An approach toward the alkaloid (±)-mersicarpine using a rhodium(II) carbenoid cyclization-cycloaddition cascade of an α-diazo dihydroindolinone

Article abstract of DOI:10.1016/j.tet.2011.09.118

A tandem carbonyl ylide/1,3-dipolar cycloaddition cascade of α-diazo indole-2,3-dione with several different dipolarophiles was investigated. The intermolecular Rh(II)-catalyzed reaction occurs efficiently and affords dipolar cycloadducts in high yields. The analogous intramolecular reaction also takes place and gives an azapolycyclic product derived from trapping of the carbonyl ylide dipole with a tethered alkene. The power of the intramolecular cascade sequence is that it rapidly assembles polycyclic ring systems containing both multiple stereocenters and adjacent quaternary carbon centers in a single step in high yield. This cascade reaction was successfully utilized in a model study directed toward the total synthesis of mersicarpine.

Full text of DOI:10.1016/j.tet.2011.09.118

Tetrahedron 67 (2011) 9829e9836
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
An approach toward the alkaloid (ꢀ)-mersicarpine using a rhodium(II) carbenoid
cyclizationecycloaddition cascade of an
a-diazo dihydroindolinone
,
Hao Li a, Bo Cheng a, Nawong Boonnak b, Albert Padwa a
*
a Department of Chemistry, Emory University, Atlanta, GA 30322, United States
b Crystal Materials Research Unit, Department of Chemistry, Faculty of Science, Prince of Songkla University Hat-Yai, Songkhla 90112, Thailand
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 17 August 2011
Received in revised form 26 September 2011
Accepted 27 September 2011
Available online 5 October 2011
A tandem carbonyl ylide/1,3-dipolar cycloaddition cascade of
a-diazo indole-2,3-dione with several
different dipolarophiles was investigated. The intermolecular Rh(II)-catalyzed reaction occurs efficiently
and affords dipolar cycloadducts in high yields. The analogous intramolecular reaction also takes place
and gives an azapolycyclic product derived from trapping of the carbonyl ylide dipole with a tethered
alkene. The power of the intramolecular cascade sequence is that it rapidly assembles polycyclic ring
systems containing both multiple stereocenters and adjacent quaternary carbon centers in a single step
in high yield. This cascade reaction was successfully utilized in a model study directed toward the total
synthesis of mersicarpine.
Dedicated with admiration and fondness to
Gilbert Stork on the occasion of his 90th
anniversary
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Rhodium(II)
Catalyst
Carbonyl ylide
Dipolar
Cycloaddition
1. Introduction
carbocyclic system 1b. This reactivity difference was attributed to
conformational effects in the transition state for the cycloaddition
Developing novel strategies for the stereoselective synthesis of
azapolycyclic ring systems is an ongoing quest for organic chem-
ists.1e7 Construction of complex nitrogen-containing heterocycles
through tandem cascade chemistry8e10 has been a fruitful area of
investigation, and the synthesis of various natural products
employing domino reactions has been carried out by numerous
investigators.11e14 A particularly interesting approach involves the
reaction.18
X
X
Rh (II)
O
N2
H
O
N
N
rhodium(II)-catalyzed reaction of a-diazo carbonyl compounds to
generate a carbonyl ylide dipole followed by 1,3-dipolar cycload-
dition as a method to assemble the polycyclic framework of indole
alkaloids.15 This powerful cascade sequence has been successfully
utilized for the construction of the Aspidosperma16 and vinca al-
kaloids.17 In a recent study from our laboratory using push-pull
O
O
CO2Et
CO2Et
1a; X = O
1b; X = CH2
2a; X = O
2b; X = CH2
Scheme 1.
carbonyl ylide dipoles,18 we found that
a-diazo dihy-
droindolinones readily undergo a highly regio- and stereoselective
cycloaddition cascade to furnish oxapolycyclic ring systems in high
yield (Scheme 1). Interestingly, tethered alkenyl substituted ethers
such as 1a exhibited much higher reactivity than the corresponding
In a further effort to explore the scope, generality, and syn-
thetic applications of the rhodium(II) catalyzed carbenoid
cyclizationecycloaddition cascade, we became interested in us-
ing this transformation as the key step in a total synthesis of the
alkaloid mersicarpine. Mersicarpine (3) is a structurally unique
natural product that was isolated from the Kopsia species of
* Corresponding author. Tel.: þ1 404 727 0283; fax: þ1 404 727 6786; e-mail
address: chemap@emory.edu (A. Padwa).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.09.118

9830
H. Li et al. / Tetrahedron 67 (2011) 9829e9836
plants by Kam and co-workers in 2004.19 It contains a seven-
membered cyclic imine and an intricately oxidized indole moi-
ety centered in the tetracyclic ring system. The first total syn-
thesis of mersicarpine was accomplished by Kerr and co-workers
via a Mn(III)-mediated malonic radical cyclization.20 More re-
cently, Fukuyama and co-workers reported the first enantiose-
lective synthesis of mersicarpine employing a combination of
a Sonogashira coupling reaction with a gold(III) catalyzed cycli-
zation.21 A formal synthesis of mersicarpine was also reported by
Zard who used an intermolecular radical addition-cyclization
cascade.22 We envisioned that the core skeleton of mersi-
carpine could also come about by utilizing an intramolecular 1,3-
dipolar cycloaddition of a carbonyl ylide dipole generated from
product and is obtained as a single diastereomer from the cascade
reaction. In a related manner, cycloadduct 8 was isolated in 74%
yield as the exo-product when N-phenylmaleimide was used as
dipolarophile.
The intramolecular dipolar cycloaddition of
a-diazo dihy-
droindolinone 13 was next explored as a model system for an
eventual approach toward mersicarpine. This compound was readily
prepared from commercially available NH-oxindole (Scheme 4).
MOM-protection of NH-oxindole followed by benzylation delivered
the expected mono-substituted product 10.25 The Mannich reaction
of 10 with diallylamine and paraformaldehyde delivered the ami-
nomethylated oxindole 11,26 which underwent
a subsequent
demethylation under acidic conditions to give alcohol 12. The re-
quired diazo functionality was then installed using ethyl
2-diazomalonyl chloride via a one-pot deprotection of the hydrox-
ymethyl group followed by an acylation reaction to provide 13.
the Rh(II)-catalyzed reaction of a masked
a
-diazo imino struc-
ture such as 5 (Scheme 2).
PG
N
PG
N
Bn
N
Et
X
X
OH
LHMDS
BnBr
NaH
O
O
O
N2
O
Et
Et
MOMCl
N
H
N
MOM
10; 51%
N
N
O
N
N
MOM
9; 79%
O
O
O
CO2Et
CO2Et
3; (+)-mersicarpine
H
5
4; X = N, O, C, or H;
N
(CH2O)n
Scheme 2.
2. Results and discussion
N
N
N
In order to establish the feasibility of this particular approach
toward mersicarpine, we chose to explore the Rh(II) catalyzed cy-
cloaddition reaction of the simpler a-diazo indole-2,3-dione 6 as
a test substrate. Compound 6 was easily prepared by treating isa-
tine with sodium hydride and ethyl 2-diazomalonyl chloride.23
Heating 6 with ethyl acrylate in the presence of 5 mol % of
Rh2(OAc)4 at 80 ꢁC proceeded with complete regio- and diaster-
eoselectivity and provided the cycloaddition product 7 in 55% yield
(Scheme 3). In contrast to our previous study, which resulted in
Bn
O
+
NaH
Bn
O
H
Bn
O
O
O
N
N
N
Cl
OEt
N2
MOM
N2
OH
O
12; 93%
11; 87%
CO2Et
13; 50%
Scheme 4.
a mixture of four diastereomeric cycloadducts when
a
-diazo
Exposure of 13 to the standard Rh(II) catalyzed cascade reaction
conditions did not give the desired cycloaddition product but in-
stead afforded the novel rearranged product 14 in quantitative yield.
Compound 14 probably arises by carbonyl cyclization onto the ini-
tially formed rhodium carbenoid, followed by a retro-Mannich re-
action of dipole 15 and a subsequent addition of the anionic center
of 16 onto the resulting diallyliminum ion (Scheme 5).
O
O
O
O
O
OEt
OEt
O
N2
+
O
N
O
N
N
Rh2(OAc)4
80 oC, 4 h
-
CO2Et
O
O
CO2Et
O
CO2Et
6
7; 55%
In order to inhibit this side reaction, a-diazo dihydroindolinone
20 was prepared with the expectation that the presence of an
acetyl group would diminish the electron density at the nitrogen
atom and thereby retard the retro-Mannich reaction. The synthesis
of 20 started with a selective mono-deallylation of oxindole 11
Ph
N
O
O
O
O
O
Ph
N
O
N2
O
N
N
27
using Pd(PPh3)4 (Scheme 6). The resulting secondary amine 17
Rh2(OAc)4
80 oC, 4 h
O
O
was then protected as the acetamide 18. MOM-deprotection fol-
lowed by acylation with ethyl 2-diazomalonyl chloride delivered
20 in good yield. Treatment of 20 with the rhodium acetate catalyst
in benzene at 80 ꢁC for 2 h now afforded the cycloaddition product
21 as a 2:1 mixture of inseparable diastereomers in 89% overall
yield. Thus, this unique intramolecular cascade sequence rapidly
assembled a pentacyclic ring system containing three new ster-
eocenters and two adjacent quaternary centers in a single step and
in high yield. Notably, the retro-Mannich/Mannich side reaction
encountered with 13 was completely suppressed by the in-
corporation of an acetyl group on the nitrogen atom of allylace-
tamide 20.
O
CO2Et
CO2Et
6
8; 74%
Scheme 3.
dihydroindolinone was treated with methyl acrylate in the pres-
ence of a Rh(II) catalyst,18 the high regioselectivity encountered in
the cycloaddition of compound 6 with the acrylate ester can be
rationalized by FMO theory.24 The most favorable FMO interaction
involves the HOMO of the carbonyl ylide dipole and the LUMO of
the dipolarophile. The preferred exo-selectivity is associated with
fewer nonbonded interactions in the transition state for the cy-
cloaddition process. Thus, cycloadduct 7 is the preferred FMO
With the successful cycloaddition of 3-aminomethyl
dihydroindolinone 20 in hand, we embarked on
a
-diazo
a
further

H. Li et al. / Tetrahedron 67 (2011) 9829e9836
9831
O
NH
O
Bn
N
Rh2(OAc)4
Bn
O
N
O
N
NH
NH2
N2
N
CO2Et
N2
O
O
CO2Et
22; 65%
O
CO2Et
O
14; 99%
13
O
N2
N
O
OR
O
O
N
CO2Et
Bn
O
+
+
N
6
ROH
N
Bn
NH
N2
+
O
-
Rh
N
Rh
O
N
CO2Et
CO2Et
CO2Et
23; R = Me; 99%
24; R = Et; 99%
O
O
16
15
Scheme 7.
Scheme 5.
H
N
NC
N
KCN
N
HN
+
O
Ac
H
N
Ac2O
O
Bn
O
N
H
Bn
O
Pd(PPh3)4
Bn
N
DMAP
H
O
N
N
26; 50%
Ac2O
N
MOM
25
MOM
O
O
MOM
18; 90%
17; 53%
11
DMAP
Cl
OEt
+
N2
H
Ac
N
Ac
H
N
H
N
NC
NC
N
Bn
Bn
NAc
H
Bn
O
NaH
O
O
N
O
N
O
O
Rh(II)
N2
N
O
N
N
H
N2
Ac
Cl
OEt
O
N2
O
CO2Et
27; 88%
19; 71%
O
CO2Et
CO2Et
Rh(II)
NC
28; 48%
20; 72%
21; 89%
H
N
Scheme 6.
O
N
investigation to explore the intramolecular cycloaddition of several
3-imino substituted -diazo dihydroindolinones. This study was
O
a
CO2Et
initiated by an attempt to prepare an iminyl group in the 3-
position of the oxindole ring by reacting 2-diazo-3-(2,3-
dioxoindolin-1-yl)-3-oxopropanoate (6) with a primary amine.
However, we found that the treatment of 6 with 4-pentenylamine
only afforded the ring opened diazo amide 22 in 65% yield rather
than the desired 3-pentenylimino-2-one. A similar ring opening
reaction occurred when 6 was treated with methanol or ethanol
producing esters 23 and 24. These compounds are derived by at-
tack of the alcohol at the more electron deficient carbonyl group
corresponding to the 2-position of the indoline-2,3-dione system
(Scheme 7).
29; 83%
8:5-mixture
Scheme 8.
product 27. Interestingly, the secondary amino group present in
structure 27 was untouched in the acetylation reaction, probably
due to steric hinderance around the adjacent quaternary carbon
center. With this information on hand, the required diazo func-
tionality was selectively introduced by allowing compound 26 to
react with ethyl 2-diazomalonyl chloride, which afforded 28 as the
exclusive product. Exposure of 28 to the standard Rh(II)-catalyzed
conditions provided the polycyclic cycloaddition product 29 as an
8:5 mixture of two separable diastereomers in good yield.31 Thus,
this cascade reaction enabled us to quickly assemble a polycyclic
ring system containing four new stereocenters and three continu-
ous quaternary carbons in a single operation in high yield and we
intend to use a related cycloaddition reaction for an eventual syn-
thesis of mersicarpine.
The Strecker reaction has been one of the most important
methods used for the synthesis of amino acids.28,29 The
a-amino
nitrile product derived from the Strecker reaction of a ketimine and
HCN is usually a robust compound and has been previously
employed as a protected imine with a removable function handle.30
In this spirit, we examined the reaction of imine 25 and KCN in
presence of HCl in methanol. The resulting cyano amine product 26
was isolated in 50% yield (Scheme 8). Acetylation of 26 with acetic
anhydride and DMAP proceeded smoothly to deliver the acetylated

9832
H. Li et al. / Tetrahedron 67 (2011) 9829e9836
3. Conclusion
159.5, 159.9, and 180.1; HRMS calcd for [C13H9N3O5ꢂN2þHþ]:
260.0553; found: 260.0550.
In
tionecycloaddition reaction of an
been employed for an efficient synthesis of a complex azapolycyclic
ring system from an easily prepared substrate. 3-Amino -diazo
dihydroindolinone 28 was quickly assembled using the Strecker re-
action in order to mask the sensitive imino functionality. The success
of this model study provides an insightful hint for an eventual total
synthesis of mersicarpine and related natural products. We are
continuing to explore the scope, generality, and synthetic applica-
tions of the Rh(II)-catalyzed tandem cyclizationecycloaddition re-
conclusion,
an
intramolecular
tandem
cycliza-
a-diazo dihydroindolinone has
4.2.2. Diethyl 6,10-dioxo-7,8,9,10-tetrahydro-6H-7,9a-epoxypyrido
[1,2-a]indole-7,9-dicarboxylate (7). To
a 10 mL pressure tube
a
charged with a solution containing diazo 6 (28 mg, 0.1 mmol) in
benzene (2 mL) were sequentially added Rh2(OAc)4 (2 mg,
0.005 mmol) and ethyl acrylate (15 mg, 0.15 mmol). The mixturewas
heated at reflux for 4 h. After cooling to room temperature, the re-
action mixture was concentrated under reduced pressure and sub-
jected to flash silica gel chromatography to furnish 20 mg (55%) of
the title compound as a colorless oil; IR (thin film) 2964, 1735, 1605,
action of 3-amino
a-diazo dihydroindolinones and will report
and 1506 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
0.79 (t, 3H, J¼7.2 Hz),
additional findings at a later date.
1.36 (t, 3H, J¼7.2 Hz), 2.82 (dd, 1H, J¼13.2 and 10.8 Hz), 2.97 (dd, 1H,
J¼13.2 and 4.8 Hz), 3.84 (dd, 1H, J¼10.8 and 4.8 Hz), 3.86e3.90 (m,
1H), 4.01e4.06 (m, 1H), 4.39 (q, 2H, J¼7.2 Hz), 7.31 (t, 1H, J¼7.8 Hz),
7.62 (d,1H, J¼8.4 Hz), 7.71 (t,1H, J¼7.8 Hz), 7.84 (d,1H, J¼7.2 Hz); 13C
4. Experimental
4.1. General
NMR (150 MHz, CDCl3)
d 13.5, 14.2, 31.5, 48.4, 61.9, 63.1, 91.2, 95.1,
115.7, 125.6, 125.8, 126.3, 138.1, 149.2, 163.5, 166.4, 167.9, and 188.0;
HRMS calcd for [C18H17NO7]þ: 359.0999; found: 359.0992.
1H and 13C NMR spectra were recorded on Varian Inova
600 MHz, 400 MHz spectrometers and VNMRS 400 MHz spec-
trometer in deuteriochloroform (CDCl3) with the solvent residual
peak (CDCl3: 1H¼7.26 ppm, 13C¼77.23 ppm) as internal reference
unless otherwise stated. Data are reported in the following order:
4.2.3. Ethyl 1,3,5,11-tetraoxo-2-phenyl-1,2,3,3a,4,5,11,11b-octahydro-
4,11a-epoxypyrrolo[30,40:3,4]pyrido[1,2-a]indole-4-carboxylate
(8). To a 10 mL pressure tube charged with a solution containing
diazo 6 (28 mg, 0.1 mmol) in benzene (2 mL) were sequentially
added Rh2(OAc)4 (2 mg, 0.005 mmol) and 1-phenyl-1H-pyrrole-
2,5-dione (35 mg, 0.2 mmol). The mixture was heated at reflux for
4 h. After cooling to room temperature, the reaction mixture was
concentrated under reduced pressure and subjected to flash silica
gel chromatography to furnish 32 mg (74%) of the title compound
chemical shifts are given (d); multiplicities are indicated as br
(broadened), s (singlet), d (doublet), t (triplet), q (quartet), m
(multiplet), app (apparent); coupling constants, J, are reported (Hz).
Infrared spectra were recorded on a Nicolet 510 FT-IT or ASI ReactIR
1000 spectrometer. Elemental analyses were performed by Atlantic
Microlab, Inc., Norcross, Georgia. Uncalibrated melting points were
taken on a Thomas-Hoover melting point apparatus in open capil-
lary tubes.
as a pale yellow oil; IR (thin film) 1769, 1724, 1604, and 1465 cmꢂ1
;
1H NMR (400 MHz, CDCl3)
d
1.40 (t, 3H, J¼7.2 Hz), 4.32 and 4.36
(ABq, 2H, JAB¼13.2 Hz), 4.48 (q, 2H, J¼7.2 Hz), 7.14e7.16 (m, 2H),
7.35 (t, 1H, J¼7.6 Hz), 7.39e7.46 (m, 3H), 7.66 (d, 1H, J¼8.0 Hz), 7.75
(t, 1H, J¼8.0 Hz), 7.87 (d, 1H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
Analytical thin-layer chromatography (TLC) was performed on
Merck silica gel glass plates with F-254 indicator. Visualization was
accomplished by UV light, or with solutions of K2CO3/KMnO4 in
water, phosphomolybdic acid in ethanol, or p-anisaldehyde in
ethanol. Solvents for reactions and chromatography were reagent
grade and used as received. Solvents used as reaction media were
purchased in >99% purity purged for several minutes with argon
d
14.2, 49.1, 51.6, 64.0, 91.8, 94.7, 115.8, 125.6, 126.5, 126.6, 126.7,
129.5, 129.6, 131.0, 139.1, 148.6, 161.7, 163.1, 168.8, 169.3, and 185.7;
HRMS calcd for [C23H16N2O7þHþ]: 433.1030; found: 433.1033.
4.2.4. 1-(Methoxymethyl)indolin-2-one25a (9). To a 50 mL round-
bottomed flask charged with a solution of oxindole (0.53 g,
4.0 mmol) in THF (10 mL) and DMF (10 mL) at 0 ꢁC was added NaH
(60% dispersion in mineral oil, 0.16 g, 4.0 mmol). After stirring for
30 min, MOMCl (0.40 mL, 5.2 mmol) was added and the solution
was stirred for 24 h at 23 ꢁC. The mixture was then quenched with
ice water and extracted with EtOAc. The combined organic layers
werewashed with water, brine, and dried over MgSO4. After removal
of the solvent under reduced pressure, the residue was subjected to
flash silica gel chromatography to furnish 0.56 g (79%) of the title
compound as a pink solid: mp 71e72 ꢁC (lit.25a 76e78 ꢁC); IR (thin
ꢀ
then dried and stored over 4 A molecular sieves (water content
below 10 ppm). All reactions requiring inert atmospheres were
carried out under dry argon in oven-dried glassware. Bulb-to-bulb
€
(‘Kugelrohr’) distillations were done on a Buchi GKR-50 Kugelrohr
and boiling points (bp) correspond to uncorrected air bath tem-
peratures. ‘Brine’ refers to a saturated aqueous solution of NaCl.
Unless otherwise specified, solutions of NH4Cl, NaHCO3 refer to
saturated solutions.
4.2. The Rh(II)-catalyzed dipolar cycloaddition
film) 2936, 1718, 1613, and 1486 cmꢂ1 1H NMR (600 MHz, CDCl3)
;
4.2.1. Ethyl
2-diazo-3-(2,3-dioxoindolin-1-yl)-3-oxopropanoate
d
3.35 (s, 3H), 3.61 (s, 2H), 5.13 (s, 2H), 7.02 (d, 1H, J¼7.8 Hz), 7.07 (t,
(6). To a 50 mL round-bottomed flask charged with a solution of
isatin (0.26 g, 1.8 mmol) in THF (18 mL) at 0 ꢁC was added NaH (60%
dispersion in mineral oil, 0.16 g, 4.0 mmol). After stirring for
30 min, ethyl 2-diazomalonyl chloride (0.71 g, 4.0 mmol) was
added and the solution was stirred for 3 h at 23 ꢁC. The mixture was
then quenched with water and extracted with EtOAc. The com-
bined organic layers were washed with water, brine, and dried over
Na2SO4. After removal of the solvent under reduced pressure, the
residue was subjected to flash silica gel chromatography to furnish
0.34 g (65%) of the title compound as a yellow oil. IR (thin film)
2964, 2148, 1733, 1606, and 1506 cmꢂ1; 1H NMR (600 MHz, CDCl3)
1H, J¼7.2 Hz), 7.26e7.29 (m, 2H); 13C NMR (150 MHz, CDCl3)
d 36.1,
56.5, 71.4, 109.7, 123.1, 124.1, 124.6, 128.2, 143.6, and 175.8.
4.2.5. 3-Benzyl-1-(methoxymethyl)indolin-2-one25b
a 50 mL round-bottomed flask charged with a solution of N-pro-
tected oxindole 9 (177 mg, 1.0 mmol) in THF (8 mL) and HMPA
(10). To
(1.7 mL) was added dropwise
a solution of lithium bis(-
trimethylsilyl)amide (1 M in THF, 1.2 mL, 1.2 mmol) at ꢂ78 ꢁC under
argon. The resulting solution was stirred at ꢂ78 ꢁC for 1 h, and then
BnBr (0.18 mL, 1.5 mmol) was added. After stirring for 2 h at ꢂ78 ꢁC,
the mixture was quenched with acetic acid (0.3 mL, 5% in THF). The
reaction mixture was warmed to room temperature, and saturated
aqueous NaHCO3 was added followed by extraction with EtOAc. The
combined organic layers were washed with water, brine, and dried
d
1.29 (t, 3H, J¼7.2 Hz), 4.29 (q, 2H, J¼7.2 Hz), 7.31 (t, 1H, J¼7.2 Hz),
7.70 (t, 1H, J¼7.8 Hz), 7.76 (app t, 2H, J¼6.6 Hz); 13C NMR (150 MHz,
CDCl3) d 14.4, 62.5, 63.4, 115.9, 119.1, 125.7, 126.0, 139.0, 148.2, 156.2,

H. Li et al. / Tetrahedron 67 (2011) 9829e9836
9833
over MgSO4. After removal of the solvent under reduced pressure,
the residue was subjected to flash silica gel chromatography to
furnish 136 mg (51%) of the title compound as a pale yellow oil; IR
5.52e5.59 (m, 2H), 6.84 (d, 2H, J¼7.2 Hz), 7.05e7.09 (m, 3H), 7.15 (t,
1H, J¼7.2 Hz), 7.21e7.24 (m, 2H), 7.47 (d, 1H, J¼7.8 Hz); 13C NMR
(150 MHz, CDCl3)
d 14.5, 41.5, 57.4, 57.8, 61.3, 62.0, 114.6, 117.6,
(thin film) 2932, 1718, 1612, and 1487 cmꢂ1
;
1H NMR (600 MHz,
124.3, 124.5, 127.0, 128.2, 128.4, 130.1, 130.3, 135.1, 135.3, 140.2,
158.6, 161.0, and 178.0; HRMS calcd for [C27H28N4O4þHþ]:
473.2183; found: 473.2182.
CDCl3)
d
3.03 (dd, 1H, J¼13.2 and 8.4 Hz), 3.08 (s, 3H), 3.48 (dd, 1H,
J¼13.8 and 4.8 Hz), 3.82 (dd, 1H, J¼8.4 and 4.2 Hz), 5.01 and 5.09
(ABq, 2H, JAB¼10.8 Hz), 6.89 (d, 1H, J¼7.2 Hz), 6.93 (d, 1H, J¼7.8 Hz),
6.98 (t, 1H, J¼7.8 Hz), 7.11 (d, 2H, J¼7.2 Hz), 7.17e7.23 (m, 4H); 13C
4.2.9. Ethyl 9-benzyl-2-((diallylamino)methyl)-3-oxo-2,3-
dihydrooxazolo[3,2-a]indole-2-carboxylate (14). To a 10 mL pres-
sure tube charged with a solution containing diazo 13 (10 mg,
0.021 mmol) in benzene (2 mL) was added Rh2(OAc)4 (0.9 mg,
0.002 mmol). The mixture was heated at reflux for 1.5 h. After
cooling to room temperature, the reaction mixture was concen-
trated under reduced pressure and subjected to flash silica gel
chromatography to furnish 10 mg (99%) of the title compound as
NMR (100 MHz, CDCl3)
d 36.8, 47.4, 56.0, 71.3, 109.5, 122.7, 124.7,
126.8, 127.9, 128.2, 128.4, 129.6, 137.5, 142.6, and 177.6.
4.2.6. 3-Benzyl-3-((diallylamino)methyl)-1-(methoxymethyl)-in-
dolin-2-one (11). Following a literature procedure,26 to a 50 mL
round-bottomed flask charged with a solution of 3-benzyl oxindole
10 (267 mg, 1.0 mmol) in EtOAc (20 mL) were sequentially added
paraformaldehyde (90 mg, 3.0 mmol) and diallylamine (291 mg,
3 mmol). The mixture was stirred for 72 h at 50 ꢁC. After removal of
the solvent under reduced pressure, the residue was subjected to
flash silica gel chromatography to furnish 326 mg (87%) of the title
compound as a yellow wax-like solid; IR (thin film) 2930, 1714,
a colorless oil; IR (thin film) 2923, 1769, 1668, and 1476 cmꢂ1
NMR (600 MHz, CDCl3)
;
1H
d
1.30 (t, 3H, J¼7.2 Hz), 3.14 (dd, 2H, J¼14.4
and 7.2 Hz), 3.21 (dd, 2H, J¼14.4 and 6.6 Hz), 3.32 (d,1H, J¼15.0 Hz),
3.50 (d, 1H, J¼15.0 Hz), 3.95 (s, 2H), 4.25e4.30 (m, 2H), 5.03e5.05
(m, 4H), 5.59e5.65 (m, 2H), 7.16e7.26 (m, 6H), 7.29 (d, 2H,
1640, and 1488 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
2.89 (s, 3H),
J¼7.8 Hz), 7.79 (d, 1H, J¼7.8 Hz); 13C NMR (150 MHz, CDCl3)
d 14.2,
2.91e2.93 (m, 4H), 3.03e3.10 (m, 3H), 3.20 (d, 1H, J¼13.8 Hz), 4.89
and 4.92 (ABq, 2H, JAB¼11.4 Hz), 4.97 (dd, 2H, J¼17.4 and 1.8 Hz),
5.00 (dd, 2H, J¼10.2 and 1.2 Hz), 5.49e5.55 (m, 2H), 6.81 (d, 1H,
J¼7.8 Hz), 6.84 (dd, 2H, J¼7.2 and 1.2 Hz), 6.98e7.03 (m, 3H), 7.07
(td, 1H, J¼7.2 and 0.6 Hz), 7.18 (td, 1H, J¼7.8 and 1.2 Hz), 7.30 (d, 1H,
28.1, 55.3, 57.9, 63.1, 89.8, 96.8, 113.3, 117.9, 119.1, 122.3, 125.1, 125.8,
126.4, 128.6, 134.9, 135.8, 139.5, 152.0, 161.9, and 164.9; HRMS calcd
for [C27H28N2O4þHþ]: 445.2121; found: 445.2120.
4.2.10. 3-((Allylamino)methyl)-3-benzyl-1-(methoxymethyl)indolin-
2-one (17). To a 250 mL round-bottomed flask charged with 3-
aminomethyl oxindole 11 (377 mg, 1.0 mmol), N,N0-dime-
thylbarbituric acid (468 mg, 3.0 mmol), and tetrakis(-
triphenylphosphine)palladium(0) (23 mg, 0.02 mmol) was added
degassed CH2Cl2 (50 mL). The mixture was stirred for 48 h at 23 ꢁC.
After removal of the solvent under reduced pressure, the residue
was redissolved in ether and washed with 2.5 N NaOH aqueous
solution. The organic layer was washed with water, brine, and dried
over Na2SO4. The solvent was removed under reduced pressure,
and the resulting residue was subjected to flash silica gel chroma-
tography to furnish 179 mg (53%) of the title compound as a color-
J¼7.8 Hz); 13C NMR (100 MHz, CDCl3)
d 41.0, 55.6, 57.2, 57.8, 60.8,
71.1, 109.3, 117.1, 122.2, 126.4, 126.5, 127.7, 128.1, 130.1, 130.4, 135.5,
135.9, 143.0, and 179.3.
4.2.7. 3-Benzyl-3-((diallylamino)methyl)-1-(hydroxymethyl)-in-
dolin-2-one (12). To a 50 mL round-bottomed flask charged with
a solution of 3-aminomethyl oxindole 11 (180 mg, 0.48 mmol) in
acetonitrile (18 mL) was added p-TsOH$H2O (364 mg, 1.91 mmol).
The mixture was stirred for 35 min at 85 ꢁC. After cooling to room
temperature, the reaction mixture was quenched with saturated
aqueous NaHCO3 and extracted with EtOAc. The combined organic
layers were washed with water, brine, and dried over MgSO4. After
removal of the solvent under reduced pressure, the residue was
subjected to flash silica gel chromatography to furnish 148 mg (93%)
of the title compound as a pale yellow solid: mp 80e82 ꢁC; IR (thin
less oil; 1H NMR (600 MHz, CDCl3)
d 2.87 (s, 3H), 3.08e3.19 (m, 6H),
4.92 (s, 2H), 5.02 (dd, 1H, J¼10.8 and 1.8 Hz), 5.07 (dd, 1H, J¼17.4
and 1.2 Hz), 5.69e5.71 (m,1H), 6.85 (app d, 3H, J¼7.8 Hz), 7.00e7.04
(m, 3H), 7.10 (t, 1H, J¼7.8 Hz), 7.22 (td, 1H, J¼7.8 and 1.2 Hz), 7.25 (d,
film) 3400, 2916, 1696, 1653, and 1511 cmꢂ1
CDCl3)
;
1H NMR (400 MHz,
1H, J¼7.8 Hz); 13C NMR (150 MHz, CDCl3)
d 41.1, 52.5, 55.2, 55.6,
56.0, 71.1, 109.5, 115.8, 122.6, 123.4, 126.6, 127.7, 128.4, 129.8, 130.0,
135.7, 136.8, 142.7, and 179.3.
d
2.02 (br s, 1H), 2.94 (app t, 4H, J¼6.0 Hz), 3.00 (d, 1H,
J¼12.8 Hz), 3.07e3.11 (m, 2H), 3.20 (d,1H, J¼14.0 Hz), 4.94e5.05 (m,
6H), 5.52e5.62 (m, 2H), 6.78e6.81 (m, 3H), 6.99e7.09(m, 4H), 7.19(t,
1H, J¼8.0 Hz), 7.28 (d, 1H, J¼7.6 Hz); 13C NMR (100 MHz, CDCl3)
4.2.11. N-Allyl-N-((3-benzyl-1-(methoxymethyl)-2-oxoindolin-3-yl)
methyl)acetamide (18). To a 50 mL round-bottomed flask charged
with a solution of 3-((allylamino)methyl) oxindole 17 (179 mg,
0.53 mmol) in CH2Cl2 (20 mL) were sequentially added DMAP
(129 mg, 1.06 mmol) and Ac2O (63 mg, 0.80 mmol). The mixture
was stirred for 1.5 h at 23 ꢁC. After removal of the solvent under
reduced pressure, the residue was subjected to flash silica gel
chromatography to furnish 180 mg (90%) of the title compound as
a white solid: mp 85e86 ꢁC; IR (thin film) 2930, 1712, 1651, and
d
41.6, 56.7, 57.9, 60.0, 63.6, 109.9, 117.2, 122.3, 124.6, 126.6, 127.7,
128.1, 130.1, 130.6, 135.6, 135.7, 142.5, and 179.4; HRMS calcd for
[C23H26N2O2þHþ]: 363.20671; found: 363.2059.
4.2.8. Ethyl 3-(3-benzyl-3-((diallylamino)methyl)-2-oxoindolin-1-
yl)-2-diazo-3-oxopropanoate (13). To
a 50 mL round-bottomed
flask charged with a solution of alcohol 12 (87 mg, 0.24 mmol) in
THF (8 mL) at 0 ꢁC was added NaH (60% dispersion in mineral oil,
24 mg, 0.60 mmol). After stirring for 30 min, ethyl 2-diazomalonyl
chloride (64 mg, 0.36 mmol) was added and the solution was stir-
red for 45 min at 23 ꢁC. The mixture was then quenched with water
and extracted with EtOAc. The combined organic layers were
washed with water, brine, and dried over Na2SO4. After removal of
the solvent under reduced pressure, the residue was subjected to
flash silica gel chromatography to furnish 57 mg (50%) of the title
compound as a colorless oil; IR (thin film) 2923, 2137, 1742, 1699,
1611 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 1.88 (s, 3H), 2.77 (s, 3H),
3.14 and 3.18 (ABq, 2H, JAB¼13.2 Hz), 3.68e3.81 (m, 3H), 4.47 (d, 1H,
J¼13.8 Hz), 4.79 and 4.82 (ABq, 2H, JAB¼11.4 Hz), 4.95 (d, 1H,
J¼17.4 Hz), 5.11 (d, 1H, J¼10.8 Hz), 5.56e5.62 (m, 1H), 6.74e6.77 (m,
3H), 6.95e7.03 (m, 3H), 7.11 (t, 1H, J¼7.8 Hz), 7.18 (t, 1H, J¼7.8 Hz),
7.52 (d, 1H, J¼7.2 Hz); 13C NMR (150 MHz, CDCl3)
d 21.3, 42.2, 49.8,
51.3, 55.7, 56.1, 71.4, 109.0, 116.5, 122.7, 125.3, 126.7, 127.6, 128.4,
129.9, 130.0, 132.4, 135.0, 142.2, 171.8, and 179.1.
1606, and 1496 cmꢂ1 1H NMR (600 MHz, CDCl3)
; d 1.33 (t, 3H,
J¼7.2 Hz), 2.87 (d, 4H, J¼6.6 Hz), 3.04 (d, 1H, J¼13.8 Hz), 3.09 and
3.12 (ABq, 2H, JAB¼13.8 Hz), 3.23 (d, 1H, J¼13.2 Hz), 4.32 (q, 2H,
J¼7.2 Hz), 4.96 (dd, 2H, J¼17.4 and 1.2 Hz), 5.01 (d, 2H, J¼9.6 Hz),
4.2.12. N-Allyl-N-((3-benzyl-2-oxoindolin-3-yl)methyl)acetamide
(19). To a 50 mL round-bottomed flask charged with a solution of
MOM-protected oxindole 18 (136 mg, 0.36 mmol) in acetonitrile

9834
H. Li et al. / Tetrahedron 67 (2011) 9829e9836
(13.5 mL) was added p-TsOH$H2O (274 mg,1.44 mmol). The mixture
was stirred for 35 min at 85 ꢁC. After cooling to room temperature,
the reaction mixture was quenched with saturated aqueous NaHCO3
and extracted with EtOAc. The combined organic layers were
washed with water, brine, and dried over MgSO4. After removal of
the solvent under reduced pressure, the residue was subjected to
flash silica gel chromatography to furnish 85 mg (71%) of the title
compound as a colorless oil; IR (thin film) 3061, 1709, 1635, and
flask charged with a solution of pent-4-enoic acid (0.51 mL,
5.0 mmol) in CH2Cl2 (17 mL) at 0 ꢁC was added Et3N (0.70 mL,
5.0 mmol). The mixture was stirred for 10 min, and isobutyl
chloroformate (0.72 mL, 5.5 mmol) was added dropwise. After
stirring for 1 h at 0 ꢁC, the reaction mixture was warmed to 23 ꢁC
and kept at this temperature for 30 min. The reaction mixture was
then concentrated to 7 mL followed by the addition of ammonia
(20.4 mL) at 0 ꢁC. The mixture was stirred for 24 h at 23 ꢁC, and
then diluted with CH2Cl2 followed by extraction with EtOAc. The
combined organic layers were washed with water, brine, and dried
over MgSO4. After removal of the solvent under reduced pressure,
the crude product was recrystallized from CH2Cl2/petroleum ether
to furnish 297 mg (60%) of 4-pentenamide as a white solid: mp
105e106 ꢁC (lit.32 104e106 ꢁC); IR (thin film) 1668, 1404, and
1470 cmꢂ1; 1H NMR (300 MHz, CDCl3) two rotamers
d 1.81 (s, 1.5H),
1.87 (s, 1.5H), 3.03e3.26 (m, 2H), 3.32 (br s, 1H), 3.66e3.78 (m, 2H),
4.20 (d, 0.5H, J¼14.1 Hz), 4.46 (d, 0.5H, J¼14.1 Hz), 4.77e5.14 (m, 2H),
5.33e5.44 (m, 0.5H), 5.55e5.65 (m, 0.5H), 6.60 (d, 0.5H, J¼7.5 Hz),
6.66e6.74 (m, 1.5H), 6.79e6.89 (m, 1.5H), 6.97e7.14 (m, 2.5H),
7.18e7.23 (m,1H), 7.22e7.24 (m,1H), 7.35 (d, 0.5H, J¼7.8 Hz), 7.42 (d,
0.5H, J¼7.2 Hz), 7.70 (br s, 1H); 13C NMR (100 MHz, CDCl3) two
904 cmꢂ1; 1H NMR (600 MHz, CDCl3)
d
2.33 (t, 2H, J¼7.8 Hz), 2.41 (t,
rotamers
d
21.4, 21.5, 42.3, 42.4, 49.5, 49.9, 51.0, 51.3, 56.1, 56.2,109.3,
2H, J¼7.8 Hz), 5.03 (dd, 1H, J¼10.2 and 1.2 Hz), 5.09 (dd, 1H, J¼15.6
110.3, 116.4, 116.7, 122.3, 123.2, 125.1, 125.9, 126.5, 126.7, 127.6, 127.8,
128.3,128.4,128.8,129.5,130.1,130.2,132.2,132.5,134.9,135.2,140.8,
141.5, 172.0, 179.6, and 180.8; HRMS calcd for [C21H22N2O2þHþ]:
335.1754; found: 335.1749.
and 1.2 Hz), 5.48 (br s, 2H), 5.81e5.88 (m, 1H); 13C NMR (100 MHz,
CDCl3)
d 29.4, 35.0, 115.6, 137.0, and 175.5.
To a 50 mL round-bottomed flask charged with a solution
of 4-pentenamide prepared as described above (297 mg,
3.0 mmol) in ether (10 mL) at 23 ꢁC was added LiAlH4 (1.0 M in
ether, 6 mL, 6.0 mmol). After stirring for 24 h, the reaction
mixture was cooled to 0 ꢁC and quenched by water. The reaction
mixture was filtered through Celite, washed with water, brine,
and dried over MgSO4. After removal of the solvent under re-
duced pressure at 20 ꢁC, 4-pentenylamine (179 mg, 70%) was
4.2.13. Ethyl 3-(3-((N-allylacetamido)methyl)-3-benzyl-2-
oxoindolin-1-yl)-2-diazo-3-oxopropanoate (20). To a 50 mL round-
bottomed flask charged with a solution of oxindole 19 (34 mg,
0.10 mmol) in THF (2 mL) at 0 ꢁC was added NaH (60% dispersion in
mineral oil, 10 mg, 0.25 mmol). After stirring for 30 min, ethyl 2-
diazomalonyl chloride (27 mg, 0.15 mmol) was added and the so-
lution was stirred for 1.5 h at 23 ꢁC. The mixture was then quenched
with water and extracted with EtOAc. The combined organic layers
were washed with water, brine, and dried over Na2SO4. After re-
moval of the solvent under reduced pressure, the residue was
subjected to flash silica gel chromatography to furnish 34 mg (72%)
of the title compound as a colorless oil; IR (thin film) 2924, 2140,
obtained as a colorless oil; 1H NMR (600 MHz, CDCl3)
d 1.54
(quin, 2H, J¼7.2 Hz), 2.09 (q, 2H, J¼7.2 Hz), 2.70 (t, 2H, J¼7.2 Hz),
4.97 (dd, 1H, J¼11.4 and 1.2 Hz), 5.03 (dt, 1H, J¼19.2 and 1.8 Hz),
5.78e5.85 (m, 1H).
To a 50 mL round-bottomed flask charged with a solution of
diazo 6 (240 mg, 0.84 mmol) in CH2Cl2 (10 mL) at 23 ꢁC was added
the above amine (143 mg, 1.68 mmol). After stirring for 1 h, the
solvent was removed under reduced pressure, and the residue was
subjected to flash silica gel chromatography to furnish 203 mg
(65%) of the title compound as a pale yellow oil; IR (thin film) 2934,
1741, 1655, and 1480 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d 1.32 (t, 3H,
J¼7.2 Hz), 1.91 (s, 3H), 3.17 and 3.21 (ABq, 2H, JAB¼13.6 Hz),
3.71e3.74 (m, 2H), 3.84 (d, 1H, J¼14.4 Hz), 4.26e4.33 (m, 3H), 4.99
(d, 1H, J¼17.2 Hz), 5.13 (d, 1H, J¼10.4 Hz), 5.58e5.65 (m, 1H),
6.74e6.76 (m, 2H), 7.02e7.11 (m, 3H), 7.18 (td, 1H, J¼7.2 and 1.2 Hz),
7.22e7.24 (m, 1H), 7.39 (app t, 2H, J¼7.6 Hz); 13C NMR (100 MHz,
2141, 1704, 1652, 1577, and 1521 cmꢂ1 1H NMR (600 MHz, CDCl3)
;
d
1.37 (t, 3H, J¼7.2 Hz), 1.71 (quin, 2H, J¼7.2 Hz), 2.15 (q, 2H,
J¼7.2 Hz), 3.41 (t, 2H, J¼7.2 Hz), 4.42 (q, 2H, J¼7.2 Hz), 5.02 (d, 1H,
J¼11.4 Hz), 5.07 (dd, 1H, J¼17.4 and 1.8 Hz), 5.78e5.85 (m, 1H). 7.06
(br s, 1H), 7.18 (t, 1H, J¼7.8 Hz), 7.60 (t, 1H, J¼8.4 Hz), 8.31 (d, 1H,
J¼7.8 Hz), 8.57 (d, 1H, J¼7.8 Hz), 11.64 (br s, 1H); 13C NMR (100 MHz,
CDCl3)
d 14.5, 21.4, 42.9, 50.0, 51.6, 56.3, 62.0, 114.3, 116.7, 124.6,
125.4, 127.2, 128.2, 128.7, 130.2, 132.4, 134.5, 139.6, 159.2, 160.6,
172.3, 177.9, and 180.0; HRMS calcd for [C26H26N4O5þHþ]:
475.1976; found: 475.1967.
CDCl3)
d 14.6, 28.5, 31.2, 39.3, 62.2, 115.8, 121.2, 122.3, 123.2, 134.1,
135.7, 137.5, 140.5, 159.9, 162.3, 163.6, and 190.6; HRMS calcd for
4.2.14. Ethyl
2-acetyl-11b-benzyl-6-oxo-1,2,3,3a,4,5,6,11b-octahy-
[C18H20N4O5þHþ]: 373.1506; found: 373.1499.
dro-3a-1,5-epoxyindolo[3,2,1-ij][1,6]naphthyridine-5-carboxylate
(21). To a 10 mL pressure tube charged with a solution containing
diazo 20 (14 mg, 0.03 mmol) in benzene (2 mL) was added
Rh2(OAc)4 (0.7 mg, 0.0015 mmol). The mixture was heated at reflux
for 2 h. After cooling to room temperature, the reaction mixture
was concentrated under reduced pressure and subjected to flash
silica gel chromatography to furnish 12 mg (89%) of the title com-
pound as a colorless oil with dr¼2:1; IR (thin film) 2928, 1752, 1733,
4.2.16. Ethyl 2-diazo-3-((2-(2-methoxy-2-oxoacetyl)phenyl)-amino)-
3-oxopropanoate (23). To a 10 mL round-bottomed flask charged
with diazo 6 (10 mg, 0.035 mmol) was added methanol (2 mL) at
23 ꢁC. After stirring for 10 min, the solvent was removed under re-
duced pressure, and the title product (12 mg, 99%) was obtained as
a pale yellow oil; IR (thin film) 2964, 2143, 1739, 1705, 1663, and
1558 cmꢂ1; 1H NMR (400 MHz, CDCl3)
d
1.37 (t, 3H, J¼7.2 Hz), 3.97
1652, and 1465 cmꢂ1
;
1H NMR (400 MHz, CDCl3) major isomer
(s, 3H), 4.43 (q, 2H, J¼7.2 Hz), 7.18 (t, 1H, J¼8.0 Hz), 7.64 (t, 1H,
J¼7.2 Hz), 7.70 (dd,1H, J¼8.0 and 1.6 Hz), 8.77 (d,1H, J¼8.8 Hz),11.97
d
1.41 (t, 3H, J¼7.2 Hz), 2.04 (s, 3H), 2.29e2.36 (m, 1H), 2.56e2.66
(m, 2H), 3.09e3.16 (m, 3H), 3.74 (d, 1H, J¼14.0 Hz), 3.83 (dd, 1H,
J¼12.4 and 5.2 Hz), 4.23 (d, 1H, J¼14.0 Hz), 4.39e4.47 (m, 2H), 6.44
(d, 1H, J¼7.2 Hz), 6.85 (d, 1H, J¼6.8 Hz), 6.91 (td, 1H, J¼8.0 and
0.8 Hz), 7.00e7.03 (m, 2H), 7.20e7.25 (m, 3H), 7.38 (dd, 1H, J¼8.0
(br s, 1H); 13C NMR (100 MHz, CDCl3)
d 14.6, 53.0, 62.2, 119.2, 122.2,
123.2, 133.4, 136.5, 141.3, 160.6, 163.0, 164.2, and 188.9; HRMS calcd
for [C14H13N3O6þHþ]: 320.0877; found: 320.0872.
and 4.8 Hz); 13C NMR (100 MHz, CDCl3)
d
14.4, 21.8, 32.5, 38.3, 40.6,
4.2.17. Ethyl 2-diazo-3-((2-(2-ethoxy-2-oxoacetyl)phenyl)-amino)-
3-oxopropanoate (24). To a 10 mL round-bottomed flask charged
with diazo 6 (10 mg, 0.035 mmol) was added ethanol (2 mL) at
23 ꢁC. After stirring for 10 min, the solvent was removed under
reduced pressure, and the title product (12 mg, 99%) was obtained
as a pale yellow oil; IR (thin film) 2990, 2137, 1733, 1698, 1651, and
43.6, 47.6, 48.1, 62.8, 90.4, 103.7, 113.7, 124.4, 125.9, 127.0, 127.1,
128.1, 129.5, 134.6, 134.9, 135.0, 164.2, 164.8, and 170.1; HRMS calcd
for [C26H26N2O5þHþ]: 447.1914; found: 447.1903.
4.2.15. Ethyl 2-diazo-3-oxo-3-((2-(2-oxo-2-(pent-4-en-1-yl-amino)
acetyl)phenyl)amino)propanoate (22). To a 50 mL round-bottomed
1558 cmꢂ1
;
1H NMR (600 MHz, CDCl3)
d
1.37 (t, 3H, J¼7.2 Hz), 1.41

H. Li et al. / Tetrahedron 67 (2011) 9829e9836
9835
(t, 3H, J¼7.2 Hz), 4.41e4.46 (m, 4H), 7.18 (t, 1H, J¼7.8 Hz), 7.63 (t, 1H,
J¼8.4 Hz), 7.70 (dd, 1H, J¼7.8 and 0.9 Hz), 8.77 (d, 1H, J¼8.4 Hz),
11.99 (br s, 1H).
J¼8.0 and 1.2 Hz), 7.46 (td, 1H, J¼8.0 and 1.2 Hz), 7.54 (dd, 1H, J¼7.6
and 0.8 Hz), 7.63 (d, 1H, J¼8.0 Hz); 13C NMR (100 MHz, CDCl3)
d
14.5, 22.5, 23.0, 25.4, 28.0, 38.0, 41.7, 60.6, 62.5, 114.8, 115.3, 124.1,
124.2, 125.2, 126.0, 131.6, 134.4, 139.4, 156.3, 159.9 and 168.4; HRMS
4.2.18. (Z)-3-((2-(cyclohex-1-en-1-yl)ethyl)imino)indolin-2-one
(25). To a 50 mL round-bottomed flask charged with a solution of
isatin (1.0 g, 6.8 mmol) in ethanol (13.6 mL) were sequentially
added 2-(cyclohex-1-en-1-yl)ethanamine (0.95 mL, 6.8 mmol) and
two drops of glacial acetic acid. The mixture was stirred for 4 h at
23 ꢁC. The yellow precipitate was collected by filtration to furnish
calcd for [C22H23N5O4þHþ]: 422.1822; found: 422.1822.
4.2.22. Ethyl 11b-cyano-6-oxo-2,3,4,4a,5,6,11b,12,13,14-decahydro-1H-
5,71-epoxybenzo[d]indolo[3,2,1ij][1,7]naphthyridine-5-carboxylate
(29). To a 10 mL pressure tube charged with a solution containing
diazo 28 (8 mg, 0.02 mmol) in benzene (2 mL) was added Rh2(OAc)4
(0.9 mg, 0.002 mmol). The mixture was heated at reflux for 3 h. After
cooling to room temperature, the reaction mixture was concentrated
under reduced pressure and subjected to flash silica gel chromatog-
raphy to furnish 6.5 mg (83%) of the title compound as a 8:5 dia-
steromeric mixture.
1.26 g (73%) of the title compound as
162e163 ꢁC; IR (thin film) 2924, 1719, 1652, and 1614 cmꢂ1
NMR (400 MHz, CDCl3) 1.56e1.59 (m, 2H), 1.62e1.67 (m, 2H),
a
yellow solid: mp
;
1H
d
2.02e2.04 (m, 4H), 2.59 (t, 2H, J¼8.0 Hz), 4.13 (t, 2H, J¼8.0 Hz), 5.54
(s, 1H), 6.93 (d, 1H, J¼7.6 Hz), 7.08 (t, 1H, J¼7.6 Hz), 7.39 (t, 1H,
J¼8.0 Hz), 7.70 (d, 1H, J¼7.6 Hz), 8.39 (br s, 1H); 13C NMR (100 MHz,
The major and less polar diastereomer is a colorless oil: IR (thin
CDCl3)
d
22.5, 23.1, 25.4, 28.9, 38.9, 53.6, 112.2, 117.3, 122.7, 123.1,
film) 3341, 2924, 1754, 1604, and 1480 cmꢂ1 1H NMR (400 MHz,
;
127.1, 133.6, 136.6, 145.4, 155.0, and 166.1.
CDCl3)
d
1.34 (t, 3H, J¼7.2 Hz), 1.51e1.55 (m, 2H), 1.62e1.64 (m, 2H),
1.76e1.84 (m, 3H), 1.92 (br s, 1H), 2.02e2.06 (m, 2H), 2.14 (dd, 1H,
J¼12.0 and 6.6 Hz), 2.17 (ddd, 1H, J¼13.2, 9.0, and 3.0 Hz), 3.20 (dd,
1H, J¼19.8 and 10.2 Hz), 3.42 (t, 1H, J¼10.8 Hz), 4.29e4.40 (m, 2H),
7.21 (td,1H, J¼7.8 and 1.2 Hz), 7.44 (td, 1H, J¼7.8 and 1.2 Hz), 7.47 (d,
1H, J¼8.4 Hz), 7.51 (d, 1H, J¼7.8 Hz); 13C NMR (150 MHz, CDCl3)
4.2.19. 3-((2-(Cyclohex-1-en-1-yl)ethyl)amino)-2-oxoindoline-3-
carbonitrile (26). To a 10 mL round-bottomed flask charged with
a solution of imine 25 (64 mg, 0.25 mmol) in methanol (5 mL) at
23 ꢁC were sequentially added KCN (17 mg, 0.26 mmol) and HCl
(1.25 M in methanol, 0.4 mL, 0.5 mmol). After stirring for 24 h, the
reaction was quenched with aqueous NaOH (1 N, 2 mL) and
extracted with CH2Cl2. The combined organic layers were washed
with water, brine, and dried over MgSO4. After removal of the
solvent under reduced pressure, the residue was subjected to flash
silica gel chromatography to furnish 35 mg (50%) of the title com-
pound as a pale yellow oil; IR (thin film) 3283, 2925, 1731, 1618, and
d
14.3, 16.1, 18.9, 21.6, 24.9, 27.2, 37.7, 43.6, 49.1, 60.0, 62.6, 92.3,
103.5, 114.6, 115.9, 125.1, 125.6, 130.5, 131.8, 138.4, 164.5, and 165.8;
HRMS calcd for [C22H23N3O4þHþ]: 394.1761; found: 394.1761.
The minor and more polar diastereomer is a colorless oil: IR
(thin film) 3337, 2923, 1752, 1608, and 1480 cmꢂ1
;
1H NMR
(400 MHz, CDCl3)
d
1.13e1.17 (m, 1H), 1.34 (t, 3H, J¼7.2 Hz),
1.36e1.42 (m, 3H), 1.52e1.54 (m, 1H), 1.64e1.66 (m, 1H), 1.81e1.84
(m, 1H), 1.97e2.06 (m, 2H), 2.10e2.13 (m, 1H), 2.22 (dd, 1H, J¼12.6
and 6.0 Hz), 4.09 (ddd, 1H, J¼19.8, 9.0, and 6.6 Hz), 4.25 (dd, 1H,
J¼19.8 and 6.6 Hz), 4.31e4.40 (m, 2H), 7.23 (t, 1H, J¼7.8 Hz), 7.48
(td, 1H, J¼7.8 and 0.6 Hz), 7.59 (d, 1H, J¼7.8 Hz), 7.78 (d, 1H,
1472 cmꢂ1
; d 1.56e1.62 (m, 4H),
1H NMR (300 MHz, CDCl3)
1.91e2.16 (m, 6H), 2.84e2.94 (m, 2H), 5.50 (s, 1H), 6.98 (d, 1H,
J¼7.8 Hz), 7.14 (t, 1H, J¼7.8 Hz), 7.37 (t, 1H, J¼8.0 Hz), 7.45 (d, 1H,
J¼7.2 Hz), 9.09 (br s, 1H); 13C NMR (100 MHz, CDCl3)
d 22.5, 22.9,
25.3, 28.0, 37.9, 41.9, 60.3, 111.5, 116.0, 123.9, 124.2, 125.0, 125.4,
131.4, 134.3, 140.8, and 171.8; HRMS calcd for [C17H19N3OþHþ]:
282.1600; found: 282.1597.
J¼7.2 Hz); 13C NMR (100 MHz, CDCl3)
d14.3, 16.1, 18.9, 21.8, 22.4,
30.4, 39.9, 50.1, 50.9, 62.6, 93.1, 94.3, 103.4, 115.1, 123.2, 125.1, 127.3,
133.2, 145.5, 159.4, 165.0, and 169.8; HRMS calcd for
[C22H23N3O4þHþ]: 394.1761; found: 394.1762.
4.2.20. 1-Acetyl-3-((2-(cyclohex-1-en-1-yl)ethyl)amino)-2-
oxoindoline-3-carbonitrile (27). To a 10 mL round-bottomed flask
charged with a solution of nitrile 26 (6 mg, 0.021 mmol) in CH2Cl2
(2 mL) were sequentially added DMAP (5 mg, 0.042 mmol) and
Acknowledgements
Financial support provided by the National Science Foundation
(CHE-1057350) is greatly appreciated. N.B. thanks the Development
and Promotion of Science and Technology Talent Project (DPST) for
financial support.
Ac2O (2.3 mL, 0.032 mmol). The mixture was stirred for 30 min at
23 ꢁC. After removal of the solvent under reduced pressure, the
residue was subjected to flash silica gel chromatography to furnish
6 mg (88%) of the title compound as a yellow oil; IR (thin film) 2925,
1768, 1719, and 1465 cmꢂ1 1H NMR (300 MHz, CDCl3)
; d 1.61e1.63
(m, 4H), 1.91e2.15 (m, 6H), 2.70 (s, 3H), 2.76e2.90 (m, 2H), 5.49 (s,
1H), 7.32 (t, 1H, J¼8.1 Hz), 7.46e7.52 (m, 2H), 8.28 (d, 1H, J¼9.3 Hz);
References and notes
13C NMR (100 MHz, CDCl3)
d
22.5, 22.9, 25.4, 26.8, 28.0, 37.8, 41.8,
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1.31 (t, 3H, J¼7.2 Hz), 1.54e1.65 (m, 4H), 1.91e2.16 (m, 6H),
2.84e2.89 (m, 2H), 4.23e4.34 (m, 2H), 5.49 (s, 1H), 7.29 (td, 1H,
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d
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