Preparation and electrophilic cyclization of multisubstituted dienamides leading to cyclic iminoethers

Article abstract of DOI:10.1021/jo050433q

Stereodefined multisubstituted dienamides could be concisely prepared in high yields by direct addition of 1-lithiobutadiene derivatives to both N-aryl and N-alkyl isocyanates. Electrophilic cyclization of these dienamides was achieved to generate substit

Full text of DOI:10.1021/jo050433q

Preparation and Electrophilic Cyclization of Multisubstituted
Dienamides Leading to Cyclic Iminoethers
Congyang Wang,† Jiang Lu,† Guoliang Mao,† and Zhenfeng Xi*,†,‡
Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education,
College of Chemistry, Peking University, Beijing 100871, China, and State Key Laboratory of
Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences,
Shanghai 200032, China
zfxi@pku.edu.cn
Received March 7, 2005
Stereodefined multisubstituted dienamides could be concisely prepared in high yields by direct
addition of 1-lithiobutadiene derivatives to both N-aryl and N-alkyl isocyanates. Electrophilic
cyclization of these dienamides was achieved to generate substituted cyclic iminoethers in excellent
yields with perfect selectivity. When treated with 12 N aqueous HCl, dienamides underwent efficient
and selective electrophilic cyclization to afford cyclic imidate derivatives. When treated with NBS,
monobrominated or double-brominated cyclic iminoethers were formed.
Introduction
Nonconjugated unsaturated amides 1 (Figure 1) have
been found to be very useful for the preparation of various
functionalized lactones, lactams, and oxazolines via elec-
trophilic cyclization (Scheme 1).1,2 Conjugated R,â-
unsaturated amides 2 (Figure 1) have also been applied
for the preparation of four-membered heterocycles through
endo or exo cyclization, depending on the reaction condi-
tions, the substitution patterns, and the electrophiles
used.3 Both O-attack and N-attack pathways have been
reported to predominately afford lactones or lactams as
the final products.1-3 Competition between these two
pathways from the same substrate was observed in a few
cases.1,4,5
FIGURE 1. Conjugated and nonconjugated unsaturated
amides.
SCHEME 1. Electrophilic Cyclization of
Nonconjugated Unsaturated Amides
† Peking University.
Although a number of preparative methods for dien-
‡ State Key Laboratory of Organometallic Chemistry.
(1) For a review on electrophilic cyclization of unsaturated amides,
see: Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681-13736.
(2) For a review on formation of four-membered heterocycles via
electrophilic cyclization of unsaturated amides, see: Robin, S.; Rous-
seau, G. Eur. J. Org. Chem. 2002, 3099-3114.
amides 3 have appeared in the literature6-11 and useful
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10.1021/jo050433q CCC: $30.25 © 2005 American Chemical Society
Published on Web 05/25/2005
5150
J. Org. Chem. 2005, 70, 5150-5156

Electrophilic Cyclization of Multisubstituted Dienamides
SCHEME 2. Reaction of Organolithium Reagents
5 with Isocyanates Leading to Dienamides 3
heterocycles can be expected from electrophilic cyclization
reaction of dienamides 3 (Figure 1), few examples have
been reported on this kind of investigation.3,12,13
In this paper, we report an alternative synthesis of
these conjugated unsaturated amides 3 and their ap-
plications to the preparation of heterocycles via electro-
philic cyclization. Surprisingly, our results reveal that
these multisubstituted dienamides 3 undergo the elec-
trophilic cyclization exclusively through the O-attack
pathway to afford cyclic imino ethers, which are seldom
obtained via the electrophilic cyclization.1-5
TABLE 1. Efficient Preparation of Multisubstituted
Stereodefined Dienamides 3a
Results and Discussion
Reaction of 1-Lithio-1,3-dienes 5 with Isocyan-
ates. Preparation of Multisubstituted Stereode-
fined Dienamides 3. Multisubstituted stereodefined
1-iodo-1,3-dienes 4 are readily available.14 Lithiation of
4 with t-BuLi affords their corresponding 1-lithio-1,3-
diene derivatives 5 quantitatively.15 Treatment of these
in situ formed organolithium reagents 5 with isocyanates
produced multisubstituted stereodefined dienamides 3 in
high isolation yields after hydrolysis (Scheme 2). As
shown in Table 1, a variety of aromatic isocyanates and
different types of organolithium reagents 5 could be used
to afford stereodefined dienamides 3 with various sub-
stituents.
In addition to N-aryl isocyanates, N-alkyl isocyanates
could be also applied for this reaction to prepare their
(6) Blot, V.; Reboul, V.; Metzner, P. J. Org. Chem. 2004, 69, 1196-
1201.
(7) (a) Abarbri, M.; Parrain, J. L.; Cintrat, J. C.; Duchene, A.
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Lett. 2000, 2, 407-408.
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70. (c) Pan, X.; Cai, Q.; Ma, D. Org. Lett. 2004, 6, 1809-1812 and
references therein.
(9) (a) Takahashi, T.; Li, Y.; Tsai, F. Y.; Nakajima, K. Organome-
tallics 2001, 20, 595-597. (b) van Wagenen, B. C.; Livinghouse, T.
Tetrahedron Lett. 1989, 30, 3495-3498. (c) Williams, A. C.; Sheffels,
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2003, 68, 7979-7982.
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M. Tetrahedron Lett. 2004, 45, 2063-2066.
(13) Yao, T.; Larock, R. C. J. Org. Chem. 2005, 70, 1432-1437 and
references therein.
a Reaction conditions are shown in Scheme 2. b Isolated yields.
(14) Preparative methods for 1-iodo-1,3-diene derivatives, see: (a)
Takahashi, T.; Kondakov, D. Y.; Xi, Z.; Suzuki, N. J. Am. Chem. Soc.
1995, 117, 5871-5872. (b) Takahashi, T.; Sun, W.; Xi, C.; Ubayama,
H.; Xi, Z. Tetrahedron 1998, 54, 715-726. (c) Ubayama, H.; Sun, W.;
Xi, Z.; Takahashi, T. Chem. Commun. 1998, 1931-1932. (d) Xi, Z.; Liu,
X.; Lu, J.; Bao, F.; Fan, H.; Li, Z.; Takahashi, T. J. Org. Chem. 2004,
69, 8547-8549.
(15) Reactions of 1-lithio-1,3-dienes with unsaturated organic sub-
strates, see: (a) Chen, J.; Song, Q.; Wang, C.; Xi, Z. J. Am. Chem. Soc.
2002, 124, 6238-6239. (b) Song, Q.; Li, Z.; Chen, J.; Wang, C.; Xi, Z.
Org. Lett. 2002, 4, 4627-4629. (c) Fang, H.; Song, Q.; Wang, Z.; Xi, Z.
Tetrahedron Lett. 2004, 45, 5159-5162. (d) Xi, Z. Eur. J. Org. Chem.
2004, 2773-2781. See also: (e) Shirley, D. A.; Cameron, M. D. J. Am.
Chem. Soc. 1952, 74, 664-665. (f) Fitt, J. J.; Gschwend, H. W. J. Org.
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corresponding dienamide derivatives 3 (Figure 2). Reac-
tion of n-Hex-NCO and PhCH2-NCO with 1-lithio-1,2,3,4-
tetrapropyl-1,3-diene 5b afforded dienamides 3j and 3k
as the only product in 80% and 71% isolated yields,
respectively (Figure 2). Dienamide derivatives 3l and 3m
possessing substitution patterns different from those of
3a-k were prepared in 89% and 78% isolated yields,
respectively, from 1,2-disubstituted organolithium re-
agent 5e and 2,3-disubstituted organolithium reagent 5f
(Figure 2).
J. Org. Chem, Vol. 70, No. 13, 2005 5151

Wang et al.
TABLE 2. Cyclic Imino Ethers 6 from 12 N
HCl-Promoted Cyclization of Multisubstituted
Dienamides 3a
FIGURE 2. Examples of dienamides from alkyl isocyanates
(3j and 3k) and examples of dienamides with different
substitution patterns on the dienyl skeletons (3l and 3m).
SCHEME 3. Acid-Promoted Cyclization of
Multisubstituted Dienamides 3 Affording
Exocyclic Imino Ethers 6
Electrophilic Cyclization of Conjugated Unsatur-
ated Amides 3 Leading to Cyclic Imino Ethers. It
is known that the electrophilic cyclization reaction pat-
terns of unsaturated amides remarkably depend on the
reaction solvents and the electrophiles employed.1-4 For
these cases of dienamides 3a-m, we found that the best
conditions for the cyclization reaction were the use of 12
N HCl both as a electrophile and as a solvent at room
temperature (Scheme 3). Although the substitution pat-
terns of the dienyl skeletons of 3a-k is different from
that of 3l and 3m, all these dienamides, except 3l,
underwent the same type of electrophilic cyclization. Two
unusual features were observed in this synthetically
useful reaction. One is that only O-attack pathway is
involved; the other is that exo cyclic imino ethers 6 are
obtained as the sole products in excellent isolation yields
(Table 2). No formation of either the N-attack products
7 or endo heterocyclic products were observed. The
structure of imino ether 6b has been determined by
single-crystal X-ray structural analysis (Figure 3).16 Only
one product was obtained for 6a-h, except that 6i was
obtained as a mixture of two geometric isomers at the N
atom in a ratio of 7:3, probably due to the substitution
pattern of the dienyl skeleton of 3m.17
a Reaction conditions: shown in Scheme 3. b Isolated yields.
c Combined isolated yield. Two isomers in 7:3 ratio.
To further demonstrate the usefulness of these stereo-
defined multisubstituted dienamides, we used NBS and
I2 as the electrophiles. Abarbri and co-workers reported
halocyclization reactions of (2Z,4E)-dienamides using ICl
as the best reagent and CH2Cl2 as the best solvent to
afford 5-alkylidenepyrrol-2(5H)-ones.12 This reaction must
proceed via an N-attack pathway. However, in our cases,
although the reasons are not clear yet, no N-attack
(16) CCDC: 214277.
(17) Nitta, M.; Naya, S. J. Chem. Res. 1998, 522-523.
5152 J. Org. Chem., Vol. 70, No. 13, 2005

Electrophilic Cyclization of Multisubstituted Dienamides
TABLE 3. NBS or I2-Promoted Cyclization of
Multisubstituted Dienamides 3 Affording Halogenated
Imino Ethers 9a
FIGURE 3. X-ray structure of 6b.
products were obtained; instead, O-attack products,
multisubstituted halogenated exo iminoethers 9, were
obtained as the only products in excellent isolated yields
(Table 3). Both CH2Cl2 and a 1:1 mixture of THF and
H2O could be used as the solvent to afford similar yields
of products (yields listed in Table 3 were obtained from
a 1:1 mixture of THF and H2O as the solvent). When I2
was used as the electrophile in CH2Cl2, monoiodonated
imino ethers 9 were also obtained in excellent isolated
yields (Table 3).
Furthermore, when 3 equiv of NBS was used, forma-
tion of double-brominated imino ether 10 was found
(Scheme 4). In the presence of an excess amount of NBS,
the N-phenyl ring, induced by the N atom and the Cl
atom, underwent an electrophilic substitution reaction
to afford 10 as the only product. This bromination of the
N-phenyl ring was also observed in other cases, but
generally afforded mixtures.
How are the two unusual features realized in this
synthetically useful reaction? It is assumed that substi-
tution at the 4 position and the relative stability of the
allylic carbocation might be essential for the exo products
from O-attack. By comparison of our results (our work:
the 4 position is substituted) with those (Abarbri’s
work: the 4 position is unsubstituted) by Abarbri et al.,12
it seems that substitution at position 4 is critical for
O-attack. Obviously, position 4 is more crowded when it
is substituted. On the other hand, the O atom environ-
ment of the amide moiety is less bulky than the N atom
environment. Thus, if the 4 position is substituted,
O-attack will take place. Otherwise, if the 4 position is
not substituted, N-attack will occur. For 3l which does
not possess substituent at the 4 position, we have tried
several times reactions of 3l with different electrophiles,
but a messy mixture has always been obtained, which
indicates that the 4 position substituent is critical for the
O-attack path. The relative stability of the allylic car-
bocation generated in situ in the reaction mixtures is
proposed to be essential for the formation of exo products
from O-attack.
a In the case of iodocyclization, CH2Cl2 was used as the solvent.
b Isolated yields. c Two isomers in 8:2 ratio.
Conclusions
We have reported a convenient high-yield preparation
of stereodefined multisubstituted dienamides and elec-
trophilic cyclization of these dienamides affording sub-
stituted cyclic iminoethers in excellent yields with perfect
selectivity. Only O-attack exo cyclic imino ethers are
J. Org. Chem, Vol. 70, No. 13, 2005 5153

Wang et al.
119.4, 123.8, 129.9, 131.1, 134.5, 134.6, 139.5, 139.8, 145.3,
170.3; HRMS calcd for C23H34NOCl 375.2329, found 375.2329.
3f: colorless solid; mp 63-64 °C, isolated yield 86% (323
mg); 1H NMR (CDCl3, TMS) δ 0.77-0.98 (m, 12H), 1.18-1.51
(m, 8H), 1.92-1.99 (m, 2H), 2.10-2.19 (m, 4H), 2.34-2.39 (m,
2H), 5.46 (t, J ) 7.2 Hz, 1H), 7.22-7.27 (m, 3H), 7.39-7.42
(m, 2H); 13C NMR (CDCl3, TMS) δ 13.9, 14.1, 14.8, 21.4, 22.3,
22.7, 22.9, 30.2, 32.25, 32.3, 33.1, 120.4, 128.7, 128.9, 131.1,
134.6, 136.9, 139.9, 145.1, 170.2; HRMS calcd for C23H34NOCl
375.2329, found 375.2324.
SCHEME 4. Formation of Double-Brominated
Imino Ether 10
3g: colorless solid; mp 167-168 °C, isolated yield 78% (286
1
mg); H NMR (CDCl3, TMS) δ 1.82 (s, 3H), 2.08 (s, 3H), 2.22
obtained as the sole products. No formation of the
N-attack products and O-attack endo heterocyclic prod-
ucts is found. This methodology should prove quite useful
for the synthesis of otherwise unavailable dienamides
and functionalized cyclic iminoethers. Further synthetic
applications of these dienamides and cyclic iminoethers
can be expected.
(s, 3H), 6.72 (s, 1H), 6.96-7.24 (m, 14H), 7.53 (br, 1H); 13C
NMR (CDCl3, TMS) δ 16.8, 19.0, 20.8, 120.2, 126.9, 127.7,
127.9, 128.6, 129.3, 129.4, 129.6, 131.9, 133.7, 135.2, 136.7,
138.1, 139.9, 143.1, 169.6; HRMS calcd for C26H25NO 367.1936,
found 367.1929. Anal. Calcd for C26H25NO: C, 84.98; H, 6.86;
N, 3.81. Found: C, 84.74; H, 6.91; N, 3.81.
3h: colorless solid; mp 94-95 °C, isolated yield 84% (273
mg); 1H NMR (CDCl3, TMS) δ 0.72 (t, J ) 7.5 Hz, 3H), 0.93 (t,
J ) 7.2 Hz, 3H), 1.10-1.18 (m, 2H), 1.44-1.52 (m, 2H), 1.70
(br, 4H), 1.84-1.92 (m, 2H), 2.27-2.35 (m, 9H), 5.44 (t, J )
7.5 Hz, 1H), 7.03-7.05 (m, 2H), 7.17 (br, 1H), 7.30-7.33 (m,
2H); 13C NMR (CDCl3, TMS) δ 13.8, 14.0, 20.8, 22.2, 22.7, 27.3,
27.6, 29.6, 29.7, 31.2, 31.9, 119.8, 127.4, 129.2, 131.7, 133.2,
135.9, 138.5, 143.6, 170.7; HRMS calcd for C22H31NO 325.2406,
found 325.2399.
3i: colorless solid; mp 113-114 °C, isolated yield 82% (283
mg); 1H NMR (CDCl3, TMS) δ 0.72 (t, J ) 7.5 Hz, 3H), 0.93 (t,
J ) 7.2 Hz, 3H), 1.06-1.18 (m, 2H), 1.41-1.53 (m, 2H), 1.71
(br, 4H), 1.84-1.92 (m, 2H), 2.28-2.35 (m, 6H), 5.42 (t, J )
7.5 Hz, 1H), 7.00-7.03 (m, 1H), 7.14-7.27 (m, 3H), 7.58 (br,
1H); 13C NMR (CDCl3, TMS) δ 13.7, 14.0, 22.3, 22.7, 27.2, 27.6,
29.7, 29.7, 31.3, 31.9, 117.5, 119.6, 123.8, 127.9, 129.8, 131.4,
134.5, 138.4, 139.6, 144.6, 170.9; HRMS calcd for C21H28NOCl
345.1859, found 345.1851.
3j: colorless solid; mp 39-40 °C, isolated yield 80% (280 mg);
1H NMR (CDCl3, TMS) δ 0.86-0.98 (m, 15H), 1.28-1.42 (m,
16H), 1.96-2.11 (m, 6H), 2.28 (t, J ) 7.5 Hz, 2H), 3.17 (q, J )
6.9 Hz, 2H), 5.35 (t, J ) 7.2 Hz, 1H), 5.45 (br, 1H); 13C NMR
(CDCl3, TMS) δ 14.0, 14.05, 14.07, 14.1, 14.8, 21.4, 22.1, 22.5,
22.7, 23.0, 26.8, 29.6, 30.2, 31.6, 32.3, 32.8, 39.5, 129.9, 134.7,
139.8, 143.0, 172.1; HRMS calcd for C23H43NO 349.3345, found
349.3347.
Experimental Section
Typical Procedure for the Preparation of Stereode-
fined Dienamides 3a-m from the Corresponding Mono-
iodo Compounds. To a diethyl ether (5 mL) solution of 1-iodo-
1,3-butadiene (1.0 mmol) at -78 °C was added t-BuLi (2.0
mmol, 1.5 M in pentane). The above reaction mixture was then
stirred at -78 °C for 1 h to generate 1-lithio-1,3-diene, which
was monitored by GC analysis or by TLC. After addition of
isocyanates (1.2 mmol) at -78 °C, the mixture was stirred at
room temperature for 2 h. The above reaction mixture was
then quenched with saturated aqueous NaHCO3 and extracted
with diethyl ether. The extract was washed with brine and
dried over MgSO4. The solvent was evaporated in vacuo to give
a red-orange oil, which was purified by column chromatograph
(silica, CH2Cl2/hexane ) 1:1) to afford 3a-m.
1
3a: colorless liquid, isolated yield 83% (248 mg); H NMR
(CDCl3, TMS) δ 0.86 (t, J ) 7.5 Hz, 3H), 0.96-1.12 (m, 9H),
1.97-2.04 (m, 2H), 2.16-2.25 (m, 4H), 2.30 (s, 3H), 2.38-2.45
(m, 2H), 5.44 (t, J ) 7.2 Hz, 1H), 7.09 (d, J ) 8.4 Hz, 2H),
7.25 (br, 1H), 7.34 (d, J ) 8.4 Hz, 2H); 13C NMR (CDCl3, TMS)
δ 12.8, 13.6, 13.8, 14.3, 20.8, 21.3, 22.8, 23.3, 24.4, 119.3, 129.4,
132.03, 133.4, 135.8, 135.8, 140.4, 145.1, 169.8; HRMS calcd
for C20H29NO 299.2249, found 299.2247.
1
1
3k: colorless liquid; isolated yield 71% (252 mg); H NMR
3b: colorless liquid; isolated yield 85% (271 mg); H NMR
(CDCl3, TMS) δ 0.84-0.95 (m, 12H), 1.17-1.50 (m, 8H), 1.86-
2.11 (m, 6H), 2.29-2.34 (m, 2H), 4.37 (d, J ) 5.7 Hz, 2H), 5.32
(t, J ) 7.2 Hz, 1H), 5.75 (br, 1H), 7.23-7.32 (m, 5H); 13C NMR
(CDCl3, TMS) δ 14.0, 14.1, 14.7, 21.4, 22.2, 22.3, 22.9, 30.1,
32.3, 32.3, 33.0, 43.8, 127.4, 128.1, 128.6, 130.0, 134.1, 138.3,
139.9, 143.7, 171.8; HRMS calcd for C24H37NO 355.2875, found
355.2872.
(CDCl3, TMS) δ 0.82-1.10 (m, 12H), 1.97-2.45 (m, 8H), 5.44
(t, J ) 7.5 Hz, 1H), 7.02-7.38 (m, 4H), 7.64 (br, 1H); 13C NMR
(CDCl3, TMS) δ 12.8, 13.7, 13.8, 14.3, 21.3, 22.8, 23.3, 24.3,
117.1, 119.3, 123.8, 129.9, 132.4, 134.6, 135.4, 139.5, 140.3,
146.0, 170.0; HRMS calcd for C19H26NOCl 319.1703, found
319.1710.
3c: colorless solid; mp 65-66 °C, isolated yield 84% (297
mg); 1H NMR (CDCl3, TMS) δ 0.93-1.18 (m, 12H), 2.03-2.47
(m, 8H), 5.43 (t, J ) 7.2 Hz, 1H), 7.07-7.12 (m, 1H), 7.29-
7.32 (m, 3H); 13C NMR (CDCl3, TMS) δ 12.6, 13.2, 14.1, 14.2,
21.5, 22.9, 23.7, 24.3, 127.8, 128.5, 132.2, 132.4, 133.0, 133.9,
139.9, 146.8, 168.9; HRMS calcd for C19H25NOCl2 353.1313,
found 353.1308.
3d: colorless solid; mp 74-75 °C, isolated yield 81% (288
mg); 1H NMR (CDCl3, TMS) δ 0.81 (t, J ) 7.5 Hz, 3H), 0.90-
0.98 (m, 9H), 1.21-1.52 (m, 8H), 1.93-2.01 (m, 2H), 2.10-
2.19 (m, 4H), 2.29 (s, 3H), 2.34-2.40 (m, 2H), 5.47 (t, J ) 7.5
Hz, 1H), 7.08 (d, J ) 8.4 Hz, 2H), 7.17 (br, 1H), 7.33 (d, J )
8.4 Hz, 2H); 13C NMR (CDCl3, TMS) δ 13.9, 14.1, 14.8, 20.8,
21.4, 22.5, 22.6, 22.9, 30.2, 32.3, 33.2, 119.4, 129.4, 130.8, 133.4,
134.9, 135.8, 139.9, 144.4, 170.0. Anal. Calcd for C24H37NO:
C, 81.07; H, 10.49; N, 3.94. Found: C, 81.10; H, 10.46; N, 3.80.
3e: colorless solid; mp 59-60 °C, isolated yield 90% (337
mg); 1H NMR (CDCl3, TMS) δ 0.78-0.99 (m, 12H), 1.19-1.53
(m, 8H), 1.93-2.39 (m, 8H), 5.47 (t, J ) 7.5 Hz, 1H), 7.01-
7.29 (m, 4H), 7.63 (br, 1H); 13C NMR (CDCl3, TMS) δ 13.9,
14.1, 14.8, 21.4, 22.3, 22.7, 22.9, 30.2, 32.2, 32.3, 33.1, 117.2,
3l: colorless liquid; isolated yield 89% (284 mg); 1H NMR
(CDCl3, TMS) δ 0.83-0.97 (m, 6H), 1.26-1.49 (m, 8H), 2.25
(t, J ) 7.2 Hz, 2H), 2.38 (t, J ) 7.8 Hz, 2H), 5.12-5.35 (m,
2H), 6.48-6.58 (m, 1H), 7.04-7.07 (m, 1H), 7.17-7.22 (m, 1H),
7.38-7.41 (m, 1H), 7.70 (t, J ) 2.1 Hz, 1H), 7.77 (br, 1H); 13
C
NMR (CDCl3, TMS) δ 13.9, 22.9, 23.1, 27.2, 30.5, 30.9, 31.1,
115.6, 117.9, 120.0, 124.3, 129.9, 134.6, 134.7, 137.5, 137.6,
139.1, 170.1; HRMS calcd for C19H26NOCl 319.1703, found
319.1704.
1
3m: colorless liquid; isolated yield 78% (293 mg); H NMR
(CDCl3, TMS) δ 0.83-0.88 (m, 6H), 1.26-1.47 (m, 16H), 2.18-
2.25 (m, 4H), 4.99 (s, 1H), 5.19 (s, 1H), 5.75 (s, 1H), 7.01-7.34
(m, 3H), 7.64 (br, 1H), 8.34 (br, 1H); 13C NMR (CDCl3, TMS)
δ 14.1, 14.1, 22.6, 27.3, 27.7, 28.9, 29.2, 31.7, 35.8, 38.5, 112.9,
117.5, 119.6, 120.4, 123.9, 129.9, 134.6, 139.4, 150.0, 156.6,
164.71; HRMS calcd for C23H34NOCl 375.2329, found 375.2325.
A Typical Procedure for the Preparation of Com-
pound 6a-i. To a diethyl ether (5 mL) solution of compound
3 (1.0 mmol) at room temperature was added 12 N HCl (4.0
mL). The above reaction mixture was then stirred at room
5154 J. Org. Chem., Vol. 70, No. 13, 2005

Electrophilic Cyclization of Multisubstituted Dienamides
temperature for 18 h. After addition of NaOH (48 mmol, 1.92
g) at 0 °C, the mixture was stirred at room temperature for 5
min. The above reaction mixture was then extracted with
diethyl ether. The extract was washed with brine and dried
over MgSO4. The solvent was evaporated in vacuo to give an
orange solid, which was purified by column chromatograph
(silica, CH2Cl2/hexane ) 1:3) to afford 6a-i.
Typical Procedure for the Preparation of Compounds
9a,c-e,g,h,j-l. To a THF and H2O (1:1, 10 mL) solution of
compound 3b (1.0 mmol) at room temperature was added NBS
(1.0 mmol). The above reaction mixture was then stirred at
room temperature for 3 h to generate compound 9a, which was
monitored by GC analysis or by TLC. The above reaction
mixture was then extracted with diethyl ether. The extract
was washed with brine and dried over MgSO4. The solvent
was evaporated in vacuo to give a red-orange oil, which was
purified by column chromatograph (silica, CH2Cl2/hexane )
1:3) to afford 9a.
1
6a: colorless liquid; isolated yield 92% (294 mg); H NMR
(CDCl3, TMS): δ 0.71 (t, J ) 7.5 Hz, 3H), 0.85 (t, J ) 7.2 Hz,
3H), 1.02-1.28 (m, 8H), 1.52-1.89 (m, 4H), 2.21 (q, J ) 7.8
Hz, 2H), 2.38 (q, J ) 7.5 Hz, 2H), 6.96-7.05 (m, 2H), 7.15-
7.21 (m, 2H); 13C NMR (CDCl3, TMS): δ 7.3, 12.6, 13.6, 14.1,
16.4, 17.4, 18.9, 30.0, 39.3, 94.6, 121.7, 122.9, 123.6, 129.4,
133.5, 133.8, 149.3, 156.2, 163.5; HRMS calcd for C19H26NOCl
319.1703, found 319.1702.
1
9a: colorless liquid; isolated yield 91% (361 mg); H NMR
(CDCl3, TMS) δ 0.69 (t, J ) 7.2 Hz, 3H), 1.04-1.22 (m, 9H),
1.62-1.84(m, 3H), 2.14-2.44(m, 5H), 4.01 (dd, J1 ) 2.7 Hz,
J2 ) 10.8 Hz, 1H), 6.99-7.27 (m, 4H); 13C NMR (CDCl3, TMS)
δ 7.3, 12.6, 13.0, 13.4, 17.6, 19.2, 26.6, 28.9, 63.2, 95.2, 122.1,
123.5, 124.0, 129.4, 133.8, 135.9, 148.3, 153.5, 162.0; HRMS
calcd for C19H25NOClBr 397.0808, found 397.0792.
6b: colorless solid; mp 95-96 °C; isolated yield 91% (321
1
mg); H NMR (CDCl3, TMS) δ 0.70-1.87 (m, 18H), 2.21 (q, J
) 7.8 Hz, 2H), 2.45 (q, J ) 7.5 Hz, 2H), 6.83-6.88 (m, 1H),
7.24-7.26 (m, 2H); 13C NMR (CDCl3, TMS) δ 7.2, 12.6, 13.6,
14.1, 16.1, 17.6, 19.0, 29.8, 39.3, 95.2, 123.3, 127.3, 127.7, 132.6,
144.2, 157.2, 164.0; HRMS calcd for C19H25NOCl2 353.1313,
found 353.1303. Anal. Calcd for C19H25NOCl2: C, 64.41; H,
7.11; N, 3.95. Found: C, 64.56; H, 7.16; N, 3.89. CCDC: 214277
9c: colorless solid; mp 124-125 °C; isolated yield 95% (409
mg); 1H NMR (CDCl3, TMS) δ 0.72 (t, J ) 7.2 Hz, 3H), 1.04 (t,
J ) 7.2 Hz, 3H), 1.18 (t, J ) 7.5 Hz, 3H), 1.27 (t, J ) 7.2 Hz,
3H), 1.61-1.85 (m, 3H), 2.13-2.39 (m, 3H), 2.47 (q, J ) 7.5
Hz, 2H), 3.90 (dd, J1 ) 3.3 Hz, J2 ) 10.5 Hz, 1H), 6.85-6.90
(m, 1H), 7.24-7.27 (m, 2H); 13C NMR (CDCl3, TMS) δ 7.2, 12.6,
13.0, 13.3, 17.7, 19.3, 26.4, 28.5, 62.6, 95.6, 123.6, 126.8, 127.7,
134.5, 143.5, 155.1, 162.8; HRMS calcd for C19H24NOCl2Br
431.0418, found 431.0430.
1
6c: colorless liquid; isolated yield 92% (327 mg); H NMR
(CDCl3, TMS) δ 0.81-1.28 (m, 18H), 1.45-1.81 (m, 8H), 2.10-
2.15 (m, 2H), 2.30-2.35 (m, 5H), 7.07 (br, 4H); 13C NMR
(CDCl3, TMS) δ 14.0, 14.1, 14.3, 15.0, 16.3, 21.0, 21.6, 21.9,
22.7, 25.1, 26.3, 28.5, 37.2, 39.8, 93.8, 123.3, 129.0, 132.2, 132.3,
145.3, 154.7, 162.6; HRMS calcd for C24H37NO 355.2875, found
355.2871.
9d: colorless solid; mp 67-68 °C; isolated yield 91% (394
mg); 1H NMR (CDCl3, TMS) δ 0.82-1.77 (m, 22H), 2.08-2.37
(m, 9H), 4.09 (dd, J1 ) 2.4 Hz, J2 ) 10.8 Hz, 1H), 7.08-7.21
(m, 4H); 13C NMR (CDCl3, TMS) δ 13.3, 13.9, 14.4, 15.0,
16.3, 21.0, 21.3, 21.6, 21.8, 26.5, 28.7, 35.0, 38.3, 61.4, 94.4,
123.9, 129.1, 132.9, 134.8, 144.2, 151.9, 161.0; HRMS calcd
for C24H36NOBr 433.1980, found 433.1978.
1
6d: colorless liquid; isolated yield 95% (356 mg); H NMR
(CDCl3, TMS) δ 0.82-1.34 (m, 18H), 1.46-1.81 (m, 8H), 2.11-
2.16 (m, 2H), 2.29-2.34 (m, 2H), 6.96-7.03 (m, 2H), 7.15-
7.20 (m, 2H); 13C NMR (CDCl3, TMS) δ 14.0, 14.1, 14.2, 15.0,
16.3, 21.6, 21.9, 22.7, 25.1, 26.2, 28.5, 37.0, 39.6, 94.4, 121.7,
122.9, 123.6, 129.4, 132.0, 133.8, 149.4, 156.1, 163.6; HRMS
calcd for C23H34NOCl 375.2329, found 375.2321.
1
9e: colorless liquid; isolated yield 92% (417 mg); H NMR
(CDCl3, TMS) δ 0.84-1.75 (m, 23H), 2.12-2.36 (m, 5H), 4.09
(dd, J1 ) 2.7 Hz, J2 ) 10.5 Hz, 1H), 6.99-7.02 (m, 1H), 7.12-
7.25 (m, 3H); 13C NMR (CDCl3, TMS) δ 13.3, 13.9, 14.3, 15.0,
16.3, 21.3, 21.5, 21.7, 26.4, 28.8, 35.0, 38.1, 60.9, 94.9, 122.0,
123.4, 124.1, 129.4, 133.8, 134.4, 148.3, 153.3, 162.2; HRMS
calcd for C23H33NOClBr 453.1434, found 453.1451.
1
6e: colorless liquid; isolated yield 91% (296 mg); H NMR
(CDCl3, TMS) δ 0.85-2.33 (m, 26H), 2.71-2.76 (m, 1H), 7.08
(br, 4H); 13C NMR (CDCl3, TMS) δ 13.9, 14.0, 21.0, 22.0, 22.8,
23.1, 25.0, 25.3, 25.5, 27.3, 34.2, 39.1, 90.2, 123.3, 126.9, 129.0,
132.3, 145.1, 156.3, 162.6; HRMS calcd for C22H31NO 325.2406,
found 325.2396.
1
9g: colorless liquid; isolated yield 93% (375 mg); H NMR
(CDCl3, TMS) δ 0.86-0.96 (m, 6H), 1.26-2.00 (m, 12H), 2.27-
2.36 (m, 5H), 2.75-2.87 (m, 2H), 4.35 (dd, J1 ) 2.1 Hz, J2 )11.1
Hz, 1H), 7.09-7.11 (m, 2H), 7.24-7.27 (m, 2H); 13C NMR
(CDCl3, TMS) δ 13.3, 14.0, 21.0, 21.3, 21.3, 22.3, 25.5, 25.7,
27.3, 33.9, 39.1, 57.1, 90.6, 124.1, 129.1, 129.5, 133.2, 143.8,
153.2, 160.8; HRMS calcd for C22H30NOBr 403.1511, found
403.1506.
6f: colorless liquid; isolated yield 90% (311 mg); 1H NMR
(CDCl3, TMS) δ 0.86-2.33 (m, 23H), 2.73-2.77 (m, 1H), 6.97-
7.25 (m, 4H); 13C NMR (CDCl3, TMS) δ 13.9, 14.0, 21.9,
22.7, 23.1, 25.0, 25.3, 25.4, 27.3, 34.1, 39.0, 90.8, 121.8, 122.9,
123.6, 126.7, 129.4, 133.8, 149.2, 157.5, 163.5; HRMS calcd
for C21H28NOCl 345.1859, found 345.1861.
1
9h: colorless liquid; isolated yield 91% (385 mg); H NMR
1
6g: colorless liquid; isolated yield 90% (314 mg); H NMR
(CDCl3, TMS): δ 0.86-0.96 (m, 6H), 1.27-2.01 (m, 12H), 2.30-
2.35 (m, 2H), 2.76-2.89 (m, 2H), 4.31-4.36 (m, 1H), 7.00-
7.33 (m, 4H); 13C NMR (CDCl3, TMS) δ 13.3, 13.9, 21.3, 21.8,
22.3, 25.55, 25.59, 27.3, 33.9, 39.1, 56.6, 91.1, 122.4, 123.6,
124.4, 129.2, 129.4, 133.9, 148.0, 154.5, 162.0; HRMS calcd
for C21H27NOClBr 423.0965, found 423.0963.
(CDCl3, TMS) δ 0.83-1.79 (m, 37H), 2.04-2.10 (m, 2H), 2.19-
2.24 (m, 2H), 3.32 (t, J ) 7.2 Hz, 2H); 13C NMR (CDCl3, TMS)
δ 14.0, 14.1, 14.2, 14.2, 15.0, 16.3, 21.7, 21.9, 22.7, 22.8, 25.1,
26.3, 27.4, 28.4, 31.0, 31.9, 37.4, 40.1, 47.2, 92.2, 131.64 152.7,
163.4; HRMS calcd for C23H43NO 349.3345, found 349.3342.
9j: colorless liquid; isolated yield 96% (410 mg); 1H NMR
(CDCl3, TMS) δ 0.86-1.71 (m, 33H), 2.06-2.37 (m, 6H), 3.35-
3.39 (m, 2H), 4.04-4.08 (m, 1H); 13C NMR (CDCl3, TMS) δ
13.3, 14.0, 14.1, 14.3, 15.0, 16.4, 21.2, 21.7, 21.8, 22.7, 26.4,
27.3, 28.6, 30.7, 31.8, 34.8, 38.6, 47.1, 61.9, 93.1, 133.9, 150.6,
162.3; HRMS calcd for C23H42NOBr 427.2450, found 427.2443.
6h: reaction time 3 days; colorless liquid; isolated yield 89%
(316 mg); 1H NMR (CDCl3, TMS) δ 0.81-1.77 (m, 26H), 2.06-
2.11 (m, 2H), 2.24-2.29 (m, 2H), 4.57 (s, 2H), 7.14-7.37 (m,
5H); 13C NMR (CDCl3, TMS) δ 14.0, 14.2, 14.3, 15.0, 16.3, 21.7,
21.9, 22.8, 25.1, 26.3, 28.4, 37.3, 39.9, 50.7, 92.8, 125.9, 127.6,
128.0, 131.6, 141.8, 153.6, 164.5; HRMS calcd for C24H37NO
355.2875, found 355.2877.
1
9k: colorless liquid; isolated yield 92% (399 mg); H NMR
(CDCl3, TMS) δ 0.81-1.64 (m, 23H), 2.01-2.39 (m, 5H), 4.04
(q, J1 ) 9.6 Hz, J2 ) 3.6 Hz, 1H), 4.59 (s, 2H), 7.15-7.40 (m,
5H); 13C NMR (CDCl3, TMS) δ 13.3, 14.0, 14.3, 15.0, 16.3, 21.1,
21.6, 21.7, 26.5, 28.6, 34.6, 38.6, 50.9, 61.7, 93.4, 126.0, 127.8,
128.0, 133.9, 141.3, 150.9, 163.1; HRMS calcd for C24H36NOBr
433.1980, found 433.1975.
6i: two isomers in 7:3 ratio; colorless liquid; combined
1
isolated yield 95% (357 mg); H NMR (CDCl3, TMS) δ 0.84-
2.13 (m, 29H), 5.77 (br, 0.3H), 5.90 (br, 0.7H), 6.79-7.23 (m,
4H); 13C NMR (CDCl3, TMS) δ 14.0, 14.1, 22.5, 22.5, 22.6, 22.6,
23.1, 24.3, 24.5, 26.8, 26.8, 27.2, 29.0, 29.1, 29.2, 29.3, 31.5,
31.6, 31.7, 37.5, 37.7, 91.4, 94.1, 110.3, 118.2, 120.7, 122.0,
122.5, 123.0, 123.3, 123.7, 129.4, 129.9, 133.9, 134.3, 148.5,
150.7, 163.2, 166.8, 167.4, 170.6; HRMS calcd for C23H34NOCl
375.2329, found 375.2337.
9l: two isomers in 8:2 ratio; colorless liquid; combined
1
isolated yield 94% (426 mg); H NMR (CDCl3, TMS) δ 0.83-
2.23 (m, 26H), 3.45-3.76 (m, 2H), 5.94 (br, 0.2H), 6.08 (br,
J. Org. Chem, Vol. 70, No. 13, 2005 5155

Wang et al.
0.8H), 6.80-7.27 (m, 4H); 13C NMR (CDCl3, TMS) δ 14.0,
14.0, 14.1, 22.5, 22.6, 23.2, 26.5, 26.7, 27.1, 29.0, 29.1, 29.2,
31.5, 31.5, 31.6, 35.0, 35.2, 35.9, 36.0, 91.1, 93.4, 113.4, 120.6,
121.2, 121.8, 122.3, 123.2, 123.5, 123.6, 129.5, 129.9, 133.9,
134.3, 148.2, 150.2, 162.3, 162.7, 165.8, 166.3. HRMS calcd
for C23H33NOClBr 453.1434, found 453.1437.
23.4, 25.6, 25.7, 27.2, 35.5, 39.0, 42.1, 91.4, 122.6, 123.7, 124.5,
129.4, 133.9, 147.8, 153.7, 161.5; HRMS calcd for C21H27NOClI
471.0826, found 471.0818.
Typical Procedure for the Preparation of Compound
10. To a THF and H2O (1:1, 10 mL) solution of compound 3e
(1.0 mmol) at room temperature was added NBS (3.0 mmol).
The above reaction mixture was then stirred at room temper-
ature for 6h to generate compound 10, which was monitored
by TLC. The above reaction mixture was then extracted with
diethyl ether. The extract was washed with brine and dried
over MgSO4. The solvent was evaporated in vacuo to give a
red-orange oil, which was purified by column chromatograph
(silica, CH2Cl2/hexane ) 1:3) to afford 10.
Typical Procedure for the Preparation of Compound
9b,f,i. To a dry dichloromethane (5 mL) solution of compound
3b (1.0 mmol) at room temperature was added iodine (1.2
mmol). The above reaction mixture was stirred at room
temperature for 8 h to generate compound 9b, which was
monitored by TLC. The above reaction mixture was hydrolyzed
by addition of a 5% solution of sodium thiosulfate until the
solution became clear, then the solution was extracted with
diethyl ether. The extract was washed with brine and dried
over MgSO4. The solvent was evaporated in vacuo to give an
orange oil, which was purified by column chromatograph
(silica, CH2Cl2/hexane ) 1:3) to afford 9b.
1
10: colorless liquid; isolated yield 84% (446 mg); H NMR
(CDCl3, TMS) δ 0.84-1.73 (m, 23H), 2.15-2.36 (m, 5H), 4.10
(dd, J1 ) 3.0 Hz, J2 ) 10.5 Hz, 1H), 7.02-7.06 (m, 1H), 7.37-
7.38 (m, 1H), 7.47-7.50 (m, 1H); 13C NMR (CDCl3, TMS) δ
13.3, 13.9, 14.3, 15.0, 16.3, 21.3, 21.5, 21.7, 26.4, 28.8, 35.0,
38.1, 60.7, 95.2, 116.0, 123.8, 125.9, 133.2, 133.8, 134.4, 147.4,
153.8, 162.6; HRMS calcd for C23H32NOClBr2 531.0539, found
531.0539.
1
9b: colorless liquid; isolated yield 95% (423 mg); H NMR
(CDCl3, TMS) δ 0.69 (t, J ) 7.5 Hz, 3H), 1.05 (t, J ) 7.2 Hz,
3H), 1.16-1.23 (m, 6H), 1.56-1.77 (m, 3H), 2.17-2.44 (m, 5H),
4.16 (dd, J1 ) 3.0 Hz, J2 ) 10.8 Hz, 1H), 7.00-7.04 (m, 1H),
7.15-7.32 (m, 3H); 13C NMR (CDCl3, TMS) δ 7.6, 12.5, 13.3,
15.1, 17.7, 19.2, 28.3, 31.5, 46.2, 95.2, 122.2, 123.5, 124.1, 129.4,
133.8, 135.9, 148.2, 152.9, 161.6; HRMS calcd for C19H25NOClI
445.0669, found 445.0658.
Acknowledgment. This work was supported by
the Natural Science Foundation of China (29825105,
20172003, 20232010) and the Major State Basic Re-
search Development Program (G2000077502-D). Che-
ung Kong Scholars Program, Qiu Shi Science & Tech-
nologies Foundation, and Dow Corning Corp. are
gratefully acknowledged.
9f: colorless liquid; isolated yield 93% (466 mg); 1H NMR
(CDCl3, TMS) δ 0.84-1.77 (m, 22H), 2.13-2.37 (m, 6H), 4.21-
4.25 (m, 1H), 7.00-7.03 (m, 1H), 7.14-7.31 (m, 3H); 13C NMR
(CDCl3, TMS) δ 13.1, 13.9, 14.4, 15.0, 16.5, 21.4, 21.8, 23.4,
26.5, 28.8, 36.5, 40.6, 43.7, 94.9, 122.2, 123.5, 124.2, 129.4,
133.9, 134.5, 148.2, 152.8, 161.8; HRMS calcd for C23H33NOClI
501.1295, found 501.1287.
Supporting Information Available: Experimental de-
tails and spectroscopic characterization of all new compounds;
structures and tables of crystallographic data, atomic coordi-
nates, thermal parameters, and bond lengths and angles for
6b. This material is available free of charge via the Internet
at http://pubs.acs.org.
9i: colorless liquid; isolated yield 92% (433 mg); 1H NMR
(CDCl3, TMS) δ 0.86-0.96 (m, 6H), 1.19-2.02 (m, 12H), 2.25-
2.40 (m, 2H), 2.76-2.79 (m, 2H), 4.44 (dd, J1 ) 2.7 Hz, J2 )
10.8 Hz, 1H), 7.01-7.04 (m, 1H), 7.18-7.25 (m, 2H), 7.39-
7.40 (m, 1H); 13C NMR (CDCl3, TMS) δ 13.1, 13.9, 21.8, 22.4,
JO050433Q
5156 J. Org. Chem., Vol. 70, No. 13, 2005