Synthesis of rhazinilam through intramolecular arylcyanation of alkenes catalyzed cooperatively by nickel/aluminum

Article abstract of DOI:10.1016/j.tet.2015.03.012

Intramolecular arylcyanation across a tri-substituted double bond proceeds to give a primary alkyl cyanide product through functionalization of C-CN and allylic C-H bonds and double C-C bond formation in a 1,3-manner by cooperative nickel/AlMe₂

Full text of DOI:10.1016/j.tet.2015.03.012

Tetrahedron xxx (2015) 1e5
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Synthesis of rhazinilam through intramolecular arylcyanation of
alkenes catalyzed cooperatively by nickel/aluminum
,
,
Yuuya Yamada a, Shiro Ebata a, Tamejiro Hiyama a b, Yoshiaki Nakao a
*
a Department of Material Chemistry, Graduate School of Engineering, Kyoto University, Nishikyo-ku, Kyoto 615-8510, Japan
b Research and Development Initiative, Chuo University, Kasuga, Bunkyo-ku, Tokyo 112-8551, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Intramolecular arylcyanation across a tri-substituted double bond proceeds to give a primary alkyl cy-
anide product through functionalization of CeCN and allylic CeH bonds and double CeC bond formation
in a 1,3-manner by cooperative nickel/AlMe2Cl catalysis. The transformation is applied to the synthesis of
rhazinilam, a tubulin-binding alkaloid containing unique structural motifs such as axially chiral biaryl
and strained nine-membered lactam as well as quaternary carbon.
Received 20 January 2015
Received in revised form 2 March 2015
Accepted 3 March 2015
Available online xxx
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
Rhazinilam
Nickel
Aluminum
Carbocyanation
CeC bond activation
1. Introduction
substituted double bond in addition to an expected secondary alkyl
cyanide product as a minor component (Eq. 1). The major product
Activation and functionalization of CeC bonds have gained in-
creasing interest as a novel strategy to streamline organic synthe-
sis.1 Thanks to the development of transition metal catalysis,
a variety of modes for CeC bond cleavage have been introduced to
the synthetic community. Even applications of CeC bond activation
to natural product syntheses have emerged recently.2 Therefore,
the strategies for CeC bond activation have started to show their
potential to innovate retro-synthetic analysis of target molecules as
has also been the case with the recent developments of metal-
catalyzed CeH bond functionalization.3
was likely derived from intramolecular arylnickelation across the
double bond followed by -hydride elimination, reinsertion of the
resulting double bond into NieH, and reductive elimination (vide
infra). This particular transformation represents formally simulta-
neous AreCN and allylic CeH bond functionalizations to result in
double CeC bond formation in a 1,3-manner.
b
Our group has engaged in the field of catalytic CeC bond acti-
vation, focusing our attention particularly on activation of CeCN
bonds of nitriles.4 We have developed CeC bond forming addition
reactions through insertion of unsaturated bonds into CeCN bonds
catalyzed cooperatively by nickel and Lewis acids, namely carbo-
cyanation reaction.5 The transformation allows simultaneous for-
mation of two newly formed CeC bonds with no byproduct
formation, and has been applied to the syntheses of several small
natural products,2a,6 which have particular biological activities.
During our studies on the intramolecular arylcyanation of alkene-
s,2a,7b we observed an intriguing product in the reaction across a tri-
ð1Þ
* Corresponding author. Tel.: þ81 75 383 2443; fax: þ81 75 383 2445; e-mail
address: nakao.yoshiaki.8n@kyoto-u.ac.jp (Y. Nakao).
http://dx.doi.org/10.1016/j.tet.2015.03.012
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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2
Y. Yamada et al. / Tetrahedron xxx (2015) 1e5
The unexpected observation prompted us to imagine its appli-
MeOeC6H4)3 (15 mol %), and AlMe2Cl (10 mol %) in toluene at
100 ꢀC for 8 h proceeded with full conversion of 3 to give 2 in 80%
yield as estimated by GC as well as a small amount of 5 (9%) as
a byproduct (entry 1). The reaction was successfully scaled-up to
give 2 in 81% yield after isolation (entry 2). The use of less
electron-donating triarylphosphine (entry 3) and tri-
alkylphosphine ligands (entries 4e6) was ineffective. Under these
reaction conditions, we rarely observed the formation of second-
ary alkyl cyanide products.
cation to the synthesis of rhazinilam. Rhazinilam was isolated in
1965,8 and its structure was characterized in 1972.9 It has gained
attention of synthetic organic chemists owing to its unique structure
containing axially chiral biaryl, strained nine-membered lactam
structures, and quaternary stereocenter as well as its taxol-like tu-
bulin-binding activity.10 Therefore, several research groups have al-
ready reported its concise synthesis11 including asymmetric one,
taking advantages of modern synthetic methodologies. Our own
synthetic plan set highly substituted pyrrole 1 as a target, which was
reported to be an intermediate of the total synthesis by Nelson and
co-workers (Scheme 1).11f We imagined that 1 could be accessed by
hydrolysis of the cyano group of 2, for which the intramolecular 1,3-
heteroarylcyanation using 2-cyanopyrrole 3 was envisaged. We re-
port herein the successful application of the carbocyanation chem-
istry to the racemic synthesis of rhazinilam.
Table 1
Intramolecular 1,3-heteroarylcyanation of 3 catalyzed by nickel/AlMe2Cl
Entry
Ligand
Time (h)
Yield of 2a (%)
Yield of 5a (%)
1
P(4-MeOeC6H4)3
P(4-MeOeC6H4)3
P(4-F3CeC6H4)3
PMe3
P(c-Hex)3
P(t-Bu)3
8
5
22
22
22
22
80
81c
20
33
6
9
11c
5
4
5
2b
3
4
5
6
<1
<1
a
Estimated by GC.
Reaction run on a 1.0 mmol-scale.
Isolated yield.
b
c
A plausible catalytic cycle of the present transformation is
shown in Scheme 3. The reaction is initiated by the oxidative ad-
dition of the AreCN bond of 3 after
2-coordination to nickel and
1-coordination to aluminum of the cyano group.2a Coordination
followed by migratory insertion of the tri-substituted double bond
gives a secondary alkylnickel intermediate. This then undergoes
h
h
Scheme 1. Synthetic plan for the synthesis of rhazinilam through intramolecular
arylcyanation.
b
-
hydride elimination to give an alkeneenickel complex, from which
reinsertion of the double bond into the NieH bond takes place to
give primary alkylnickel species. CeC bond forming reductive
elimination affords 2 and regenerate catalytically active nickel(0)
and the Lewis acid catalyst upon ligand exchange. Byproduct 5 is
most likely derived from liberation of the alkene ligand before the
reinsertion event.
2. Results and discussion
2.1. Intramolecular 1,3-arylcyanation
A substrate for the key 1,3-arylcyanation reaction was obtained
in a straightforward manner (Scheme 2). Literature precedented
methyl 5-formyl-1H-pyrrole-2-carboxylate12 was treated with hy-
droxylamine and then with phosphorus oxychloride to give methyl
5-cyano-1H-pyrrole-2-carboxylate (4) through the formation of
oxime and the subsequent dehydration. N-Alkylation of the 2,5-
difunctionalized pyrrole with known alkyl tosylate11l containing
a tri-substituted double bond gave the targeted substrate 3.
Scheme 2. Synthesis of starting material 3.
We then briefly investigated the conditions for the intra-
molecular arylcyanation reaction of 3 (Table 1). The reaction of 3
(0.10 mmol) in the presence of Ni(cod)2 (5 mol %), P(4-
Scheme 3. Plausible catalytic cycle.
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Y. Yamada et al. / Tetrahedron xxx (2015) 1e5
3
2.2. Synthesis of rhazinilam
spectrometer with solvent resonance as the internal standard (1H
NMR, CHCl3 at 7.26 ppm; 13C NMR, CDCl3 at 77.0 ppm). 1H NMR data
are reported as follows: chemical shift, multiplicity (s¼singlet,
d¼doublet, t¼triplet, q¼quartet, quint¼quintet, sext¼sextet,
br¼broad, m¼multiplet), coupling constants (Hz), and integration.
Melting points were determined using an OptiMelt MPA100. High-
resolution mass spectra were obtained with a JEOL JMS-700 (EI).
Medium pressure chromatography (MPLC) was performed with
SHOKO Scientific Purif-espoir 2 chromatograph equipped with
Having had key intermediate 2 through the formal simultaneous
CeC and CeH functionalization, subsequent transformations to
access rhazinilam were examined (Scheme 4). The cyano group of 2
was hydrolyzed under basic conditions, and the resulting carbox-
ylic acid was subjected to esterification to give dimethyl ester 1.
Following the procedure reported by Nelson and co-workers with
a slight modification in the final step,11f electrophilic iodination of 1
proceeded regioselectively at the position ortho to the fused alkyl
chain to give 6 in high yield. The SuzukieMiyaura cross-coupling of
6 with 2-aminophenylboronate ester was nicely catalyzed by
a palladium complex ligated by the Buchwald’s SPhos ligand to
provide 7. Intramolecular lactamization was effected by HATU after
hydrolysis of the aliphatic methyl ester moiety and N-deprotection,
giving 8. Hydrolysis of another methyl ester of crude 8 followed by
decarboxylation at high temperature under vacuum11a afforded
racemic rhazinilam.13
Purif-Pack (SHOKO Scientific, 20 mmꢁ60 mm, spherical, 30
mm).
Preparative recycling silica gel chromatography was performed
with a JAI LC-908 chromatograph equipped with COSMOSIL 5SL-II
(Nacalai Tesque, 20 mmꢁ250 mm, spherical, 5
mm). GC analysis was
performed on a Shimadzu GC 2014 equipped with an ENV-1 col-
umn (Kanto Chemical, 0.25 mmꢁ30 m, pressure¼31.7 kPa, detec-
tor¼FID, 290 ꢀC) with helium gas as a carrier. Unless otherwise
noted, commercially available chemicals were used after distilled
and degassed before use. Ni(cod)2 was purchased from STREM and
used without further purification. Anhydrous toluene was pur-
chased from Kanto Chemical, degassed by purging vigorously with
argon for 20 min, and further purified by passage through activated
alumina under positive argon pressure as described by Grubbs and
co-workers.14
3.2. Methyl 5-cyano-1H-pyrrole-2-carboxylate (4)
NH2OH$HCl (0.58 g, 8.4 mmol) and NaOAc (0.63 g, 7.6 mmol)
were added to
a solution of methyl 5-formyl-1H-pyrrole-2-
carboxylate12 (1.14 g, 7.6 mmol) in anhydrous MeOH (8 mL), and
the mixture was heated at the reflux temperature for 1 h. The
resulting solution was quenched with NaHCO3 aq, and the aqueous
layer was extracted with CH2Cl2 for three times. The combined
organic layers were dried over anhydrous MgSO4 and concentrated
in vacuo to give the corresponding aldoxime (1.11 g, <87%). The
crude oxime (5.8 g, 34 mmol) thus obtained was dissolved in an-
hydrous N,N-dimethylformamide (DMF, 28 mL), and the solution
was added dropwise POCl3 (8.4 g, 55 mmol) at ꢂ20 ꢀC. After being
stirred for 30 min at ꢂ20 ꢀC and then at rt for 2 h, the reaction was
quenched with water. The aqueous layer was extracted with CH2Cl2
for three times. The combined organic layers were washed with
water for five times, dried over anhydrous MgSO4, and concen-
trated in vacuo to give the title compound (4.2 g, w71%) as a col-
orless solid (mp¼173.7e174.8 ꢀC), Rf 0.23 (hexane/ethyl
Scheme 4. Synthesis of rhazinilam.
In conclusion, we have demonstrated the synthesis of rhazinilam,
taking advantage of the intramolecular arylcyanation of alkenes
across a tri-substituted double bond to give a primary alkyl cyanide
product having quaternary carbon through formal CeC and CeH
functionalizations and double 1,3-CeC bond formation by co-
operative nickel/aluminum catalysis. Though racemic, this synthesis
shows the power of metal-catalyzed CeC bond activation as an
emerging tool for synthetic organic chemistry. Efforts toward further
developments of CeC and CeH bond functionalizations by co-
operative metal catalysis are currently under investigation.
acetate¼3:1). 1H NMR (400 MHz, CDCl3)
d 9.92 (br, 1H), 6.89 (dd,
J¼3.9, 2.5 Hz, 1H), 6.84 (dd, J¼4.0, 2.6 Hz, 1H), 3.94 (s, 3H); 13C NMR
(101 MHz, CDCl3)
d 160.9, 126.7, 120.1, 115.2, 112.8, 105.7, 52.7;
HRMS (EI) calcd for C7H6N2O2: Mþ, 150.0429. Found: m/z 150.0430.
3.3. (E)-Methyl 5-cyano-1-(4-ethylhex-4-en-1-yl)-1H-pyrrole-
2-carboxylate (3)
A solution of crude 4 (2.3 g, 15.0 mmol) in anhydrous DMF
(15 mL) was added dropwise at 0 ꢀC to a suspension of sodium
hydride (0.38 g 15.0 mmol) in anhydrous DMF (35 mL), and the
mixture was stirred for 1 h before addition of (E)-4-ethylhex-4-en-
1-yl 4-methylbenzenesulfonate11l (3.2 g, 11.5 mmol) at 0 ꢀC. After
being stirred for 12 h at rt, the reaction was quenched with water.
The aqueous layer was extracted with ethyl acetate for three times.
The combined organic layers were washed with water for five
times, dried over anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by MPLC to give the title compound (1.28 g,
43%) as a colorless oil, Rf 0.23 (hexane/ethyl acetate¼20:1). 1H NMR
3. Experimental section
3.1. General
All manipulations of oxygen- and moisture-sensitive materials
were conducted with a standard Schlenk technique or in a dry box
under an argon atmosphere. Medium pressure chromatography
was performed using Kanto Chemical silica gel (spherical,
40e50 mm). Analytical thin layer chromatography (TLC) was per-
formed on Merck Kieselgel 60 F254 (0.25 mm) plates. Visualization
was accomplished with UV light (254 nm) and/or an aq alkaline
KMnO4 solution followed by heating. Proton and carbon nuclear
magnetic resonance spectra (1H NMR and 13C NMR) were recorded
on a Varian Mercury 400 (1H NMR, 400 MHz; 13C NMR, 101 MHz)
(400 MHz, CDCl3)
d
6.89 (d, J¼4.2 Hz, 1H), 6.73 (d, J¼4.2 Hz, 1H),
5.20 (q, J¼6.7 Hz, 1H), 4.46 (t, J¼7.6 Hz, 2H), 3.86 (s, 3H), 2.05 (q,
J¼7.4 Hz, 4H), 1.94e1.82 (m, 2H), 1.58 (d, J¼6.8 Hz, 3H), 0.95 (t,
J¼7.6 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 160.2, 140.0, 126.2,118.8,
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4
Y. Yamada et al. / Tetrahedron xxx (2015) 1e5
118.1, 117.2, 112.7, 110.1, 51.8, 48.2, 33.3, 29.8, 22.6, 13.0, 12.7; HRMS
1.9 mmol) in anhydrous CHCl3 (55 mL) at 0 ꢀC. After being stirred at
rt for 16 h, the reaction was quenched with satd Na2S2O5 aq The
aqueous layer was extracted with ethyl acetate for three times. The
combined organic layers were washed with satd NaHCO3 aq and
brine, dried over anhydrous MgSO4, and concentrated in vacuo. The
residue was purified by MPLC to give the title compound (0.76 g,
96%) as a colorless oil, Rf 0.11 (hexane/ethyl acetate¼10:1). 1H NMR
(EI) calcd for C15H20N2O2: Mþ, 260.1525. Found: m/z 260.1516.
3.4. Intramolecular heteroarylcyanation of 3 catalyzed by
nickel/AlMe2Cl
To
a solution of Ni(cod)2 (13.8 mg, 50 mmol) and P(4-
MeOeC6H4)3 (53 mg, 0.15 mmol) dissolved in toluene (1.0 mL)
prepared in a 3 mL vial in a dry box were added 3 (0.26 g,1.0 mmol),
a 1.04 M solution of AlMe2Cl in hexane (96 mL, 0.10 mmol), and
undecane (internal standard, 57 mg, 0.33 mmol) sequentially. The
vial was sealed with a screw-cap, taken outside the dry box, and
heated at 100 ꢀC for 5 h. The resulting mixture was filtered through
a silica gel pad, and then concentrated in vacuo. The residue was
purified by MPLC to give 2 (0.21 g, 81%) and 5 (26 mg, 11%).
(400 MHz, CDCl3)
d
7.09 (s,1H), 4.40 (dt, J¼13.5, 5.8 Hz,1H), 4.26 (dt,
J¼13.5, 7.0 Hz, 1H), 3.77 (s, 3H), 3.65 (s, 3H), 2.68e2.53 (m, 1H),
2.27e2.00 (m, 3H), 1.98e1.49 (m, 6H), 0.80 (t, J¼7.5 Hz, 3H); 13C
NMR (101 MHz, CDCl3) d 174.0, 160.6, 139.9, 126.9, 122.6, 57.8, 51.7,
51.1, 46.1, 39.4, 33.2, 31.4, 29.7, 28.5, 20.3, 8.6. 1H NMR and 13C NMR
spectra were identical to those reported in the literature.11f
3.7. Methyl 1-{2-[(tert-butoxycarbonyl)amino]phenyl-8-
ethyl-8-(3-methoxy-3-oxopropyl)-5,6,7,8-
3.4.1. Methyl 8-(2-cyanoethyl)-8-ethyl-5,6,7,8-tetrahydroindolizine-
tetrahydroindolizine-3-carboxylate (7)11f
3-carboxylate (2). A colorless oil, Rf 0.23 (hexane/ethyl
acetate¼3:1). 1H NMR (400 MHz, CDCl3)
d
6.94 (d, J¼4.0 Hz, 1H),
Pd2(dba)3 (3.3 mg, 3.7
dimethoxybiphenyl (SPhos, 6.0 mg, 14.6
(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate
(93 mg, 0.29 mmol) were placed in a 15 mLevial. The vial was
transferred into a dry box, and K3PO4 (0.12 g, 0.58 mmol) and
m
mol), 2-dicyclohexylphosphino-20,60-
mol), and tert-butyl-N-[2-
5.90 (d, J¼4.0 Hz, 1H), 4.37e4.23 (m, 2H), 3.78 (s, 3H), 2.26e2.17 (m,
m
2H), 2.06e2.00 (m, 4H),1.81e1.68 (m, 4H), 0.83 (t, J¼7.5 Hz, 3H); 13
C
NMR (101 MHz, CDCl3)
d 161.6, 140.8, 121.1, 120.0, 117.6, 105.7, 50.9,
45.1, 38.3, 35.7, 33.3, 28.7, 19.8, 12.8, 8.4; HRMS (EI) calcd for
C
15H20N2O2: Mþ, 260.1525. Found: m/z 260.1524.
a 0.90 M solution of 6 in THF (163 mL, 0.15 mmol) were added se-
quentially to the vial. The vial was sealed with a screw-cap, and
taken outside the dry box. To the vial were added THF (5.8 mL) and
degassed water (1.5 mL). After being stirred at rt for 1 h and then at
40 ꢀC for 40 h, the reaction was quenched with satd NH4Cl aq. The
aqueous layer was extracted with ethyl acetate for three times. The
combined organic layers were washed with satd NaHCO3 aq, dried
over anhydrous MgSO4, and concentrated in vacuo. The residue was
purified by MPLC to give the title compound (49 mg, 69%) as a 3:2
mixture of rotamers as a brownish oil, Rf 0.18 (hexane/ethyl
3.4.2. Methyl 8-ethyl-8-vinyl-5,6,7,8-tetrahydroindolizine-3-
carboxylate (5). A colorless oil, Rf 0.46 (hexane/ethyl
acetate¼10:1). 1H NMR (400 MHz, CDCl3)
d
6.97 (d, J¼4.0 Hz, 1H),
5.97 (d, J¼4.0 Hz,1H), 5.83 (dd, J¼17.3,10.5 Hz,1H), 5.04 (dd, J¼10.4,
0.7 Hz,1H), 4.72 (dd, J¼17.3, 0.8 Hz,1H), 4.58 (dt, J¼13.7, 4.5 Hz,1H),
4.05e3.94 (m, 1H), 3.78 (s, 3H), 2.13e1.84 (m, 2H), 1.79e1.67 (m,
4H), 0.85 (t, J¼7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 161.7, 145.2,
141.6, 120.5, 117.5, 113.9, 106.5, 50.8, 45.5, 43.1, 33.8, 28.8, 19.5, 8.5;
HRMS (EI) calcd for C14H19NO2: Mþ, 233.1416. Found: m/z 233.1415.
acetate¼5:1). 1H NMR (400 MHz, CDCl3)
d
8.17 (d, J¼9.0 Hz, 0.4H),
8.09 (d, J¼8.2 Hz, 0.6H), 7.30 (t, J¼7.4 Hz, 1H), 7.12 (d, J¼7.3 Hz, 1H),
6.96 (t, J¼7.4 Hz, 1H), 6.81 (s, 0.4H), 6.80 (s, 0.6H), 6.44 (s, 0.4H),
6.31 (s, 0.6H), 4.54e4.40 (m, 1H), 4.38e4.21 (m, 1H), 3.80 (s, 3H),
3.63 (s, 1.8H), 3.56 (s, 1.2H), 2.32e1.22 (m, 19H), 0.82e0.67 (m, 3H);
3.5. Methyl 8-ethyl-8-(3-methoxy-3-oxopropyl)-5,6,7,8-
tetrahydroindolizine-3-carboxylate (1)11f
A solution of 2 (0.21 g, 0.81 mmol) and KOH (1.2 g, 21.4 mmol) in
MeOH (1.8 mL) and water (2.4 mL) was heated at the reflux tem-
perature for 16 h. After being cooled at 0 ꢀC, the resulting solution
was acidified with 1 M HCl aq, and the aqueous layer was extracted
with CH2Cl2 for three times. The combined organic layers were dried
over anhydrous MgSO4 and concentrated until the volume became
about 3 mL. The residue and N,N0-dicyclohexylcarbodiimide (0.67 g,
3.2 mmol) were sequentially added to a solution of N,N-dimethyl-4-
aminopyridine (15 mg, 0.12 mmol) in anhydrous CH2Cl2 (10.8 mL)
and anhydrous MeOH (3.6 mL) at rt under an argon atmosphere.
After being stirred at rt for 21 h, the resulting solution was diluted
with water. The aqueous layer was extracted with CH2Cl2 for three
times. The combined organic layers were dried over anhydrous
MgSO4 and concentrated in vacuo. The residue was purified by MPLC
to give the title compound (0.13 g, 53%) as a colorless oil, Rf 0.21
13C NMR (101 MHz, CDCl3)
d 173.7, 173.6, 161.5, 161.4, 152.44, 152.37,
139.9, 139.4, 137.2, 131.2, 131.1, 128.53, 128.49, 125.5, 125.3, 121.8,
121.6, 120.8, 120.1, 119.9, 118.2, 117.9, 116.2, 116.0, 80.3, 51.6, 51.0,
45.8, 45.7, 40.1, 35.7, 34.0, 33.6, 33.3, 30.2, 29.9, 29.7, 28.8, 28.30,
28.26, 28.21, 21.0, 20.4, 9.4, 9.1. 1H NMR and 13C NMR spectra were
identical to those reported in the literature.11f
3.8. Rhazinilam11f
Ba(OH)2$8H2O (1.5 g, 4.9 mmol) was added to a solution of 7
(94 mg, 0.19 mmol) in MeOH. After being stirred at rt for 2 h, the
solution was acidified with 1 M HCl aq The aqueous layer was
extracted with ethyl acetate for three times. The combined organic
layers were washed with water, dried over anhydrous MgSO4, and
concentrated in vacuo. The residue was dissolved in CH2Cl2 (3.0 mL)
and trifluoroacetic acid (6.1 mL), and the mixture was stirred at rt
for 1 h before concentration in vacuo to give a brown oil. The crude
product was dissolved in anhydrous CH2Cl2 (23 mL) and added
dropwise over 17 h to a stirred solution of O-(7-azabenzotiazol-1-
yl)-N,N,N0,N0-tetramethyluronium hexafluorophosphate (HATU,
0.22 g, 0.58 mmol) and N,N0-diisopropylethylamine (0.13 g,
0.97 mmol) in anhydrous DMF (38 mL) and CH2Cl2 (15 mL). After
being stirred at rt for additional 4 h, the resulting solution was
diluted with water. The aqueous layer was extracted with ethyl
acetate for three times. The combined organic layers were washed
with 1 M HCl aq, 1 M NaOH aq, brine, and NaHCO3 aq, dried over
anhydrous MgSO4, and concentrated in vacuo. The residue was
passed through MPLC to give crude 8 (55 mg, w81%). Crude 8
(hexane/ethyl acetate¼5:1). 1H NMR (400 MHz, CDCl3)
d 6.93 (d,
J¼4.0 Hz, 1H), 5.92 (d, J¼4.2 Hz, 1H), 4.29 (t, J¼6.2 Hz, 2H), 3.77 (s,
3H), 3.63 (s, 3H), 2.32e2.10 (m, 2H), 2.05e1.85 (m, 4H),1.76e1.49 (m,
4H), 0.82 (t, J¼7.4 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d 174.2, 161.7,
142.6, 120.5, 117.6, 105.8, 51.6, 50.8, 45.1, 38.0, 34.9, 33.5, 29.6, 29.0,
19.9, 8.5. 1H NMR and 13C NMR spectra of the title compound were
identical to those reported in the literature.11f
3.6. Methyl 8-ethyl-1-iodo-8-(3-methoxy-3-oxopropyl)-
5,6,7,8-tetrahydroindolizine-3-carboxylate (6)11f
Silver trifluoroacetate (0.50 g, 2.3 mmol) and iodine (0.58 g,
2.3 mmol) were added sequentially to a solution of 1 (0.55 g,
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Y. Yamada et al. / Tetrahedron xxx (2015) 1e5
5
Berlin, Germany, 2014; Vol. 346; (e) Chen, F.; Wang, T.; Jiao, N. Chem. Rev. 2014,
114, 8613.
dissolved in MeOH (6.0 mL) and 50% NaOH aq (1.8 mL) was heated
at 50 ꢀC for 40 min. The solution was acidified with 1 M HCl aq, and
the aqueous layer was extracted with ethyl acetate for three times.
The combined organic layers were dried over MgSO4 and
concentrated. The residue was heated at 290 ꢀC for 30 min un-
der 1.5 Torr, and the volatiles were collected. The collected solid
was purified by MPLC to give rhazinilam (23 mg, 40%) as a white
solid, Rf 0.18 (hexane/ethyl acetate¼1:2). 1H NMR (400 MHz, CDCl3)
2. (a) Nakao, Y.; Ebata, S.; Yada, A.; Hiyama, T.; Ikawa, M.; Ogoshi, S. J. Am. Chem.
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d
7.43 (dd, J¼7.4, 1.7 Hz, 1H), 7.34 (td, J¼7.5, 1.9 Hz, 1H), 7.30 (td,
J¼7.3, 1.6 Hz, 1H), 7.20 (dd, J¼7.3, 1.0 Hz, 1H), 6.67 (br s, 1H), 6.51 (d,
J¼2.9 Hz, 1H), 5.75 (d, J¼2.7 Hz, 1H), 4.01 (dd, J¼12.1, 5.2 Hz, 1H),
3.79 (td, J¼12.2, 4.8 Hz, 1H), 2.46 (t, J¼12.8 Hz, 1H), 2.37 (t,
J¼12.9 Hz, 1H), 2.30e2.14 (m, 1H), 2.05e1.91 (m, 1H), 1.86 (dt,
J¼13.7, 2.3 Hz, 1H), 1.72 (td, J¼13.4, 3.2 Hz, 1H), 1.58e1.38 (m, 3H),
1.36e1.17 (m, 1H), 0.72 (t, J¼7.5 Hz, 3H); 13C NMR (101 MHz, CDCl3)
d
177.3, 140.4, 138.0, 131.4, 130.5, 128.0, 127.2, 126.8, 119.1, 117.3,
109.5, 46.0, 38.8, 36.6, 33.0, 30.1, 28.1,19.4, 8.1. 1H NMR and 13C NMR
spectra were identical to those reported in the literature.11f
Acknowledgements
This work has been supported financially by Grant-in-Aid for
Scientific Research on Innovative Areas ‘Molecular Activation Di-
rected toward Straightforward Synthesis’ (no. 22105003) from
Ministry of Education, Culture, Sports, Science, and Technology and
The Asahi Glass Foundation.
12. Schmuck, C.; Bickert, V.; Merschky, M.; Geiger, L.; Rupprecht, D.; Dudaczek, J.;
Wich, P.; Rehm, T.; Machon, U. Eur. J. Org. Chem. 2008, 324.
13. Attempted decarboxylation under acidic conditions demonstrated by Nelson
and co-workers (Ref. 11f) resulted in lower conversion in our hands.
14. Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.; Timmers, F. J.
Organometallics 1996, 15, 1518.
References and notes
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Please cite this article in press as: Yamada, Y.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.03.012