Synthesis of polysubstituted 3-iodopyrans by electrophilic cyclization

Article abstract of DOI:10.1002/ejoc.200801259

A variety of polysubstituted 3-iodopyrans were readily prepared in good to excellent yield under mild reaction conditions by the reaction of alkynyl carboxamides with ICl, I₂, and NIS. The products obtained from this process are versatile mater

Full text of DOI:10.1002/ejoc.200801259

FULL PAPER
DOI: 10.1002/ejoc.200801259
Synthesis of Polysubstituted 3-Iodopyrans by Electrophilic Cyclization
Yong-Xin Xie,[a] Ze-Yi Yan,[b] Dan-Zhu Wang,[a] Lu-Yong Wu,[a] Bo Qian,[a]
Xue-Yuan Liu,[a] and Yong-Min Liang*[a,c]
Keywords: Iodine / Cyclization / Oxygen heterocycles / Alkynes
A variety of polysubstituted 3-iodopyrans were readily pre-
pared in good to excellent yield under mild reaction condi-
tions by the reaction of alkynyl carboxamides with ICl, I2,
and NIS. The products obtained from this process are versa-
tile materials that can be used to construct other complex
functionalized pyran structures of importance. The occur-
rence of the pyranyl group in both natural products and phar-
maceuticals confers important value to this study.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2009)
Pd-catalyzed routes.[21] Very recently, we completed the elec-
trophilic cyclization of various propargylic oxirane com-
pounds and I2 and explored an efficient route to highly sub-
stituted iodofurans under mild reaction conditions.[22] This
successful electrophilic cyclization strategy encouraged us
to develop a simple methodology for the synthesis of other
oxygen- or nitrogen-containing heterocyclic compounds.
On the basis of a similar approach, we devised, therefore, a
new process that makes the facile electrophilic cyclization
of alkynyl carboxamides with ICl, I2, and NIS possible
(Scheme 1). Because the obtained pyrans contain several
active functional groups, such as a three-membered ring,
hydroxy and iodine groups, etc., this method is thus par-
ticularly valuable for the construction of complex pyran-
type compounds.
Introduction
Substituted pyrans are ubiquitous building blocks in nat-
ural products having important biological activities.[1] One
of strategies used frequently for the synthesis of these het-
erocycles conjoins carbon nucleophiles with monosaccha-
ride-based starting materials.[2] Though highly valuable, this
approach for pyran assembly is generally restricted to cer-
tain nucleophilic structural types.[1a,2f] Recently, the electro-
philic cyclization of aryl-substituted alkynes has provided
an extremely useful route for the synthesis of a wide variety
of heterocyclic and carbocyclic compounds.[3] The reported
works have shown the electrophilic cyclization of function-
ally substituted alkynes to be an efficient approach of gen-
erating benzo[b]thiophenes,[4] benzofurans,[5] bicyclic β-lac-
tams,[6] cyclic carbonates,[7] 2,3-dihydropyrroles and pyr-
roles,[8] furans,[9] furopyridines,[10] indoles,[11] isochro-
menes,[12] isocoumarins and α-pyrones,[13] isoquinolines and
naphthyridines,[14] isoxazoles,[15] oxazoles,[16] naphtha-
lenes,[17] polycyclic romatics,[18] quinolines,[3b] indoles,[19]
and chromones[20] under mild reaction. As a result of the
importance of heterocycles as pharmacologically active
molecules, the development of new synthetic approaches
using mild reaction conditions remains an active research
area. Our work in this field has led to the development of
methods for the synthesis of polysubstituted furans and
other heterocyclic compounds via an ammonium ylide and
Scheme 1.
[a] State Key Laboratory of Applied Organic Chemistry, Lanzhou
University,
Results and Discussion
Lanzhou 730000, P. R. China
Fax: +86-931-8912582
E-mail: liangym@lzu.edu.cn
Herein, we wish to report our results on the electrophilic
cyclization of alkynyl carboxamides to polysubstituted pyr-
ans. This chemistry generally produces the desired pyrans
in good to excellent yield under very mild reaction condi-
tions. The iodide products can be further extended to com-
plex polysubstituted pyran compounds by a Pd-catalyzed
coupling reaction.
[b] Laboratory of Radiochemistry, School of Nuclear Science and
Technology, Lanzhou University,
Lanzhou 730000, P. R. China
[c] State Key Laboratory of Solid Lubrication, Lanzhou Institute
of Chemical Physics, Chinese Academy of Science,
Lanzhou 730000, P. R. China
Supporting information for this article is available on the
WWW under http://www.eurjoc.org or from the author.
Eur. J. Org. Chem. 2009, 2283–2288
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y.-X. Xie, Z.-Y. Yan, D.-Z. Wang, L.-Y. Wu, B. Qian, X.-Y. Liu, Y.-M. Liang
FULL PAPER
Our investigations began with the reaction of compound
1a in CH3CN under typical iodocyclization conditions (I2
with an excess amount of NaHCO3). For all cases in which
CH3CN, MeOH, and CHCl3 were used as the solvent, 1a
remained unchanged even during a prolonged time (24 h)
at room temperature (Table 1, Entries 1–3). By changing the
solvent to THF, the corresponding pyran was isolated in
41% yield under the above conditions (Table 1, Entry 4).
The structure of the product was discerned by spectroscopic
analysis and further confirmed by X-ray diffraction to be
3-iodopyran 1a (Figure 1).[23] Apparently, the product was
the unexpected conjugated iminolactone rather than the us-
ual lactam, which was similar to the reported result by
Hashmi et al.[24] In the presence of K2CO3 and Cs2CO3,
only 24 and 35% yield of the product was obtained, respec-
tively (Table 1, Entries 5 and 6). In an attempt to utilize the
stronger tBuOK base, the reaction failed (Table 1, Entry 7).
Although NaHCO3 is indispensable in the THF reaction
system, a higher yield was still obtained when CH2Cl2 was
used as the solvent (Table 1, Entry 8). This indicated that
the solvent played an important role in this process. To our
delight, in the case of a base-free reaction, the most satisfac-
tory result was observed in CH2Cl2 (Table 1, Entry 9). To
explore the scope of our electrophilic cyclization strategy,
the reactions of ylamide 1a with other common electro-
philes (NIS ICl, NBS) in CH2Cl2 at room temperature were
Figure 1. 3-Iodopyran 1a.
To test the generality of this chemistry, alkynyl carbox-
also studied (Table 1, Entries 10–13). However, the results amides bearing different substituents on the nitrogen atom
are distinct for the above electrophiles. Yields of 60 and and the carbon–carbon triple bond were prepared in three
65% of the corresponding iodine-containing pyran were ob- steps as depicted in Scheme 2: (1) starting substituted 3-
tained when NIS was used as the electrophile in both cases oxobutanamides 15 were synthesized by the reaction of
(with or without excess NaHCO3), respectively (Table 1, ethyl acetoacetate with different anilines;[25] (2) a three-
Entries 10 and 11). Disappointingly, none of the desired io- membered ring was successfully introduced into the 3-
dine- or bromine-containing product was observed when oxobutanamides by using 1,2-dibromoethane;[26] (3) the
ICl or NBS was used (Table 1, Entries 12 and 13). Thus, we phenylacetylene was added dropwise into a solution of the
chose the following optimized reaction conditions for all Grignard reagent derived from bromoethane, followed by
subsequent electrophilic cyclizations: a mixture of alkynyl the addition of 1-acetylcyclopropanecarboxamide 17 to ob-
carboxamide (0.25 mmol) and NIS (2 equiv.) in CH2Cl2 tain finally the expected adducts.[25] The resulting pent-4-
(3 mL) stirred at room temperature for an appropriate ynamides were then allowed to react under the standard
amount of time.
electrophilic cyclization conditions to afford the corre-
sponding polysubstituted pyran products in good to excel-
lent yield. The results are summarized in Table 2. The iodo-
cyclization of both N-phenyl- and N-(4-methoxyphenyl)-
substituted pent-4-ynamides (2a, 3a) by using NIS gener-
ated the corresponding 3-iodopyrans in 72 and 76% yield,
respectively, with only a trace amount of side products
(Table 2, Entries 2 and 3). Excellent results were obtained
with N-(4-methylphenyl) substrate 4a (Table 2, Entry 4). In
general, introducing electron-withdrawing groups on the N-
aromatic ring significantly increased the yields and de-
creased the reaction times (Table 2, Entries 5–8). It is wor-
thy to note that the presence of a strong electron-with-
drawing p-NO2 group on the N-aromatic moiety markedly
lowered the yield of the corresponding cyclization product
(Table 2, Entry 5). The best result obtained was for N-(4-
chlorophenyl) substrate 6a (Table 2, Entry 6), which gave
95% yield of the product in only 5 h. The reaction also
proceeded with a naphthyl substituent on the nitrogen
atom. Thus, substrate 9a was smoothly converted into the
Table 1. Iodocyclization of 1a under various conditions.
Entry
Solvents
E
Base
Yield [%][a]
1
2
3
4
CH3CN
MeOH
CHCl3
THF
I2
I2
I2
I2
I2
I2
I2
I2
I2
NIS
NIS
NBS
ICl
NaHCO3
NaHCO3
NaHCO3
NaHCO3
K2CO3
Cs2CO3
tBuOK
NaHCO3
–
NR
NR
NR
41
24
35
NR
45
58
65
60
5
6
THF
THF
7
8
9
10
11
12
13
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
–
NaHCO3
NaHCO3
–
NR
NR
[a] Isolated yield.
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Eur. J. Org. Chem. 2009, 2283–2288

Synthesis of Polysubstituted 3-Iodopyrans by Electrophilic Cyclization
corresponding 3-iodopyran 9b in 79% yield (Table 2, En- Table 2. Iodocyclization of cyclization of alkynyl carboxamides to
polysubstituted pyrans.
try 9). The product was also obtained when the α-position
of the carbonyl compound was substituted with an alkyl
group. In contrast, substituents in the α-position of the car-
bonyl group have an important effect on the efficiency of
the iodocyclization process. In comparison to the yield of
93% (Table 2, Entry 4), 5-butyl-3-iodopyran can be synthe-
sized in a moderate 70% yield by the cyclization of corre-
sponding adduct 1a (Table 2, Entry 10).
Scheme 2.
We continued to elucidate the scope of the reaction by
examining the effect of various substituents on the alkyne
terminus. In comparison to the reaction of substrate 1a, the
adducts containing electron-withdrawing groups (Cl, Br) in
the para position of the aromatic ring on the distal end of
the carbon–carbon triple bond were only isolated in ca.
80% yield (Table 2, Entries 11 and 12). Cyclization with
NIS still proceeded when the terminus of the carbon–car-
bon triple bond was substituted with an alkyl group. There-
fore, 2-propyl-3-iodopyran 13b and 2-butyl-3-iodopyran
14b can be synthesized in 83 and 75% yield, respectively
(Table 2, Entries 13 and 14).
We believe that this approach to 3-iodopyrans should
prove very useful for the synthesis of additional highly sub-
stituted pyrans (Scheme 3). As mentioned in the introduc-
tion, the presence of the iodide functional group on the
pyran ring provides an opportunity for further functionali-
zation. For example, product 7b underwent Sonogashira
coupling with phenyl acetylene to afford polysubstituted
pyran 7c in 76% yield (Scheme 3).
On the basis of the results obtained above, we propose
the following mechanism for this process (Scheme 4): (1)
coordination of the carbon–carbon triple bond to NIS or
attack of the iodine cation on the triple bond to generate
iodonium intermediate A; (2) intramolecular nucleophilic
attack of the oxygen of the carboxamides group on the acti-
vated iodonium intermediate to produce pyran salt B; (3)
deprotonation of B to afford product C, promoted by the
[a] Isolated yields.
iodide nucleophile present in the reaction mixture.
Eur. J. Org. Chem. 2009, 2283–2288
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Y.-X. Xie, Z.-Y. Yan, D.-Z. Wang, L.-Y. Wu, B. Qian, X.-Y. Liu, Y.-M. Liang
FULL PAPER
Scheme 3.
149.99, 156.29 ppm. IR (KBr): ν = 3284, 2923, 1537, 1097, 752,
˜
511 cm–1. C21H20INO3 (461.1): calcd. C 54.68, H 4.37, N 3.04;
found C 54.65, H 4.32, N 3.09.
Compound 2b: Colorless solid; m.p. 82–83 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.86–1.05 (m, 1 H), 1.06–1.12 (m, 1 H), 1.35–1.41 (m,
4 H), 1.73–1.80 (m, 1 H), 2.02 (s, 1 H), 3.69 (s, 3 H), 6.75–6.79 (m,
2 H), 6.98–7.02 (m, 2 H), 7.22–7.35 (m, 3 H), 7.48–7.51 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.25, 13.48, 27.16,
27.74, 55.29, 69.63, 89.64, 113.61, 124.29, 127.82, 129.35, 129.42,
135.09, 138.13, 147.63, 153.89, 156.18 ppm. IR (KBr): ν = 3426,
˜
1680, 1503, 1241, 1069, 696 cm–1. C21H20INO3 (461.1): calcd. C
54.68, H 4.37, N 3.04; found C 54.64, H 4.34, N 3.02.
Compound 3b: Colorless solid; m.p. 85–86 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.89–0.96 (m, 1 H), 1.08–1.15 (m, 1 H), 1.38–1.44 (m,
1 H), 1.47 (s, 3 H), 1.74–1.81 (m, 1 H), 1.93 (s, 1 H), 6.94–7.03 (m,
3 H), 7.19–7.25 (m, 2 H), 7.27–7.31 (m, 3 H), 7.44–7.48 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.32, 13.69, 27.22,
27.61, 69.64, 89.63, 122.30, 123.79, 127.77, 128.40, 129.34, 129.46,
Scheme 4.
Conclusions
134.90, 145.48, 147.58, 154.85 ppm. IR (KBr): ν = 3331, 1689,
˜
1225, 755, 550 cm–1. C20H18INO2 (431.0): calcd. C 55.70, H 4.21,
N 3.25; found C 55.73, H 4.24, N 3.28.
In summary, we have developed a new approach to the
formation of polysubstituted 3-iodopyrans. The process
showed considerable synthetic advantages in terms of mild
reaction conditions, the simplicity of the reaction pro-
cedure, and good to excellent yields. Iodocyclization of alk-
ynyl carboxamides followed by palladium-catalyzed coup-
ling afforded products with an increased molecular com-
plexity and has provided a powerful tool for the preparation
of a wide range of functionalized and polysubstituted py-
rans. Further work based on the three-membered ring to
extend this method for the synthesis of complex active mo-
lecular structures is in progress.
Compound 4b: Colorless solid; m.p. 135–136 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.87–1.06 (m, 1 H), 1.07–1.13 (m, 1 H),
1.36–1.42 (m, 1 H), 1.46 (s, 3 H), 1.73–1.80 (m, 1 H), 1.90 (s, 1 H),
2.26 (m, 3 H), 6.88–6.91 (d, J = 6.0 Hz, 2 H), 7.01–7.03 (d, J =
4.0 Hz, 2 H), 7.30–7.34 (m, 3 H), 7.46–7.50 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 8.28, 13.56, 20.86, 27.21, 27.70,
69.65, 89.62, 122.54, 127.79, 128.98, 129.39, 133.32, 135.06, 142.57,
147.68, 154.33 ppm. IR (KBr): ν = 3559, 2972, 1680, 1069, 733,
˜
537 cm–1. C21H20INO2 (445.0): calcd. C 56.64, H 4.53, N 3.15;
found C 56.68, H 4.56, N 3.12.
Compound 5b: Colorless solid; m.p. 178–179 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.96–1.01 (m, 1 H), 1.06–1.22 (m, 1 H),
1.50–1.54 (m, 4 H), 1.74–1.80 (m, 1 H), 2.04 (s, 1 H), 6.96–6.98 (m,
2 H), 7.31–7.33 (d, J = 4.0 Hz, 3 H), 7.40–7.42 (m, 2 H), 8.0–8.1
(m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.87, 14.67,
27.27, 27.49, 69.30, 90.58, 122.37, 124.43, 127.98, 129.13, 129.76,
Experimental Section
General: Commercially available reagents and solvents were used
without further purification. Melting points were determined with
a microscopic apparatus and are uncorrected. Column chromatog-
raphy was carried out on silica gel. 1H NMR spectra were recorded
with a 400 MHz spectrometer in CDCl3 by using TMS as the in-
ternal standard. 13C NMR spectra were recorded with a 100 MHz
spectrometer in CDCl3. Mass spectra were recorded with a HP5998
MS spectrometer by using the EI method. IR spectra were recorded
with an FTIR spectrometer and only the major peaks are reported.
All new compounds were further characterized by element analysis.
Compound 1b: Colorless solid; m.p. 140–141 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.93–1.00 (m, 1 H), 1.09–1.16 (m, 1 H),
1.36–1.43 (m, 1 H), 1.51 (s, 3 H), 1.55–1.84 (m, 1 H), 2.03 (s, 2 H),
7.28 (s, 1 H), 3.73 (s, 3 H), 6.80–6.85 (m, 3 H), 6.94–7.00 (m, 1 H),
7.22–7.27 (m, 3 H), 7.38–7.41 (m, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 8.15, 13.47, 27.05, 27.50, 55.57, 69.73, 89.42, 111.07,
120.52, 122.03, 124.19, 127.66, 129.26, 129.30, 135.06, 135.45,
134.39, 143.79, 147.21, 152.52, 157.24 ppm. IR (KBr): ν = 3504,
˜
1684, 1339, 1066, 732, 521 cm–1. C20H17IN2O4 (476.0): calcd. C
50.44, H 3.60, N 5.88; found C 50.37, H 3.68, N 5.82.
Compound 6b: Yellow crystal; m.p. 88–89 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.87–1.07 (m, 1 H), 1.08–1.15 (m, 1 H), 1.39–1.44 (m,
4 H), 1.46–1.79 (m, 1 H), 1.94 (s, 1 H), 6.86–7.15 (m, 2 H), 7.16–
7.23 (m, 2 H), 7.31–7.34 (m, 3 H), 7.43–7.47 (m, 2 H) ppm. 13C
NMR (100 MHz, CDCl3): δ = 8.45, 13.93, 27.21, 27.59, 69.51,
89.96, 123.81, 127.89, 128.45, 128.99, 129.26, 129.58, 134.75,
144.01, 147.45, 155.56 ppm. IR (KBr): ν = 3563, 1679, 1486, 1069,
˜
733, 524 cm–1. C20H17ClINO2 (465.0): calcd. C 51.58, H 3.68, N
3.01; found C 51.51, H 3.73, N 3.08.
Compound 7b: Colorless solid; m.p. 128–129 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.89–0.94 (m, 1 H), 1.09–1.14 (m, 1 H),
1.40–1.46 (m, 4 H), 1.73–1.78 (m, 1 H), 1.92 (s, 1 H), 6.82–6.84
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Synthesis of Polysubstituted 3-Iodopyrans by Electrophilic Cyclization
(m, 2 H), 7.31–7.34 (m, 5 H), 7.43–7.46 (m, 2 H) ppm. 13C NMR
27.21, 27.53, 69.54, 90.48, 123.66, 123.88, 128.53, 129.12, 130.88,
(100 MHz, CDCl3): δ = 8.49, 13.96, 27.23, 27.62, 69.50, 90.01, 131.20, 133.65, 143.96, 146.51, 155.28 ppm. IR (KBr): ν = 3558,
˜
116.80, 124.23, 127.91, 129.27, 129.60, 131.41, 134.77, 144.55,
1223, 786, 456 cm–1. C20H17ClINO2 (465.7): calcd. C 51.58, H 3.68,
N 3.01; found C 51.49, H 3.61, N 3.12.
147.48, 155.54 ppm. IR (KBr): ν = 3432, 1679, 1483, 1068, 733,
˜
520 cm–1. C20H17BrINO2 (508.9): calcd. C 47.09, H 3.36, N 2.75;
found C 47.05, H 3.39, N 2.81.
Compound 14b: Colorless solid; m.p. 88–89 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.87–0.94 (m, 2 H), 1.09–1.15 (m, 1 H),
1.40–1.46 (m, 5 H), 1.73–1.78 (m, 1 H), 1.87 (s, 1 H), 6.85–6.87 (m,
2 H), 7.17–7.19 (m, 2 H), 7.29–7.31 (m, 2 H), 7.38–7.40 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.52, 14.04, 27.24,
27.56, 69.52, 90.87, 123.73, 127.41, 128.55, 129.21, 129.33, 129.56,
Compound 8b: Colorless solid; m.p. 90–91 °C. 1H NMR (400 MHz,
CDCl3): δ = 0.89–0.94 (m, 1 H), 1.10–1.15 (m, 1 H), 1.41–1.46 (m,
4 H), 1.73–1.78 (m, 1 H), 1.96 (s, 1 H), 6.84–6.87 (m, 1 H), 7.05–
7.09 (t, J = 8.0 Hz, 1 H), 7.12–7.16 (m, 2 H), 7.31–7.33 (m, 3 H),
7.46–7.49 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.52,
14.09, 27.23, 27.54, 69.52, 89.94, 121.14, 121.93, 125.50, 126.69,
127.87, 129.30, 129.61, 129.71, 134.61, 147.02, 147.36, 156.11 ppm.
129.72, 133.84, 136.46, 143.92, 146.16, 155.18 ppm. IR (KBr): ν =
˜
3532, 1249, 711, 488 cm–1. C19H23ClINO2 (459.1): calcd. C 49.64,
H 5.04, N 3.05; found C 49.49, H 5.13, N 3.11.
IR (KBr): ν = 3559, 1678, 1067, 734, 477 cm–1. C H BrINO
Compound 7c: Colorless oil. 1H NMR (400 MHz, CDCl3): δ =
0.83–0.89 (m, 1 H), 0.97–1.02 (m, 1 H), 1.13–1.18 (m, 1 H), 1.42–
1.57 (m, 1 H), 1.62 (s, 3 H), 1.63–2.34 (m, 1 H), 2.34 (s, 1 H), 6.88–
6.90 (d, J = 4.0 Hz, 2 H), 7.25–7.40 (m, 5 H), 7.40–7.43 (m, 3 H),
7.82–7.84 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.61,
13.59, 27.01, 27.94, 67.82, 83.50, 98.19, 106.81, 116.72, 122.81,
124.00, 127.56, 127.95, 128.03, 128.49, 129.31, 129.75, 131.22,
˜
20 17
2
(508.9): calcd. C 47.09, H 3.36, N 2.81; found C 47.06, H 3.32, N
2.72.
Compound 9b: Colorless solid; m.p. 125–126 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.83–0.88 (m, 1 H), 1.08–1.13 (m, 1 H),
1.20–1.26 (m, 2 H), 1.51–1.59 (m, 4 H), 1.92 (s, 1 H), 1.95–2.00 (m,
1 H), 6.98–6.99 (d, J = 2.0 Hz, 1 H), 7.17–7.23 (m, 3 H), 7.29–7.35
(m, 2 H), 7.41–7.44 (m, 2 H), 7.51–7.53 (d, J = 4.0 Hz, 1 H), 7.76–
7.78 (m, 1 H), 7.89 (s, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ
= 8.64, 14.34, 27.45, 27.88, 69.65, 89.61, 116.61, 123.37, 123.68,
125.29, 125.52, 125.73, 127.63, 127.69, 127.86, 129.30, 129.40,
131.54, 132.44, 144.99, 150.91, 155.61 ppm. IR (neat): ν = 3562,
˜
1682, 1111, 691, 527 cm–1. C28H22BrNO2 (483.2): calcd. C 69.43,
H 4.58, N 2.89; found C 69.52, H 4.51, N 2.83.
Supporting Information (see footnote on the first page of this arti-
1
cle): H and 13C NMR spectra, elemental analysis data.
134.03, 134.76, 142.00, 147.64, 155.61 ppm. IR (KBr): ν = 3558,
˜
1683, 1071, 775, 569 cm–1. C24H20INO2 (481.0): calcd. C 59.89, H
4.19, N 2.91; found C 59.85, H 4.23, N 2.98.
Acknowledgments
Compound 10b: Colorless oil. 1H NMR (400 MHz, CDCl3): δ =
0.82–0.86 (m, 2 H), 0.87–0.93 (m, 3 H), 1.42–1.51 (m, 2 H), 1.53
(s, 3 H), 1.62–1.65 (m, 2 H), 2.01–2.13 (m, 1 H), 2.30 (s, 3 H), 2.96–
2.99 (m, 1 H), 6.94–6.96 (d, J = 8.0 Hz, 2 H), 7.06–7.08 (d, J =
4.0 Hz, 2 H), 7.32–7.33 (d, J = 2.0 Hz, 2 H), 7.41–7.44 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 13.96, 20.90, 22.65,
26.34, 29.11, 29.44, 50.05, 88.17, 120.58, 122.39, 127.88, 127.95,
129.07, 129.46, 129.55, 133.79, 142.41, 147.70, 153.62 ppm. IR
The authors thank the NSF (NSF-20621091) and the “Hundred
Scientist” from the Chinese Academy of Sciences for the financial
support of this work.
[1] a) M. M. Faul, B. E. Huff, Chem. Rev. 2000, 100, 2407–2473;
b) D. J. Faulkner, Nat. Prod. Rep. 2000, 17, 7–55.
[2] a) C. Jaramillo, S. Knapp, Synthesis 1994, 1–20; b) M. J. Clon-
inger, L. E. Overman, J. Am. Chem. Soc. 1999, 121, 1092–1093;
c) H. Huang, J. S. Panek, J. Am. Chem. Soc. 2000, 122, 9836–
9837; d) B. Schmidt, H. Wildemann, Eur. J. Org. Chem. 2000,
3145–3163; e) W. R. Roush, G. J. Dilley, Synlett 2001, 955–959;
f) D. P. Steinhuebel, J. J. Fleming, J. D. Bois, Org. Lett. 2002,
4, 293–295.
[3] a) M. Barreau, G. Ponsinet, Synthesis 1987, 262–265; b) J. Bar-
luenga, J. M. Gonzalez, P. J. Campos, G. Asensio, Angew.
Chem. Int. Ed. Engl. 1988, 27, 1546–1547; c) X. Zhang, M. A.
Campo, T. Yao, R. C. Larock, Org. Lett. 2005, 7, 763–766; d)
M. Nishizawa, H. Takao, V. K. Yadav, H. Imagawa, T. Sugih-
ara, Org. Lett. 2003, 5, 4563–4565.
[4] a) R. C. Larock, D. Yue, Tetrahedron Lett. 2001, 42, 6011–
6013; b) D. Yue, R. C. Larock, J. Org. Chem. 2002, 67, 1905–
1909; c) B. L. Flynn, P. Verdier-Pinard, E. Hamel, Org. Lett.
2001, 3, 651–654.
[5] A. Arcadi, S. Cacchi, G. Fabrizi, F. Marinelli, L. Moro, Synlett
1999, 1432–1434.
(neat): ν = 3452, 1026, 865, 532 cm–1. C H INO (475.1): calcd.
˜
23 26
2
C 58.11, H 5.51, N 2.95; found C 58.13, H 5.54, N 2.90.
Compound 11b: Colorless solid; m.p. 80–81 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.83–0.87 (m, 3 H), 1.02–1.04 (m, 1 H),
1.05–1.27 (m, 8 H), 1.30–1.42 (m, 2 H), 1.66–1.77 (m, 1 H), 1.79
(s, 1 H), 2.43–2.44 (d, J = 2.0 Hz, 1 H), 6.82–6.84 (d, J = 2.0 Hz,
2 H), 7.20–7.22 (d, J = 4.0 Hz, 2 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 8.39, 13.85, 13.93, 22.27, 25.86, 27.30, 27.64, 30.68,
35.60, 68.81, 88.96, 123.50, 128.42, 128.81, 144.42, 149.60,
156.14 ppm. IR (KBr): ν = 3389, 2923, 1678, 1090, 1002, 838,
˜
517 cm–1. C20H16BrClINO2 (542.1): calcd. C 44.11, H 2.96, N 2.57;
found C 44.25, H 2.89, N 2.64.
Compound 12b: Colorless solid; m.p. 98–99 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.82–0.84 (m, 1 H), 0.85–0.89 (m, 3 H),
1.02–1.07 (m, 1 H), 1.30–1.35 (m, 4 H), 1.42–1.47 (m, 2 H), 1.64–
1.71 (m, 1 H), 1.75 (s, 1 H), 6.83–6.85 (m, 2 H), 7.20–7.23 (m, 2
H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.38, 10.24, 13.12,
13.23, 13.92, 15.46, 19.73, 19.80, 27.32, 27.67, 27.74, 37.45, 37.67,
68.81, 89.32, 123.52, 128.45, 144.42, 149.37, 156.06 ppm. IR (KBr):
[6] X.-F. Ren, M. I. Konaklieva, H. Shi, S. Dickey, D. V. Lim, J.
Gonzalez, E. Turos, J. Org. Chem. 1998, 63, 8898–8917.
[7] J. A. Marshall, M. M. Yanik, J. Org. Chem. 1999, 64, 3798–
3799.
[8] D. W. Knight, A. L. Redfern, J. Gilmore, Chem. Commun.
1998, 2207–2208.
ν = 3555, 2965, 1679, 997, 837, 516 cm–1. C H Cl INO (498.1):
˜
20 16
2
2
calcd. C 48.03, H 3.22, N 2.80; found C 48.11, H 3.29, N 2.83.
[9] a) S. P. Bew, D. W. Knight, Chem. Commun. 1996, 1007–1008;
b) E. Djuardi, E. McNelis, Tetrahedron Lett. 1999, 40, 7193–
7196; c) A. Sniady, K. A. Wheeler, R. Dembinski, Org. Lett.
2005, 7, 1769–1772; d) T. Yao, X. Zhang, R. C. Larock, J. Org.
Chem. 2005, 70, 7679–7685; e) Y. Liu, S. Zhou, Org. Lett. 2005,
7, 4609–4611.
Compound 13b: Colorless solid; m.p. 121–122 °C. 1H NMR
(400 MHz, CDCl3): δ = 0.91–0.94 (m, 1 H), 1.09–1.14 (m, 1 H),
1.40–1.46 (m, 4 H), 1.72–1.78 (m, 1 H), 1.94 (s, 1 H), 6.85–6.87 (d,
J = 4.0 Hz, 2 H), 7.17–7.19 (m, 2 H), 7.31–7.33 (m, 2 H), 7.45–
7.47 (m, 2 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 8.52, 14.02,
Eur. J. Org. Chem. 2009, 2283–2288
© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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2287

Y.-X. Xie, Z.-Y. Yan, D.-Z. Wang, L.-Y. Wu, B. Qian, X.-Y. Liu, Y.-M. Liang
FULL PAPER
[10] A. Arcadi, S. Cacchi, S. Di Giuseppe, G. Fabrizi, F. Marinelli, [21]
Org. Lett. 2002, 4, 2409–2412.
[11] a) J. Barluenga, M. Trincado, E. Rublio, J. M. Gonzalez, An-
gew. Chem. Int. Ed. 2003, 42, 2406–2409; b) A. Muhammad,
D. W. Knight, Tetrahedron Lett. 2004, 45, 539–542; c) D. Yue,
R. C. Larock, Org. Lett. 2004, 6, 1037–1040.
[12] a) J. Barluenga, H. Vazque-Villa, A. Ballesteros, J. M. Gonza-
lez, J. Am. Chem. Soc. 2003, 125, 9028–9029; b) D. Yue, N.
Della Ca, R. C. Larock, Org. Lett. 2004, 6, 1581–1584.
[13] a) T. Yao, R. C. Larock, Tetrahedron Lett. 2002, 43, 7401–7404;
b) T. Yao, R. C. Larock, J. Org. Chem. 2003, 68, 5936–5942; c)
M. A. Oliver, R. D. Gandour, J. Org. Chem. 1984, 49, 558–
a) Z. J. Yang, M. J. Fan, R. Z. Mu, W. M. Liu, Y. M. Liang,
Tetrahedron 2005, 61, 9140–9146; b) M. J. Fan, Z. Y. Yan,
W. M. Liu, Y. M. Liang, J. Org. Chem. 2005, 70, 8204–8207; c)
X. H. Duan, X. Y. Liu, L. N. Guo, M. C. Liao, W. M. Liu,
Y. M. Liang, J. Org. Chem. 2005, 70, 6980–6983; d) H. P. Bi,
X. Y. Liu, F. R. Gou, L. N. Guo, X. H. Duan, Y. M. Liang,
Org. Lett. 2007, 9, 3527–3529; e) H. P. Duan, X. H. Guo, L. N.
Bi, X. Y. Liu, Y. M. Liang, Org. Lett. 2006, 8, 5777–5780; f)
X. H. Duan, L. N. Guo, X. Y. Bi, H. P. Liu, Y. M. Liang, Org.
Lett. 2006, 8, 3053–3056; g) H. P. Bi, X. Y. Liu, F. R. Gou,
L. N. Guo, X. H. Duan, Y. Z. Shu, M. X. Liang, Angew. Chem.
Int. Ed. 2007, 46, 7068–7071.
559; d) M. Biagetti, F. Bellina, A. Carpita, P. Stabile, R. Rossi,
Tetrahedron 2002, 58, 5023–5038; e) R. Rossi, A. Carpita, F.
Bellina, P. Stabile, L. Mannina, Tetrahedron 2003, 59, 2067–
2081.
[22]
[23]
Y.-X. Xie, X.-Y. Liu, L.-Y. Wu, Y. Hao, L.-B. Zhao, M.-J. Fan,
Y.-M. Liang, Eur. J. Org. Chem. 2008, 1013–1018.
The atomic coordinates for 1a have been deposited at the Cam-
bridge Crystallographic Data Centre. CCDC-710206 contains
the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge Crys-
tallographic Data Centre via www.ccdc.cam.ac.uk/data_requ-
est/cif.
[14] a) Q. Huang, J. A. Hunter, R. C. Larock, Org. Lett. 2001, 3,
2973–2976; b) Q. Huang, J. A. Hunter, R. C. Larock, J. Org.
Chem. 2002, 67, 3437–3444.
[15] J. P. Waldo, R. C. Larock, Org. Lett. 2005, 7, 5203–5205.
[16] A. S. K. Hashmi, J. P. Weyrauch, W. Frey, J. W. Bats, Org. Lett.
2004, 6, 4391–4394.
[17] J. Barluenga, H. Vazquez-Villa, A. Ballesteros, J. M. Gonzalez,
Org. Lett. 2003, 5, 4121–4123.
[18] a) T. Yao, M. A. Campo, R. C. Larock, Org. Lett. 2004, 6,
2677–2680; b) T. Yao, M. A. Campo, R. C. Larock, J. Org.
Chem. 2005, 70, 3511–3517.
[19] a) D. Yue, R. C. Larock, Org. Lett. 2004, 6, 1037–1040; b) J.
Barluenga, M. Trincado, E. Rubio, J. M. Gonzalez, Angew.
Chem. Int. Ed. 2003, 42, 2406–2409.
[20] C. Zhou, A. V. Dubrovsky, R. C. Larock, J. Org. Chem. 2006,
71, 1626–1632.
[24] M. S. Rao, N. Esho, C. Sergeant, R. Dembinski, J. Org. Chem.
2003, 68, 6788–6790.
[25] K. N. Campbell, R. S. Tipson, R. C. Elderfield, B. K.
Campbell, M. A. Clapp, W. J. Gensler, D. Morrison, W. J. Mo-
ran, J. Org. Chem. 1946, 11, 803–811.
[26] a) W. Pan, D. W. Dong, K. W. Wang, J. Zhang, W. Rigenhada,
D. X. Xiang, Q. Liu, Org. Lett. 2007, 9, 2421–2423; b) Z. G.
Zhang, Q. Zhang, S. G. Sun, T. Xiong, Q. Liu, Angew. Chem.
Int. Ed. 2007, 46, 1726–1729.
Received: December 18, 2008
Published Online: March 24, 2009
2288
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© 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2009, 2283–2288