Study on halolactamization-γ-hydroxylation or haloiminolactonization of 2,3-alkadienamides

Article abstract of DOI:10.1016/j.tet.2004.10.050

The reactions of 4-mono- or 4-unsubstituted 2,3-alkadienamides with CuX₂ afforded 5-hydroxypyrrol-2(5H)-ones via the sequential lactamization and γ-hydroxylation process in aqueous THF while those of 4,4-disubstituted 2,3-alkadienamides with CuX₂ in THF afforded iminolactones in high yields. Iodoiminolactonization and iodolactamization/ γ-hydroxylation were achieved by the corresponding reaction with I ₂ in THF at rt. The structures of the products depend on the steric hindrance at the 4-position of the starting allenamides. Relatively electron-rich allenes afforded the corresponding products in much higher yields under milder reaction conditions implying the intramolecular electrophilic nature of the cyclization reaction. Graphical abstract.

Full text of DOI:10.1016/j.tet.2004.10.050

Tetrahedron 61 (2005) 251–258
Study on halolactamization-g-hydroxylation or
haloiminolactonization of 2,3-alkadienamides
*
Shengming Ma and Hexin Xie
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
354 Fenglin Lu, Shanghai 200032, People’s Republic of China
Received 29 June 2004; revised 3 October 2004; accepted 8 October 2004
Available online 30 October 2004
Abstract—The reactions of 4-mono- or 4-unsubstituted 2,3-alkadienamides with CuX2 afforded 5-hydroxypyrrol-2(5H)-ones via the
sequential lactamization and g-hydroxylation process in aqueous THF while those of 4,4-disubstituted 2,3-alkadienamides with CuX2 in
THF afforded iminolactones in high yields. Iodoiminolactonization and iodolactamization/g-hydroxylation were achieved by the
corresponding reaction with I2 in THF at rt. The structures of the products depend on the steric hindrance at the 4-position of the starting
allenamides. Relatively electron-rich allenes afforded the corresponding products in much higher yields under milder reaction conditions
implying the intramolecular electrophilic nature of the cyclization reaction.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
provide new methods for the synthesis of pyrrol-2(5H)-ones
(Scheme 1).1,8 In a preliminary communication,9 we have
shown that the reaction of 2,3-allenamides with CuX2
Allenes are a class of compounds with interesting chemical
and physical properties due to the presence of the unique
cumulated diene unit.1,2 For a long period of time or even
now they are still considered unstable, which limits the
study of their chemistry as compared to the chemistry of
alkenes and alkynes.1,2 During the last 5–10 years, much
attention has been paid to the chemistry of allenes probably
due to the observed fact during research that they are not so
unstable and showed nice reactivities and selectivity in
some cases.3–5 We have developed some methodologies
based on the ionic addition of allenes.6 We have also
develop the transition metal-mediated cyclization of allenes
with an a-functionality, which provides efficient and diverse
routes for the selective synthesis of aminoalcohols, carbo-
cycles, and heterocycles.7 Lactams especially 5-membered
lactams are a class of important heterocycles, which exhibit
interesting biological activities. Thus, we turned our
attention to the chemistry of 2,3-allenamides, which may
Scheme 1.
Keywords: g-Hydroxylation; Iminolactones; Allenes.
* Corresponding author. Tel.: C86 216 416 3300; fax: C86 216 416 7510;
e-mail: masm@mail.sioc.ac.cn
Scheme 2.
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.10.050

252
S. Ma, H. Xie / Tetrahedron 61 (2005) 251–258
Scheme 3.
(XZBr, Cl) afforded 5-hydroxypyrrol-2(5H)-ones in THF–
H2O. In this paper we wish to disclose the details of this
reaction.
propargylic bromides/tosylate and amines in the presence
of Et3N and CO (Scheme 2).10,11
N-Benzyl 2-methyl-2,3-butadienamide 2h was prepared by
the reaction of 2-methyl-2,3-butadienoyl chloride with
BnNH2 (Scheme 3).12
2. Results and discussion
2,3-Allenamides 2i–j were synthesized by the DMAP-
catalyzed amidation of the related carboxylic acids with
amines (Scheme 4).10
2.1. Synthesis of starting materials
2,3-Allenamides 2a–g were prepared by the Pd(PPh3)4-
catalyzed carbonylation of 1,2-allenylic bromides or
2.2. Cyclization of 2,3-allenamides with CuBr2
Following our study of 2,3-allenoic acids with CuBr2,13,14
we studied the halolactamization of N-benzyl 2-methyl-
deca-2,3-dienamide 2a with 1.1 equiv of CuBr2. After some
screening, it was observed that the solvent is important.
The reaction proceeded in aqueous THF or acetone to afford
5-hydroxypyrrol-2(5H)-one 4a in w70% yield. Obviously,
a 5-hydoxylation reaction occurred to the initially formed
pyrrol-2(5H)-one 3a (Scheme 5).
Scheme 4.
Some typical results are summarized in Table 1. From the
results in Table 1, it should be noted that (1) R1 can be alkyl
or aryl; R2 can be H or alkyl; R3 can be H, benzyl, or alkyl,
(2) the reaction with CuBr2 is usually faster than that with
CuCl2, (3) the yields are from moderate to good.
The reaction of CuBr2 and a substrate without a substituent
at 4-position, i.e. 2h, afforded the corresponding products
4h in THF/H2O (1:1) in only 48% yield. Thus, optimi-
zation of the reaction condition was conducted. Finally
EtOH–H2O (3:2) was found to be a better reaction
medium for this transformation with the results shown in
Scheme 6.
Scheme 5.
Table 1. Halolactamization–hydroxylation reaction of 2,3-allenamides with CuX2
Entry
2
CuX2, X (equiv)
Temperature (8C)
Time (h)
Yield of 4 (%)a
R1
R2
R3
1
2
3
4
5
6
7
n-C6H13
n-C6H13
n-C7H15
n-C7H15
n-C7H15
Ph
Me
Me
H
H
H
Bn (2a)
Bn (2a)
H (2b)
Bn (2c)
Bn (2c)
n-C4H9 (2d)
n-C4H9 (2d)
Br (1.1)
Cl (1.1)
Br (1.1)
Br (1.1)
Cl (2)
50
18.5
21
22
32
36
24
60
72 (4a)
57 (4b)
69 (4c)
78 (4d)
78 (4e)
94 (4f)
71 (4g)
Reflux
50
50
50
Reflux
Reflux
Me
Me
Br (2)
Cl (4)
Ph
a Isolated yields.

S. Ma, H. Xie / Tetrahedron 61 (2005) 251–258
253
Furthermore, when we ran this reaction with 4,4-disubsti-
tuted 2,3-alkadienamides, instead of 5-hydroxypyrrol-
2(5H)-one, iminolactones 515 were formed smoothly in
THF at rt in fairly high yield. In the preliminary
communication,9 we assigned it to pyrrol-2(5H)-ones,
which was proven to be a wrong structure based on the
further 13C NMR analysis and its conversion to the known
derivative 616 by the related Pd-catalyzed coupling reaction
(Scheme 7). It should be noted that only Z-5e was obtained
in this reaction. The configuration of C]N bond in others
products 5 was tentatively assigned based on this coupling
result. From the typical results shown in Table 2, it can be
concluded that the reaction was very fast (completed within
2 h) and the scope is broad.
Scheme 6.
2.3. Iodoiminolactonization/lactamization–
hydroxylation of 2,3-alkadienamides
The reaction of 4,4-disubstituted 2,3-alkadienamides with I2
in THF at rt also proceeded to produce 4-iodoiminolactones
Z-5k–n in good yields (Table 3).
The reaction of 4-mono or 4-unsubstituted 2,3-alkadien-
amides with I2 in THF followed by oxidation with O2 at rt
afforded 5-hydroxypyrrol-2(5H)-ones 4j–k (Scheme 8).
Scheme 7.
Table 2. Synthesis of iminolactones via the reaction of 4,4-disubstituted 2,3-alkadienamides with CuX2
Entry
2
CuX2
XZ
Time (h)
Yield of 5 (%)a (Z-5:E-5)b
R1
R2
R3
R4
(equiv)
1
2
3
4
5
6
7
8
9
10
Me
Me
Ph
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
H
H
H
H
Bn
Bn
H
H
Me
Me
Bn (2e)
Bn (2e)
Bn (2g)
Bn (2g)
Bn (2i)
Bn (2i)
n-Bu (2f)
n-Bu (2f)
Bn (2j)
Bn (2j)
Br
Cl
Br
Cl
Br
Cl
Br
Cl
Br
Cl
1.1
1.1
3
3
3
1
1
1
2
1
1
1
1
2
1
85 (5a) (O97:3)
85 (5b) (O98:2)
99 (5c) (O99:1)
98 (5d) (96:4)
94 (5e) (100:0)
97 (5f) (100:0)
78 (5g) (O98:2)
68 (5h) (O96:4)
82 (5i) (100:0)
95 (5j) (100:0)
Ph
Me
Me
Me
Me
Me
Me
3
1.1
1.1
1.1
1.1
a Isolated yield.
b The ratios were determined by 1H NMR spectra.
Table 3. Synthesis of 4-iodoiminolactones via the reaction of I2 with 4,4-disubstituted 2,3-alkadienamides
Entry
2
Time (h)
Yield of 5 (%)a (Z-5:E-5)b
R1
R2
R3
1
2
3
4
Me
Me
Me
Me
Me
Ph
Me
Me
H (2e)
H (2g)
Bn (2i)
Me (2j)
3
75 (5k) (95:5)
84 (5l) (96:4)
92 (5m) (100:0)
99 (5n) (100:0)
26
16
16
a Isolated yield.
b The ratios were determined by 1H NMR spectra.

254
S. Ma, H. Xie / Tetrahedron 61 (2005) 251–258
Pd(PPh3)4 (64 mg, 0.05 mmol) sequentially. The autoclave
was charged with CO with a pressure of 18 atm. After the
mixture was stirred for 1 h at rt, CO was released. The
reaction was quenched with water followed by the addition
of CH2Cl2. After separation, the organic phase was washed
sequentially with 1 N HCl and brine. After evaporation, the
residue was purified by flash chromatography on silica gel
1
to afford 1.12 g (83%) of allenamide 2a: colorless oil; H
NMR (300 MHz, CDCl3) d 7.36–7.24 (m, 5H), 6.32 (bs,
1H), 5.52–5.45 (m, 1H), 4.48 (d, JZ6 Hz, 2H), 2.08 (q, JZ
7 Hz, 2H), 1.91 (d, JZ2.7 Hz, 3H), 1.45–1.18 (m, 8H), 0.87
(t, JZ6.6 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) d 205.0,
166.8, 138.5, 128.5, 127.4, 127.2, 98.1, 96.0, 43.6, 31.4,
28.7, 28.7, 28.3, 22.5, 14.4, 14.0; MS m/z 271 (MC, 19.43),
91 (100); IR (neat) 3347, 1955, 1655 cmK1; HRMS cacld
for C18H25NO 271.1936; found 271.1949.
Scheme 8.
It is quite obvious that the reaction is electrophilic in nature
since the relatively electron richer amides provided the
corresponding products in generally higher yields at a lower
temperature (compare the results of Tables 1 and 2). Both
the nitrogen and the carbonyl oxygen in starting materials
may act as the intramolecular nucleophile. The selectivity
clearly depends on the steric hindrance of 4-position of the
amides, i.e. with 4-mono or 4-non-substituted 2,3-alka-
dienamides, pyrrol-2(5H)-ones were formed highly selec-
tively, which was followed by g-hydroxylation affording
5-hydroxypyrrol-2(5H)-ones while the reaction of 4,4-di-
substituted 2,3-alkadienamides afforded iminolactones
(Scheme 9).
The following compounds 2b–2c were prepared according
to Typical procedures A.
3.1.2. 2,3-Undecadienamide (2b).
The reaction of 3-bromo-1-decyne (1.02 g, 4.7 mmol),
NH3$H2O (0.4 mL, 5.2 mmol), Et3N (0.72 mL, 5.2 mmol),
Scheme 9.
In conclusion, we have developed the haloiminolactoniza-
tion and halolactamization–hydroxylation reaction of
2,3-allenanimdes providing an efficient route for the highly
selective synthesis of iminolactones or 5-hydroxypyrrol-
2(5H)-ones, respectively, depending on the steric hindrance
of 4-position of 2,3-allenamides. Further studies in this area
are being carried out in our laboratory.
and Pd(PPh3)4 (54 mg, 0.047 mmol) in THF (25 mL) at rt
for 2 h afforded 0.58 g (68% yield) of 2b; white solid; mp
1
88–99 8C (n-hexane); H NMR (300 MHz, CDCl3) d 5.75
(bs, 1H), 5.67–5.52 (m, 3H), 2.18–2.10 (m, 2H), 1.55–1.20
(m, 10H), 0.87 (t, JZ6.6 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) d 208.4, 168.2, 96.5, 90.7, 31.6, 28.9, 28.9, 28.7,
27.7, 22.5, 13.9; MS m/z 180 (MCK1, 1.46), 96 (100); IR
(KBr) 3339, 3176, 1962, 1658 cmK1. Anal. Calcd for
C11H19NO: C, 72.88; H, 10.56; N, 7.73. Found: C, 72.82; H,
10.64; N, 7.52.
3. Experimental
3.1. Synthesis of starting materials
3.1.3. N-Benzyl 2,3-undecadienamide (2c). The reaction
of 3-bromo-1-decyne (1.09 g, 5.0 mmol), BnNH2 (0.6 mL,
5.5 mmol), Et3N (0.77 mL, 5.5 mmol), and Pd(PPh3)4
(64 mg, 0.05 mmol) in THF (20 mL) at rt for 1.5 h afforded
0.92 g (68% yield) of 2c; white solid; mp 88–90 8C
The known compounds 2e–2g, and 2i–2j were prepared
according to the reported procedure.10
1
3.1.1. N-Benzyl 2-methyl-2,3-decadienamide (2a). Typical
procedure A. A stainless steel autoclave (250 mL) fitted
with a glass reactor with a stirring bar inside was charged
with THF (20 mL), 3-bromo-2-decyne (1.09 g, 5 mmol),
BnNH2 (0.6 mL, 5.5 mmol), Et3N (0.77 mL, 5.5 mmol), and
(n-hexane); H NMR (300 MHz, CDCl3) d 7.38–7.20 (m,
5H), 6.22 (bs, 1H), 5.63–5.57 (m, 2H), 4.47 (d, JZ5.7 Hz,
2H), 2.15–2.06 (m, 2H), 1.50–1.20 (m, 10H), 0.88 (t, JZ
6.9 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) d 207.5, 165.1,
138.3, 128.6, 127.5, 127.3, 96.9, 91.2, 43.5, 31.6, 29.0, 28.9,

S. Ma, H. Xie / Tetrahedron 61 (2005) 251–258
255
28.7, 27.8, 22.5, 14.0; MS m/z 271 (MC, 22.04), 186 (100);
IR (KBr) 3279, 1961, 1629 cmK1. Anal. Calcd for
C18H25NO: C, 79.66; H, 9.28; N, 5.16. Found: C, 79.67;
H, 9.23; N, 4.94.
CDCl3) d 7.36–7.26 (m, 5H), 6.30 (bs, 1H), 5.09 (q, JZ
3.0 Hz, 2H), 4.48 (d, JZ6.0 Hz, 2H), 1.92 (t, JZ3.0 Hz,
3H); 13C NMR (75.4 MHz, CDCl3) d 209.7, 166.1, 138.4,
128.6, 127.6, 127.3, 97.6, 79.7, 43.7, 13.9; MS m/z 187
(MC, 18.39), 91 (100); IR (KBr) 3422, 1944, 1641 cmK1
.
Anal. Calcd for C12H13NO: C, 76.98; H, 7.00; N, 7.48.
Found: C, 76.91; H, 7.13; N, 7.35.
3.1.4. N-Benzyl 4-phenyl-2,3-pentadienamide (2g). The
reaction of 1-bromo-3-phenyl-1,2-butadiene (0.87 g,
4.1 mmol), BnNH2 (0.5 mL, 4.5 mmol), Et3N (0.65 mL,
4.5 mmol), and Pd(PPh3)4 (49 mg, 0.04 mmol) in THF
(25 mL) at rt for 1.5 h afforded 0.77 g (71% yield) of 2g;
white solid; mp 139–140 8C (Et2O–CH2Cl2); 1H NMR
(300 MHz, CDCl3) d 7.42–7.26 (m, 10H), 6.04 (bs, 1H),
5.98 (q, JZ2.7 Hz, 1H), 4.59–4.43 (m, 2H), 2.21 (d, JZ
2.7 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) d 208.6, 164.5,
138.2, 134.0, 128.5, 128.5, 127.8, 127.4, 127.2, 125.9,
106.4, 92.9, 43.4, 16.3; MS m/z 263 (MC, 19.88), 91 (100);
IR (KBr) 3273, 1947, 1639 cmK1. Anal. Calcd for
C18H17NO: C, 82.10; H, 6.51; N, 5.32. Found: C, 82.03;
H, 6.26; N, 5.12.
3.2. Halolactamization-g-hydroxylation of 2,3-
allenamides with CuX2. General procedure B
A solution of 2,3-allenamide (2) (0.5 mmol) and CuX2 (1.1–
4 equiv) in THF/H2O (1:1) (or enthanol/H2O (3:2)) (8 mL)
was stirred at 50 8C. When the reaction was complete, the
mixture was then quenched with saturated NH4Cl and
extracted five times with chloroform. The organic layer was
combined and dried over Na2SO4. After evaporation, the
residue was purified via flash chromatography on silica gel
to afford 4a–g. All of the solid products were recrystallized
from petroleum ether.
3.1.5. N-Butyl 2-methyl-4-phenyl-2,3-butadienamide
(2d). In a dry flask containing 1-phenyl-2-butyn-1-ol
(580 mg, 4.0 mmol) in 40 mL THF was added n-BuLi
(2.5 mL (1.6 M in hexane), 4.0 mmol) dropwise at K60 8C.
After stirring for 30 min at K60 8C, TsCl (762 mg,
4.0 mmol) was added. The mixture was stirred for 15 min
at K60 8C and then for 2 h at rt. Then, n-BuNH2 (0.35 mL,
4.0 mmol), Et3N (0.56 mL, 4.0 mmol), and Pd(PPh3)4
(46 mg, 0.04 mmol) were added sequentially at K78 8C.
The autoclave was charged with CO with a pressure of 25
atm. After the mixture was stirred for 1 h at rt, CO was
released. The reaction was quenched with water followed by
the addition of CH2Cl2. After separation, the organic phase
was washed sequentially with 1 N HCl and brine. After
evaporation, the residue was purified by flash chromato-
3.2.1. 4-Bromo-1-benzyl-5-n-hexyl-5-hydroxy-3-methyl-
pyrrol-2(5H)-one (4a). The reaction of 1a (75 mg,
0.28 mmol) and CuBr2 (68 mg, 0.30 mmol) in THF
(4 mL) and H2O (4 mL) at 50 8C for 18.5 h afforded
73 mg (72% yield) of 2a: white solid; mp 119–119.5 8C;
1H NMR (300 MHz, CDCl3) d 7.43–7.35 (m, 2H), 7.35–
7.25 (m, 3H), 4.65 (d, JZ15.00 Hz, 1H), 4.42 (d, JZ
15.00 Hz, 1H), 2.98 (s, 1H), 1.92 (s, 32H), 2.10–1.59 (m,
2H), 1.12–0.45 (m, 8H), 0.79 (t, JZ7.14 Hz, 3H); 13C NMR
(75.4 MHz, CDCl3) d 168.8, 139.2, 137.9, 134.1, 128.8,
128.5, 127.5, 92.5, 42.7, 34.3, 31.4, 28.5, 22.6, 22.4, 14.0,
10.5; MS m/z 368 (MC(81Br)C1, 22.17), 366 (MC(79Br)C
1, 23.76), 91 (100); IR (KBr) 3303, 1677, 1072, 1026 cmK1
.
Anal. Calcd for C18H24BrNO2: C 59.02, H 6.60, N 3.82.
Found: C 59.15, H 6.74, N 3.82.
1
graphy on silica gel to afford 0.59 g (65%) of 2d: oil; H
NMR (300 MHz, CDCl3) d 7.34–7.20 (m, 5H), 6.48 (q, JZ
3 Hz, 1H), 6.07 (bs, 1H), 3.33–3.14 (m, 2H), 1.99 (d, JZ
3 Hz, 3H), 1.48–1.39 (m, 2H), 1.33–1.21 (m, 2H), 0.87 (t,
JZ7.1 Hz, 3H); 13C NMR (75.4 MHz, CDCl3) d 206.6,
165.3, 132.3, 128.7, 127.7, 126.9, 102.0, 98.4, 39.4, 31.5,
19.8, 14.2, 13.5; MS m/z 229 (MC, 10.01), 84 (100); IR
(neat) 3333, 1943, 1651 cmK1; HRMS cacld for C15H19NO
229.14666, found 229.14891.
The compounds 4b–4i9 were prepared according to Typical
procedure B in the text, and the data of these compounds can
be found in the supporting information of Ref. 2.
3.3. Haloiminolactonization of 2,3-alkadienamide.
General procedure C
A solution of 2,3-allenamide (0.5 mmol) and CuX2 (1.1–
3 equiv) in THF (5 mL) was stirred at rt. When the reaction
was complete, 10 mL of Et2O and 10 mL of saturated
NH4Cl were added. The mixture was stirred for 5 min and
extracted three times with Et2O. The organic layer was
combined and dried over Na2SO4. After evaporation, the
residue was purified via flash chromatography on silica gel
to afford 5a–5j.
3.1.6. N-Benzyl 2-methyl-2,3-butadienamide (2h). In a
dry flask containing 2-methylbuta-2,3-dienoic acid
(922 mg, 9.4 mmol) was added SOCl2 (1.4 mL,
18.8 mmol). After stirring for 30 min at rt, the excess
SOCl2 was removed under reduced pressure to afford
2-methylbuta-2,3-dienoyl chloride, which was dissolved in
dry ether (30 mL) for conversion in the next step.
To a mixture of benzylamine (1.1 mL, 10.3 mmol) and Et3N
(1.4 mL, 10.3 mmol) in dry ether (30 mL) was added
2-methyl buta-2,3-dienoyl chloride in dry ether dropwise at
rt. After the mixture was stirred overnight, the reaction
was quenched with water followed by the addition of ether.
After separation, the water phase was extracted twice with
ether and the combined organic layer was dried over
MgSO4. After evaporation, the residue was purified by flash
chromatography on silica gel to afford 655 mg (38%) of 2h
3.3.1. Z-2-Benzylimino-4-bromo-5,5-dimethyl-2,5-dihy-
drofuran (5a). The reaction of 2e (112 mg, 0.56 mmol)
and CuBr2 (137 mg, 0.61 mmol) in THF (5 mL) at rt for 1 h
afforded 132 mg (85% yield) of 5a (Z-5a:E-5aO97:3); light
1
yellow oil; H NMR (300 MHz, CDCl3) Z-5a: d 7.37–7.22
(m, 5H), 6.25 (s, 1H), 4.51 (s, 2H), 1.51 (s, 6H). The
following data were discernible for the E isomer, E-5a: 6.54
(s, 1H); 13C NMR (75.4 MHz, CDCl3) d 160.5, 144.3, 140.5,
128.3, 127.8, 126.4, 123.7, 90.8, 50.8, 25.4; MS m/z 281
(MC(81Br), 30.18), 279 (MC(79Br), 32.65), 91 (100); IR
1
white solid; mp 76–78 8C (n-hexane); H NMR (300 MHz,

256
S. Ma, H. Xie / Tetrahedron 61 (2005) 251–258
(neat) 1687 cmK1; HRMS cacld for C13H BrNO 279.0259;
found 279.0264.
(75.4 MHz, CDCl3) d 159.5, 148.2, 141.0, 137.8, 128.8,
128.8, 128.3, 128.1, 127.3, 126.3, 126.1, 87.3, 50.2, 29.8,
25.2; MS m/z 327 (MC(37Cl), 36.93), 325 (MC(35Cl),
84.57), 91 (100); IR (neat) 1683 cmK1. Anal. Calcd for
C20H20ClNO: C 73.72, H 6.19, N 4.30. Found: C 73.36, H
6.09, N 4.20.
79
14
3.3.2. Z-2-Benzylimino-4-chloro-5,5-dimethyl-2,5-dihy-
drofuran (5b). The reaction of 2e (119 mg, 0.59 mmol)
and CuCl2$2H2O (111 mg, 0.65 mmol) in THF (5 mL) at rt
for 1 h afforded 119 mg (85% yield) of 5b (Z-5b:E-5bO
1
98:2), colorless oil; H NMR (300 MHz, CDCl3) Z-5b: d
3.3.7. Z-2-n-Butylimino-4-bromo-5,5-dimethyl-2,5-dihy-
drofuran (5g). The reaction of 2f (119 mg, 0.71 mmol) and
CuBr2 (175 mg, 0.78 mmol) in THF (5 mL) at rt for 1 h
afforded 137 mg (78% yield) of 5g (Z-5g:E-5gO98:2); light
7.37–7.25 (m, 5H), 6.09 (s, 1H), 4.53 (s, 2H), 1.51 (s, 6H).
The following data were discernible for the E isomer, E-5b:
d 6.38 (s, 1H), 4.50 (s, 2H); 13C NMR (75.4 MHz, CDCl3) d
159.6, 154.1, 140.5, 128.3, 127.8, 126.4, 119.2, 89.5, 50.8,
25.0; MS m/z 237 (MC(37Cl), 12.82), 235 (MC(35Cl),
1
yellow oil; H NMR (300 MHz, CDCl3) Z-5g: d 6.14 (s,
1H), 3.25 (t, JZ6.9 Hz, 2H), 1.56–1.51 (m, 2H), 1.44 (s,
6H), 1.38–1.30 (m, 2H), 0.90 (t, JZ7.4 Hz, 3H). The
following data were discernible for the E isomer, E-5g: d
6.42 (s, 1H); 13C NMR (75.4 MHz, CDCl3) d 159.7, 143.8,
123.7, 90.4, 46.4, 32.9, 25.4, 20.5, 13.8; MS m/z 248
(MC(81Br)C1, 23.52), 246 (MC(79Br)C1, 27.67), 160
38.02), 91 (100); IR (neat) 1689, 1631 cmK1; HRMS cacld
35
for C13H ClNO 235.0764; found 235.0757.
14
3.3.3. Z-2-Benzylimino-4-bromo-5-phenyl-5-methyl-2,5-
dihydrofuran (5c). The reaction of 2g (67 mg, 0.25 mmol)
and CuBr2 (168 mg, 0.75 mmol) in THF (5 mL) at rt for 1 h
afforded 86 mg (99% yield) of 5c (Z-5c:E-5cO99:1); light
(100); IR (neat) 1692, 1604 cmK1; HRMS cacld for
79
C10H BrNO 245.0415; found 245.0370.
16
1
yellow oil; H NMR (300 MHz, CDCl3) Z-5c: d 7.43–7.26
(m, 10H), 6.38 (s, 1H), 4.63 (s, 2H), 1.95 (s, 3H). The
following data were discernible for the E isomer, E-5c: d
6.63 (s, 1H); 13C NMR (75.4 MHz, CDCl3) d 160.7, 144.6,
140.3, 138.4, 128.6, 128.5, 128.3, 127.9, 126.5, 125.5,
123.8, 92.5, 51.1, 23.8; MS m/z 344 (MC(81Br)C1, 5.47),
342 (MC(79Br)C1, 6.58), 105 (100); IR (neat) 1687,
3.3.8. Z-2-n-Butylimino-4-chloro-5,5-dimethyl-2,5-dihy-
drofuran (5h). The reaction of 2f (126 mg, 0.75 mmol) and
CuCl2$2H2O (142 mg, 0.83 mmol) in THF (6 mL) at rt for
1 h afforded 103 mg (68% yield) of 5h (Z-5h:E-5hO96:4);
1
colorless oil; H NMR (300 MHz, CDCl3) Z-5h: d 5.96 (s,
1H), 3.24 (t, JZ7.1 Hz, 2H), 1.52–1.46 (m, 2H), 1.41 (s,
6H), 1.34–1.27 (m, 2H), 0.86 (t, JZ7.2 Hz, 3H). The
following data were discernible for the E isomer, E-5h: d
6.23 (s, 1H), 3.19 (t, JZ7.2 Hz, 2H); 13C NMR (75.4 MHz,
CDCl3) d 158.8, 153.5, 119.1, 88.9, 46.3, 32.9, 24.9, 20.5,
13.8; MS m/z 203 (MC(37Cl), 4.27), 201 (MC(35Cl), 12.79),
1602 cmK1; HRMS cacld for C18H BrNO 341.04153;
79
16
found 341.04516.
3.3.4. Z-2-Benzylimino-4-chloro-5-phenyl-5-methyl-2,5-
dihydrofuran (5d). The reaction of 2g (85 mg, 0.32 mmol)
and CuCl2$2H2O (165 mg, 0.97 mmol) in THF (5 mL) at rt
for 2 h afforded 94 mg (98% yield) of 5d (Z-5d:E-5dZ
96:4); light yellow oil; 1H NMR (300 MHz, CDCl3) Z-5d: d
7.34–7.20 (m, 5H), 6.14 (s, 1H), 4.57 (s, 2H), 1.87 (s, 3H).
The following data were discernible for the E isomer, E-5d:
d 6.39 (s, 1H), 4.53 (s, 2H); 13C NMR (75.4 MHz, CDCl3) d
159.7, 154.0, 140.4, 138.4, 128.6, 128.5, 128.3, 127.8,
126.5, 125.3, 119.3, 91.2, 51.0, 23.6; MS m/z 299
(MC(37Cl), 0.79), 297 (MC(35Cl), 1.92), 105 (100); IR
130 (100); IR (neat) 1694, 1614 cmK1; HRMS cacld for
35
C10H ClNO 201.09204; found 201.08779.
16
3.3.9. Z-2-Benzylimino-3-methyl-4-bromo-5,5-dimethyl-
2,5-dihydrofuran (5i). The reaction of 2i (96 mg,
0.45 mmol) and CuBr2 (110 mg, 0.49 mmol) in THF
(5 mL) at rt for 2 h afforded 108 mg (82% yield) of Z-5i;
1
light yellow oil; H NMR (300 MHz, CDCl3) d 7.41–7.22
(m, 5H), 4.57 (s, 2H), 1.91 (s, 3H), 1.47 (s, 6H); 13C NMR
(75.4 MHz, CDCl3) d 161.0, 140.8, 139.1, 129.7, 128.2,
127.6, 126.3, 88.4, 50.5, 25.6, 10.9; MS m/z 294
(MC(81Br)K1, 37.11), 292 (MC(79Br)K1, 36.26), 105
(neat) 1687, 1612 cmK1; HRMS cacld for C18H ClNO
35
16
297.0920; found 297.0932.
(100); IR (neat) 1691, 1655 cmK1; HRMS cacld for
3.3.5. Z-2-Benzylimino-3-benzyl-4-bromo-5,5-dimethyl-
2,5-dihydrofuran (5e). The reaction of 2i (62 mg,
0.21 mmol) and CuBr2 (143 mg, 0.61 mmol) in THF
(4 mL) at rt for 1 h afforded 74 mg (94% yield) of Z-5e;
79
13
C13H BrNO (MCKCH3) 278.0179; found 278.0177.
3.3.10.
Z-2-Benzylimino-3-methyl-4-chloro-5,5-di-
1
yellow oil; H NMR (300 MHz, CDCl3) d 7.48–7.22 (m,
methyl-2,5-dihydrofuran (5j). The reaction of 2j
(105 mg, 0.49 mmol) and CuCl2$2H2O (92 mg,
0.54 mmol) in THF (5 mL) at rt for 1 h afforded 116 mg
10H), 4.51 (s, 2H), 3.70 (s, 2H), 1.48 (s, 6H); 13C NMR
(75.4 MHz, CDCl3) d 159.9, 141.0, 140.0, 137.7, 132.5,
128.8, 128.3, 128.1, 127.3, 126.3, 126.1, 88.4, 50.2, 31.1,
25.7; MS m/z 371 (MC(81Br), 52.32), 369 (MC(79Br),
54.98), 91 (100); IR (neat) 1682 cmK1. Anal. Calcd for
C20H20BrNO: C 64.87, H 5.44, N 3.78. Found: C 64.75, H
5.50, N 3.97.
1
(95% yield) of Z-5j; light yellow oil; H NMR (300 MHz,
CDCl3) d 7.42–7.23 (m, 5H), 4.60 (s, 2H), 1.92 (s, 3H), 1.48
(s, 6H); 13C NMR (75.4 MHz, CDCl3) d 160.7, 147.4, 140.8,
128.1, 127.6, 126.3, 125.8, 87.3, 50.4, 25.1, 9.3; MS m/z 251
(MC(37Cl), 30.49), 249 (MC(35Cl), 58.32), 91 (100); IR
35
16
(neat) 1693,1664 cmK1; HRMS cacld for C14H ClNO
249.0920; found 249.0932.
3.3.6. Z-2-Benzylimino-3-benzyl-4-chloro-5,5-dimethyl-
2,5-dihydrofuran (5f). The reaction of 2i (48 mg,
0.16 mmol) and CuCl2$2H2O (84 mg, 0.45 mmol) in THF
(4 mL) at rt for 1 h afforded 52 mg (97% yield) of Z-5f;
3.4. Iodoiminolactonization of 2,3-alkadienamide.
General procedure D
1
yellow oil; H NMR (300 MHz, CDCl3) d 7.43–7.24 (m,
10H), 4.64 (s, 2H), 3.75 (s, 2H), 1.53 (s, 6H); 13C NMR
A solution of 2,3-allenamide (0.5 mmol) and I2 (2 equiv) in

S. Ma, H. Xie / Tetrahedron 61 (2005) 251–258
257
THF (4 mL) was stirred at rt. When the reaction was
complete, 10 mL of Et2O was added, and then a solution
of Na2S2O3 was added to remove the excess I2. After
extraction with Et2O, drying over Na2SO4, and evaporation,
the residue was purified via flash chromatography on silica
gel to afford 5k–5n.
over Na2SO4, and evaporation, the residue was purified via
flash chromatography on silica gel to afford 4j–k.
3.5.1. 1-Benzyl-5-hydroxy-5-heptyl-4-iodopyrrol-2(5H)-
one (4j). The reaction of 2b (63 mg, 0.23 mmol) and I2
(118 mg, 0.46 mmol) in THF (5 mL) at rt for 24 h afforded
85 mg (89% yield) of 4j: light yellow solid; mp 106–108 8C
(n-hexane–Et2O); 1H NMR (300 MHz, CDCl3) d 7.37–7.19
(m, 5H), 6.52 (s, 1H), 4.58 (d, JZ15 Hz, 1H), 4.42 (d, JZ
15 Hz, 1H), 2.78 (s, 1H), 1.76–1.58 (m, 2H), 1.19–0.45 (m,
10H), 0.79 (t, JZ7.4 Hz, 3H); 13C NMR (75.4 MHz,
CDCl3) d 169.0, 137.6, 135.3, 128.8, 128.4, 127.5, 123.1,
95.0, 42.8, 34.8, 31.5, 28.8, 28.7, 22.5, 22.2, 14.0; MS m/z
413 (MC, 1.66), 91 (100); IR (KBr) 3197, 1673, 1652 cmK
1. Anal. Calcd for C18H24INO2: C, 52.31; H, 5.85; N, 3.39.
Found: C, 52.45; H, 6.02; N, 3.19.
3.4.1. Z-2-Benzylimino-4-iodo-5,5-dimethyl-2,5-dihydro-
furan (5k). The reaction of 2e (106 mg, 0.53 mmol) and I2
(268 mg, 1.06 mmol) in THF (4 mL) at rt for 3 h afforded
129 mg (75% yield) of 5k (Z-5k:E-5kZ95:5); light yellow
oil; 1H NMR (300 MHz, CDCl3) Z-5k: d 7.37–7.20 (m, 5H),
6.43 (s, 1H), 4.50 (s, 2H), 1.47 (s, 6H). The following data
were discernible for the E isomer, E-5k: 6.73 (s, 1H), 4.49
(s, 2H); 13C NMR (75.4 MHz, CDCl3) d 162.03, 140.37,
131.86, 128.19, 127.70, 126.35, 119.54, 92.67, 50.75, 25.92;
MS m/z 327 (MC, 42.23), 95 (100); IR (neat) 1758,
1681 cmK1; HRMS cacld for C13H14INO 327.0120; found
327.0128.
3.5.2. 1-Benzyl-5-hydroxy-4-iodo-3-methylpyrrol-2(5H)-
one (4k). The reaction of 2k (70 mg, 0.37 mmol) and I2
(191 mg, 0.75 mmol) in THF (5 mL) at rt for 42 h afforded
71 mg (58% yield) of 4k: white solid; mp 108–109 8C
(n-hexane–Et2O); 1H NMR (300 MHz, CDCl3) d 7.33–7.26
(m, 5H), 5.03 (d, JZ6.9 Hz, 1H), 4.94 (d, JZ14.4 Hz, 1H),
4.26 (d, JZ14.4 Hz, 1H), 4.11 (bs, 1H), 1.86 (s, 3H); 13C
NMR (75.4 MHz, CDCl3) d 167.3, 142.0, 136.5, 128.7,
128.3, 127.7, 112.5, 84.7, 43.5, 13.3; MS m/z 329 (MC,
11.56), 124 (100); IR (KBr) 3317, 1678 cmK1. Anal. Calcd
for C12H12INO2: C, 43.79; H, 3.67; N, 4.26. Found: C,
43.89; H, 3.67; N, 4.06.
3.4.2. Z-2-Benzylimino-4-iodo-5-methyl-5-phenyl-2,5-di-
hydrofuran (5l). The reaction of 2g (47 mg, 0.18 mmol)
and I2 (91 mg, 0.36 mmol) in THF (5 mL) at rt for 26 h
afforded 59 mg (84% yield) of 5l (Z-5l:E-5lZ96:4); light
1
yellow oil; H NMR (300 MHz, CDCl3) d 7.41–7.22 (m,
10H), 6.56 (s, 1H), 4.60 (s, 2H), 1.91 (s, 3H). The following
data were discernible for the E isomer, E-5l: d 6.84 (s, 1H);
13C NMR (75.4 MHz, CDCl3) d 162.4, 140.3, 138.6, 131.8,
128.6, 128.5, 128.3, 127.9, 126.5, 125.8, 120.7, 94.5, 51.1,
24.2; MS m/z 389 (MC, 5.86), 129 (100); IR (neat)
1680 cmK1; HRMS cacld for C18H16INO 389.0277; found
389.0318.
Acknowledgements
3.4.3. Z-2-Benzylimino-3-benzyl-4-iodo-5,5-dimethyl-
2,5-dihydrofuran (5m). The reaction of 2i (78 mg,
0.27 mmol) and I2 (136 mg, 0.54 mmol) in THF (5 mL) at
rt for 16 h afforded 103 mg (92% yield) of Z-5m; colorless
oil; 1H NMR (300 MHz, CDCl3) d 7.48–7.26 (m, 10H), 4.63
(s, 2H), 3.77 (s, 2H), 1.50 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) d 160.5, 141.0, 139.3, 137.7, 128.9, 128.2, 128.1,
127.3, 126.3, 126.1, 118.4, 89.8, 50.3, 33.4, 26.3; MS m/z
We are grateful to the Major State Basic Research
Development Program (Grant No. G2000077500), National
Natural Science Foundation of China, and Shanghai
Municipal Committee of Science and Technology for
financial support.
417 (MC, 25.25), 91 (100); IR (neat) 1681, 1629 cmK1
HRMS cacld for C20H20INO 417.0590; found 417.0569.
;
References and notes
3.4.4. Z-2-Benzylimino-3-methyl-4-iodo-5,5-dimethyl-
2,5-dihydrofuran (5n). The reaction of 2j (21 mg,
0.10 mmol) and I2 (50 mg, 0.20 mmol) in THF (3 mL) at
rt for 16 h afforded 33 mg (99% yield) of Z-5n; colorless oil;
1H NMR (300 MHz, CDCl3) d 7.39–7.21 (m, 5H), 4.55 (s,
2H), 1.94 (s, 3H), 1.45 (s, 6H); 13C NMR (75.4 MHz,
CDCl3) d 161.5, 140.8, 136.7, 128.2, 127.7, 126.3, 117.3,
89.7, 50.6, 26.3, 13.8; MS m/z 341 (MC, 43.86), 81 (100);
IR (neat) 1686, 1639 cmK1; HRMS cacld for C14H16INO
341.0277; found 341.0253.
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