2.5 mmol), triethylamine (0.5 mL,
3.8 mmol), a catalytic amount (ca. 5 mg) of 4-(dimethylamino)-
pyridine in CH2Cl2 (5 mL) was added tosyl chloride (572 mg,
3.0 mmol) under a nitrogen atmosphere, and the reaction mixture
was stirred for 3 h. The reaction mixture was quenched with H2O
and extracted with ethyl acetate. The combined extracts were wa-
Although the precise mechanism of the present reaction is
still an open question, one possible reaction pathway is shown
in Fig. 1. In the present carbonylation, copper might work not
only as an oxidant, but also as a co-catalyst to generate active
species. That is, copper salts react with CO to give the copper-
carbonyl complex 8,11 followed by a reaction with homoallyl-
amine derivatives 1 to afford 10. The aminocarbonyl group
Scheme 2.

T. Mizutani et al.
Bull. Chem. Soc. Jpn., 76, No. 6 (2003) 1253
Fig. 1.
shed with H2O and brine and dried over Na2SO4; the solvent was
removed under reduced pressure. The residue was purified by
flash column chromatography (SiO2, hexane/ethyl acetate = 4/1,
v/v) to give 1A in 64% yield (383 mg). An oil; MS m=z 225
(Mþ, 2.28%), 210 (0.36), 184 (100.00), 155 (98.36), 139 (2.34),
91 (6.27); IR (neat) 3283, 3079, 2925, 1639, 1597, 1495, 1424,
(1C): To a toluene (15 mL) solution of 4-phenylbutanenitrile
(726 mg, 5.0 mmol) was added diisobutylaluminum hydride (1.0
ꢃ
M solution in toluene, 5.0 mL, 5.0 mmol) at ꢂ78 C under a ni-
trogen atmosphere and the reaction mixture was gradually warmed
to room temperature over a period of 6 h. To the solution, allyl-
magnesium bromide (1.0 M solution in Et2O, 6.0 mL, 6.0 mmol)
was added and the reaction mixture was stirred overnight. After
1
1324, 1159, 1093, 1019, 990, 919, 872, 815, 661 cmꢂ1; H NMR
ꢃ
(CDCl3) ꢂ 2.20 (2H, q, J ¼ 6:83 Hz), 2.43 (3H, s), 3.01 (2H, q,
J ¼ 6:83 Hz), 4.56–4.68 (1H, br), 5.02 (1H, d, J ¼ 17:31 Hz),
5.05 (1H, d, J ¼ 10:48 Hz), 5.62 (1H, ddt, J ¼ 17:31, 10.48,
6.83 Hz), 7.31 (2H, d, J ¼ 8:29 Hz), 7.75 (2H, d, J ¼ 8:29 Hz).
N-(1-Phenyl-3-butenyl)-p-toluenesulfonamide (1B):18 To a
suspension of N-benzylidene-p-toluenesulfonamide (781 mg, 3.0
mmol) and Zn powder (351 mg, 5.4 mmol) in DMF (3 mL) was
slowly added allyl bromide (0.38 mL, 4.5 mmol) under a nitrogen
atmosphere and the solution was stirred overnight. After the ad-
dition of sat. aqueous NH4Cl, the solution was extracted several
times with ether. The combined extracts were washed by water
and brine, dried over Na2SO4, and condensed under reduced
pressure. The residue was purified by recrystallization (hexane/
toluene) to give 1B (623 mg, 69%). Mp 74.5–75.3 ꢃC (from hex-
ane/toluene), (lit., an oil);18 IR (KBr) 3254, 3063, 3031, 2977,
2897, 1642, 1601, 1497, 1458, 1319, 1310, 1289, 1165, 1096,
1059, 992, 955, 933, 919, 833, 813, 760, 702, 680 cmꢂ1; 1H NMR
(CDCl3) ꢂ 2.37 (3H, s), 2.36–2.54 (2H, m), 4.37 (1H, q, J ¼ 6:58
Hz), 4.78–4.87 (1H, br), 5.06 (1H, d, J ¼ 16:09 Hz), 5.07 (1H, d,
J ¼ 10:72 Hz), 5.50 (1H, ddt, J ¼ 16:09, 10.72, 7.07 Hz), 7.04–
7.12 (2H, m), 7.14 (2H, d, J ¼ 8:05 Hz), 7.15–7.24 (3H, m),
7.55 (2H, d, J ¼ 8:05 Hz). Found: C, 67.54; H, 6.44; N,
4.63%. Calcd for C17H19NO2S: C, 67.75; H, 6.35; N, 4.65%.
N-[1-(3-Phenylpropyl)-3-butenyl]-p-toluenesulfonamide
quenching with sat. aqueous Na2SO4 (0.36 mL) at 0 C, the pre-
cipitate was filtered off. To the filtrate was added 6 M HCl with
stirring and the organic layer was separated. The aqueous solution
was made basic by adding an aqueous NaOH solution and extract-
ed several times with ether. The combined extracts were washed
by brine and dried over Na2SO4, and condensed under reduced
pressure to give almost pure 4-amino-7-phenyl-1-heptene (493
mg, 52%). The obtained homoallylamine (300 mg, 1.58 mmol)
was tosylated without further purification according to the proce-
dure described for 1A to give 1C (455 mg, 83%). An oil; MS m=z
343 (Mþ, 0.39%), 342 (Mþ ꢂ 1, 0.88), 302 (88.82), 279 (6.88),
224 (11.25), 172 (29.33), 155 (47.84), 131 (97.51), 91 (100.00),
65 (13.21); IR (neat) 3280, 3062, 3026, 2939, 2860, 1640, 1598,
1495, 1453, 1425, 1325, 1304, 1159, 1092, 1028, 997, 916, 814,
749, 700, 665 cmꢂ1 1H NMR (CDCl3) ꢂ 1.32–1.64 (4H, m),
;
2.08 (2H, t, J ¼ 6:83 Hz), 2.40 (3H, s), 2.46–2.52 (2H, m),
3.26–3.37 (1H, m), 4.31 (1H, d, J ¼ 8:05 Hz), 4.94 (1H, dd,
J ¼ 17:07, 1.70 Hz), 5.01 (1H, d, J ¼ 10:24 Hz), 5.52 (1H, ddt,
J ¼ 17:07, 10.24, 7.31 Hz), 7.07 (2H, d, J ¼ 8:53 Hz), 7.14–
7.20 (1H, m), 7.22–7.28 (4H, m), 7.73 (2H, d, J ¼ 8:53 Hz).
N-(1-Allylcyclohexyl)-p-toluenesulfonamide (1D): 1-Allyl-
cyclohexanecarboxylic acid (1.682 g, 10 mmol) was treated with
thionyl chloride (10 mL) and the solution was refluxed for 2 h and
condensed under reduced pressure to give the corresponding acyl

1254 Bull. Chem. Soc. Jpn., 76, No. 6 (2003)
Carbonylation of Homoallylic Amine Derivatives
chloride (2.104 g). To an acetone (6 mL) solution of the crude
acyl chloride was added a H2O (3 mL) solution of sodium azide
(90% purity) (1.083 g, 15 mmol) and the solution was stirred
for 30 min.19 After the addition of H2O (15 mL), the reaction mix-
ture was extracted with toluene several times and the combined
extracts were dried over Na2SO4. After filtration of Na2SO4, the
filtrate was refluxed for 1 h, followed by cooling to room tempera-
ture and evaporating the solvent under reduced pressure. To the
residue, 6 M HCl (1M = 1 mol dmꢂ3) (8 mL) was added, and
the mixture was gradually warmed and refluxed for 30 min.20
After cooling to room temperature, the mixture was washed with
ether and the resulting aqueous layer was made basic by adding
sodium carbonate and extracted with ether. The combined ex-
tracts were dried over Na2SO4, and the solvent was evaporated un-
der reduced pressure to give almost pure 1-allyl-1-aminocyclohex-
ane (1.188 g, 85%). The obtained homoallylamine was tosylated
without further purification.
(CDCl3) ꢂ 1.18 (3H, d, J ¼ 7:07 Hz), 2.15–2.26 (2H, m), 2.40
(3H, s), 2.80 (1H, ddq, J ¼ 10:49, 8.53, 7.07 Hz), 5.41 (1H, dd,
J ¼ 6:83, 2.92 Hz), 7.08–7.13 (2H, m), 7.19 (2H, d, J ¼ 8:29
Hz), 7.24–7.32 (3H, m), 7.62 (2H, d, J ¼ 8:29 Hz). Found: C,
65.48; H, 5.82; N, 4.10%. Calcd for C18H19NO3S: C, 65.63; H,
ꢃ
5.81; N, 4.25%. Diastereomer 2: Mp 117.2–118.0 C (from hex-
ane/AcOEt); IR (KBr) 3030, 2971, 2927, 2877, 1714, 1598,
1495, 1461, 1361, 1334, 1268, 1221, 1186, 1166, 1096, 1043,
1
988, 922, 870, 810, 771, 729, 698, 669 cmꢂ1; H NMR (CDCl3)
ꢂ 1.22 (3H, d, J ¼ 7:07 Hz), 1.63 (1H, ddd, J ¼ 12:44, 9.75,
7.80 Hz), 2.40 (3H, s), 2.65 (1H, tq, J ¼ 9:75, 7.07 Hz), 2.74
(1H, ddd, J ¼ 12:44, 9.75, 7.80 Hz), 5.20 (1H, t, J ¼ 7:80 Hz),
7.15–7.20 (2H, m), 7.19 (2H, d, J ¼ 8:53 Hz), 7.25–7.32 (3H,
m), 7.56 (2H, d, J ¼ 8:53 Hz). Found: C, 65.62; H, 5.91; N,
4.15%. Calcd for C18H19NO3S: C, 65.63; H, 5.81; N, 4.25%.
3-Methyl-5-(3-phenylpropyl)-1-tosyl-2-pyrrolidone (3C):
Diastereomer 1: An oil; MS m=z 371 (Mþ, 64.76%), 307 (6.31),
252 (14.71), 216 (100.00), 203 (4.80), 188 (4.90), 155 (35.14),
131 (7.47), 98 (16.58), 91 (79.81), 65 (10.20); IR (neat) 3061,
3026, 2932, 2862, 1733, 1598, 1496, 1454, 1359, 1291, 1213,
1170, 1124, 1091, 1065, 1031, 1019, 924, 896, 815, 749, 703,
The obtained 1-allyl-1-aminocyclohexane (557 mg, 4.0 mmol)
was treated with tosyl chloride (991 mg, 5.2 mmol) and triethyl-
amine (0.85 mL, 6.0 mmol), as describeꢃd for 1A to give 1D
(752 mg) in 64% yield. Mp 123.5–124.4 C (from hexane/ethyl
acetate); IR (KBr) 3302, 3264, 3073, 2938, 2863, 1639, 1598,
1493, 1445, 1420, 1331, 1310, 1288, 1152, 1093, 1038, 1018,
1
667 cmꢂ1; H NMR (CDCl3) ꢂ 1.09 (3H, d, J ¼ 6:83 Hz), 1.50–
1.72 (3H, m), 1.77 (1H, td, J ¼ 12:44, 8.56 Hz), 1.98 (1H, ddd,
J ¼ 11:22, 8.29, 3.17 Hz), 2.06 (1H, dd, J ¼ 12:44, 8.56 Hz),
2.43 (3H, s), 2.50–2.71 (3H, m), 4.31 (1H, td, J ¼ 8:56, 3.71
Hz), 7.14 (2H, d, J ¼ 8:29 Hz), 7.17–7.25 (1H, m), 7.25–7.33
(4H, m), 7.89 (2H, d, J ¼ 8:29 Hz). Diastereomer 2: An oil;
MS m=z 371 (Mþ, 40.80%), 307 (9.33), 252 (13.01), 216
(100.00), 203 (6.25), 188 (5.63), 155 (34.68), 143 (4.86), 131
(4.71), 98 (16.51), 91 (83.35), 65 (10.53); IR (neat) 3061, 3026,
2970, 2932, 2866, 1732, 1598, 1496, 1454, 1361, 1307, 1293,
1213, 1169, 1121, 1089, 1043, 934, 869, 815, 752, 726, 702,
996, 916, 853, 813, 775, 753, 705, 647, 660 cmꢂ1 1H NMR
;
(CDCl3) ꢂ 1.22–1.46 (8H, m), 1.68–1.80 (2H, m), 2.39 (2H, d, J ¼
7:33 Hz), 2.42 (3H, s), 4.30 (1H, br), 5.07 (1H, d, J ¼ 17:23 Hz),
5.11 (1H, d, J ¼ 10:27 Hz), 5.73 (1H, ddt, J ¼ 17:23, 10.27, 7.33
Hz), 7.27 (2H, d, J ¼ 8:25 Hz), 7.77 (2H, d, J ¼ 8:25 Hz).
Found: C, 65.23; H, 8.00; N, 4.67%. Calcd for C16H23NO2S: C,
65.49; H, 7.90; N, 4.77%.
The Representative Procedure for Monocarbonylation of
1A: A mixed solution of N-(3-butenyl)-p-toluenesulfonamide
(1A) (112 mg, 0.5 mmol), [PdCl2(CH3CN)2] (5.78 mg, 0.025
mmol), and CuCl2 (101 mg, 0.75 mmol) in PhOH (2 mL) and
THF (2 mL) was stirred under a CO/O2 (ca. 1/1, v/v, 1 atm) atmo-
sphere for 37 h at room temperature. After the addition of a 10%
aqueous NaHCO3 solution, the insoluble substance was filtered off
through Celite. The filtrate was extracted with ethyl acetate, and
the combined extracts were washed with water and brine, dried
over Na2SO4, and condensed in vacuo. The residue was purified
by TLC (SiO2, benzene/ethyl acetate = 6/1, v/v) to give 3-methyl-
1-tosyl-2-pyrrolidone (3A) (112 mg, 88%).
1
665 cmꢂ1; H NMR (CDCl3) ꢂ 1.13 (3H, d, J ¼ 6:58 Hz), 1.28–
1.40 (1H, m), 1.52–1.66 (3H, m), 2.30–2.50 (3H, m), 2.43 (3H,
s), 2.57–2.73 (2H, m), 4.15–4.25 (1H, m), 7.15 (2H, d, J ¼ 8:29
Hz), 7.16–7.25 (1H, m), 7.25–7.33 (4H, m), 7.90 (2H, d,
J ¼ 8:29 Hz).
3-Methyl-1-tosyl-1-azaspiro[4.5]decan-2-one (3D):
Mp
120.5–120.7 ꢃC (from hexane/ethyl acetate); IR (KBr) 3071,
3038, 2985, 2931, 2868, 1728, 1597, 1494, 1452, 1405, 1366,
1346, 1308, 1255, 1211, 1188, 1171, 1157, 1122, 1076, 1028,
1003, 975, 939, 906, 866, 813, 799, 712, 705, 683, 657 cmꢂ1
;
In a similar manner, 3-methyl-2-pyrrolidone 3B–D were pre-
pared from the corresponding homoallylamine derivatives 1B–
D. Diastereomers of 3B,C were carefully separated by HPLC
and subjected to analyses.
1H NMR (CDCl3) ꢂ 1.11 (3H, d, J ¼ 6:58 Hz), 1.24–1.51 (4H,
m), 1.64–1.88 (5H, m), 2.42 (3H, s), 2.47 (1H, ddq, J ¼ 10:97,
9.03, 6.58 Hz), 2.38–2.60 (1H, m), 2.55 (1H, dd, J ¼ 12:19,
9.03 Hz), 2.88 (1H, td, J ¼ 12:19, 4.14 Hz), 7.29 (2H, d,
J ¼ 8:29 Hz), 7.93 (2H, d, J ¼ 8:29 Hz). Found: C, 63.42; H,
7.37; N, 4.29%. Calcd for C17H23NO3S: C, 63.53; H, 7.21; N,
4.36%.
The Representative Procedure for Dicarbonylation of 1A:
A mixed solution of N-(3-butenyl)-p-toluenesulfonamide (1A)
(112 mg, 0.5 mmol), PdCl2 (4.43 mg, 0.025 mmol), and CuCl
(74 mg, 0.75 mmol) in THF (2 mL) and MeOH (2 mL) was stirred
under a CO/O2 (ca. 1/1, v/v, 1 atm) atmosphere for 46 h at room
temperature. After the addition of a 10% aqueous NaHCO3 solu-
tion, the insoluble substance was filtered off through Celite. The
filtrate was extracted with ethyl acetate several times and the com-
bined extracts were washed with water and brine, dried over
Na2SO4, and condensed in vacuo. The residue was purified by
TLC (SiO2, benzene/ethyl acetate = 5/1, v/v) to give methyl 2-
oxo-1-tosyl-3-pyrrolidineacetate (6A) (131 mg, 84%) and 1A (8
mg, 6%).
3-Methyl-1-tosyl-2-pyrrolidone (3A):
Mp 85.0–85.9 ꢃC
(from hexane/ethyl acetate); IR (KBr) 3095, 3057, 2979, 2938,
2898, 2879, 1735, 1595, 1493, 1455, 1398, 1355, 1294, 1233,
1204, 1168, 1104, 1052, 1015, 984, 918, 902, 817, 801, 722,
712, 661 cmꢂ1
;
1H NMR (CDCl3) ꢂ 1.14 (3H, d, J ¼ 7:07 Hz),
1.70 (1H, dddd, J ¼ 12:44, 10.49, 9.76, 8.29 Hz), 2.26 (1H, dddd,
J ¼ 12:44, 8.29, 6.83, 2.44 Hz), 2.47 (1H, ddq, J ¼ 10:49, 8.29,
7.07 Hz), 2.44 (3H, s), 3.68 (1H, td, J ¼ 9:76, 6.83 Hz), 3.95
(1H, ddd, J ¼ 9:76, 8.29, 2.44 Hz), 7.31 (2H, d, J ¼ 8:29 Hz),
7.92 (2H, d, J ¼ 8:29 Hz). Found: C, 56.79; H, 5.99; N,
5.55%. Calcd for C12H15NO3S: C, 56.90; H, 5.97; N, 5.53%.
3-Methyl-5-phenyl-1-tosyl-2-pyrrolidone (3B): Diastereo-
mer 1: Mp 133.4–134.6 ꢃC (from hexane/AcOEt); IR (KBr)
3066, 3035, 2978, 2940, 2896, 2879, 1728, 1594, 1492, 1455,
1361, 1332, 1302, 1262, 1224, 1192, 1169, 1122, 1085, 1072,
1046, 994, 930, 912, 817, 800, 762, 700, 671 cmꢂ1 1H NMR
;

T. Mizutani et al.
Bull. Chem. Soc. Jpn., 76, No. 6 (2003) 1255
In a similar manner, 3-(methoxycarbonylmethyl)-2-pyrroli-
dones 6B–D were prepared from the corresponding homoallyl-
amine derivatives 1B–D. Diastereomers of 6B,C were carefully
separated by HPLC and subjected to analyses.
4.14 Hz), 2.95 (1H, ddd, J ¼ 12:44, 8.53, 4.14 Hz), 3.63 (3H,
s), 4.36 (1H, td, J ¼ 8:53, 3.41 Hz), 7.15 (2H, d, J ¼ 8:24 Hz),
7.17–7.24 (1H, m), 7.26–7.33 (4H, m), 7.88 (2H, d, J ¼ 8:24 Hz).
Methyl 2-Oxo-1-tosyl-1-azaspiro[4.5]decan-3-acetate (6D):
Mp 159.7–161.3 C (from hexane/ethyl acetate); IR (KBr) 2979,
2938, 2867, 1723, 1596, 1442, 1363, 1342, 1311, 1301, 1261,
1215, 1178, 1161, 1152, 1089, 1066, 998, 882, 826, 740, 706,
683, 656 cmꢂ1 1H NMR (CDCl3) ꢂ 1.22–1.38 (2H, m), 1.38–
;
ꢃ
Methyl 2-Oxo-1-tosyl-3-pyrrolidineacetate (6A): Mp 63.0–
ꢃ
64.2 C (from hexane/ethyl acetate); IR (KBr) 2953, 1734, 1595,
1437, 1357, 1267, 1228, 1166, 1123, 1089, 1018, 992, 893, 814,
760, 718, 659 cmꢂ1
;
1H NMR (CDCl3) ꢂ 1.81 (1H, dddd,
J ¼ 12:74, 10.97, 10.00, 8.78 Hz), 2.38 (1H, dddd, J ¼ 12:74,
8.78, 7.07, 1.71 Hz), 2.40 (1H, dd, J ¼ 16:80, 8.78 Hz), 2.44
(3H, s), 2.79 (1H, dd, J ¼ 16:80, 4.14 Hz), 2.86 (1H, dtd,
J ¼ 10:97, 8.78, 4.14 Hz), 3.64 (3H, s), 3.72 (1H, td, J ¼ 10:00,
7.07 Hz), 3.99 (1H, ddd, J ¼ 10:00, 8.78, 1.71 Hz), 7.33 (2H, d,
J ¼ 8:05 Hz), 7.92 (2H, d, J ¼ 8:05 Hz). Found: C, 53.84; H,
5.51; N, 4.53%. Calcd for C14H17NO5S: C, 54.01; H, 5.50; N,
4.50%.
1.54 (2H, m), 1.64–1.72 (2H, m), 1.74–1.89 (3H, m), 2.32 (1H,
dd, J ¼ 16:78, 8.53 Hz), 2.42 (3H, s), 2.48 (1H, td, J ¼ 13:44,
3.68 Hz), 2.66 (1H, dd, J ¼ 12:68, 9.03 Hz), 2.80 (1H, dd,
J ¼ 16:78, 3.90 Hz), 2.84–2.94 (2H, m), 3.65 (3H, s), 7.31 (2H,
d, J ¼ 8:53 Hz), 7.92 (2H, d, J ¼ 8:53 Hz). Found: C, 59.92;
H, 6.66; N, 3.65%. Calcd for C19H25NO5S: C, 60.14; H, 6.64;
N, 3.69%.
Methyl 2-Oxo-5-phenyl-1-tosyl-3-pyrrolidineacetate (6B):
Diastereomer 1: Mp 139.0–140.2 ꢃC (from hexane/AcOEt); IR
(KBr) 3033, 2980, 2953, 2932, 1736, 1726, 1593, 1492, 1457,
1437, 1383, 1360, 1335, 1290, 1250, 1223, 1171, 1145, 1121,
1105, 1089, 1030, 1016, 996, 970, 898, 814, 763, 717, 704, 668
The present work was partially supported by the Asahi
Glass Foundation and Grant-in-Aid for Scientific Research
from the Ministry of Education, Culture, Sports, Science and
Technology.
1
cmꢂ1; H NMR (CDCl3) ꢂ 2.29 (1H, ddd, J ¼ 12:44, 8.53, 1.21
References
Hz), 2.34 (1H, ddd, J ¼ 12:44, 11.71, 8.53 Hz), 2.40 (3H, s),
2.46 (1H, dd, J ¼ 17:07, 8.53 Hz), 2.83 (1H, dd, J ¼ 17:07,
4.39 Hz), 3.17 (1H, dtd, J ¼ 11:71, 8.53, 4.39 Hz), 3.64 (3H, s),
5.45 (1H, dd, J ¼ 8:53, 1.21 Hz), 7.09–7.15 (2H, m), 7.19 (2H,
d, J ¼ 8:29 Hz), 7.25–7.34 (3H, m), 7.61 (2H, d, J ¼ 8:29 Hz).
Found: C, 61.90; H, 5.54; N, 3.60%. Calcd for C20H21NO5S: C,
62.00; H, 5.46; N, 3.62%. Diastereomer 2: Mp 105.5–106.4 ꢃC
(from hexane/AcOEt); IR (KBr) 3068, 3033, 2955, 2927, 1733,
1597, 1496, 1459, 1436, 1404, 1362, 1327, 1237, 1198, 1161,
1 H. M. Colquhoun, D. J. Thompson, and M. V. Twigg,
‘‘Carbonylation,’’ Plenum Press, New York (1991).
2
3
4
J. Falbe and F. Korte, Chem. Ber., 98, 1928 (1965).
J. F. Knifton, J. Organomet. Chem., 188, 223 (1980).
I. Ojima, A. Korda, and W. R. Shay, J. Org. Chem., 56,
2024 (1991).
5
B. E. Ali, K. Okuro, G. Vasapollo, and H. Alper, J. Am.
Chem. Soc., 118, 4264 (1996); K. Okuro, H. Kai, and H. Alper,
Tetrahedron: Asymmetry, 8, 2307 (1997).
1
1104, 1089, 1006, 983, 890, 817, 767, 701, 665 cmꢂ1; H NMR
(CDCl3) ꢂ 1.79 (1H, ddd, J ¼ 12:91, 10.72, 8.29 Hz), 2.40 (3H,
s), 2.53 (1H, dd, J ¼ 17:31, 8.29 Hz), 2.79 (1H, dt, J ¼ 12:91,
8.29 Hz), 2.84 (1H, dd, J ¼ 17:31, 3.90 Hz), 3.00 (1H, dtd,
J ¼ 10:72, 8.29, 3.90 Hz), 3.65 (3H, s), 5.21 (1H, t, J ¼ 8:29
Hz), 7.18 (2H, d, J ¼ 8:29 Hz), 7.18–7.24 (2H, m), 7.26–7.32
(3H, m), 7.53 (2H, d, J ¼ 8:29 Hz). Found: C, 61.83; H, 5.54;
N, 3.54%. Calcd for C20H21NO5S: C, 62.00; H, 5.46; N, 3.62%.
Methyl 2-Oxo-5-(3-phenylpropyl)-1-tosyl-3-pyrrolidineace-
6
123, 10214 (2001).
B. G. Van den Hoven and H. Alper, J. Am. Chem. Soc.,
7
Examples for ꢀ-lactams: M. Pinza, C. Farina, A. Cerri, U.
Pfeiffer, M. T. Riccaboni, S. Banfi, R. Biagetti, O. Pozzi, M.
Magnani, and L. Dorigotti, J. Med. Chem., 36, 4214 (1993); P.
A. Reddy, B. C. H. Hsiang, T. N. Latifi, M. W. Hill, K. E.
Woodward, S. M. Rothman, J. A. Ferrendelli, and D. F. Covey,
J. Med. Chem., 39, 1898 (1996); A. Spaltenstein, M. R. Almond,
W. J. Bock, D. G. Cleary, E. S. Furfine, R. J. Hazen, W. M.
Kazmierski, F. G. Salituro, R. D. Tung, and Wright, Bioorg.
Med. Chem. Lett., 10, 1159 (2000).
tate (6C):
Diastereomer 1: An oil; MS m=z 429 (Mþ,
89.95%), 398 (15.78), 370 (19.91), 365 (9.00), 310 (13.13), 306
(17.04), 274 (61.99), 242 (55.24), 214 (7.95), 155 (25.48), 124
(12.50), 91 (100.00), 65 (9.97); IR (neat) 3060, 3027, 2951,
2927, 2861, 1733, 1597, 1496, 1454, 1438, 1362, 1262, 1234,
8
Examples for transformation of ꢀ-lactams to ꢀ-amino acid
derivatives: P. Jouin, B. Castro, and D. Nisato, J. Chem. Soc., Per-
kin Trans. 1, 1987, 1177; to proline derivatives: D. A. DeGoey,
H.-J. Chen, W. J. Flosi, D. J. Grampovnik, C. M. Yeung, L. L.
Klein, and D. J. Kempf, J. Org. Chem., 67, 5445 (2002); S.
Hanessian, M. Bayrakdarian, and X. Luo, J. Am. Chem. Soc.,
124, 4716 (2002); to Sceletium alkaloid: H. Ishibashi, T. S. So,
K. Okochi, T. Sato, N. Nakamura, H. Nakatani, and M. Ikeda,
J. Org. Chem., 56, 95 (1991).
1169, 1115, 1090, 1019, 995, 896, 816, 752, 703, 667 cmꢂ1
;
1H NMR (CDCl3) ꢂ 1.41 (1H, ddd, J ¼ 12:92, 10.00, 8.05 Hz),
1.52–1.66 (3H, m), 2.34 (1H, dd, J ¼ 17:80, 10.00 Hz), 2.35–
2.45 (1H, m), 2.43 (3H, s), 2.52 (1H, ddd, J ¼ 12:92, 10.00,
8.05 Hz), 2.57–2.72 (2H, m), 2.78 (1H, dd, J ¼ 17:80, 3.90 Hz),
2.82 (1H, qd, J ¼ 10:00, 3.90 Hz), 3.63 (3H, s), 4.23 (1H, qd,
J ¼ 8:05, 2.68 Hz), 7.15 (2H, d, J ¼ 8:29 Hz), 7.17–7.25 (1H,
m), 7.26–7.40 (4H, m), 7.89 (2H, d, J ¼ 8:29 Hz). Diastereomer
2: An oil; MS m=z 429 (Mþ, 37.81%), 398 (11.57), 370 (5.55),
365 (11.62), 310 (9.24), 306 (5.93), 274 (72.10), 242 (94.16),
214 (7.77), 155 (31.09), 124 (11.82), 91 (100.00), 65 (12.80);
IR (neat) 3061, 3025, 2951, 2927, 2863, 1733, 1597, 1495,
1454, 1437, 1362, 1168, 1088, 1029, 995, 887, 815, 754, 702,
9
a) K. Inomata, S. Toda, and H. Kinoshita, Chem. Lett.,
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Inomata, Bull. Chem. Soc. Jpn., 64, 3600 (1991). c) Y. Ukaji,
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Chem. Soc. Jpn., 69, 735 (1996). d) S. Takeuchi, Y. Ukaji, and
K. Inomata, Bull. Chem. Soc. Jpn., 74, 955 (2001).
10 Recent examples of related alkoxycarbonylation using
palladium salts: Y. Tamaru, M. Hojo, and Z. Yoshida, J. Org.
Chem., 56, 1099 (1991); O. Hamed, A. El-Qisairi, and P. M.
Henry, J. Org. Chem., 66, 180 (2001); T. Yokota, S. Sakaguchi,
1
662 cmꢂ1; H NMR (CDCl3) ꢂ 1.52–1.76 (3H, m), 1.89 (1H, td,
J ¼ 12:44, 8.53 Hz), 1.98 (1H, ddd, J ¼ 10:97, 7.31, 3.14 Hz),
2.17 (1H, dd, J ¼ 12:44, 8.53 Hz), 2.33 (1H, dd, J ¼ 17:07,
8.53 Hz), 2.43 (3H, s), 2.63 (2H, m), 2.76 (1H, dd, J ¼ 17:07,

1256 Bull. Chem. Soc. Jpn., 76, No. 6 (2003)
Carbonylation of Homoallylic Amine Derivatives
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11 M. I. Bruce, J. Organomet. Chem., 44, 209 (1972).
12 Although the role of copper salt to regenerate Pd(b) species
is not clear in our system, cooperative action of copper salt could
be considered as described for the Wacker process: T.
Hosokawa and S.-I. Murahashi, Acc. Chem. Res., 23, 49 (1990);
T. Hosokawa, M. Takano, S.-I. Murahashi, H. Ozaki, Y.
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Murahashi, J. Am. Chem. Soc., 118, 3990 (1996).
13 At present, the reaction pathways through amine-directed
hydropalladation/intramolecular carbonylation in the present
monocarbonylation14 and amine-directed (carbomethoxy)pallada-
tion/intramolecular carbonylation15 in the dicarbonylation cannot
be ruled out, respectively.
16 R. C. Larock, H. Yang, S. M. Weinreb, and R. J. Herr, J.
Org. Chem., 59, 4172 (1994).
17 Z. K. M. Abd El Samii, M. I. Al Ashmawy, and J. M.
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18 S. Jiang, G. E. Agoston, T. Chen, M.-P. Cabal, and E.
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19 R. D. Miller and P. Goelitz, J. Org. Chem., 46, 1616
(1981).
20 C. Kaiser and J. Weinstock, Org. Synth., Coll. Vol. f, 910
(1988).