Tandem synthesis of pyrroloisoquinolines through 5-endo iodolactamization, oxidative functionalization and α-amidoalkylation reaction

Article abstract of DOI:10.1016/j.tet.2015.04.057

Pyrroloisoquinolines formation through 5-endo halocyclization of unsaturated amides, direct C-H oxidative functionalization and N-acyliminium cyclization is described. A range of β-iodo-pyrrolidinones can be efficiently synthesized using this method, maki

Full text of DOI:10.1016/j.tet.2015.04.057

Tetrahedron 71 (2015) 4334e4343
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Tetrahedron
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Tandem synthesis of pyrroloisoquinolines through
5-endo iodolactamization, oxidative functionalization
and
a-amidoalkylation reaction
*
Yu Tang , Ranran Han, Mingcan Lv, Yang Chen, Pan Yang
Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency, School of Pharmaceutical Science and Technology, Tianjin University, Tianjin
300072, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pyrroloisoquinolines formation through 5-endo halocyclization of unsaturated amides, direct CeH oxi-
dative functionalization and N-acyliminium cyclization is described. A range of b-iodo-pyrrolidinones
can be efficiently synthesized using this method, making it an excellent approach for constructing
natural products containing pyrrolidinones. Besides, we have developed convenient alternative routes
for the synthesis of pyrroloisoquinolines in two separated steps or one pot.
Ó 2015 Elsevier Ltd. All rights reserved.
Received 15 March 2015
Received in revised form 13 April 2015
Accepted 18 April 2015
Available online 26 April 2015
Keywords:
CeH oxidative functionalization
5-endo Halocyclization
N-Acyliminium cyclization
b-Iodo-pyrrolidinone
Pyrroloisoquinoline
1. Introduction
radical cyclization for the formation of unsaturated lactams; the
reaction was promoted by vinylic iodine substitution.6 The same
t
Halocyclizations of unsaturated compounds are of great interest
since they could allow one to access to functionalized lactones,
lactams, oxazoline and cyclic amides, which have generally been
proved to be interesting synthons for natural product synthesis.1
These cyclizations generally follow Baldwin’s ring closure rules.2
3- to 7-membered ring closures often favours exo-trig and 6- to
7-endo processes, but not 3- to 5-endo ones. The regioselectivity of
the reaction can be governed electronically and structurally; for
example, substituents on the double bond can dramatically affect
the selectivity. Numerous electrophiles, for example NBS, NIS, NCS,
Br2, I2, PhSeCl, m-CPBA, have been used in these transformations.
The most common electrophile used for this cyclization is iodo-
nium (Iþ) equivalent, generated from its molecular form or from
more complex reagents.1
Numerous studies have examined 5-exo halocyclization, espe-
cially 5-exo iodolactonization of unsaturated carboxylic acids and
amides.3,4 In contrast, 5-endo halocyclization of unsaturated com-
pounds have less been investigated. In particular, few studies have
examined lactam formation through 5-endo halocyclization of un-
saturated amides.5 Li and co-workers described a 5-endo amidyl
group found BuOCl/I2 to be an efficient iodinating reagent for the
synthesis of iminolactones.7 Our interest focus on whether a tan-
dem sequence of 5-endo halolactamization and CeH oxidative
functionalization8,9 could be applied to the synthesis of
pyrroloisoquinolines.
Pyrrolidinones10 and its derivatives exhibit a wide range of
biological activities and they have been used widely for the syn-
thesis of alkaloid natural products (Fig. 1),11 that can be easily
transformed into pyrroloisoquinoline ring system,12 which is
found as a major structural motif of the erythrina alkaloid group of
natural products (Fig. 1),13,14 via intramolecular
a-amidoalkylation
of formative highly reactive N-acyliminium ions.15,16 These re-
actions are achieved with Lewis acids that include TiCl4, SnCl4,
15a
TMSOTf, BF3$OEt2
or Sc(OTf)3,17Brønsted acid such as
TFA,15c,18,19superacidic reagents20e22 or in situ generated acids
(Scheme 1).23
Recently, we developed sequential 5-endo halolactamization
and CeH oxidative functionalization for the synthesis of b-halo-
pyrrolidinones [Eq. (1)]. In our case, the reactions underwent hal-
ocyclization processes rather than radical cyclization, which have
been reported previously in Li’s pyrrolidinone synthesis. Herein we
report an approach to the formation of pyrroloisoquinoline16b,c ring
system involving sequential 5-endo halolactamization, CeH
* Corresponding author. Tel.: þ86 02227402904; fax: þ86 02227404031; e-mail
address: yutang@tju.edu.cn (Y. Tang).
http://dx.doi.org/10.1016/j.tet.2015.04.057
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.

Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
4335
provided our desired pyrrolidinone 3a in 65% yield (entry 6). Fur-
ther increasing the amount of NIS (6 equiv) led to a slight decline
(entry 7). In the presence of NIS and commercial acetonitrile, 3a
was obtained in 19% yield (entry 8).
Our success in transforming vinyl iodide
1 into iodo-
pyrrolidinones 3 through sequential 5-endo halolactamization
and CeH oxidative functionalization8 prompted us to further ex-
tend the use of the N-phenethylamine 2ae2k as the substrates
(Table 2). We investigated the effect of R3 group in this trans-
formation. In these cases, the electron-with drawing groups (p-Cl,
p-NO2) and the electron-donating group (p-OMe) exhibited no
significant difference on the activity and iodo-pyrrolidinones 4a-4k
were obtained with desired yields. Besides, when R2 were CO2Me,
i
t
CO2 Pr and CO2 Bu, there were almost no effect on the yields.
Substrate 4 can be easily transformed into highly reactive N-
acyliminium ions that have been generated by Lewis acid or
Brønsted acid promoted cyclization. In screening experiments, we
selected 4d and DCM as the solvent in order to determine optimal
reaction conditions. First, we screened a series of acids that in-
cluded BF3$E2O, CAS, TsOH, AcOH, Tf2NH, TFA (Table 3). Other acids,
such as BF3$E2O and CAS turned out to be inferior in this reaction.
Using 4 equiv of BF3$E2O provided the desired product 5d in 50%
yield along with minor byproduct 6d. Comparatively, with the in-
crease in the amount of BF3$E2O, byproduct 6d was improved
(entry 1e3). CAS and TsOH could transform substrates into
byproduct 6d in low and moderate yield (entry 4e5). The use of
AcOH led to no reactivity (entry 6). The use of 3 equiv Tf2NH
afforded major byproduct 6d in 87% yield. Under the condition of
refluxed, Tf2NH could give the desired product 5d in 52% yield
(entry 7e8). Interestingly, Cyclization with TFA led to product 5d in
72% yield at room temperature. Eventually the reaction with TFA at
elevated temperature produced desired 5d in 79% yield as a single
product (entry 9e10). The structure of 5d was determined by X-ray
crystallography in Fig. 2.
Fig. 1. Examples
pyrroloisoquinolines.
of
natural
products
containing
pyrrolidinones
and
Scheme 1. Synthesis of b-iodo-pyrrolidinones and pyrroloisoquinolines.
With a workable reaction condition in hand, We turned our
attention to explore of the influences on the reaction by the sub-
stituent groups R1, R2 and R3. As shown in Table 4, substrates 4 gave
desired tricyclic product pyrroloisoquinolines 5 in moderate-to-
excellent yields (Table 4). The substrates containing electron-
withdrawing group at para position could only afford eliminated
products, either at room temperature or elevated temperature
oxidative functionalization and N-acyliminium cyclization,24,25 in
two separated steps or one step [Eq. (2)].
2. Results and discussion
(entries 7e8). We also realized that a suitably substituted a-amino
During the initial screening experiments, in order to determine
optimal reaction conditions, we selected 1a and CH3CN/H2O as the
reactant/solvent combination. First, we screened a series of iodin-
ating reagents that included I2/Na2CO3, ICl, IPyBF4 (BPIT), NIS, and
tBuOCl/I2 (Table 1, entries 1e5). NIS and tBuOCl/I2 were moderately
active, but in most of the cases, the reaction showed no or poor
activity. Then we examined the loading of NIS. Using 4 equiv of NIS
acid maybe act as a precursor for diastereoselective approach to the
core of erythrinane ring system. Unfortunately, there are poor dia-
stereoselectivities with the optimized reaction conditions (entries
9ꢀ10). The observed relative diastereochemistry of the minor iso-
mer 5i was proved by analysis of coupling constants in its 1H NMR
spectrum as well as by 1D NOESY experiments.27
As both reactions were very efficient and high yielding, we
performed a ‘telescoped’ version whereby the reaction mixture
from the first 5-endo iodocyclization was subjected to the next set
Table 1
Optimization of reaction conditions
of intramolecular a-amidoalkylation conditions, following a solvent
swap. Gratifyingly we found that this approach led to moderate to
good overall yields of 5 being obtained from 2 (Table 5).
The halo-pyrrolidinones can be used as synthetic intermediates
as illustrated in Scheme 2. The presence of the vinylic halogen
makes possible numerous cross-coupling reactions catalyzed by
transition metals. To demonstrate that the compounds prepared
with our method can function as intermediates, 3a was subjected to
standard Suzuki coupling conditions28 and the corresponding
coupling product 7 was obtained in good yield. Parham-Type Cy-
clizations to 4l (was determined by X-ray crystallography in
Scheme 2) allowed the construction of a second ring with TFA and
afforded compound 5la and 5lb, which contains the core structure
of the alkaloid crispine A.29
Entry
Iþ(equiv)
Solvent
Time (h)
Yield (%)
1
2
3
4
5
6
7
8
I2/Na2CO3 (3)
ICl (3)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O (1:1)
CH3CN/H2O(1:1)
CH3CN/H2O (1:1)
CH3CN
96
1
da
21b
Trace
38
58
65
BPIT (3)
NIS (2)
96
72
15
20
10
96
tBuOCl/I2 (3/2)
NIS (4)
NIS (6)
NIS (6)
63
19
a
No product was identified by TLC.
The Cl-substituted product was formed in 34% yield.
b

4336
Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
Table 2
Formation of iodo-pyrrolidinones 4a
Entry
1
Substrate
Product
Yield (%)
77
Entry
7
Substrate
Product
Yield (%)
93
2a
2g
4a
4g
2
3
76
98
8
9
88
2b
2c
2h
2i
4b
4h
4i
90 (dr¼1:1)
4c
4
5
86
10
11
88 (dr¼1:1)
61 (dr¼1:1)
2d
4j
4d
4e
2j
86
98
2e
2f
4k
2k
6
a
Substrate (1 equiv) was mixed with NIS (4 equiv) at room temperature for 11 h in CH3CN/H2O (1:1).
2.1. Mechanism
Elimination of hydrogen iodide generates enamides 10, which un-
dergoes allylic oxidative functionalization to yield intermediates 11.
Working up affords iodo-pyrrolidinones 4. Finally, The pyrroloiso-
We propose the mechanism for the formation of 5 in Scheme 3.
First, electrophilic attack by Iþ on the olefin gives iodonium species
8. Then, closure through the amide nitrogen gives the lactams 9.
quinolines 5 is obtained through intramolecular
of reactive N-acyliminium.
a-amido alkylation
Table 3
3. Conclusion
Optimization of reaction conditions
In summary, we have developed an efficient strategy for the
synthesis of halo-pyrrolidinones and pyrroloisoquinolines. This
approach with simple experimental conditions provided an access
to useful synthetic intermediates. We believe that the developed
reaction strategy will be used to the synthesis of bioactive
compounds.
Entry Acid (equiv) Solvent T (ꢁC) Time (h) 5d Yield (%) 6d Yield (%)
1
2
BF3$Et2O (4) DCM
BF3$Et2O (10) DCM
BF3$Et2O (20) DCM
rt
rt
rt
rt
rt
rt
rt
90
rt
80
20
10
10
12
10
96
12
12
1
50
11
35
d
d
d
7
8 (Z/E¼2.9:1)a
72 (Z/E¼3.6:1)b
45 (Z/E¼5:1)b
22 (Z/E¼4.4:1)a
55 (Z/E¼6:1)a
d
3
4
5
6
7
8
9
CSA (2)
TsOH (2.5)
AcOH (2)
Tf2NH (3)
Tf2NH (3)
d
DCM
DCM
DCM
DCM
DCM
TFA
87 (Z/E¼3.5:1)b
52
72
79
d
d
10
d
TFA
1
d
a
Z/E was determined by 1H NMR.26
Z/E was determined by isolation.
b
Fig. 2. X-ray crystallography of 5d.

Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
4337
Table 4
Formation of pyrroloisoquinolines via a-amidoalkylation cyclizations
Entry
1
Substrate
Product
Yield (%)
91a
Entry
6
Substrate
Product
Yield (%)b
70
2
78b
7
92c
3
4
89
79
94
8
9
75c
45d
66e
5
10
a
The eliminated product 6a was obtained in 90% yield at room temperature.
The tricyclic product 5b was obtained in 66% at room temperature.
The eliminated products 6g and 6h were obtained.
10S:10R¼4.5:1.
b
c
d
e
10S:10R¼3.5:1. d.r. was determined by 1H NMR analysis of the crude reaction mixture.
4. Experimental section
4.1. General information
23 ꢁC. After 20 h, the reaction was quenched with saturated aqueous
Na2S2O3 (3 mL), then extracted three times with ethyl acetate
(5 mLꢂ3). The organic phases were combined, washed with brine,
dried over anhydrous MgSO4, filtered and concentrated. The residue
was purified via flash chromatography on silica gel (eluent: EtOAc/
PE¼30/70), to provide desired product3a in65% yieldas awhite solid.
All reactions were carried out at room temperature without
precaution of air and stirred magnetically. 1H and 13C NMR spectra
were recorded on a VARIAN AM-600 MHz BRUKER AVANCE spec-
trometer at 25 ꢁC. Chemical shifts values are given in parts per
million and referred as the internal standard to TMS: 0.00 ppm. The
peak patterns are indicated as follows: s, singlet; d, doublet; t,
triplet; q, quartet; qui, quintet; m, multiplet and dd, doublet of
doublets. The coupling constants J, are reported in Hertz (Hz). IR was
recorded on a Bio Rad FTS-185 Fourier Transform Infrared Spec-
trometer. Mass spectrum was obtained on Agilent 6310 Ion Trap and
HP5989A mass spectrometer. High resolution mass spectrometry
(HRMS) was obtained on a Q-TOF micro (BRUKER) spectrometer.
Melting points were determined with a national Micro Melting
point apparatus without corrections. Element analysis was recorded
on a Carlo-ERBA 1106 Elemental Analyzer. Organic solutions were
concentrated by rotary evaporation below 40 ꢁC in vacuum. TLC
plates were visualized by exposure to ultraviolet light.
4.2.2. 5-Hydroxy-4-iodo-5-methyl-1-phenyl-1H-pyrrol-2(5H)-one
(3a). Following the general procedure 4.2.1, Starting from 1a
(0.05 g, 0.17 mmol), iodine (0.13 g, 0.50 mmol) and t-BuOCl
(56.00
m
L, 0.51 mmol), 3a (43.00 mg, 83%) was synthesized as
a white solid. Mp: 101e103 ꢁC; 1H NMR (600 MHz, CDCl3)
d
1.42 (s,
3H), 3.07 (br s, 1H), 6.61 (s, 1H), 7.30 (t, 1H, J¼7.2 Hz), 7.39 (t, 2H,
J¼7.2 Hz), 7.44 (d, 2H, J¼7.2 Hz); 13C NMR (150 MHz, CDCl3)
d 24.0,
93.6, 123.9, 126.6, 127.4, 129.1, 135.3, 135.4, 167.2; IR (neat): ymax
3127, 1655, 1593, 1495, 1398, 1178, 1125, 861, 740, 704 cmꢀ1; mass
spectrum (ESI): m/e (% relative intensity) 316 (100) (MþH)þ; HRMS
(ESI) m/z calcd for C11H11INOþ2 (MþH)þ 315.9829, found 315.9830.
4.2.3. 5-Hydroxy-4-iodo-5-methyl-1-phenethyl-1H-pyrrol-2(5H)-
one (4a). Following the general procedure 4.2.1, Starting from 2a
(0.10 g, 0.30 mmol), and N-iodosuccinimide (0.27 g, 1.20 mmol) in
CH3CN/H2O (1:1) (3 mL) at 23 ꢁC for 12 h, purified by silical gel
chromatography (EtOAc/PE¼10/90), 4a (0.08 g, 77%) was synthesized
4.2. Synthetic procedures and characterization data
as a white solid. Mp: 151e153 ꢁC; 1H NMR (600 MHz, CDCl3)
d 1.36 (s,
4.2.1. General procedure for preparation of 5-hydroxypyrrole-2 (5H)-
one (3a, 4ae4l). A solution of N-iodosuccinimide (0.67 mmol) in
CH3CN/H2O (1:1) (2 mL) was added amide 1a (0.17 mmol), stirred at
3H), 2.87e2.93 (m, 1H), 3.03e3.08 (m, 1H), 3.45e3.51 (m, 1H),
3.67e3.73 (m, 1H), 6.45 (s, 1H), 7.22 (d, 3H, J¼7.2 Hz), 7.28 (t, 2H,

4338
Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
Table 5
Formation of pyrroloisoquinolines in one pota
Entry
Substrate
Product
Yield (%)b
72
1
2
3
4
5
71
51
81
76
Scheme 2. Application of vinyl iodo amides.
6
56
Scheme 3. Proposed mechanism for formation of 5.
7
66
(100) (MþNa)þ; HRMS (ESI) m/z calcd for C14H16INO2Naþ (MþNa)þ
380.0123, found 380.0136.
a
Substrate (1 equiv) was mixed with NIS (4 equiv) at room temperature for 11 h
in CH3CN/H2O (1:1), after removal of the solvents, TFA (0.5 mL) was added to the
resulted mixtures, stirred for 4 h at refluxed.
4.2.5. 5-Hydroxy-4-iodo-1-(4-methoxyphenethyl)-5-methyl-1H-pyr-
rol-2(5H)-one (4c). Following the general procedure 4.2.1, Starting
from 2c (0.10 g, 0.28 mmol), and N-iodosuccinimide (0.25 g,
1.10 mmol) in CH3CN/H2O (1:1) (4 mL) at 23 ꢁC for 12 h, purified by
silical gel chromatography (EtOAc/PE¼20/80), 4c (0.063 g, 61%) was
synthesized as a white solid. Mp: 99e101 ꢁC; 1H NMR (600 MHz,
b
isolated yield after aqueous work-up and purified by silica gel chromatography.
J¼7.2 Hz); 13C NMR (150 MHz, CDCl3)
d 23.5, 34.8, 41.7, 92.1, 123.6,
126.6,128.6,128.9,135.0,138.9,168.0;IR (neat): ymax 2955, 2925, 2870,
2853, 1667, 1643, 1502, 1455, 1417, 807, 761, 701 cmꢀ1; mass spectrum
(ESI): m/e (% relative intensity) 344 (100) (MþH)þ; HRMS (ESI) m/z
calcd for C13H14INO2Naþ (MþNa)þ 365.9967, found 365.9967.
CDCl3)
d 1.37 (s, 3H), 2.83e2.88 (m, 1H), 3.00e3.05 (m, 1H),
3.42e3.47 (m, 1H), 3.69e3.75 (m, 1H), 3.78 (s, 3H), 6.48 (s, 1H), 6.83
(d, 2H, J¼8.4 Hz), 7.14 (d, 2H, J¼8.4 Hz); 13C NMR (150 MHz, CDCl3)
d
23.5, 33.8, 41.9, 55.3, 92.0, 114.0, 123.2, 129.9, 131.0, 135.3, 158.3,
4.2.4. 5-Hydroxy-4-iodo-5-methyl-1-(4-methylphenethyl)-1H-pyr-
rol-2(5H)-one (4b). Following the general procedure 4.2.1, Starting
from 2b (0.10 g, 0.29 mmol), and N-iodosuccinimide (0.26 g,
1.20 mmol) in CH3CN/H2O (1:1) (3 mL) at 23 ꢁC for 12 h, purified by
silical gel chromatography (EtOAc/PE¼10/90), 4b (0.079 g, 76%) was
synthesized as a white solid. Mp: 114e117 ꢁC; 1H NMR (600 MHz,
167.8; IR (neat): ymax 3229, 2980, 2969, 2937, 2935, 1671,1643,1512,
1455, 1413, 1027, 823, 745, 705 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 374 (100) (MþH)þ; HRMS (ESI) m/z calcd for
C
14H16INO3Naþ (MþNa)þ 396.0073, found 396.0073.
4.2.6. 5-Butyl-5-hydroxy-4-iodo-1-phenethyl-1H-pyrrol-2(5H)-one
(4d). Following the general procedure 4.2.1, Starting from 2d
(0.95 g, 2.55 mmol), and N-iodosuccinimide (2.30 g, 10.20 mmol) in
CH3CN/H2O (1:1) (30 mL) at 23 ꢁC for 12 h, purified by silical gel
chromatography (EtOAc/PE¼10/90), 4d (0.81 g, 86%) was synthe-
sized as a white solid. Mp: 132e134 ꢁC; 1H NMR (600 MHz, CDCl3)
CDCl3)
1H), 3.42e3.48 (m, 1H), 3.66e3.72 (m, 1H), 6.45 (s, 1H), 7.08e7.11
(m, 4H); 13C NMR (150 MHz, CDCl3)
21.1, 23.5, 34.4, 41.8, 92.1,
123.6, 128.8, 129.3, 135.0, 135.8, 136.1, 168.0; IR (neat): ymax 3257,
2997, 2986, 2948, 2935, 1673, 1644, 1515, 1455, 1414, 1165, 954, 856,
761, 702 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity) 380
d 1.36 (s, 3H), 2.31 (s, 3H), 2.82e2.88 (m, 1H), 2.99e3.05 (m,
d

Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
4339
d
0.78e0.91 (m, 5H), 1.27e1.34 (m, 2H), 1.75 (td, 1H, J¼6.0, 13.2 Hz),
(m, 2H), 3.33e3.38 (m, 1H), 3.74e3.80 (m, 1H), 6.53 (s, 1H), 7.45 (d,
2H, J¼8.4 Hz), 8.16 (d, 2H, J¼8.4 Hz); 13C NMR (150 MHz, CDCl3)
1.83 (td, 1H, J¼6.0, 13.2 Hz), 2.88e2.93 (m, 1H), 3.08e3.14 (m, 1H),
3.27e3.33 (m, 1H), 3.79e3.85 (m, 1H), 6.56 (s, 1H), 7.23 (d, 2H,
d
13.9, 22.3, 24.6, 34.6, 35.0, 40.6, 94.6, 122.9, 123.7, 129.7, 135.7,
J¼8.4 Hz), 7.31 (t, 3H, J¼8.4 Hz); 13C NMR (150 MHz, CDCl3)
d
13.9,
146.7,146.9,168.6; IR (neat): ymax 3113, 2952, 2867,1658,1604,1517,
1460, 1347, 1131, 870, 746, 697 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 431 (100) (MþH)þ; HRMS (ESI) m/z calcd for
22.2, 24.6, 34.2, 34.7, 41.7, 94.5, 122.3, 126.7, 128.7, 128.9, 136.0,
139.0, 168.6; IR (neat): ymax 3178, 2959, 2923, 2860, 1774, 1696,
1452, 1412, 1188, 849, 722, 699 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 408 (100) (MþNa)þ; HRMS (ESI) m/z calcd for
C
16H19IN2O4Naþ (MþNa)þ 453.0287, found 453.0287.
C
16H21INOþ2 (MþH)þ 386.0248, found 386.0246.
4.2.11. (S)-Methyl-2-(2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-dihydro-
1H-pyrrol-1-yl)-3-phenylpropanoate (4i). Following the general
procedure 4.2.1, Starting from 2i (0.24 g, 0.55 mmol), and N-iodo-
succinimide (0.50 g, 2.20 mmol) in CH3CN/H2O (1:1) (8 mL) at 23 ꢁC
for 12 h, purified by silical gel chromatography (EtOAc/PE¼10/90),
4i (0.20 g, 81%) was synthesized. diastereomer-I: (S)-methyl 2-((S)-
2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-
phenylpropanoate. a white solid. Mp: 126e128 ꢁC; 1H NMR
4.2.7. 5-Butyl-5-hydroxy-4-iodo-1-(4-methylphenethyl)-1H-pyrrol-
2(5H)-one (4e). Following the general procedure 4.2.1, Starting
from 2e (0.10 g, 0.26 mmol), and N-iodosuccinimide (0.23 g,
1.04 mmol) in CH3CN/H2O (1:1) (3 mL) at 23 ꢁC for 12 h, purified by
silical gel chromatography (EtOAc/PE¼10/90), 4e (0.089 g, 86%) was
synthesized as a white solid. Mp: 100e102 ꢁC; 1H NMR (600 MHz,
CDCl3)
d
0.75e0.88 (m, 5H), 1.25e1.30 (m, 2H), 1.75 (td, 1H, J¼6.0,
(600 MHz, CDCl3) d 0.50 (br s, 1H), 0.81e0.88 (m, 4H), 1.14e1.23 (m,
13.2 Hz), 1.83 (td, 1H, J¼6.0, 13.2 Hz), 2.31 (s, 3H), 2.62 (br s, 1H),
2.84e2.86 (m, 1H), 3.02e3.05 (m, 1H), 3.27e3.30 (m, 1H),
3.29e3.75 (m, 1H), 6.51 (s, 1H), 7.09e7.13 (m, 4H); 13C NMR
3H), 1.49 (td, 1H, J¼3.0, 12.6 Hz), 1.67 (td, 1H, J¼6.0, 12.6 Hz), 3.37
(dd, 1H, J¼6.0, 12.0 Hz), 3.67 (td, 1H, J¼2.4, 13.2 Hz), 3.78 (s, 3H),
4.27 (dd, 1H, J¼6.0, 12.0 Hz), 6.54 (s, 1H), 7.17 (d, 2H, J¼7.2 Hz),
(150 MHz, CDCl3)
d
13.9, 21.1, 22.2, 24.6, 34.3, 41.8, 94.5,122.4,128.8,
7.24e7.33 (m, 3H); 13C NMR (150 MHz, CDCl3)
d 13.8, 22.4, 24.5,
129.3, 135.9, 136.0, 136.2, 168.6; IR (neat): ymax 3215, 2958, 2923,
2860, 1686, 1514, 1456, 1412, 847, 758 cmꢀ1; mass spectrum (ESI):
m/e (% relative intensity) 422 (100) (MþNa)þ; HRMS (ESI) m/z calcd
for C17H23INOþ2 (MþH)þ 400.0773, found 400.0792.
34.4, 34.5, 52.6, 56.5, 94.1, 122.7, 127.4, 128.9, 129.5, 135.7, 138.1,
168.0, 170.4; IR (neat): ymax 3169, 2960, 2931, 2860, 1762, 1666,
1454, 1347, 1216, 1131, 848, 746, 702 cmꢀ1; mass spectrum (ESI): m/
e (% relative intensity) 466 (100) (MþNa)þ; HRMS (ESI) m/z calcd
for
C
18H22INO4Naþ (MþNa)þ 466.0491, found 466.0508. di-
4.2.8. 5-Butyl-5-hydroxy-4-iodo-1-(4-methoxyphenethyl)-1H-pyr-
rol-2(5H)-one (4f). Following the general procedure 4.2.1, Starting
from 2f (0.25 g, 0.62 mmol), and N-iodosuccinimide (0.56 g,
2.50 mmol) in CH3CN/H2O (1:1) (8 mL) at 23 ꢁC for 12 h, purified by
silical gel chromatography (EtOAc/PE¼15/85), 4f (0.25 g, 98%) was
synthesized as a white solid. Mp: 81e83 ꢁC; 1H NMR (600 MHz,
astereomer-II: (S)-methyl 2-((R)-2-butyl-2-hydroxy-3-iodo-5-oxo-
2,5-dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate. a white solid. Mp:
122e124 ꢁC 1H NMR (600 MHz, CDCl3)
d
ꢀ0.32eꢀ0.27 (m, 1H),
0.34e0.42 (m, 1H), 0.59e0.67 (m, 4H), 0.76e0.85 (m, 1H), 1.08 (td,
1H, J¼6.0, 13.2 Hz), 1.54 (td, 1H, J¼3.6, 13.2 Hz), 3.42 (br s, 1H), 3.50
(dd, 1H, J¼6.0, 13.2 Hz), 3.77 (td, 1H, J¼2.4, 13.2 Hz), 3.83 (s, 3H),
4.26 (dd, 1H, J¼6.0, 12.0 Hz), 6.49 (s, 1H), 7.20e7.30 (m, 5H); 13C
CDCl3)
d
0.78e0.87 (m, 5H), 1.26e1.31 (m, 2H), 1.78 (td, 1H, J¼6.0,
13.2 Hz), 1.84 (td, 1H, J¼6.0, 13.2 Hz), 2.70 (br s, 1H), 2.82e2.85 (m,
1H), 3.00e3.03 (m,1H), 3.26e3.29 (m,1H), 3.71e3.75 (m,1H), 3.78 (s,
3H), 6.51 (s,1H), 6.83 (d, 2H, J¼8.4 Hz), 7.14 (d, 2H, J¼8.4 Hz); 13C NMR
NMR (150 MHz, CDCl3) d 13.6, 22.5, 23.7, 34.4, 35.0, 53.4, 57.9, 94.6,
124.3, 126.9, 128.6, 129.2, 135.8, 138.0, 170.9, 173.2; IR (neat): ymax
3446, 2956, 2931, 2861, 1731, 1703, 1593, 1497, 1456, 1387, 1233,
1084, 850, 752, 701 cmꢀ1; mass spectrum (ESI): m/e (% relative
intensity) 466 (100) (MþNa)þ; HRMS (ESI) m/z calcd for
(150 MHz, CDCl3) d 13.9, 22.2, 24.6, 33.8, 34.3, 41.8, 55.3, 94.5, 114.0,
122.4,129.8,131.0,136.0,158.3,168.6; IR (neat):ymax 3213, 2957, 2931,
2857, 2832, 1684, 1512, 1413, 846, 759, 656 cmꢀ1; mass spectrum
(ESI): m/e (% relative intensity) 438 (100) (MþNa)þ; HRMS (ESI) m/z
calcd for C17H22INO3Naþ (MþNa)þ 438.0542, found 438.0563.
C
18H22INO4Naþ (MþNa)þ 466.0491, found 466.0493.
4.2.12. (S)-Isopropyl-2-(2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-
dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate (4j). Following the
general procedure 4.2.1, Starting from 2j (0.13 g, 0.27 mmol), and N-
iodosuccinimide (0.25 g, 1.10 mmol) in CH3CN/H2O (1:1) (3 mL) at
23 ꢁC for 12 h, purified by silical gel chromatography (EtOAc/PE¼10/
90), 4j (0.11 g, 88%) was synthesized. diastereomer-I: (S)-isopropyl 2-
((R)-2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-
3-phenylpropanoate. a white solid. Mp: 99e101 ꢁC; 1H NMR
4.2.9. 5-Butyl-1-(4-chlorophenethyl)-5-hydroxy-4-iodo-1H-pyrrol-
2(5H)-one (4g). Following the general procedure 4.2.1, Starting from
2g (0.12 g, 0.30 mmol), and N-iodosuccinimide (0.27 g, 1.18 mmol) in
CH3CN/H2O (1:1) (8 mL) at 23 ꢁC for 12 h, purified by silical gel
chromatography (EtOAc/PE¼15/85), 4g (0.11 g, 93%) was synthesized
as a white solid. Mp: 161e163 ꢁC; 1H NMR (600 MHz, CDCl3)
d
0.75e0.83(m,1H), 0.84e0.92(m, 4H),1.24e1.33(m, 2H),1.77(td,1H,
(600 MHz, CDCl3)
d
ꢀ0.27eꢀ0.20 (m, 1H), 0.36e0.45 (m, 1H),
J¼6.0, 13.2 Hz), 1.87 (td, 1H, J¼6.0, 13.2 Hz), 2.50 (br s, 1H), 2.85e2.90
(m, 1H), 3.00e3.05 (m, 1H), 3.26e3.32 (m, 1H), 3.72e3.78 (m, 1H),
6.53 (s, 1H), 7.16 (d, 2H, J¼8.4 Hz), 7.27 (d, 2H, J¼8.4 Hz); 13C NMR
0.60e0.70 (m, 4H), 0.78e0.87 (m, 1H), 1.10 (td, 1H, J¼6.0, 13.2 Hz),
1.28 (d, 3H, J¼6.0 Hz), 1.32 (d, 3H, J¼6.0 Hz), 1.54 (td, 1H, J¼6.0,
13.2 Hz), 3.48 (dd, 1H, J¼6.0, 13.2 Hz), 3.55 (br s, 1H), 3.73 (td, 1H,
J¼3.0, 13.2 Hz), 4.20 (dd, 1H, J¼6.0, 12.0 Hz), 5.06e5.13 (m, 1H), 6.48
(150 MHz, CDCl3) d 13.9, 22.2, 24.6, 34.2, 34.3, 41.3, 94.5, 122.2, 128.8,
130.2, 132.4, 136.1, 137.3, 168.5; IR (neat): ymax 3215, 2959, 2923, 2862,
1682, 1663, 1589, 1452, 1413, 1084, 849, 808, 706 cmꢀ1; mass spec-
trum (ESI): m/e (% relative intensity) 420 (100) (MþH)þ; HRMS (ESI)
m/z calcd for C16H19ClINO2Naþ (MþNa)þ 442.0047, found 442.0048.
(s, 1H), 7.19e7.29 (m, 5H); 13C NMR (150 MHz, CDCl3)
d 13.6, 21.7,
21.8, 22.5, 23.8, 34.5, 35.1, 58.1, 70.8, 94.6, 124.4, 126.8, 128.6, 129.2,
135.8, 138.2, 170.9, 172.3; IR (neat): ymax 3421, 2976, 2955, 2926,
2870, 1734, 1708, 1596, 1454, 1389, 1380, 1270, 1233, 1077, 847, 747,
697 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity) 472 (100)
(MþH)þ; HRMS (ESI) m/z calcd for C20H26INO4Naþ (MþNa)þ
494.0804, found 494.0803. diastereomer-II: (S)-isopropyl 2-((S)-2-
butyl-2-hydroxy-3-iodo-5-oxo-2,5-dihydro-1H-pyrrol-1-yl)-3-
4.2.10. 5-Butyl-5-hydroxy-4-iodo-1-(4-nitrophenethyl)-1H-pyrrol-
2(5H)-one (4h). Following the general procedure 4.2.1, Starting
from 2h (0.10 g, 0.24 mmol), and N-iodosuccinimide (0.22 g,
0.96 mmol) in CH3CN/H2O (1:1) (4 mL) at 23 ꢁC for 12 h, purified by
silical gel chromatography (EtOAc/PE¼40/60), 4h (0.09 g, 88%) was
synthesized as a white solid. Mp: 159e161 ꢁC; 1H NMR (600 MHz,
phenylpropanoate.
(600 MHz, CDCl3)
a
white solid. Mp: 118e120 ꢁC; 1H NMR
d 0.76 (br s, 1H), 0.80e0.89 (m, 4H), 1.15e1.27 (m,
9H), 1.50 (td, 1H, J¼3.0, 13.2 Hz), 1.67 (td, 1H, J¼6.0, 13.2 Hz), 3.38
(dd, 1H, J¼6.0, 13.2 Hz), 3.64 (td, 1H, J¼3.0, 13.2 Hz), 4.30 (dd, 1H,
J¼6.0,12.0 Hz), 5.07e5.14 (m, 1H), 6.53 (s,1H), 7.18 (d, 2H, J¼7.2 Hz),
CDCl3)
d 0.74e0.83 (m, 1H), 0.84e0.94 (m, 4H), 1.26e1.34 (m, 2H),
1.80 (td, 1H, J¼6.0, 13.2 Hz), 1.89 (td, 1H, J¼6.0, 13.2 Hz), 3.04e3.15

4340
Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
7.24 (t, 1H, J¼7.2 Hz), 7.31 (t, 2H, J¼7.2 Hz); 13C NMR (150 MHz,
synthesized as
(600 MHz, CDCl3) d
a
white solid. Mp: 134e136 ꢁC; 1H NMR
1.67 (s, 3H), 2.70 (dd, 1H, J¼3.0, 16.2 Hz), 3.00
CDCl3)
d
13.7, 21.7 (21.71, 21.72), 22.4, 24.4, 34.5, 34.8, 56.8, 69.7,
94.1, 122.9, 127.3, 128.8, 129.4, 135.7, 138.2, 168.0, 169.6; IR (neat):
ymax 3169, 2976, 2958, 2945, 2875, 1753, 1666, 1590, 1454, 1404,
1211, 1129, 1109, 848, 746, 702 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 494 (100) (MþNa)þ; HRMS (ESI) m/z calcd for
(td, 1H, J¼6.0, 14.4 Hz), 3.20 (td, 1H, J¼3.6, 12.6 Hz), 4.52 (ddd, 1H,
J¼0.6, 6.0, 13.2 Hz), 6.61 (s, 1H), 7.14 (d, 1H, J¼7.8 Hz), 7.22 (td, 1H,
J¼1.2, 7.8 Hz), 7.28 (t, 1H, J¼7.8 Hz), 8.00 (d, 1H, J¼7.8 Hz); 13C
NMR (150 MHz, CDCl3)
d 28.5, 30.3, 36.6, 68.5, 123.8, 126.3, 126.7,
C
20H26INO4Naþ (MþNa)þ 494.0804, found 494.0807.
127.5, 129.8, 133.9, 136.0, 136.6, 169.7; IR (neat): ymax 2975, 2925,
2887, 2850, 1673, 1491, 1383, 1300, 867, 748, 621 cmꢀ1; mass
spectrum (ESI): m/e (% relative intensity) 348 (100) (MþNa)þ;
HRMS (ESI) m/z calcd for C13H12INONaþ (MþNa)þ 347.9861,
found 347.9861.
4.2.13. (S)-tert-Butyl-2-(2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-
dihydro-1H-pyrrol-1-yl)-3-phenylpropanoate (4k). Following the
general procedure 4.2.1, Starting from 2k (0.10 g, 0.21 mmol), and
N-iodosuccinimide (0.19 g, 0.85 mmol) in CH3CN/H2O (1:1) (3 mL)
at 23 ꢁC for 12 h, purified by silical gel chromatography (EtOAc/
PE¼10/90), 4k (0.062 g, 61%) was synthesized. diastereomer-I (S)-
tert-butyl 2-((R)-2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-dihydro-1H-
pyrrol-1-yl)-3-phenylpropanoate. a white solid. Mp: 102e104 ꢁC; 1H
4.2.17. 1-Iodo-9,10b-dimethyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-
3(10bH)-one (5b). Starting from amide 4b (0.054 g, 0.15 mmol) in
TFA (1 mL) was stirred, refluxed for 12 h, purified by silical gel
chromatography (EtOAc/PE¼10/90), 5b (0.04 g, 78%) was synthe-
sized as a white solid. Mp: 191e193 ꢁC; 1H NMR (600 MHz, CDCl3)
NMR (600 MHz, CDCl3)
d
ꢀ0.27eꢀ0.20 (m, 1H), 0.36e0.44 (m, 1H),
0.59e0.69 (m, 4H),0.79e0.85 (m, 1H), 1.08 (td, 1H, J¼6.0, 13.2 Hz),
1.50 (s, 9H),1.55 (td,1H, J¼6.0,13.2 Hz), 3.44 (dd,1H, J¼6.0,13.2 Hz),
3.66 (br s, 1H), 3.71 (td, 1H, J¼2.4, 13.2 Hz), 4.15 (dd, 1H, J¼6.0,
12.0 Hz), 6.47 (s, 1H), 7.20e7.29 (m, 5H); 13C NMR (150 MHz, CDCl3)
d
1.66 (s, 3H), 2.37 (s, 3H), 2.65 (dd, 1H, J¼3.0, 16.2 Hz), 2.95 (td, 1H,
J¼6.0, 14.4 Hz), 3.18 (td, 1H, J¼3.6, 13.2 Hz), 4.50 (ddd, 1H, J¼0.6, 6.0,
13.2 Hz), 6.59 (s, 1H), 7.03 (t, 2H, J¼7.8 Hz), 7.81 (s, 1H); 13C NMR
(150 MHz, CDCl3)
d 21.2, 28.5, 29.9, 36.7, 68.4, 123.9, 127.2, 128.3,
d
13.6, 22.5, 23.8, 28.0, 34.5, 35.3, 58.6, 83.9, 94.5,124.5,126.8,128.5,
129.6, 130.7, 135.8, 135.9, 136.6, 169.7; IR (neat): ymax 2961, 2932,
1668, 1495, 1453, 1384, 821, 702 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 340 (100) (MþH)þ; HRMS (ESI) m/z calcd for
129.2, 135.8, 138.4, 171.0, 171.9; IR (neat): ymax 3420, 2972, 2958,
2929, 2870, 1737, 1708, 1600, 1457, 1394, 1374, 1278, 1238, 1156,
1074, 846, 748, 699 cmꢀ1; mass spectrum (ESI): m/e (% relative
intensity) 508 (100) (MþNa)þ; HRMS (ESI) m/z calcd for
C
14H15INOþ (MþH)þ 340.0198, found 340.0207.
C
21H28INO4Naþ (MþNa)þ 508.0961, found 508.0966. diastereomer-
4.2.18. 1-Iodo-9-methoxy-10b-methyl-5,6-dihydropyrrolo[2,1-a]iso-
quinolin-3(10bH)-one (5c). Starting from amide 4c (0.05 g,
0.13 mmol) in TFA (1 mL) was stirred, refluxed for 16 h, purified by
silical gel chromatography (EtOAc/PE¼15/85), 5c (0.042 g, 89%) was
synthesized as a white solid. Mp: 122e124 ꢁC; 1H NMR (600 MHz,
II (S)-tert-butyl 2-((S)-2-butyl-2-hydroxy-3-iodo-5-oxo-2,5-dihydro-
1H-pyrrol-1-yl)-3-phenylpropanoate.
a
white
solid.
Mp:
138e140 ꢁC; 1H NMR (600 MHz, CDCl3)
d
0.79e0.86 (m, 4H), 1.06
(br s, 1H),1.13e1.21 (m, 3H), 1.47 (s, 9H), 1.50 (td, 1H, J¼6.0, 13.2 Hz),
1.67 (td, 1H, J¼6.0, 13.2 Hz), 3.33 (dd, 1H, J¼6.0, 13.2 Hz), 3.65 (td,
1H, J¼2.4, 13.2 Hz), 4.33 (dd, 1H, J¼6.0, 12.0 Hz), 6.52 (s, 1H), 7.20 (d,
2H, J¼7.2 Hz), 7.23 (t, 1H, J¼7.2 Hz), 7.30 (t, 2H, J¼7.2 Hz); 13C NMR
CDCl3)
d
1.67 (s, 3H), 2.64 (dd,1H, J¼3.0,15.6 Hz), 2.93 (td, 1H, J¼6.0,
14.4 Hz), 3.16 (td, 1H, J¼3.6, 13.2 Hz), 3.85 (s, 3H), 4.50 (ddd, 1H,
J¼0.6, 6.0, 13.2 Hz), 6.61 (s, 1H), 6.80 (dd, 1H, J¼2.4, 8.4 Hz), 7.05 (d,
1H, J¼8.4 Hz), 7.55 (d, 1H, J¼8.4 Hz); 13C NMR (150 MHz, CDCl3)
(150 MHz, CDCl3)
d 13.7, 22.5, 24.4, 27.9, 34.6, 34.9, 57.5, 82.7, 94.2,
123.1, 127.2, 128.8, 129.3, 135.8, 138.2, 168.3, 169.5; IR (neat): ymax
3170, 2969, 2936, 2861, 1750, 1666, 1590, 1497, 1454, 1405, 1346,
1232, 1151, 1093, 1082, 848, 743, 702 cmꢀ1; mass spectrum (ESI): m/
e (% relative intensity) 508 (100) (MþNa)þ; HRMS (ESI) m/z calcd
for C21H28INO4Naþ (MþNa)þ 508.0961, found 508.0970.
d 28.5, 29.3, 36.7, 55.5, 68.4, 112.1, 113.6, 123.5, 125.7, 130.6, 136.7,
137.0, 157.7, 169.5; IR (neat): ymax 3055, 2986, 2961, 2933, 2832,
1669, 1613, 1572, 1496, 1497, 1465, 1453, 1388, 1260, 1049, 905, 870,
814, 724, 699 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity)
378 (100) (MþNa)þ; HRMS (ESI) m/z calcd for C14H15INOþ2 (MþNa)þ
377.9967, found 377.9988.
4.2.14. 5-Hydroxy-4-iodo-1-(2-iodo-4,5-dimethoxyphenethyl)-5-
methyl-1H-pyrrol-2(5H)-one (4l). Following the general procedure
4.2.1, Starting from 2l (0.10 g, 0.26 mmol), and N-iodosuccinimide
(0.26 g,1.03 mmol) in CH3CN/H2O (1:1) (3 mL) at 23 ꢁC for 12 h, purified
by silical gel chromatography (EtOAc/PE¼20/80), 4l (0.091 g, 67%) was
synthesized as a white solid. Mp: 109e111 ꢁC; 1H NMR (600 MHz,
4.2.19. 10b-Butyl-1-iodo-5,6-dihydropyrrolo[2,1-a]isoquinolin-
3(10bH)-one (5d). Starting from amide 4d (0.061 g, 0.16 mmol) in
TFA (1 mL) was stirred, refluxed for 12 h, purified by silical gel
chromatography (EtOAc/PE¼10/90), 5d (0.046 g, 80%) was syn-
thesized as a white solid. Mp: 111e113 ꢁC; 1H NMR (600 MHz,
CDCl3)
(m,1H), 3.64e3.70 (m,1H), 3.83 (s, 3H), 3.84 (s, 3H), 6.48 (s,1H), 6.79 (s,
1H), 7.20 (s,1H); 13C NMR (150 MHz, CDCl3)
23.6, 39.0, 40.1, 56.1, 56.2,
d
1.43 (s, 3H), 2.96e3.02 (m, 1H), 3.06e3.12 (m, 1H), 3.44e3.49
CDCl3)
d
0.90 (t, 3H, J¼7.8 Hz), 1.05e1.12 (m, 2H), 1.25e1.35 (m, 2H),
1.86e1.92 (m, 1H), 2.09e2.15 (m, 1H), 2.69 (dd, 1H, J¼3.0, 15.6 Hz),
3.01 (td, 1H, J¼6.0, 14.4 Hz), 3.12 (td, 1H, J¼3.6, 12.6 Hz), 4.50 (ddd,
1H, J¼0.6, 6.0,13.2 Hz), 6.65 (s, 1H), 7.14 (d, 1H, J¼7.2 Hz), 7.22 (t, 1H,
J¼7.2 Hz), 7.27 (t, 1H, J¼7.8 Hz), 8.00 (d, 1H, J¼7.8 Hz); 13C NMR
d
88.0, 92.3, 112.9, 121.7, 123.8, 134.0, 135.0, 148.3, 149.5, 168.1; IR (neat):
ymax 3264, 2990, 2960, 2924, 2850, 1691, 1594, 1506, 1455, 1412, 1261,
1212,1163,1028, 860, 849, 742, 701 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 530 (100) (MþH)þ; HRMS (ESI) m/z calcd for
(150 MHz, CDCl3) d 13.9, 22.4, 24.7, 30.1, 36.4, 39.1, 71.0, 122.1, 126.2,
126.5, 127.4, 129.8, 133.7, 136.6, 137.7, 170.2; IR (neat): ymax 3107,
2948, 2934, 2868, 1673, 1576, 1486, 1464, 1453, 1430, 1389, 1295,
886, 863, 778, 766, 751, 659 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 390 (100) (MþNa)þ; HRMS (ESI) m/z calcd for
C
15H17I2NO4Naþ (MþNa)þ 551.9145, found 551.9154.
4.2.15. General procedure for preparation of 5. A solution of amide 4
(0.15 mmol) in TFA (1.00 mL) refluxed and stirred, then quenched
with sat.NaHCO3, extracted with ethyl acetate, washed with brine,
the organic layer was dried over Na2SO4, and concentrated, The
residue was purified by column chromatography.
C
16H18INONaþ (MþNa)þ 390.0331, found 390.0343.
4.2.20. 10b-Butyl-1-iodo-9-methyl-5,6-dihydropyrrolo[2,1-a]isoqu-
inolin-3(10bH)-one (5e). Starting from amide 4e (0.051 g,
0.13 mmol) in TFA (1 mL) was stirred, refluxed for 12 h, purified by
silical gel chromatography (EtOAc/PE¼10/90), 5e (0.046 g, 94%)
was synthesized as a white solid. Mp: 160e162 ꢁC; 1H NMR
4.2.16. 1-Iodo-10b-methyl-5,6-dihydropyrrolo[2,1-a]isoquinolin-
3(10bH)-one (5a). Starting from amide 4a (0.051 g, 0.15 mmol) in
TFA (1 mL) was stirred, refluxed for 12 h, purified by silical gel
chromatography (EtOAc/PE¼10/90), 5a (0.044 g, 91%) was
(600 MHz, CDCl3)
1.28e1.34 (m, 2H), 1.86e1.89 (m, 1H), 2.10e2.13 (m, 1H), 2.37 (s,
d
0.90 (t, 3H, J¼7.8 Hz), 1.06e1.11 (m, 2H),

Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
4341
3H), 2.64 (dd, 1H, J¼2.4, 15.6 Hz), 2.96 (td, 1H, J¼6.0, 14.4 Hz), 3.10
(td, 1H, J¼3.6, 12.6 Hz), 4.49 (ddd, 1H, J¼0.6, 6.0, 13.2 Hz), 6.64 (s,
1H), 7.03 (s, 2H), 7.82 (s, 1H); 13C NMR (150 MHz, CDCl3)
14.0,
21.2, 22.4, 24.7, 29.7, 36.5, 39.0, 71.0, 122.2, 127.0, 128.3, 129.6,
130.5, 135.8, 136.4, 137.7, 170.3; IR (neat): ymax 3099, 2944, 2893,
2867, 1667, 1630, 1573, 1498, 1453, 1431, 1384, 1292, 1267, 866, 828,
728, 707 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity) 382
(100) (MþH)þ; HRMS (ESI) m/z calcd for C17H21INOþ (MþH)þ
382.0668, found 382.0696.
(150 MHz, CDCl3)
d
14.0, 21.6, 21.7, 22.3, 24.4, 30.6, 38.8, 52.3, 69.4,
71.7, 121.9, 124.9, 126.9, 127.8, 129.2, 132.3, 136.9, 137.8, 170.2, 171.2;
(5S,10bR)-isopropyl 10b-butyl-1-iodo-3-oxo-3,5,6,10b-tetrahy-
dropyrrolo[2,1-a]isoquinoline-5-carboxylate 1H NMR (600 MHz,
CDCl3)
0.91 (t, 3H, J¼7.2 Hz), 1.12e1.20 (m, 1H), 1.25 (d, 3H,
d
d
J¼6.6 Hz), 1.28 (d, 3H, J¼6.6 Hz), 1.30e1.40 (m, 2H), 1.63e1.68 (m,
1H), 1.88 (td, 1H, J¼4.2, 13.2 Hz), 2.20 (td, 1H, J¼4.2, 13.2 Hz), 3.06
(dd, 1H, J¼6.6, 15.6 Hz), 4.05 (dd, 1H, J¼6.6, 15.6 Hz), 3.26 (t, 1H,
J¼7.2 Hz), 5.09e5.16 (m, 1H), 6.60 (s, 1H), 7.09e7.20 (m, 3H), 7.95
(d, 1H, J¼7.8 Hz); 13C NMR (150 MHz, CDCl3) 14.0, 21.6, 21.8, 22.3,
24.8, 31.4, 38.0, 53.1, 69.1, 72.9, 122.6, 126.1, 126.6, 127.6, 130.1,
133.1, 137.0, 137.6, 168.6, 170.2; IR (neat): ymax 2958, 2932, 2871,
4.2.21. 10b-Butyl-1-iodo-9-methoxy-5,6-dihydropyrrolo[2,1-a]iso-
quinolin-3(10bH)-one (5f). Starting from amide 4f (0.068 g,
0.16 mmol) in TFA (1 mL) was stirred, refluxed for 16 h, purified by
silical gel chromatography (EtOAc/PE¼15/85), 5f (0.045 g, 70%) was
synthesized as a white solid. Mp: 98e100 ꢁC; 1H NMR (600 MHz,
1738, 1697, 1575, 1454, 1374, 1294, 1193, 1106, 976, 853, 757 cmꢀ1
;
mass spectrum (ESI): m/e (% relative intensity) 454 (100) (MþH)þ;
HRMS (ESI) m/z calcd for C20H25INOþ3 (MþH)þ 454.0879, found
454.0889.
CDCl3)
d
0.90 (t, 3H, J¼7.2 Hz), 1.06e1.11 (m, 2H), 1.28e1.33 (m, 2H),
1.87e1.91 (m, 1H), 2.08e2.12 (m, 1H), 2.64 (dd, 1H, J¼3.0, 14.4 Hz),
2.95 (td, 1H, J¼6.0, 14.4 Hz), 3.10 (td, 1H, J¼3.6, 12.6 Hz), 3.85 (s, 3H),
4.48 (ddd, 1H, J¼0.6, 6.0, 13.2 Hz), 6.65 (s, 1H), 6.80 (dd, 1H, J¼2.4,
8.4 Hz), 7.06 (d, 1H, J¼8.4 Hz), 7.56 (d, 1H, J¼2.4 Hz); 13C NMR
4.2.24. (Z/E)-5-Butylidene-4-iodo-1-phenethyl-1H-pyrrol-2(5H)-one
(6d). Starting from amide 4d (0.08 g, 0.20 mmol) in TFA (1 mL) was
stirred for 1 h at rt, purified by silical gel chromatography (EtOAc/
PE¼10/90), (Z)-5-butylidene-4-iodo-1-phenethyl-1H-pyrrol-2(5H)-
one (28.50 mg, 38%), (E)-5-butylidene-4-iodo-1-phenethyl-1H-pyr-
rol-2(5H)-one (5.70 mg, 7%) was synthesized as colorless oils. (Z)-5-
(150 MHz, CDCl3) d 13.9, 22.4, 24.7, 29.2, 36.5, 39.0, 55.5, 71.0, 112.0,
113.4, 121.8, 125.6, 130.5, 137.5, 137.8, 157.7, 170.2; IR (neat): ymax
2950, 2926, 2868, 1689, 1672, 1611, 1500, 1453, 1387, 1291, 1269,
1247, 1044, 863, 821 cmꢀ1; mass spectrum (ESI): m/e (% relative
intensity) 420 (100) (MþNa)þ; HRMS (ESI) m/z calcd for
butylidene-4-iodo-1-phenethyl-1H-pyrrol-2(5H)-one:
(600 MHz, CDCl3)
1H
NMR
d
1.02 (t, 3H, J¼7.2 Hz), 1.57e1.64 (m, 2H), 2.52 (q,
C
17H21INOþ2 (MþH)þ 398.0617, found 398.0640.
2H, J¼7.8 Hz), 2.88 (t, 2H, J¼7.8 Hz), 4.02 (t, 2H, J¼7.8 Hz), 5.39 (t,
1H, J¼7.8 Hz), 6.56 (s, 1H), 7.20e7.26 (m, 3H), 7.30 (t, 2H, J¼7.2 Hz);
13C NMR (150 MHz, CDCl3) 13.9, 23.3, 29.1, 35.9, 42.7, 107.3, 121.3,
126.7, 128.6, 128.7, 132.0, 137.9, 138.0, 170.1; IR (neat): ymax 3027,
2959, 2930, 2871, 1695, 1649, 1547, 1497, 1454, 1403, 1354, 1301,
1267, 1148, 1091, 836, 749, 699 cmꢀ1; mass spectrum (ESI): m/e (%
relative intensity) 468 (100) (MþH)þ; HRMS (ESI) m/z calcd for
4.2.22. (S)-Methyl10b-butyl-1-iodo-3-oxo-3,5,6,10b-tetrahy-
dropyrrolo[2,1-a]isoquinoline-5-carboxy-late (5i). Starting from
amide 4i (0.12 g, 0.26 mmol) in TFA (2 mL) was stirred, refluxed for
10 h, purified by silical gel chromatography (EtOAc/PE¼10/90),
isomers 5i (0.05 g, 45%) was synthesized as a yellow oil; (5S,10bS)-
methyl 10b-butyl-1-iodo-3-oxo-3,5,6,10b-tetrahydropyrrolo[2,1-a]
C
16H19INOþ (MþH)þ 368.0511, found 368.0513. (E)-5-butylidene-4-
isoq-uinoline-5-carboxylate 1H NMR (600 MHz, CDCl3)
d
0.91 (t,
iodo-1-phenethyl-1H-pyrrol-2(5H)-one: 1H NMR (600 MHz, CDCl3)
3H, J¼6.6 Hz), 0.97e1.05 (m, 1H), 1.25e1.33 (m, 2H), 1.42e1.50 (m,
1H), 1.71 (td, 1H, J¼3.0, 14.4 Hz), 2.07 (td, 1H, J¼3.0, 14.4 Hz), 3.15
(dd, 1H, J¼6.6, 15.6 Hz), 3.29 (dd, 1H, J¼6.0, 15.6 Hz), 3.74 (s, 3H),
5.08 (t, 1H, J¼6.6 Hz), 6.75 (s, 1H), 7.18e7.30 (m, 3H), 7.98 (d, 1H,
d
0.99 (t, 3H, J¼7.2 Hz), 1.48e1.53 (m, 2H), 2.76e2.84 (m, 4H), 3.83
(t, 2H, J¼7.8 Hz), 5.52 (t, 1H, J¼8.4 Hz), 6.74 (s, 1H), 7.18e7.24 (m,
3H), 7.30 (t, 2H, J¼7.2 Hz); 13C NMR (150 MHz, CDCl3) 13.8, 23.7,
27.9, 35.0, 40.5, 93.4, 119.8, 126.7, 128.6, 128.8, 136.1, 136.7, 138.4,
167.8; mass spectrum (ESI): m/e (% relative intensity) 468 (100)
(MþH)þ; HRMS (ESI) m/z calcd for C16H18INONaþ (MþNa)þ
390.0331, found 390.0339.
J¼7.2 Hz); 13C NMR (150 MHz, CDCl3)
d 14.0, 22.4, 24.5, 30.3, 39.0,
51.1, 52.4, 71.5, 122.3, 125.2, 126.8, 127.9, 129.3, 132.0, 136.5, 137.5,
171.0, 171.2; (5S,10bR)-methyl10b-butyl-1-iodo-3-oxo-3,5,6,10b-tet-
rahydropyrrolo[2,1-a]isoquinoline-5-carboxylate 1H NMR (600 MHz,
CDCl3)
d
0.91 (t, 3H, J¼6.6 Hz), 1.10e1.20 (m, 1H), 1.34e1.40 (m,
4.2.25. (Z/E)-5-Butylidene-1-(4-chlorophenethyl)-4-iodo-1H-pyrrol-
2(5H)-one (6g). Starting from amide 4g (0.041 g, 0.10 mmol) in TFA
(1 mL) was stirred for 1 h at rt, purified by silical gel chromatography
(EtOAc/PE¼10/90), (Z)-5-butylidene-1-(4-chlorophenethyl)-4-iodo-
1H-pyrrol-2(5H)-one (0.028 g, 72%), (E)-5-butylidene-1-(4-
chlorophenethyl)-4-iodo-1H-pyrrol-2(5H)-one (8.00 mg, 20%) was
synthesized as white solids. (Z)-5-butylidene-1-(4-chlorophenethyl)-
4-iodo-1H-pyrrol-2(5H)-one. Mp: 110e112 ꢁC; 1H NMR (600 MHz,
2H), 1.75e1.85 (m, 1H), 1.90 (td, 1H, J¼3.0, 14.4 Hz), 2.18 (td, 1H,
J¼3.0, 14.4 Hz), 3.05 (dd, 1H, J¼6.6, 15.6 Hz), 3.83 (s, 3H), 3.30 (dd,
1H, J¼6.0, 15.6 Hz), 4.05 (dd, 1H, J¼3.6, 10.8 Hz), 6.59 (s, 1H),
7.10e7.30 (m, 3H), 7.95 (d, 1H, J¼7.2 Hz); 13C NMR (150 MHz,
CDCl3)
d 13.9, 22.3, 24.7, 31.5, 38.1, 51.1, 52.5, 73.0, 123.2, 126.3,
126.7, 127.7, 130.1, 132.9, 136.7, 137.3, 169.8, 170.4; IR (neat): ymax
2957, 2921, 1745, 1675, 1631, 1546, 1517, 1457, 1343, 1144, 1089,
998 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity) 426
(100) (MþH)þ; HRMS (ESI) m/z calcd for C18H21INOþ3 (MþH)þ
426.0566, found 426.0581.
CDCl3)
d
1.02 (t, 3H, J¼7.2 Hz), 1.57e1.64 (m, 2H), 2.46e2.50 (q, 2H,
J¼7.8 Hz), 2.85 (t, 2H, J¼7.8 Hz), 4.00 (t, 2H, J¼7.8 Hz), 5.40 (t, 1H,
J¼7.8 Hz), 6.55 (s, 1H), 7.12 (d, 2H, J¼8.4 Hz), 7.27 (d, 2H, J¼7.8 Hz);
13C NMR (150 MHz, CDCl3)
d 13.9, 23.3, 29.1, 35.2, 42.4, 107.4, 121.2,
4.2.23. (S)-Isopropyl 10b-butyl-1-iodo-3-oxo-3,5,6,10btetrahydropy
rrolo[2,1-a]isoquinoline-5-carboxylate (5j). Starting from amide 4j
(0.08 g, 0.16 mmol) in TFA (1 mL) was stirred, refluxed for 10 h,
purified by silical gel chromatography (EtOAc/PE¼10/90),isomers
5j (0.05 g, 66%) was synthesized as a yellow oil; (5S,10bS)-isopropyl
10b-butyl-1-iodo-3-oxo-3,5,6,10b-tetrahydropyrrolo[2,1-a]isoquino-
128.8, 130.1, 132.0, 132.6, 136.4, 138.0, 170.1; IR (neat): ymax 2963,
2931, 2872, 1678, 1650, 1547, 1491, 1456, 1406, 1357, 1269, 1015, 851,
809 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity) 424 (100)
(MþNa)þ; HRMS (ESI) m/z calcd for C16H17ClINONaþ (MþNa)þ
423.9941, found 423.9950. (E)-5-butylidene-1-(4-chlorophenethyl)-
4-iodo-1H-pyrrol-2(5H)-one. Mp: 92e94 ꢁC; 1H NMR (600 MHz,
line-5-carboxylate 1H NMR (600 MHz, CDCl3)
d
0.91 (t, 3H,
CDCl3)
d
1.00 (t, 3H, J¼7.2 Hz), 1.47e1.54 (m, 2H), 2.76e2.82 (m, 4H),
J¼7.2 Hz), 0.98e1.04 (m, 1H), 1.23 (d, 3H, J¼6.6 Hz), 1.26 (d, 3H,
J¼6.6 Hz), 1.30e1.40 (m, 2H), 1.54e1.63 (m, 1H), 1.82 (td, 1H, J¼4.2,
13.2 Hz), 2.05 (td, 1H, J¼4.2, 13.2 Hz), 3.15 (dd, 1H, J¼6.6, 15.6 Hz),
3.24 (dd, 1H, J¼7.2, 15.6 Hz), 4.90 (t, 1H, J¼7.2 Hz), 5.00e5.08 (m,
1H), 6.75 (s, 1H), 7.21e7.30 (m, 3H), 7.98 (d, 1H, J¼7.8 Hz); 13C NMR
3.80 (t, 2H, J¼7.8 Hz), 5.46 (t, 1H, J¼8.4 Hz), 6.73 (s, 1H), 7.11 (d, 2H,
J¼8.4 Hz), 7.25 (d, 2H, J¼7.8 Hz); 13C NMR (150 MHz, CDCl3)
d 13.7,
23.7, 27.9, 34.3, 40.2, 93.5,119.6,128.7,130.1,132.5,136.1,136.7,136.8,
167.7. IR (neat): ymax 2961, 2929, 2871, 1678, 1650, 1547, 1491, 1455,
1407, 1357, 1090, 1015, 810 cmꢀ1; mass spectrum (ESI): m/e (%

4342
Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
relative intensity) 402 (100) (MþH)þ; HRMS (ESI) m/z calcd for
spectrum (ESI): m/e (% relative intensity) 512 (100) (MþH)þ; HRMS
(ESI) m/z calcd for C15H15I2NO3Naþ (MþNa)þ 533.9039, found
533.9036.
C
16H18ClINOþ (MþH)þ 402.0122, found 402.0119.
4.2.26. (Z/E)-5-Butylidene-4-iodo-1-(4-nitrophenethyl)-1H-pyrrol-
2(5H)-one (6h). Starting from amide 4h (0.12 g, 0.27 mmol) in TFA
(2 mL) was stirred for 1 h at rt, purified by silical gel chroma-
Acknowledgements
tography
(EtOAc/PE¼10/90),
(Z)-5-butylidene-4-iodo-1-(4-
Y.T. thanks National Natural Science Foundation of China for
generous founding [21172169]. Open Fund of Zhejiang Provincial
Top Key Discipline of Biology (2012D10) and the National Basic
Research Project (2014CB932201) for financial support. We also
thank Dr. Haibin Song of Nankai University for providing X-ray
structure and data analysis.
nitrophenethyl)-1H-pyrrol-2(5H)-one (0.05 g, 46%), (E)-5-
butylidene-4-iodo-1-(4-nitrophenethyl)-1H-pyrrol-2(5H)-one
(0.03 g, 29%) was synthesized as white solids. (Z)-5-butylidene-4-
iodo-1-(4-nitrophenethyl)-1H-pyrrol-2(5H)-one. Mp: 123e126 ꢁC;
1H NMR (600 MHz, CDCl3)
d
1.03 (t, 3H, J¼7.2 Hz), 1.59e1.66 (m,
2H), 2.50 (q, 2H, J¼7.8 Hz), 2.99 (t, 2H, J¼7.8 Hz), 4.08 (t, 2H,
J¼7.8 Hz), 5.42 (t, 1H, J¼8.4 Hz), 6.55 (s, 1H), 7.35 (d, 2H, J¼8.4 Hz),
Supplementary data
8.17 (d, 2H, J¼9.0 Hz); 13C NMR (150 MHz, CDCl3)
d 13.9, 23.2, 29.2,
35.7, 41.8, 107.7, 121.2, 123.9, 129.7, 131.9, 137.9, 145.6, 147.0, 170.1;
IR (neat): ymax 2963, 2934, 2874, 1675, 1649, 1602, 1545, 1517, 1456,
1404, 1340, 1271, 1146, 1107, 868, 853, 822, 795, 743 cmꢀ1; mass
spectrum (ESI): m/e (% relative intensity) 413 (100) (MþH)þ;
HRMS (ESI) m/z calcd for C16H18IN2Oþ3 (MþH)þ 413.0362, found
413.0366. (E)-5-butylidene-4-iodo-1-(4-nitrophenethyl)-1H-pyrrol-
Supplementary data (NMR spectra of compounds.) associated
with this article can be found in the online version, at http://
dx.doi.org/10.1016/j.tet.2015.04.057. These data include MOL files
and InChiKeys of the most important compounds described in this
article.
2(5H)-one. Mp: 116e118 ꢁC; 1H NMR (600 MHz, CDCl3)
d 1.00 (t,
References and notes
3H, J¼7.2 Hz), 1.48e1.55 (m, 2H), 2.80 (q, 2H, J¼7.8 Hz), 2.96 (t, 2H,
J¼7.2 Hz), 3.89 (t, 2H, J¼7.2 Hz), 5.51 (t, 1H, J¼8.4 Hz), 6.72 (s, 1H),
7.33 (d, 2H, J¼8.4 Hz), 8.14 (d, 2H, J¼8.4 Hz); 13C NMR (150 MHz,
1. For recent reviews on halocyclizations, see: (a) Robin, S.; Rousseau, G. Tetra-
hedron 1998, 54, 13681; (b) Robin, S.; Rousseau, G. Eur. J. Org. Chem. 2002, 3099;
(c) Harding, K. E.; Tiner, T. H. In Comprehensive Organic Synthesis; Trost, B. M.,
Ed.; Pergamon: New York, NY, 1991; Vol. 4, p 363; (d) Cardillo, G.; Orena, M.
Tetrahedron 1990, 46, 3321; (e) Godoi, B.; Schumacher, R. F.; Zeni, G. Chem. Rev.
2011, 111, 2937.
CDCl3)
d 13.7, 23.8, 27.9, 34.7, 39.5, 93.7, 119.4, 123.8, 129.7, 136.0,
136.7, 146.0, 146.9, 167.7. IR (neat): ymax 2960, 2932, 2870, 1692,
1675, 1650, 1603, 1545, 1515, 1455, 1407, 1342, 1271, 1107, 852, 837,
743, 696 cmꢀ1; mass spectrum (ESI): m/e (% relative intensity) 435
(100) (MþNa)þ; HRMS (ESI) m/z calcd for C16H17IN2O3Naþ
(MþNa)þ 435.0182, found 435.0220.
2. Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734.
3. For recent examples, see: (a) Blot, V.; Reboul, V.; Metzner, P. J. Org. Chem. 2004,
69, 1196; (b) Wang, M.; Gao, L. X.; Mai, W. P.; Xia, A. X.; Wang, F.; Zhang, S. B. J.
Org. Chem. 2004, 69, 2874; (c) Shen, M.; Li, C. J. Org. Chem. 2004, 69, 7906; (d)
Mellegaard, S. R.; Tunge, J. A. J. Org. Chem. 2004, 69, 8979; (e) Peng, A. Y.; Ding,
Y. X. Org. Lett. 2004, 6, 1119; (f) Galeazzi, R.; Martelli, G.; Mobblili, G.; Orena, M.;
Rinaldi, S. Org. Lett. 2004, 6, 2571; (g) Kang, S. H.; Lee, S. B.; Park, C. M. J. Am.
Chem. Soc. 2003, 125, 15748; (h) Hessian, K. O.; Flynn, B. L. Org. Lett. 2003, 5,
4377; (i) Homsi, F.; Rousseau, G. J. Org. Chem. 1999, 64, 81; (j) Mehta, S.; Yao, T.;
Larock, R. C. J. Org. Chem. 2012, 77, 10938; (k) Gai, R. M.; Schumacher, R. F.; Back,
D. F.; Zeni, G. Org. Lett. 2012, 14, 6072.
4. (a) Hu, T.; Liu, K.; Shen, M.; Yuan, X.; Tang, Y.; Li, C. J. Org. Chem. 2007, 72, 8555;
(b) Kundig, E. P.; Laxmisha, M. S.; Cannas, R.; Tchertchian, S.; Liu, R. Helv. Chim.
Acta 2005, 88, 1063; (c) Kundig, E. P.; Cannas, R.; Laxmisha, M.; Ronggang, L.;
Tchertchian, S. J. Am. Chem. Soc. 2003, 125, 5642; (d) Lee, C.-W.; Gil, J. M.; Oh, D.
Y. Heterocycles 1997, 45, 943; (e) Cairns, P. M.; Howes, C.; Jenkins, P. R. J. Chem.
Soc., Perkin Trans. 1 1990, 627; (f) Takano, S.; Sato, S.; Goto, E.; Ogasawara, K. J.
Chem. Soc., Chem. Commun. 1986, 156; (g) Fleet, G. W. J.; Spensley, C. R. C. Tet-
rahedron Lett. 1982, 23, 109.
4.2.27. 1,4-Diphenyl-5-hydroxyl-5-methyl-pyrrol-2(5H)-one
(7). White solid. 1H NMR (600 MHz, CDCl3)
d 1.51 (s, 3H), 6.23 (s,
1H), 7.22e7.25 (m, 1H), 7.32 (t, 2H, J¼7.8 Hz), 7.39e7.42 (m, 3H),
7.48 (d, 2H, J¼7.8 Hz), 7.76e7.78 (m, 2H); 13C NMR (150 MHz, CDCl3)
d
23.8, 93.0, 120.0, 126.4, 126.7, 127.8, 128.8, 128.9, 130.2, 130.7,
135.4, 160.0, 168.7; IR (neat): ymax 3326, 3095, 2924, 1672, 1592,
1494,1449,1392,1116, 878, 763, 693 cmꢀ1; mass spectrum (ESI): m/
e (% relative intensity) 266 (100) [MþH]þ; HRMS (ESI) m/z calcd for
C
17H16NOþ2 (MþH)þ 266.1176, found 266.1179.
4.2.28. Iodo-8,9-dimethoxy-10b-methyl-5,6-dihydropyrrolo[2,1-a]
isoquinolin-3(10bH)-one (5la). Starting from amide 4l (0.08 g,
0.15 mmol) in TFA (1 mL) was stirred for 1 h at rt, purified by silical
gel chromatography (EtOAc/PE¼30/70), 5la (0.025 g, 43%). was
5. (a) Dias-Jurberg, I.; Gagosz, F.; Zard, S. Z. Org. Lett. 2010, 12, 416; (b) Biloski, A. J.;
Wood, R. D.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 3233; (c) Corey, E. J.; Fleet, G.
W.; Kato, M. Tetrahedron Lett. 1973, 14, 3963; (d) Rajendra, G.; Miller, M. J.
Tetrahedron Lett. 1987, 28, 6257; (e) Nagaka, W.; Takeda, K. J. Pharm. Soc. Jpn.
1952, 72, 1566; (f) Tilley, J. W.; Clader, J. W.; Wirkus, M.; Blount, J. F. J. Org. Chem.
1985, 50, 2220; (g) Yamawaki, Y.; Wantanaki, M.; Yamamura, S.; Saito, T. J.
Pharm. Soc. Jpn. 1977, 97, 127; (h) Hino, T.; Uehara, H.; akashima, M.; Kawate, T.;
Seki, H.; Hara, R.; Kuramochi, T.; Nakagawa, M. Chem. Pharm. Bull. 1990, 38,
2632.
synthesized as a white solid. 1H NMR (600 MHz, CDCl3)
d 1.66 (s,
3H), 2.60 (dd, 1H, J¼3.0, 15.6 Hz), 2.95 (td, 1H, J¼6.0, 15.6 Hz), 3.18
(td, 1H, J¼3.0, 13.2 Hz), 3.85 (s, 3H), 3.95 (s, 3H), 4.50 (ddd, 1H,
J¼0.6, 6.0, 13.2 Hz), 6.59 (s, 1H), 6.60 (s, 1H), 7.50 (s, 1H); 13C NMR
6. Tang, Y.; Li, C. Org. Lett. 2004, 6, 3229.
7. Tang, Y.; Li, C. Tetrahedron Lett. 2006, 47, 3823.
8. Tang, Y.; Lv, M.-C.; Liu, X.-F. Org. Lett. 2013, 15, 1382.
(150 MHz, CDCl3)
d 28.3, 29.7, 36.6, 55.9, 56.2, 68.2, 109.8, 111.8,
123.7, 126.2, 127.8, 136.4, 147.3, 148.3, 169.5; IR (neat): ymax 2971,
2925, 1693, 1606, 1574, 1523, 1510, 1460, 1402, 1381, 1258, 1209,
1052, 859, 847 cmꢀ1; mass spectrum (ESI): m/e (% relative in-
tensity) 386 (100) (MþH)þ; HRMS (ESI) m/z calcd for C15H17INOþ3
(MþH)þ 386.0253, found 386.0257.
9. For selected recent reviews ꢀH oxidative functionalization, see: (a) Wendlandt,
A. E.; Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062; (b) Liu, C.;
Zhang, H.; Shi, W.; Lei, A. W. Chem. Rev. 2011, 111, 1780; (c) Li, C. J. Acc. Chem. Res.
2009, 42, 335; (d) Li, Z.; Bohle, D. S.; Li, C. J. Proc. Natl. Acad. Sci. U.S.A. 2006, 103,
8928.
10. (a) Celmer, W. D.; Solomons, I. A. J. Am. Chem. Soc. 1955, 77, 2861 and papers
cited therein; (b) Simmons, C. J.; Marner, F.-J.; Cardellina, J. H., II; Moore, R. E.;
Seff, K. Tetrahedron Lett. 1979, 2003; (c) Cardellina, J. H., II; Moore, R. E. Tetra-
hedron Lett. 1979, 2007; (d) Abdullaev, N. D.; Samikov, K.; Antsupova, T. P.;
Yagudaev, M. R.; Yunusov, S. Yu. Khim. Prir. Soedin. 1987, 5, 692; (e) Zhang, Q.;
Tu, G.; Zhao, Y.; Cheng, T. Tetrahedron 2002, 58, 6795; (f) Boukouvalas, J.; Loach,
R. P.; Ouellet, E. Tetrahedron Lett 2011, 52, 5047; (g) Boukouvalas, J.; Xiao, Y. F.;
Cheng, Y.-X.; Loach, R. P. Synlett 2007, 20, 3198.
11. (a) de Koning, H.; Speckamp, W. N. In Stereoselective Synthesis; Helmchen, G.,
Hoffmann, R. W., Mulzer, J., Schaumann, E., Eds.; 1995; Vol. E 21b, p 1953
Stuttgart, Germany; (b) Wang, Y.; Zhu, L.; Zhang, Y.; Hong, R. Angew. Chem., Int.
Ed. 2011, 50, 2787.
12. For some examples, see: (a) Hubert, J. C.; Speckamp, W. N.; Huisman, H. O.
Tetrahedron Lett. 1972, 4493; (b) Winn, M.; Zaugg, H. E. J. Org. Chem. 1968, 33,
4.2.29. 1,7-Diiodo-9,10-dimethoxy-10b-methyl-5,6-dihydropyrrolo
[2,1-a]isoquinolin-3(10bH)-one (5lb). Starting from amide 4l
(0.08 g, 0.15 mmol) in TFA (1 mL) was stirred for 1 h at rt, purified by
silical gel chromatography (EtOAc/PE¼30/70), 5lb (0.011 g, 14%)
was synthesized as a white solid. 1H NMR (600 MHz, CDCl3)
d 1.68
(s, 3H), 2.74e2.83 (m, 2H), 3.16 (td, 1H, J¼6.0, 12.0 Hz), 3.83 (s, 3H),
3.95 (s, 3H), 4.50 (ddd, 1H, J¼1.8, 6.0, 13.2 Hz), 6.61 (s, 1H), 7.61 (s,
1H); 13C NMR (150 MHz, CDCl3)
d 28.3, 36.2, 36.6, 56.3, 60.2, 67.8,
101.3, 111.2, 123.1, 129.4, 133.0, 137.0, 148.4, 150.3, 169.1; mass

Y. Tang et al. / Tetrahedron 71 (2015) 4334e4343
4343
3779; (c) Okano, T.; Sakaida, T.; Eguchi, S. Heterocycles 1997, 44, 227; (d)
Hitchings, G. J.; Vernon, J. M. J. Chem. Soc., Perkin Trans. 1 1990, 1757; (e) Cas-
sayre, J.; Quiclet-Sire, B.; Saunier, J.-P.; Zard, S. Z. Tetrahedron Lett. 1998, 39,
8995; (f) Padwa, A.; Waterson, A. G. J. Org. Chem. 2000, 65, 235.
13. Tanaka, H.; Hattori, H.; Tanaka, T.; Etoh, H. J. Nat. Med. 2008, 62, 228.
14. Tanaka, H.; Tanaka, T.; Etoh, H.; Goto, S.; Terada, Y. Heterocycles 1999, 51,
2759.
15. For reviews on generating N-acyliminium ions, see: (a) Speckamp, W. N.;
Moolenaar, M. J. Tetrahedron 2000, 56, 3817; (b) Maryanoff, B. E.; Zhang, H.-C.;
Cohen, J. H.; Turchi, I. J.; Maryanoff, C. A. Chem. Rev. 2004, 104, 1431; (c) Royer, J.;
Bonin, M.; Micouin, L. Chem. Rev. 2004, 104, 2311.
21. For a selection of contributions by others: (a) Okitsu, O.; Suzuki, R.; Kobayashi,
S. J. Org. Chem. 2001, 66, 809; (b) Camilo, N. S.; Pilli, R. A. Tetrahedron Lett. 2004,
45, 2821; (c) de Godoy, L. A. F.; Soares Camilo, N.; Pilli, R. A. Tetrahedron Lett.
2006, 47, 7853; (d) Kinderman, S. S.; Wekking, M. M. T.; van Maarseveen, J. H.;
Schoemaker, H. E.; Hiemstra, H.; Rutjes, F. P. J. T. J. Org. Chem. 2005, 70, 5519; (e)
Maity, A. K.; Roy, S. J. Org. Chem. 2012, 77, 2935.
22. For a selection of impressive catalytic enantioselective approaches: (a) Raheem,
I. T.; Thiara, P. S.; Peterson, E. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2007, 129,
13404; (b) Peterson, E. A.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2009, 48, 6328;
(c) Muratore, M. C.; Holloway, C. A.; Pilling, A. W.; Storer, R. I.; Trevitt, G.; Dixon,
D. J. J. Am. Chem. Soc. 2009, 131, 10796.
16. For some representative examples, see: (a) Allin, S. M.; James, S. L.; Martin, W.
P.; Smith, T. A. D.; Elsegooda, M. R. J. J. Chem. Soc., Perkin Trans. 1 2001, 3029; (b)
Allin, S. M.; James, S. L.; Martin, W. P.; Smith, T. A. D. Tetrahedron Lett. 2001, 42,
3943; (c) Collado, M. I.; Manteca, I.; Sotomayor, N.; Villa, M.-J.; Lete, E. J. Org.
Chem. 1997, 62, 2080.
17. Harry, H.; Michael, T. S.; Alexandra, M. Z. S.; Robert, G. G. Synlett 1998, 640.
18. Ainhoa, A.; Eva, G.; Sonia, A.; Esther, L.; Nuria, S. Tetrahedron Lett. 2003, 44,
8445.
23. Hamon, M.; Dickinson, N.; Dalla, V. J. Org. Chem. 2014, 79, 1900.
24. Reviews: (a) Speckamp, W. N. Rec. Trav. Chim. Pays-Bas 1981, 100, 345; (b)
Speckamp, W. N.; Hiemstra, H. Tetrahedron 1985, 41, 4367; (c) Hiemstra, H.;
Speckamp, W. N. The Alkaloids; Academic: New York, NY, 1988, Vol. 32, p 271;
(d) Hiemstra, H.; Speckamp, W. N. Additions to N-acyliminium ions InTrost, B.
M., Fleming, I., Eds.. Comprehensive Organic Chemistry; Pergamon: Oxford, UK,
1991; Vol. 2, p 1047; (e) Maryanoff, B. E.; Rebarchak, M. C. Synthesis 1992, 1245
and references therein.
ꢀ
19. Lim, C. H.; Kim, S. H.; Kim, J. N. Bull. Korean Chem. Soc. 2012, 33, 1622.
20. (a) Othman, R. B.; Bousquet, T.; Othman, M.; Dalla, V. Org. Lett. 2005, 7, 5335;
(b) Devineau, A.; Pousse, G.; Taillier, C.; Blanchet, J.; Rouden, J.; Dalla, V. Adv.
Synth. Catal. 2010, 352, 2881; (c) Saber, M.; Comesse, S.; Dalla, V.; Daïch, A.;
Netchitaïlo, P. Synlett 2011, 2425; (d) Ben Othman, R.; Affani, R.; Tranchant,
25. Pin, F.; Comesse, S.; Garrigues, B.; Marchalln, S.; Daych, A. J. Org. Chem. 2007, 72,
1181.
ꢁ
ꢀ
26. Merce, R.; PujoL, M.; Ribo, J. M. Monatsh. Chem. 1986, 117, 631.
27. See Supplementary data.
28. Zhou, X. B.; Zhang, H. M.; Xie, X.; Li, Y. Z. J. Org. Chem. 2008, 73, 3958.
29. Chiou, W. H.; Lin, G. H.; Hsu, C. C.; Chaterpaul, S. J.; Ojima, I. Org. Lett. 2009, 11,
2659.
~
M. J.; Antoniotti, S.; Dunnach, E.; Dalla, V. Angew. Chem., Int. Ed. 2010, 49,
776.