Synthesis and unexpected oxidization of the tricyclic core of ugibohlin, isophakellin, and styloguanidine

Article abstract of DOI:10.1021/jo401911a

A series of 4-substituted 5,6,7,9-tetrahydropyrrolo[2,3-f]indolizin-9-ones, representing the tricyclic core skeleton of ugibohlin, isophakellin, and styloguanidine, were synthesized via an intramolecular Vilsmeier-Haack reaction. This reaction allows the chemoselective C-C bond formation between the pyrrole C3 and proline C5 of N-[(pyrrol-2-yl)carbonyl]prolinamides to construct the B-ring without the protection of the pyrrole nitrogen. Unexpected oxidizative property of the tricyclic core skeleton was observed, which could illuminate understanding of the biological formation of these marine secondary metabolites.

Full text of DOI:10.1021/jo401911a

Article
pubs.acs.org/joc
Synthesis and Unexpected Oxidization of the Tricyclic Core of
Ugibohlin, Isophakellin, and Styloguanidine
Chia-Wei Chang, Chi-Cheng Wu, Yung-Yu Chang, Chia-Chi Lin, and Tun-Cheng Chien*
Department of Chemistry, National Taiwan Normal University, Taipei 11677, Taiwan
S
* Supporting Information
ABSTRACT: A series of 4-substituted 5,6,7,9-tetrahydro-
pyrrolo[2,3-f ]indolizin-9-ones, representing the tricyclic core
skeleton of ugibohlin, isophakellin, and styloguanidine, were
synthesized via an intramolecular Vilsmeier−Haack reaction.
This reaction allows the chemoselective C−C bond formation
between the pyrrole C3 and proline C5 of N-[(pyrrol-2-
yl)carbonyl]prolinamides to construct the B-ring without the
protection of the pyrrole nitrogen. Unexpected oxidizative
property of the tricyclic core skeleton was observed, which
could illuminate understanding of the biological formation of
these marine secondary metabolites.
challenging synthesis of palau’amine has recently been disclosed
INTRODUCTION
■
in the literature.11 Nevertheless, the synthesis toward
ugibohlin12 (3) and dibromoisophakellin10,12 (2) was achieved
only from the chemical conversion of the presynthesized
dibromophakellin. Moreover, the total synthesis of styloguani-
dine (1) remains intangible. Since ugibohlin (3), dibromoiso-
phakellin (2) and styloguanidine (1) all possess the same
tricyclic core structure (Figure 1), the formation of the tricyclic
A−B−C ring skeleton could be a common approach for the
synthesis of these marine natural products.
A variety of structurally novel secondary metabolites from
marine sponges have been identified to contain pyrrole and
pyrrolidine ring units.1 The most intriguing molecules in this
family are the isomeric hexacyclic palau’amine2,3 and
styloguanidine3,4 (1). Their A−B−C−D ring units are identical
to dibromophakellin5 and dibromoisophakellin (cantharelline)6
(2), respectively. In addition, ugibohlin7 (3) is the D-ring seco-
isomer of dibromoisophakellin (2) with an aromatized B-ring
(Figure 1). These marine alkaloids exhibit interesting biological
The tricyclic core structure simply consists of pyrrole-2-
carboxylic acid and proline skeletons as ring A and C
counterparts, respectively. The retrosynthetic analysis, de-
lineated in Scheme 1, suggested that the construction of the
tricyclic core could be attained by the N-acylation of the proline
derivatives with pyrrole-2-carboxylic acid followed by the C−C
Scheme 1. Retrosynthetic Analysis of the Tricyclic Core
Figure 1. Marine natural products possessing tetrahydropyrrolo[2,3-
f ]indolizin-9-one core structure.
properties such as antitumor activities, substantial immunosup-
pressive activities, and low toxicities.8 The biological profiles
combined with their characteristic structural motifs have made
these alkaloids attractive targets for total synthesis.
To date, the total synthesis of phakellin has been
Received: August 28, 2013
accomplished by several research groups.9,10 Even the
© XXXX American Chemical Society
A
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bond formation between pyrrole ring-carbon (C3) and proline
carbonyl carbon (C5). Although numerous methods have been
developed, the electrophilic aromatic substitution is still one of
the most promising reactions for the C−C bond formation at
pyrrole ring carbons. Hence, the acid-promoted electrophilic
aromatic substitution reaction, Friedel−Crafts acylation, and
Vilsmeier−Haack reaction should be the most applicable
methods for the preparation of various tricyclic A−B−C ring
precursors.
RESULTS AND DISCUSSIONS
■
The N-[(pyrrol-2-yl)carbonyl]prolinamide substrates for the
intramolecular Vilsmeier−Haack reaction were prepared by two
different routes. N-[(1-Methylpyrrol-2-yl)carbonyl]proline16
(5b), readily prepared from commercially available 1-
methylpyrrole and proline, as the acid component was reacted
with a series of primary and secondary amines in the presence
of EDC and HOBt to afford the corresponding N-[(1-
methylpyrrol-2-yl)carbonyl]prolinamides (8a−h) (Scheme 4).
From a literature survey, Al-Mourabit13 and Lindel14 both
demonstrated that the acid-promoted electrophilic aromatic
substitution of N-[(pyrrol-2-yl)carbonyl]pyrrolidine-2-carbalde-
hydes effectively afforded the tricyclic pyrrolo[2,3-f ]indolizine
skeleton (Scheme 2). But their further elaboration at the C4-
and C4a-positions of the pyrroloindolizine achieved only
limited success.
Scheme 4. Preparation of N-[(1-Methylpyrrol-2-
a
yl)carbonyl]prolinamides (8)
Scheme 2. Previous Works by Al-Mourabit13 and Lindel14
a
Reagents and conditions: (a) R2R3NH, EDC, HOBt, Et3N, CH2Cl2,
rt.
Our study focused on the construction of the tricyclic core
and the introduction of functionality at the 4-position on the B
ring. In our initial investigation, we recognized that the 4-
hydroxy-tricyclic A−B−C ring (7a,b) could be presented as its
tautomeric keto form, and retrosynthetic disconnection
between C-3a and C-4 would provide N-[(pyrrol-2-yl)-
carbonyl]proline derivatives (5a,b, 6a,b) as the ring A−C
adducts (Scheme 3). The C−C bond formation between the
The same approach, however, failed to yield the pyrrole-N-
unsubstituted N-[(pyrrol-2-yl)carbonyl]prolinamides (9a−f).
Alternatively, a series of prolinamides (12a−f), prepared from
N-Boc-proline (10), were coupled with pyrrole-2-carboxylic
acid (13) to form the desired pyrrole-N-unsubstituted N-
[(pyrrol-2-yl)carbonyl]prolinamides (9a−f) (Scheme 5).
Scheme 5. Preparation of N-[(Pyrrol-2-
yl)carbonyl]prolinamides (9)
a
Scheme 3. Unsuccessful Attempts by Friedel−Crafts
Cyclization
a
Reagents and conditions: (a) R2R3NH, EDC, HOBt, Et3N, CH2Cl2, 0
°C to rt; (b) aq. HCl/1,4-dioxane, rt; (c) EDC, HOBt, Et3N, CH2Cl2,
0 °C to rt.
pyrrole C3 and the proline C5 was originally anticipated to be
accomplished by Friedel−Crafts acylation reaction. However,
attempts to promote the intramolecular Friedel−Crafts
acylation of the ring A−C adducts (5a,b, 6a,b)13,15,16 by
various Lewis acids or activating agents were all unsuccessful,
which prompted us to investigate other strategies for the ring
construction. We report herein the concise synthesis of the
tricyclic core structure from pyrrole-2-carboxylic acid and
proline via the Vilsmeier−Haack reaction as the key-step
reaction and the unexpected oxidizative property of the
pyrrolo[2,3-c]pyridin-7-one (the A−B ring).
In the initial trials, N-[(1-methylpyrrol-2-yl)carbonyl]proline
dimethylamide (8a) was chosen as a model compound to
explore the reaction conditions for the Vilsmeier−Haack
cyclization. Using a conventional approach, the dimethylamide
8a was reacted with phosphorus oxychloride in acetonitrile at
65 °C, and the reaction proceeded to give 31% of the product
14a, which was identified as the desired tricyclic adduct (entry
6 in Table 1). The preliminary success has confirmed that the
Vilsmeier−Haack reaction is amenable for the construction of
the tetrahydropyrrolo[2,3-f ]indolizin-9-one ring with a dime-
thylamino substituent at the C4-position. Subsequently, various
B
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Table 1. Optimization for the Vilsmeier−Haack Cyclization
Table 2. Vilsmeier−Haack Cyclization of Dialkylamides 8a−
d and 9a−d
base
temperature
time
a
yield
b
entry reactant (2 equiv)
solvent
(°C)
(h)
(%)
1
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
9a
9a
9a
9a
9a
9a
9a
9a
CH2Cl2
CH2Cl2
THF
reflux
reflux
reflux
reflux
rt
24
24
8
39
21
59
15
4
2
NMM
NMM
3
4
THF
8
5
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH2Cl2
THF
36
2
6
65
31
c
7
K2CO3
DIPEA
DBU
65
2
N.D.
11
8
65
3
9
65
3
47
10
11
12
13
14
15
16
17
18
19
20
21
Et3N
65
3
59
NMM
NMM
NMM
65
2
68
a
Condition A: POCl3 (3 equiv), NMM (2 equiv), CH3CN, 65 °C.
45
24
2
71
b
Condition B: POCl3 (3 equiv), THF, reflux. The reaction time was
reflux
reflux
rt
57
determined by TLC analysis based on the complete consumption of
3
39
c
d
e
the reactant. Isolated yields. Table 1, entry 11. Table 1, entry 16.
24
3
36
THF
reflux
reflux
85
58
hydroxy ketones (16, 1713 in Table 3), which were purified and
characterized by spectroscopic analysis. The α-hydroxy ketones
c
c
NMM
THF
3
N.D.
39
DME
3
CH3CN
CH3CN
CH3CN
45
3
35
Table 3. Vilsmeier−Haack Cyclization of Monoalkylamides
8e−h and 9e,f
65
3
53
NMM
65
3
N.D.
a
The reaction time was determined by TLC analysis based on the
b
c
complete consumption of the reactant (8a, 9a). Isolated yields. N.D.
= no desired product.
conditions including different base, solvent, temperature, time
and the amount of the reagents were screened in order to
optimize the cyclization reaction (Table 1). The optimum
condition was to carry out the reaction with 3 equiv of POCl3
and 2 equiv of N-methylmorpholine (NMM) in CH3CN at 65
°C, and the reaction could be completed within 2 h (entry 11 in
Table 1). However, when this condition was applied to the
pyrrole-N-unsubstituted N-[(pyrrol-2-yl)carbonyl]proline di-
methylamide (9a), the reaction did not result in any desired
product. Thus, the reaction conditions were screened again,
and the best cyclization condition for 9a was to carry out the
reaction with 3 equiv of POCl3 in THF at reflux for 3 h (entry
16 in Table 1). It is noteworthy that the ring closure took place
chemoselectively at the C3-position of pyrrole (C3−C5′ bond
formation) regardless the pyrrole nitrogen has a substituent.
With the optimized conditions in hand, a series of N-
[(pyrrol-2-yl)carbonyl]proline dialkylamides (8a−d, 9a−d)
were subjected to the Vilsmeier−Haack cyclization conditions,
and the corresponding 4-dialkylamino-substituted 5,6,7,9-
tetrahydropyrrolo[2,3-f ]indolizin-9-ones (14a−d, 15a−d)
were obtained in good yields (Table 2). When the
Vilsmeier−Haack cyclization conditions were applied to N-
[(pyrrol-2-yl)carbonyl]proline monoalkyl amides (8e−h, 9e,f),
the initially formed products from individual reactions were
observed on the TLC plates after workup. However, attempts
to purify these products by flash column chromatography were
unsuccessful, but all the initial products from individual
reactions were converted to the same oxidized products, α-
a
b
c
entry reactant
R2
condition
time (h) product(s) (yield, %)
1
2
3
4
5
6
8e
8f
Me
Allyl
Bu
A
A
A
A
B
B
9
16 (59)
21
3
16 (3) + 18 (15)
16 (29)
8g
8h
9e
9f
Bn
5.5
12
14
16 (21)
Me
Allyl
17 (24)
17 (21) + 19 (7)
a
Condition A: POCl3 (3 equiv), NMM (2 equiv), CH3CN, 65 °C.
Condition B: POCl3 (3 equiv), THF, reflux. The reaction time was
determined by TLC analysis based on the complete consumption of
b
c
the reactant. Isolated yields.
(16, 17) have a higher oxidation state than the natural products
at C4-carbon. Attempts to reduce the α-hydroxy ketones (16,
17) to the dihydroxyl functionality were unsuccessful.
The conversion of the initial products, which might be the
desired cyclized products, into the oxidized adducts likely
involved an autoxidation after the Vilsmeier−Haack cyclization.
The unexpected oxidation prompted us to examine the reaction
more closely. When N-allylamides of N-[(pyrrol-2-yl)-
carbonyl]prolines (8f, 9f) were subjected to the Vilsmeier−
Haack cyclization conditions, 4a-allyl-4,4a,5,6,7,9-hexahydro-
pyrrolo[2,3-f ]indolizine-4,9-diones (18, 19) were obtained
C
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accompanied with the α-hydroxy ketones (16, 17). We
rationalized that the α-allyl ketone byproducts (18, 19) were
resulted from the aza-Claisen rearrangement of the allylamino
adducts (14f, 15f) followed by hydrolysis of the imine
intermediates (20, 21). This sequence of putative reactions
provided evidence for the formation of the desired products
from the Vilsmeier−Haack cyclization (Scheme 6).
system, N-methylpyrrole-2-carboxylic acid (23) was coupled
with N-benzylglycine methyl ester, and the resulting ester 24
was saponified followed by coupling with dimethylamine
hydrochloride to afford N-benzyl-N-[(pyrrol-2-yl)carbonyl]-
glycine dimethylamide (26). The dimethylamide substrate 26
was subjected to the Vilsmeier−Haack cyclization condition,
1
and the H NMR analysis suggested that the initial product
obtained from the reaction immediately after column
chromatography was 1-methyl-4-dimethylamino-6-benzyl-
pyrrolo[2,3-c]pyridin-7-one (27). However, upon exposure to
the air for a short period of time, the cyclized adduct 27 was
oxidized into the corresponding pyrrolo[2,3-c]pyridine-4,5,7-
trione 28,17 the structure of which was confirmed by X-ray
crystallographic analysis (Scheme 8). It is notable that even
Scheme 6. Mechanism for the Formation of the α-Allyl
Ketones 18 and 19
Scheme 8. Synthesis and Oxidation of 4-Amino-Substituted
a
Pyrrolo[2,3-c]pyridin-7-one
Meanwhile, the crude mixture obtained from the reaction of
N-[(1-methylpyrrol-2-yl)carbonyl]proline butylamide (8g)
after workup was immediately subjected to mass spectrometric
analysis in order to gain insight into the reaction details. The
molecular ion (M+, m/z = 259) for the expected Vilsmeier−
Haack cyclization adduct was observed if the crude mixture was
immediately preserved under argon. Upon exposure to air for
an extended time, the appearance of the predominant M+32
ion (m/z = 291), corresponding to a hydroperoxide (22a) or a
dioxetane (22b) intermediate, reflected the immediate
autoxidation of the Vilsmeier−Haack cyclization product. The
hydroperoxide 22b was degraded in the slightly acidic silica gel
column to form the oxidized product 16 (Scheme 7).
a
Reagents and conditions: (a) EDC, HOBt, Et3N, CH2Cl2, rt, 18 h;
(b) (i) aq. NaOH/MeOH, reflux, 3 h; (ii) HCl; (c) Me2NH.HCl,
EDC, HOBt, Et3N, CH2Cl2, rt, 18 h; (d) POCl3, NMM, CH3CN, 65
°C, 20 h, 37% for 28 (from 26).
though the tricyclic 4-diakylamino-substituted tetrahydro-
pyrrolo[2,3-f ]indolizin-9-ones (14a−d, 15a−d) were stable
enough to be purified and characterized, a gradual oxidative
degradation of 14a−d and 15a−d into 16 and 17, respectively,
and other unidentified decomposition products was observed in
a prolonged time period.
To further clarify the role of the 4-amino-substituents in the
autoxidation, the 4-unsubstituted tetrahydropyrrolo[2,3-f ]-
indolizin-9-one 29 was prepared by adopting Lindel’s
approach.14 N-[(1-Methylpyrrol-2-yl)carbonyl]proline methyl
ester 5a was first reduced by lithium borohydride and then
oxidized by IBX18 to form the corresponding aldehyde 5d.
Subsequently, the acid-promoted electrophilic ring-closure
afforded the 4-unsubstituted tricyclic core skeleton 29. Unlike
the 4-amino-substituted congeners, the 4-unsubstituted tricyclic
core 29 shows substantial stability under aerobic conditions.
Therefore, the electron-donating character of the 4-amino-
substituents is responsible for the unexpected aerobic oxidation
of the pyrrolo[2,3-c]pyridin-7-one heterocycle. Furthermore,
attempts to carry out the dihydroxylation and epoxidation13 at
the C4−C4a double bond of the tricyclic core 29 were
unsuccessful, but interestingly, both resulted in the formation of
the α-hydroxyketone adduct 16 (Scheme 9).
We postulated that the unexpected oxidization was attributed
to the oxidizable tendency of the A−B ring unit. Thus, we
embarked on the synthesis of the A−B ring unit in order to test
whether the amino-substituted pyrrolo[2,3-c]pyridine-7-one
would be aerobically oxidizable. Analogous to the tricyclic
Scheme 7. Mechanism for the Formation of the α-Hydroxy
Ketones 16 and 17
CONCLUSION
■
In summary, we have developed a facile and practical synthesis
for the tricyclic core skeleton, tetrahydropyrrolo[2,3-f ]-
indolizin-9-one, of ugibohlin, isophakellin, and styloguanidine
via an intramolecular Vilsmeier−Haack reaction. Our inves-
tigation also revealed that the nitrogen-substituent at the 4-
D
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125.7, 126.7 (CH), 161.7, 172.0; MS (EI, 20 eV) m/z 108 (52), 177
(100), 249 (20) (M+); HRMS (EI, magnetic sector) calcd for
C13H19N3O2 249.1477, found 249.1485.
Scheme 9. Synthesis and Oxidation of the 4-Unsubstituted
Tetrahydropyrrolo[2,3-f]indolizin-9-one (29)
a
N-[(1-Methylpyrrol-2-yl)carbonyl]proline diethylamide (8b).
Compound 8b was prepared from 5b by the method described for 8a.
The reaction was purified by flash column chromatography (Hex/
1
EtOAc = 4:6, Rf = 0.1) to give 8b (oil, 1.0546 g, 95%): H NMR
(CDCl3, 400 MHz) δ 0.83−0.95 (m, 3 H), 1.07−1.25 (m, 3 H), 1.84−
1.90 (m, 2 H), 2.02−2.08 (m, 1 H), 2.10−2.18(m, 1 H), 3.12−3.23
(m, 1 H), 3.23−3.26 (m, 1 H), 3.31−3.33 (m, 1 H), 3.43−3.56 (m, 1
H), 3.76−3.81 (m, 5 H), 4.91 (bs, 1 H), 6.01 (bs, 1 H), 6.53 (bs, 1 H),
6.60 (bs, 1 H); 13C NMR (CDCl3, 100 MHz) δ 12.8 (CH3), 14.5
(CH3), 25.3 (CH2), 29.2 (CH2), 36.1 (CH3), 40.6 (CH2), 41.8 (CH2),
50.0 (CH2), 56.5 (CH), 106.6 (CH), 113.7 (CH), 125.8, 126.3 (CH),
161.7, 171.5; MS (EI, 20 eV) m/z 108 (50), 177 (100), 277 (17)
(M+); MS (EI, 20 eV) m/z 108 (50), 177 (100), 277 (17) (M+);
HRMS (EI, magnetic sector) calcd for C15H23N3O2 277.1790, found
277.1797.
a
Reagents and conditions: (a) NaBH4/LiCl, THF/EtOH, 0 °C to rt, 8
h; (b) IBX, EtOAc, reflux, 3 h; (c) MsOH, CH2Cl2, rt, 1.5 h; (d) cat.
OsO4, NMO, acetone, rt, 3 h, 58%; (e) mCPBA, CH2Cl2, 0 °C to rt, 2
h, 63%.
N-[(1-Methylpyrrol-2-yl)carbonyl]proline (pyrrolidin-1-yl)-
amide (8c). Compound 8c was prepared from 5b by the method
described for 8a. The reaction was purified by flash column
chromatography (EtOAc, Rf = 0.1) to give 8c (colorless oil, 0.5623
position of the tricyclic core provoked the aerobic oxidation of
the heterocycle. The highly oxidizable tendency of the
pyrrolo[2,3-c]pyridine-7-one ring unit (A−B ring) could
illuminate understanding of the biological formation of these
marine secondary metabolites and also present a challenge for
the total synthesis of these marine natural products.
1
g, 89%): H NMR (CDCl3, 400 MHz) δ 1.76−1.89 (m, 6 H), 2.07−
2.14 (m, 2 H), 3.35−3.37 (m, 2 H), 3.47−3.49 (m, 1 H), 3.75−3.78
(m, 9 H), 4.73 (bs, 1 H), 5.99 (bs, 1 H), 6.52 (bs, 1 H), 6.58 (bs, 1
H); 13C NMR (CDCl3, 100 MHz) δ 23.8 (CH2), 25.3 (CH2), 25.9
(CH2), 28.2 (CH2), 36.2 (CH3), 45.7 (CH2), 45.9 (CH2), 49.9 (CH),
58.1 (CH2), 106.4 (CH), 113.8 (CH), 125.5, 126.4 (CH), 161.5,
170.3; MS (EI, 20 eV) m/z 108 (100), 177 (70), 275 (11) (M+);
HRMS (EI, magnetic sector) calcd for C15H21N3O2 275.1634, found
275.1642.
EXPERIMENTAL SECTION
■
General Chemical Procedures. The chemical shift values are
reported in δ values (parts per million, ppm) relative to the standard
chemical shift for the hydrogen residue peak and carbon-13 peak in the
deuterated solvent, CDCl3, or DMSO-d6.19 The coupling constant (J)
values are expressed in hertz (Hz). The numbers of protons directly
attached to the individual carbons were determined by 13C NMR
DEPT experiments. High-resolution mass spectrometry (HRMS) was
obtained by the following ionization methods/mass analyzers: EI/
magnetic sector, ESI/TOF or FAB/magnetic sector. Thin-layer
chromatography (TLC) was performed on silica gel plates.
Compounds on TLC were visualized by illumination under UV light
(254 nm), or using the following reagents: phosphomolybdic acid
reagent, anisaldehyde reagent, ninhydrin reagent or 10% ethanolic
sulfuric acid followed by charring on a hot plate. Silica gel (230−400
mesh) was used for flash column chromatography, and this technique
has been described by Still et al.20 Evaporations were carried out under
reduced pressure (water aspirator or vacuum pump) with the bath
temperature below 50 °C unless specified otherwise. Materials
obtained from commercial suppliers were used without further
purification.
N-[(1-Methylpyrrol-2-yl)carbonyl]proline (morpholin-1-yl)-
amide (8d). Compound 8d was prepared from 5b by the method
described for 8a. The reaction was purified by flash column
chromatography (EtOAc, Rf = 0.2) to give 8d (oil, 0.3902 g, 84%):
1H NMR (CDCl3, 400 MHz) δ 1.84−1.91 (m, 2 H), 2.09−2.21 (m, 2
H), 3.60−3.83 (m, 13 H), 4.95−4.97 (m, 1 H), 6.04 (bs, 1 H), 6.58
(bs, 1 H), 6.63 (bs, 1 H); 13C NMR (CDCl3, 100 MHz) δ 25.4 (CH2),
28.8 (CH2), 36.3 (CH3), 42.3 (CH2), 46.0 (CH2), 49.9 (CH2), 56.4
(CH), 66.5 (CH2), 66.7 (CH2), 106.7 (CH), 114.1 (CH), 125.5, 126.8
(CH), 161.7, 170.7; MS (EI, 20 eV) m/z 108 (32), 177 (100), 291
(14) (M+); MS (EI, 70 eV) m/z 108 (33), 177 (100), 291 (13) (M+);
HRMS (EI, magnetic sector) calcd for C15H21N3O3 291.1583, found
291.1589.
N-[(1-Methylpyrrol-2-yl)carbonyl]proline methylamide (8e).
Compound 8e was prepared from 5b by the method described for 8a.
The reaction was purified by flash column chromatography (EtOAc, Rf
= 0.1) to give 8e (amorphous solid, 1.4702 g, 45%): mp 114−117 °C;
1H NMR (CDCl3, 400 MHz) δ 1.84−1.92 (m, 1 H), 1.98−2.07 (m, 2
H), 2.30−2.36 (m, 1 H), 2.78 (s, 3 H), 3.66−3.74 (m, 1 H), 3.80−3.87
(m, 4 H), 4.71 (dd, 1 H, J = 4.9 and 7.3 Hz), 6.08 (dd, 1 H, J = 2.6 and
3.8 Hz), 6.54 (bs, 1 H), 6.71 (t, 1 H, J = 1.9 Hz); 13C NMR (CDCl3,
100 MHz) δ 25.2, 26.2, 27.5, 36.7, 50.1, 60.3, 107.1, 114.6, 125.0,
127.6, 163.3, 172.2; MS (EI, 20 eV) m/z 108 (100), 177 (95), 235
(43) (M+); HRMS (EI, magnetic sector) calcd for C12H17N3O2
235.1321, found 235.1321.
N-[(1-Methylpyrrol-2-yl)carbonyl]proline dimethylamide
(8a). A mixture of N-[(1-methylpyrrol-2-yl)carbonyl]proline16 (5b)
(4.0869 g, 18.39 mmol), EDC (5.1816 g, 27.03 mmol, 1.5 equiv) and
HOBt (3.6397 g, 26.94 mmol, 1.5 equiv) in CH2Cl2 (100 mL) was
stirred for 30 min at room temperature under argon. Dimethylammo-
nium chloride (2.9351 g, 36.0 mmol, 2 equiv) and triethylamine (12.6
mL, 89.65 mmol, 5 equiv) were added to the solution. The reaction
mixture was stirred for an additional 6 h at ambient temperature under
argon and then concentrated under reduced pressure. The residue was
dissolved in CHCl3 (50 mL), washed with 1 N aqueous HCl solution,
saturated aqueous Na2CO3 solution, and saturated aqueous NaCl
solution. The organic layer was dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (Hex/EtOAc = 1:9, Rf = 0.1) to give 8a
N-[(1-Methylpyrrol-2-yl)carbonyl]proline allylamide (8f).
Compound 8f was prepared from 5b by the method described for
8a. The reaction was purified by flash column chromatography (Hex/
1
EtOAc = 2:8, Rf = 0.25) to give 8f (colorless oil, 0.69 g, 53%): H
NMR (CDCl3, 400 MHz) δ 1.84−1.87 (m, 1 H), 1.97−2.04 (m, 2 H),
2.27−2.28 (m, 1 H), 3.66−3.74 (m, 1 H), 3.77−3.86 (m, 6 H), 4.71
(bs, 1 H), 5.02 (dd, 1 H, J = 1.2 and 10.3 Hz), 5.11 (d, 1 H, J = 17.1
Hz), 5.71−5.78 (m, 1 H), 6.04−6.05 (m, 1 H), 6.51 (bs, 1 H), 6.67
(bs, 1 H), 7.04 (bs, 1 H); 13C NMR (CDCl3, 100 MHz) δ 25.3, 27.8,
36.7, 41.8, 50.0, 60.5, 107.1, 114.4, 115.9, 125.2, 127.5, 134.1, 163.2,
171.6; MS (EI, 20 eV) m/z 108 (42), 177 (100), 261 (33) (M+);
HRMS (EI, magnetic sector) calcd for C14H19N3O2 261.1477, found
261.1480.
1
(amorphous solid, 3.37 g, 13.5 mmol, 75%): mp 125−128 °C; H
NMR (CDCl3, 400 MHz) δ 1.84−1.89 (m, 2 H), 1.92−2.24 (m, 2 H),
2.95 (bs, 3 H), 3.15 (bs, 3 H), 3.81 (bs, 3 H), 3.85 (bs, 2 H), 4.99 (bs,
1 H), 6.05 (bs, 1 H), 6.59 (bs, 1 H), 6.64 (bs, 1 H); 13C NMR
(CDCl3, 100 MHz) δ 25.4 (CH2), 28.5 (CH2), 35.9 (CH3), 36.5
(CH3), 37.0 (CH3), 50.0 (CH2), 56.8 (CH), 106.7 (CH), 114.1 (CH),
E
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The Journal of Organic Chemistry
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N-[(1-Methylpyrrol-2-yl)carbonyl]proline n-butylamide (8g).
Compound 8g was prepared from 5b by the method described for 8a.
The reaction was purified by flash column chromatography (Hex/
EtOAc = 7:3, Rf = 0.1) to give 8g (pale-yellow oil, 0.7280 g, 73%): 1H
NMR (CDCl3, 400 MHz) δ 0.81 (t, 3 H, J = 7.4 Hz), 1.22−1.28 (m, 2
H), 1.38−1.42 (m, 2 H), 1.83−1.89 (m, 1 H), 1.97−2.02 (m, 2 H),
2.25−2.26 (m, 1 H), 3.15−3.19 (m, 2 H), 3.67−3.69 (m, 1 H), 3.77−
3.78 (m, 4 H), 4.64−4.66 (m, 1 H), 6.03−6.04 (m, 1 H), 6.49 (bs, 1
H), 6.66 (m, 1 H), 6.86; 13C NMR (CDCl3, 100 MHz) δ 13.7, 20.0,
25.2 27.8, 31.5, 36.6, 39.2, 49.9, 60.7, 107.1, 114.4, 125.2, 127.4, 163.2,
171.7; MS (EI, 20 eV) m/z 108 (47), 177 (100), 277 (27) (M+);
HRMS (EI, magnetic sector) calcd for C15H23N3O2 277.1790, found
277.1801.
(500 MHz, CDCl3) δ 1.85−1.88 (m, 2 H), 1.96−2.06 (m, 4 H), 2.14−
2.16 (m, 1 H), 2.32−2.34 (m, 1 H), 3.39−3.49 (m, 2 H), 3.58−3.63
(m, 1 H), 3.86−3.91 (m, 2 H), 4.02 (bs, 1 H), 4.82−4.85 (m, 1 H),
6.25 (d, 1 H, 2.2 Hz), 6.66 (s, 1 H), 6.91 (s, 1 H), 9.59 (bs, 1 H, NH);
13C NMR (125 MHz, CDCl3) δ 24.1 (CH2), 25.4 (CH2), 26.3 (CH2),
28.3 (CH2), 46.0 (CH2), 46.3 (CH2), 48.5 (CH2), 59.2 (CH), 109.9
(CH), 112.6 (CH), 121.1 (CH), 125.6, 160.3, 170.5; MS (EI, 70 eV)
m/z 70 (100), 94 (69), 163 (87), 261 (21) (M+); HRMS (EI,
magnetic sector) calcd for C14H19N3O2 261.1477, found 261.1482.
N-[(Pyrrol-2-yl)carbonyl]proline (morpholin-1-yl)amide (9d).
Compound 9d was prepared from 12d25,26 and 13 by the method
described for 9a. The reaction was purified by flash column
chromatography (Hex/EtOAc = 4:6 to EtOAc) to give 9d
(amorphous solid, 1.95 g, 60%, Rf = 0.10 (EtOAc)): mp 184−185
N-[(1-Methylpyrrol-2-yl)carbonyl]proline benzylamide (8h).
Compound 8h was prepared from 5b by the method described for 8a.
The reaction was purified by flash column chromatography (Hex/
EtOAc = 4:6, Rf = 0.2) to give 8h (brown amorphous solid, 1.4233 g,
1
°C; H NMR (400 MHz, CDCl3) δ 1.91−1.95 (m, 1 H), 1.99−2.07
(m, 1 H), 2.11−2.19 (m, 1 H), 2.26 (m, 1 H), 3.57−3.72 (m, 7 H),
3.79−3.81 (m, 1 H), 3.89−3.91 (m, 1 H), 3.99−4.00 (m, 1 H), 5.03−
5.06 (m, 1 H), 6.24 (d, 1 H, J = 3.0 Hz), 6.66 (s, 1 H), 6.90 (s, 1 H),
9.91 (bs, 1 H, NH); 13C NMR (100 MHz, CDCl3) δ 25.3 (CH2), 28.5
(CH2), 42.4 (CH2), 46.1 (CH2), 48.4 (CH2), 57.2 (CH), 66.6 (CH2),
66.9 (CH2), 109.9 (CH), 112.7 (CH), 121.4 (CH), 125.4, 160.3,
170.6; MS (EI, 70 eV) m/z 66 (16), 70 (100), 94 (94), 163 (99), 164
(13), 277 (5) (M+); HRMS (EI, magnetic sector) calcd for
C14H19N3O3 277.1426, found 277.1433.
1
85%): mp 108−111 °C; H NMR (CDCl3, 400 MHz) δ 1.87−1.93
(m, 1 H), 1.98−2.08 (m, 2 H), 2.33−2.36 (m, 1 H), 3.70−3.86 (m, 5
H), 4.44 (dd, 1 H, J = 5.9 and 15.0 Hz), 4.46 (dd, 1 H, J = 5.7 and 14.8
Hz), 4.76−4.78 (m, 1 H), 6.09 (bs, 1 H), 6.55 (bs, 1 H), 6.70 (bs, 1
H), 7.22−7.32 (m, 5 H); 13C NMR (CDCl3, 100 MHz) δ 25.1 (CH2),
27.9 (CH2), 36.5 (CH3), 43.2 (CH2), 49.8 (CH2), 60.5 (CH), 106.9
(CH), 114.3 (CH), 125.1, 127.1 (CH), 127.3 (CH), 128.4 (CH),
128.5 (CH), 138.3, 163.1, 171.6; MS (EI, 70 eV) m/z 108 (100), 109
(26), 177 (100), 178 (23), 311 (11) (M+); HRMS (EI, magnetic
sector) calcd for C18H21N3O2 311.1634, found 311.1643.
N-[(Pyrrol-2-yl)carbonyl]proline methylamide (9e). Com-
pound 9e was prepared from 12e22,27 and 13 by the method described
for 9a. The reaction was purified by flash column chromatography
(Hex/EtOAc = 6:4 to EtOAc) to give 9e (amorphous solid, 1.93 g,
N-[(Pyrrol-2-yl)carbonyl]proline dimethylamide (9a). To a
mixture of pyrrole-2-carboxylic acid (13, 1.67 g, 15.0 mmol), EDC
(3.45 g, 18.0 mmol, 1.2 equiv) and HOBt (2.43 g, 18.0 mmol, 1.2
equiv) in CH2Cl2 (75 mL) was added proline dimethylamide
hydrochloride salt21 (12a, obtained quantitatively from N-Boc-proline
dimethylamide22 (11a) by acidic hydrolysis without further
purification, 2.68 g, 15.0 mmol, 1.0 equiv) and triethylamine (10.5
mL, 75.0 mmol, 5.0 equiv) at 0 °C. The mixture was stirred at room
temperature for 12 h. The solvent was removed under reduced
pressure. The residue was dissolved in CH2Cl2 (100 mL), washed with
H2O and saturated aqueous NaCl solution. The organic layer was
dried over anhydrous MgSO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatography
(Hex/EtOAc = 7:3 to EtOAc) to give 9a (amorphous solid, 1.99 g,
1
77%, Rf = 0.13 (EtOAc)): mp 112−113 °C; H NMR (400 MHz,
CDCl3) δ 1.91−2.38 (m, 4 H), 2.74 (d, 3 H, J = 3.6 Hz), 3.75−3.85
(m, 2 H), 4.78 (d, 1 H, J = 4.0 Hz), 6.25 (s, 1 H), 6.66 (s, 1 H), 6.95
(s, 1 H), 7.05 (s, 1 H, NH), 10.29 (s, 1 H, NH); 13C NMR (100 MHz,
CDCl3) δ 25.5 (CH2), 26.2 (CH3), 27.2 (CH2), 48.7 (CH2), 61.1
(CH), 110.3 (CH), 113.3 (CH), 122.1 (CH), 125.0, 161.7, 172.0; MS
(EI, 70 eV) m/z 66 (6), 70 (100), 94 (58), 163 (76), 221 (6) (M+);
HRMS (EI, magnetic sector) calcd for C11H15N3O2 221.1164, found
221.1164.
N-[(Pyrrol-2-yl)carbonyl]proline allylamide (9f). Compound 9f
was prepared from 12f28 and 13 by the method described for 9a. The
reaction was purified by flash column chromatography (Hex/EtOAc =
7:3 to EtOAc) to give 9f (amorphous solid, 2.78 g, 59%, Rf = 0.33
1
8.46 mmol, 56%, Rf = 0.10 (EtOAc)): mp 182−183 °C; H NMR
1
(EtOAc)): mp 115−116 °C; H NMR (400 MHz, CDCl3) δ 1.94−
(DMSO-d6, 400 MHz) δ 1.72−1.76 (m, 1 H), 1.91−1.97 (m, 1 H),
2.00−2.05 (m, 1 H), 2.11−2.16 (m, 1 H),2.81 (s, 3 H), 3.10 (s, 3 H),
3.76−3.81 (m, 2 H), 4.92−4.95 (m, 1 H), 6.15 (s, 1 H), 6.63 (s, 1 H),
6.90 (s, 1 H), 11.35 (bs, 1 H, NH); 13C NMR (DMSO-d6, 100 MHz)
δ 25.3 (CH2), 28.3 (CH2), 35.7 (CH3), 37.1 (CH3), 48.6 (CH2), 57.6
(CH), 109.3 (CH), 112.5 (CH), 121.9 (CH), 126.0, 159.8, 172.0; MS
(EI, 70 eV) m/z 66 (16), 70 (100), 94 (86), 163 (96), 235 (8) (M+);
HRMS (EI, magnetic sector) calcd for C12H17N3O2 235.1321, found
235.1325.
2.44 (m, 4 H), 3.77−3.91 (m, 4 H), 4.83 (d, 1 H, J = 6.6 Hz), 5.06 (d,
1 H, J = 10.2 Hz), 5.15 (d, 1 H, J = 17.2 Hz), 5.79−5.80 (m, 1 H),
6.28 (s, 1 H), 6.68 (s, 1 H), 6.97 (s, 1 H), 7.20 (bs, 1 H, NH), 9.98
(bs, 1 H, NH); 13C NMR (100 MHz, CDCl3) δ 25.5 (CH2), 27.0
(CH2), 41.7 (CH2), 48.6 (CH2), 61.2 (CH), 110.4 (CH), 113.3 (CH),
115.8 (CH2), 121.9 (CH), 125.0, 134.1 (CH), 161.7, 171.2; MS (EI,
70 eV) m/z 66 (19), 70 (100), 94 (90), 163 (99), 164 (22), 247 (8)
(M+); HRMS (EI, magnetic sector) calcd for C13H17N3O2 247.1321,
found 247.1320.
N-[(Pyrrol-2-yl)carbonyl]proline diethylamide (9b). Com-
pound 9b was prepared from 12b21,23 and 13 by the method
described for 9a. The reaction was purified by flash column
chromatography (Hex/EtOAc = 4:6 to EtOAc) to give 9b
(amorphous solid, 2.44 g, 52%, Rf = 0.30 (EtOAc)): mp 118−119
°C; 1H NMR (CDCl3, 400 MHz) δ 1.08 (t, 3 H, J = 7.2 Hz), 1.25 (t, 3
H, J = 7.2 Hz), 1.87−1.99 (m, 2 H), 3.23−3.38 (m, 2 H), 3.48−3.53
(m, 2 H), 3.85−3.97 (m, 2 H), 4.95−4.98 (m, 1 H), 6.17 (s, 1 H), 6.62
(s, 1 H), 6.84 (s, 1 H), 10.51 (bs, 1 H, NH); 13C NMR (CDCl3, 100
MHz) δ 12.9 (CH3), 14.4 (CH3), 25.2 (CH2), 28.8 (CH2), 40.6
(CH2), 41.7 (CH2), 48.6 (CH2), 57.6 (CH), 109.4 (CH), 112.8 (CH),
121.5 (CH), 125.3, 160.4, 171.4; MS (EI, 70 eV) m/z 66 (11), 70
(100), 94 (82), 163 (97), 263 (9) (M+); HRMS (EI, magnetic sector)
calcd for C14H21N3O2 263.1634, found 263.1638.
4-Dimethylamino-1-methyl-5,6,7,9-tetrahydropyrrolo[2,3-
f ]indolizin-9-one (14a). To a solution of 8a (0.2501 g, 1.0 mmol) in
acetonitrile (20 mL) at 0 °C was added phosphorus oxychloride (0.28
mL, 3.05 mmol, 3 equiv) and N-methylmorpholine (0.22 mL, 2.0
mmol, 2 equiv). After the addition was completed, the reaction
mixture was heated at 65 °C for 2 h. The solution was cooled to room
temperature and then concentrated under reduced pressure. The
residue was dissolved in chloroform (25 mL), washed with saturated
aqueous Na2CO3 solution, saturated NaCl solution, dried over
anhydrous MgSO4 and concentrated under reduced pressure. The
resulting residue was purified by flash column chromatography
(EtOAc, Rf = 0.5) to give 14a (pale-yellow amorphous solid, 0.1573
1
g, 0.68 mmol, 68%): mp 94−97 °C; H NMR (CDCl3, 500 MHz) δ
2.08−2.14 (m, 2 H), 2.76 (s, 6 H), 3.05 (t, 2 H, J = 7.2 Hz), 4.08 (t, 2
H, J = 7.3 Hz), 4.11 (s, 3 H), 6.31 (s, 1 H), 6.89 (s, 1 H); 13C NMR
(CDCl3, 125 MHz) δ 22.4 (CH2), 29.1 (CH2), 35.5 (CH3), 44.0
(CH3), 47.4 (CH2), 100.3 (CH), 123.0, 123.3, 130.5 (CH), 130.9,
135.4, 154.0; MS (EI, 20 eV) m/z 108 (18), 177 (16), 216 (36), 231
N-[(Pyrrol-2-yl)carbonyl]proline (pyrrolidin-1-yl)amide (9c).
Compound 9c was prepared from 12c21,24 and 13 by the method
described for 9a. The reaction was purified by flash column
chromatography (Hex/EtOAc = 5:5 to EtOAc) to give 9c (amorphous
1
solid, 1.76 g, 70%, Rf = 0.10 (EtOAc)): mp 194−195 °C; H NMR
F
dx.doi.org/10.1021/jo401911a | J. Org. Chem. XXXX, XXX, XXX−XXX

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Article
(100) (M+); HRMS (EI, magnetic sector) calcd for C13H17N3O
231.1372, found 231.1372.
m/z 173 (34), 174 (24), 216 (58), 230 (90), 245 (100) (M+); HRMS
(EI, magnetic sector) calcd for C14H19N3O 245.1528, found 245.1530.
4-(Pyrrolidin-1-yl)-5,6,7,9-tetrahydropyrrolo[2,3-f ]indolizin-
9-one (15c). Compound 15c was prepared from 9c by the method
described for 15a. The reaction was purified by flash column
chromatography (CH2Cl2/MeOH = 97:3) to give 15c (amorphous
4-Diethylamino-1-methyl-5,6,7,9-tetrahydropyrrolo[2,3-f ]-
indolizin-9-one (14b). Compound 14b was prepared from 8b by the
method described for 14a. The reaction was purified by flash column
chromatography (Hex/EtOAc = 1:9 then EtOAc) to give 14b (brown
oil, 86.9 mg, 48%, Rf = 0.25 (EtOAc)): 1H NMR (CDCl3, 400 MHz) δ
0.89 (t, 6 H, J = 7.1 Hz), 2.04−2.11 (m, 2 H), 3.00−3.06 (m, 6 H),
4.07−4.10 (m, 5 H), 6.23 (d, 1 H, J = 2.4 Hz), 6.85 (d, 1 H, J = 2.2
Hz); 13C NMR (CDCl3, 100 MHz) δ 14.0 (CH3), 22.4 (CH2), 29.7
(CH2), 35.5 (CH3), 47.8 (CH2), 48.7 (CH2), 100.5 (CH), 118.6,
123.0, 130.4 (CH), 131.5, 139.1, 154.1; MS (EI, 70 eV) m/z 187 (20),
188 (29), 229 (18), 230 (77), 244 (73), 259 (100) (M+); HRMS (EI,
magnetic sector) calcd for C15H21N3O 259.1685, found 259.1690.
1-Methyl-4-(pyrrolidin-1-yl)-5,6,7,9-tetrahydropyrrolo[2,3-
f]indolizin-9-one (14c). Compound 14c was prepared from 8c by
the method described for 14a. The reaction was purified by flash
column chromatography (EtOAc, Rf = 0.2) to give 14c (white
amorphous solid, 81.4 mg, 34%): mp 101−104 °C; 1H NMR (CDCl3,
400 MHz) δ 1.92−1.95 (m, 4 H), 2.08−2.15 (m, 2 H), 3.06 (t, 2 H, J
= 7.6 Hz), 3.14−3.17 (m, 4 H), 4.09 (t, 2 H, J = 7.3 Hz), 4.12 (s, 3 H),
6.21 (d, 1 H, J = 2.6 Hz), 6.89 (d, 1 H, J = 2.6 Hz); 13C NMR (CDCl3,
100 MHz) δ 22.4 (CH2), 25.6 (CH2), 29.2 (CH2), 29.6 (CH2), 35.6
(CH3), 47.6 (CH2), 51.4 (CH2), 100.0 (CH), 120.0, 123.1, 130.5
(CH), 130.8, 136.3, 153.9; MS (EI, 70 eV) m/z 256 (23), 257 (100)
(M+); HRMS (EI, magnetic sector) calcd for C15H19N3O 257.1528,
found 257.1536.
1
solid, 0.21 g, 44%, Rf = 0.25 (EtOAc)): mp 225−226 °C; H NMR
(DMSO-d6, 500 MHz) δ 1.90 (bs, 4 H), 2.04−2.10 (m, 2 H), 3.02 (t,
2 H, J = 6.0 Hz), 3.34 (s, 4 H), 3.98 (t, 2 H, J = 5.6 Hz), 6.29 (s, 1 H),
7.21 (s, 1 H), 11.88 (bs, 1 H, NH); 13C NMR (DMSO-d6, 125 MHz)
δ 22.6 (CH2), 25.6 (CH2), 29.3 (CH2), 47.9 (CH2), 51.7 (CH2),
101.7 (CH), 119.5, 124.1, 126.5 (CH), 129.3, 136.2, 152.9; MS (EI, 70
eV) m/z 70 (93), 94 (100), 120 (34), 205 (35), 243 (44) (M+);
HRMS (EI, magnetic sector) calcd for C14H17N3O 243.1372, found
243.1371.
4-(Morpholin-1-yl)-5,6,7,9-tetrahydropyrrolo[2,3-f ]-
indolizin-9-one (15d). Compound 15d was prepared from 9d by the
method described for 15a. The reaction was purified by flash column
chromatography (CH2Cl2/MeOH = 99:1 to 98:2) to give 15d
(amorphous solid, 0.10 g, 13%, Rf = 0.1 (CH2Cl2/MeOH = 98/2)):
mp 198−199 °C; 1H NMR (DMSO-d6, 400 MHz) δ 2.05−2.12 (m, 2
H), 3.00 (s, 4 H), 3.08 (t, 2 H, J = 7.6 Hz), 3.69 (s, 4 H), 3.98 (t, 2 H,
J = 7.0 Hz), 6.40 (s, 1 H), 7.22 (s, 1 H), 11.89 (bs, 1 H, NH); 13C
NMR (DMSO-d6, 100 MHz) δ 22.6 (CH2), 29.2 (CH2), 47.9 (CH2),
51.8 (CH2), 67.7 (CH2), 102.0, 121.7, 123.9, 126.7, 129.8, 136.0,
152.9; MS (EI, 70 eV) m/z 173 (14), 177 (10), 200 (15), 201 (47),
259 (100) (M+); HRMS (EI, magnetic sector) calcd for C14H17N3O2
259.1321, found 259.1322.
1-Methyl-4-(morpholin-1-yl)-5,6,7,9-tetrahydropyrrolo[2,3-
f]indolizin-9-one (14d). Compound 14d was prepared from 8d by
the method described for 14a. The reaction was purified by flash
column chromatography (EtOAc, Rf = 0.25) to give 14d (brown
amorphous solid, 0.1466 g, 62%): mp 148−151 °C; 1H NMR (CDCl3,
400 MHz) δ 2.10−2.17 (m, 2 H), 3.07−3.12 (m, 6 H), 3.78 (t, 4 H, J
= 4.4 Hz), 4.01 (t, 2 H, J = 7.0 Hz), 4.13 (s, 3 H), 6.35 (d, 1 H, J = 2.8
Hz), 6.91 (d, 1 H, J = 2.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 22.4
(CH2), 29.2 (CH2), 35.5 (CH3), 47.6 (CH2), 51.5 (CH2), 68.0 (CH2),
100.3 (CH), 122.0, 122.9, 130.7 (CH), 131.2, 136.2, 154.0; MS (EI, 70
eV) m/z 108 (13), 214 (15), 215 (36), 273 (100) (M+); HRMS (EI,
magnetic sector) calcd for C15H19N3O2 273.1477, found 273.1480.
4-Dimethylamino-5,6,7,9-tetrahydropyrrolo[2,3-f ]indolizin-
9-one (15a). To a solution of 9a (0.47 g, 2.0 mmol) in THF (20 mL)
was added POCl3 (0.55 mL, 6.0 mmol, 3.0 equiv) at 0 °C. After the
addition was completed, the mixture was stirred at reflux temperature
for 3 h. The solution was cooled to room temperature, and the solvent
was removed under reduced pressure. The residue was partitioned
between CHCl3 and H2O. The aqueous layer was separated and then
neutralized with saturated aqueous Na2CO3 solution. The aqueous
solution was extracted with CHCl3, and the organic layer was dried
over anhydrous MgSO4 and concentrated under reduced pressure. The
residue was purified by flash column chromatography (Hex/EtOAc =
2:8 to EtOAc) to give 15a (yellow amorphous solid, 0.1521 g, 0.7
mmol, 35%, Rf = 0.25 (EtOAc)): mp 219−220 °C; 1H NMR (DMSO-
d6, 500 MHz) δ 2.05−2.11 (m, 2 H), 2.72 (s, 6 H), 3.04 (t, 2 H, J = 6.0
Hz), 3.97 (t, 2 H, J = 5.7 Hz), 6.39 (t, 1 H, J = 1.6 Hz), 7.21 (t, 1 H, J
= 2.0 Hz), 11.85 (bs, 1 H, NH); 13C NMR (DMSO-d6, 125 MHz) δ
22.1 (CH2), 28.7 (CH2), 43.9 (CH3), 47.3 (CH2), 101.5 (CH), 122.5,
123.5, 126.0 (CH), 129.1, 135.0, 152.4; MS (EI, 70 eV) m/z 202
(100), 217 (78) (M+); HRMS (EI, magnetic sector) calcd for
C12H15N3O 217.1215, found 217.1219.
1-Methyl-4a-hydroxy-4,4a,5,6,7,9-hexahydropyrolo[2,3-f ]-
indolizine-4,9-dione (16). Method A. To a solution of 8e (0.2340 g,
1.0 mmol) in acetonitrile (20 mL) at 0 °C was added phosphorus
oxychloride (0.28 mL, 3.05 mmol, 3 equiv) and N-methylmorpholine
(0.22 mL, 1.92 mmol, 2 equiv). After the addition was completed, the
reaction mixture was heated at 65 °C for 16 h under argon. The
reaction mixture was cooled to room temperature and then
concentrated under reduced pressure. The residue was dissolved in
chloroform (10 mL), washed with saturated aqueous Na2CO3
solution, saturated aqueous NaCl solution, dried over anhydrous
MgSO4 and concentrated under reduced pressure. The resulting
residue was purified by flash column chromatography (Hex/EtOAc =
5:5, Rf = 0.1) to give 16 (amorphous solid, 0.1299 g, 0.59 mmol, 59%).
The product was recrystallized from toluene to give an analytical
sample of 16: mp 136−137 °C (white solid, toluene).
Method B. To a solution of 29 (188 mg, 1.0 mmol) in acetone (1
mL) was added N-methylmorpholine N-oxide (NMO, 234.3 mg, 2.0
mmol, 2 equiv) and OsO4 (25.4 mg, 0.10 mmol, 0.1 equiv). The
reaction mixture was stirred at room temperature for 3 h. The reaction
mixiture was quenched with saturated aqueous Na2SO3 solution at 0
°C for 10 min. The solvent was removed under reduced pressure. The
residue was dissolved in EtOAc (50 mL), washed with H2O, saturated
aqueous Na2CO3 solution, saturated aqueous NaCl solution, and then
dried over anhydrous Na2SO4. The solvent was evaporated under
reduced pressure. The residue was purified by flash column
chromatography to give 16 (amorphous solid, 127.7 mg, 0.58 mmol,
58%).
Method C.13 To a solution of 29 (150 mg, 0.80 mmol) in CH2Cl2
(1 mL) was added m-chloroperbenzoic acid (mCPBA, 300 mg, 1.72
mmol, 2.2 equiv) at 0 °C. After the addition was completed, the
reaction temperature was raised to room temperature, and the reaction
mixture was stirred for 2 h. The mixiture was quenched with saturated
aqueous Na2SO3 solution at 0 °C for 10 min. The residue was
extracted with EtOAc, and the organic layer was washed with H2O,
saturated aqueous NaCl solution, dried over anhydrous Na2SO4 and
then concentrated under reduced pressure. The residue was purified
by flash column chromatography to give 16 (amorphous solid, 109.8
4-Diethylamino-5,6,7,9-tetrahydropyrrolo[2,3-f ]indolizin-9-
one (15b). Compound 15b was prepared from 9b by the method
described for 15a. The reaction was purified by flash column
chromatography (Hex/EtOAc = 2:8 then EtOAc) to give 15b (yellow
amorphous solid, 0.12 g, 21%, Rf = 0.18 (EtOAc)): mp 158−159 °C;
1H NMR (CDCl3, 400 MHz) δ 0.77−0.86 (m, 6 H), 2.05−2.11 (m, 2
H), 2.97−3.06 (m, 6 H), 3.23−3.38 (m, 2 H), 3.48−3.53 (m, 2 H),
3.85−3.97 (m, 6 H), 4.16 (t, 2 H, J = 7.2 Hz), 6.29 (s, 1 H), 7.17 (s, 1
H), 11.90 (bs, 1 H, NH); 13C NMR (CDCl3, 100 MHz) δ 14.0 (CH3),
22.6 (CH2), 29.6 (CH2), 29.7 (CH2), 48.2 (CH2), 48.9 (CH2), 101.9
(CH), 119.8, 124.1, 126.6 (CH), 130.8, 138.7, 153.5; MS (EI, 70 eV)
1
mg, 0.50 mmol, 63%): H NMR (400 MHz, DMSO-d6) δ 1.88−1.98
(m, 2 H), 2.02−2.12 (m, 2 H), 3.57−3.58 (m, 2 H), 3.94 (s, 3 H), 6.46
(d, 1 H, J = 2.6 Hz), 6.61 (s, 1 H), 7.15 (d, 1 H, J = 2.6 Hz); 13C NMR
(100 MHz, DMSO-d6) δ 20.1 (CH2), 34.9 (CH2), 36.0 (CH3), 44.7
(CH2), 91.4, 105.8 (CH), 122.7, 130.2, 130.9 (CH), 156.5, 188.7; MS
G
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(EI, 20 eV) m/z 108 (100), 202 (27), 220 (50) (M+); HRMS (EI,
magnetic sector) calcd for C11H12N2O3 220.0848, found 220.0849.
Anal. Calcd for C11H12N2O3: C, 59.99; H, 5.49; N, 12.72. Found: C,
59.96; H, 5.50; N, 12.51.
equiv) and HOBt (1.1482 g, 8.50 mmol, 1.2 equiv) in dichloro-
methane (50 mL) was stirred for 10 min at room temperature under
argon. N-Benzylglycine methyl ester29 (N-Bn-Gly-OMe, 1.2852 g, 7.17
mmol) and triethylamine (3.0 mL, 21.34 mmol, 3 equiv) were added
to the solution, and the reaction mixture was stirred at room
temperature for 18 h. The solution was concentrated under reduced
pressure. The residue was dissolved in chloroform (30 mL), washed
with H2O and saturated aqueous NaCl solution, dried over anhydrous
MgSO4 and then concentrated under reduced pressure. The residue
was purified by flash column chromatography (Hex/EtOAc = 9:1 then
EtOAc) to give 24 (brown amorphous solid, 1.7011 g, 5.94 mmol,
83%, Rf = 0.1 (Hex/EtOAc = 9:1)): mp 91−94 °C; 1H NMR (CDCl3,
400 MHz) δ 3.72 (s, 3 H), 3.82 (s, 3 H), 4.12 (bs, 2 H), 4.89 (bs, 1
H), 6.00 (t, 2 H, J = 2.8 Hz), 6.36−6.37 (m, 1 H), 6.71 (s, 1 H), 7.25−
7.31 (m, 3 H), 7.35−7.39 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ
36.0, 47.2, 52.1, 54.4, 107.0, 112.6, 124.3, 126.7, 127.6, 128.9, 136.7,
165.1, 169.9; MS (EI, 70 eV) m/z 91 (22), 108 (100), 178 (48), 286
(10) (M+); HRMS (EI, magnetic sector) calcd for C16H18N2O3
286.1317, found 286.1322.
1-Methyl-4a-allyl-4,4a,5,6,7,9-hexahydropyrolo[2,3-f ]indol-
izine-4,9-dione (18). To a solution of 8f (0.7727 g, 2.95 mmol) in
acetonitrile (60 mL) at 0 °C was added phosphorus oxychloride (0.81
mL, 8.85 mmol, 3 equiv) and N-methylmorpholine (0.67 mL, 5.86
mmol, 2 equiv). After the addition was completed, the reaction
mixture was heated at 65 °C for 21 h under argon. The reaction
mixture was cooled to room temperature and then concentrated under
reduced pressure. The residue was dissolved in chloroform (50 mL),
washed with saturated aqueous Na2CO3 solution, saturated aqueous
NaCl solution, dried over anhydrous MgSO4 and concentrated under
reduced pressure. The resulting residue was purified by flash column
chromatography (Hex/EtOAc = 5:5 to EtOAc) to give products 18
(amorphous solid, 0.1096 g, 0.45 mmol, 15%, Rf = 0.5 (EtOAc)) and
16 (amorphous solid, 0.0213 g, 0.10 mmol, 3%, Rf = 0.3 (EtOAc). 18:
1H NMR (CDCl3, 500 MHz) δ 1.95−2.03 (m, 3 H), 2.14−2.17 (m, 1
3-[[(1-Methylpyrrol-2-yl)carbonyl]-N-benzyl-amino]ethanic
acid (25). To a solution of N-[(1-methylpyrrol-2-yl)carbonyl]-N-
benzylglycine methyl ester (24) (1.4493 g, 5.06 mmol) in methanol
(30 mL) was added 15% aqueous NaOH solution (30 mL). The
reaction mixture was heated at reflux temperature for 3 h. The mixture
was concentrated under reduced pressure. The residue was partitioned
between water and chloroform. The pH of the aqueous layer was
adjusted to 2 with 4 N aqueous HCl solution. The aqueous solution
was then extracted with chloroform (30 mL × 3). The combined
organic layer was dried over anhydrous MgSO4 and concentrated
under reduced pressure to give 25, which was used for the subsequent
reaction without further purification (brown oil, 1.3753 g, 5.05 mmol,
H), 2.45 (ddd, 1 H, J = 5.8, 10.9, and 16.7 Hz), 3.49−3.55 (m, 1 H),
3.85−3.90 (m, 1 H), 3.97 (s, 3 H), 4.92 (t, 2 H, J = 9.3 Hz), 5.41−5.50
(m, 1 H), 6.44 (d, 1 H, J = 2.9 Hz), 6.69 (d, 1 H, J = 2.9 Hz); 13C
NMR (CDCl3, 125 MHz) δ 20.5 (CH2), 32.8 (CH2), 35.9 (CH3),
43.5 (CH2), 44.1 (CH2), 75.2, 105.1 (CH), 119.2, 124.1, 129.6 (CH),
131.2, 131.4 (CH), 156.8, 192.8; MS (EI, 20 eV) m/z 108 (15), 136
(92), 202 (77), 204 (100), 244 (35) (M+); HRMS (EI, magnetic
sector) calcd for C14H16N2O2 244.1212, found 244.1212.
4a-Hydroxy-4,4a,5,6,7,9-hexahydropyrrolo[2,3-f ]indolizine-
4,9-dione13 (17). To a solution of 9e (0.2210 g, 1.00 mmol) in THF
(10 mL) was added POCl3 (0.28 mL, 3.0 mmol, 3.0 equiv) at 0 °C.
After the addition was completed, the reaction mixture was heated at
reflux temperature for 16 h. The reaction mixture was cooled to room
temperature and then concentrated under reduced pressure. The
residue was dissolved in CHCl3/EtOH (15 mL/15 mL), and then
Na2CO3 (3.18 g, 30 mmol, 30 equiv) was added. The mixture was
stirred for 2.5 h. After filtration, the solvent was evaporated and the
residue was purified by flash column chromatography (CH2Cl2/
MeOH = 99:1 to 98:2) to give the 17 (amorphous solid, 49.4 mg,
24%, Rf = 0.28 (EtOAc)): mp 188−189 °C;13 1H NMR (DMSO-d6,
400 MHz) δ 1.88−1.96 (m, 2 H), 2.06−2.12 (m, 2 H), 3.57−3.61 (m,
2 H), 6.49 (t, 1 H, J = 2.4 Hz), 6.62 (s, 1 H, OH), 7.10 (t, 1 H, J = 2.6
Hz), 12.60 (bs, 1 H, NH); 13C NMR (DMSO-d6, 100 MHz) δ 20.2
(CH2), 34.8 (CH2), 44.5 (CH2), 91.8, 106.7 (CH), 121.7, 125.3
(CH), 132.7, 156.0, 188.9; MS (EI, 70 eV) m/z 93 (74), 94 (100), 206
(29) (M+); HRMS (EI, magnetic sector) calcd for C10H10N2O3
206.0691, found 206.0694.
1
quantitatively, Rf = 0.5 (Hex/EtOAc = 5:5)): H NMR (CDCl3, 400
MHz) δ 3.81 (s, 3 H), 4.14 (s, 2 H), 4.90 (bs, 2 H), 6.01 (t, 2 H, J =
2.8 Hz), 6.40 (t, 2 H, J = 1.0 Hz), 6.72 (s, 1 H), 7.26−7.40 (m, 5 H);
13C NMR (CDCl3, 100 MHz) δ 36.1, 47.9, 54.2, 107.2, 113.2, 123.9,
127.0, 127.5, 127.7, 129.0, 136.3, 165.6, 173.4; MS (EI, 70 eV) m/z 81
(54), 91 (31), 108 (100), 109 (29), 272 (57) (M+); HRMS (EI,
magnetic sector) calcd for C15H16N2O3 272.1161, found 272.1163.
N-[(1-Methylpyrrol-2-yl)carbonyl]-N-benzylglycine dimethy-
lamide (26). A mixture of N-[(1-methylpyrrol-2-yl)carbonyl]-N-
benzylglycine (25) (1.0106 g, 3.71 mmol), EDC (1.4180 g, 7.40
mmol, 2 equiv) and HOBt (1.0000 g, 7.40 mmol, 2 equiv) in CH2Cl2
(30 mL) was stirred for 10 min at room temperature under argon.
Dimethylammonium chloride (0.4532 g, 5.55 mmol, 1.5 equiv) and
triethylamine (2.1 mL, 14.80 mmol, 4 equiv) were added to the
solution. The reaction mixture was stirred for an additional 19 h at
ambient temperature under argon and then concentrated under
reduced pressure. The residue was dissolved in chloroform (30 mL),
washed with H2O and saturated aqueous NaCl solution, dried over
anhydrous MgSO4 and then concentrated under reduced pressure.
The residue was purified by flash column chromatography (Hex/
EtOAc = 3:7, Rf = 0.1) to give 26 (brown amorphous solid, 1.0744 g,
3.59 mmol, 97%): mp 92−95 °C; 1H NMR (CDCl3, 400 MHz) δ 2.90
(bs, 3 H), 2.95 (s, 3 H), 3.80 (s, 3 H), 4.16 (s, 2 H), 4.91 (bs, 2 H),
5.96 (bs, 1 H), 6.32 (bs, 1 H), 6.67 (bs, 1 H), 7.27−7.29 (m, 3 H),
7.34−7.37 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 35.6 (CH3),
35.8 (CH3), 36.1 (CH3), 46.1 (CH2), 54.0 (CH2), 106.7 (CH), 111.8
(CH), 124.7, 126.4 (CH), 126.7 (CH), 127.3 (CH), 127.5 (CH),
128.7 (CH), 137.1, 165.2, 167.5; MS (EI, 70 eV) m/z 91 (34), 108
(100), 191 (95), 213 (71), 299 (4) (M+); HRMS (EI, magnetic
sector) calcd for C17H21N3O2 299.1634, found 299.1626.
4a-Allyl-4,4a,5,6,7,9-hexahydropyrolo[2,3-f ]indolizine-4,9-
dione (19). To a solution of 9f (5.40 g, 21.84 mmol) in THF (218
mL) was added POCl3 (6.01 mL, 65.5 mmol, 3.0 equiv) at 0 °C. After
the addition was completed, the reaction mixture was heated at reflux
temperature for 14 h. The reaction mixture was cooled to room
temperature and then concentrated under reduced pressure. The
residue was dissolved in CH2Cl2. The solution was washed with
saturated aqueous Na2CO3 solution, dried over anhydrous MgSO4 and
concentrated under reduced pressure. The residue was purified by
flash column chromatography (Hex/CHCl3 = 1:9 then CHCl3/MeOH
= 99:1) to give the products 19 (amorphous solid, 0.34 g, 1.48 mmol,
7%, Rf = 0.45 (EtOAc)) and 17 (amorphous solid, 0.95 g, 4.61 mmol,
21%, Rf = 0.28 (EtOAc)). 19: mp 138−139 °C; 1H NMR (400 MHz,
CDCl3) δ 2.08−2.15 (m, 3 H), 2.22−2.28 (m, 1 H), 2.48−2.53 (m, 1
H), 2.59−2.64 (m, 1 H), 3.61−3.66 (m, 1 H), 3.99−4.06 (m, 1 H),
4.96−5.03 (m, 2 H), 5.47−5.57 (m, 1 H), 6.59 (s, 1 H), 7.02 (s, 1 H),
11.92 (bs, 1 H, NH); 13C NMR (100 MHz, CDCl3) δ 20.5 (CH2),
32.8 (CH2), 43.5 (CH2), 44.1 (CH2), 75.7, 106.2 (CH), 119.4 (CH2),
123.4, 125.1 (CH), 131.2 (CH), 133.0, 156.9, 192.8; MS (ESI) m/z
188 (34), 229 (100) (M − 1); HRMS (ESI, TOF) calcd for
C13H13N2O2 229.0977 (M − 1), found 229.0978.
6-Benzyl-1-methyl-4,5,6,7-tetrahydropyrrolo[2,3-c]pyridine-
4,5,7-trione (28). To a solution of N-[(1-methylpyrrol-2-yl)-
carbonyl]-N-benzylglycine dimethylamide (26) (0.2995 g, 1.0 mmol)
in acetonitrile (20 mL) at 0 °C was added phosphorus oxychloride
(0.28 mL, 3.05 mmol, 3 equiv) and N-methylmorpholine (0.23 mL,
2.01 mmol, 2 equiv). After the addition was completed, the reaction
mixture was heated at 65 °C for 21 h. The solution was cooled to
room temperature and then concentrated under reduced pressure. The
residue was dissolved in chloroform (20 mL), washed with saturated
N-[(1-Methylpyrrol-2-yl)carbonyl]-N-benzylglycine methyl
ester (24). A mixture of N-methylpyrrole-2-carboxylic acid (23)
(1.0572 g, 8.45 mmol, 1.2 equiv), EDC (1.6291 g, 8.50 mmol, 1.2
H
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aqueous Na2CO3 solution, saturated NaCl solution, dried over
anhydrous MgSO4 and concentrated under reduced pressure. The
first attempt to purify the resulting residue by flash column
chromatography (Hex/EtOAc = 3:7, Rf = 0.3) gave a part of the
crude product 27, which was characterized only by 1H NMR. 6-
Benzyl-4-dimethylamino-1-methylpyrrolo[2,3-c]pyridin-7-one (27):
1H NMR (CDCl3, 400 MHz) δ 2.70 (s, 6 H), 4.16 (s, 3 H), 5.16−
5.16 (m, 2 H), 6.29 (s, 1 H), 6.34 (d, 1 H, J = 2.9 Hz), 6.96 (d, 1 H, J
= 2.8 Hz), 7.22−7.31 (m, 5 H). Further purification by flash column
chromatography (Hex/EtOAc = 3:7, Rf = 0.5) afforded 28 (white
amorphous solid, 0.1207 g, 0.45 mmol, 45%). The solid was
recrystallized with toluene to give the analytical sample of 28 (white
solid, 0.0982 g, 0.35 mmol, 37%). 6-Benzyl-1-methyl-4,5,6,7-
tetrahydropyrrolo[2,3-c]pyridine-4,5,7-trione (28): mp 151−154 °C
(toluene); 1H NMR (CDCl3, 400 MHz) δ 4.04 (s, 3 H), 5.11 (s, 2 H),
6.71 (d, 1 H, J = 2.0 Hz), 6.92 (d, 1 H, J = 1.8 Hz), 7.23−7.31 (m, 3
H), 7.43−7.45 (m, 2 H); 13C NMR (CDCl3, 100 MHz) δ 36.7 (CH3),
43.4 (CH2), 108.2 (CH), 124.9, 127.4, 127.8 (CH), 128.5 (CH),
129.1 (CH), 132.1 (CH), 136.3, 157.1, 158.8, 169.7; MS (EI, 70 eV)
m/z 107 (70), 108 (15), 177 (14), 240 (11), 268 (100) (M+); HRMS
(EI, magnetic sector) calcd for C15H12N2O3 268.0848, found
268.0851.
N-[(1-Methylpyrrol-2-yl)carbonyl]prolinol (5c). Method A. To
a solution of N-[(1-methylpyrrol-2-yl)carbonyl]proline methyl ester
(5b, 0.24 g, 1.02 mmol) in THF/EtOH (1/2 mL) was added LiCl
(0.0861 g, 2.03 mmol, 2 equiv) and NaBH4 (0.0768 g, 2.03 mmol, 2
equiv) at 0 °C. The reaction mixture was stirred for 8 h at room
temperature then the solvent was removed under reduced pressure.
The residue was dissolved in EtOAc (20 mL), washed with H2O,
saturated aqueous NaCl solution, dried over anhydrous Na2SO4, and
then concentrated under reduced pressure. The residue was purified
by flash column chromatography (Hex/EtOAc = 6:4, Rf = 0.3) to give
5c (oil, 0.19 g, 0.92 mmol, 90%).
Method B. A mixture of 1-methyl-2-trichloroacetylpyrrole (0.23 g,
1.0 mmol), prolinol (151.6 mg, 1.50 mmol) and Na2CO3 (0.32 g, 3
mmol) in CH3CN (10 mL) was heated at reflux temperature for 4 h.
After cooling to room temperature, the solvent was removed under
reduced pressure. The residue was dissolved in EtOAc (20 mL),
washed with H2O, saturated aqueous NaCl solution, and then dried
over anhydrous Na2SO4. The solvent was evaporated under reduced
pressure. The residue was purified by flash column chromatography
(Hex/EtOAc = 6:4, Rf = 0.3) to give 5c (oil, 0.19 g, 0.92 mmol, 92%):
1H NMR (CDCl3, 400 MHz) δ 1.58−1.67 (m, 1 H), 1.73−1.96 (m, 2
H), 2.08−2.16 (m, 1 H), 3.60−3.72 (m, 2 H), 3.84 (s, 3 H), 3.90−3.95
(m, 1 H), 4.41 (dd, 1 H, J = 2.7 and 7.5 Hz), 4.96 (bs, 1 H, OH), 6.09
(dd, 1 H, J = 2.7 and 3.7 Hz), 6.54 (dd, 1 H, J = 1.5 and 3.9 Hz), 6.70
(d, 1 H, J = 1.8 Hz); 13C NMR (CDCl3, 100 MHz) δ 25.1 (CH2), 28.3
(CH2), 36.6 (CH), 50.9 (CH2), 61.5 (CH), 67.6 (CH), 106.9 (CH),
114.3 (CH), 125.6, 127.2 (CH), 164.4; MS (FAB) m/z 84 (36), 108
(100), 209 (53) (M + 1); HRMS (FAB, magnetic sector) calcd for
C11H17N2O2 209.1290 (M + 1), found 209.1300.
solid, 61.4 mg, 0.33 mmol, 68%). The solid was recrystallized with
Hex/EtOAc to give the analytical sample of 29: mp 89−91 °C (Hex/
EtOAc); 1H NMR (CDCl3, 400 MHz) δ 2.11−2.20 (m, 2 H), 3.02 (t,
2 H, J = 7.6 Hz), 4.10 (t, 2 H, 7.2 Hz), 4.15 (s, 3 H), 6.15 (d, 1 H, J =
2.4 Hz), 6.32 (s, 1 H), 6.92 (d, 1 H, J = 2.4 Hz); 13C NMR (CDCl3,
100 MHz) δ 22.7 (CH2), 30.8 (CH2), 35.6 (CH3), 47.3 (CH2), 96.1
(CH), 101.0 (CH), 121.2, 131.3, 132.7, 140.2, 155.0; MS (EI, 70 eV)
m/z 187 (100), 188 (68) (M+); HRMS (EI, magnetic sector) calcd for
C11H12ON2 188.0950, found 188.0944. Anal. Calcd for C11H12ON2: C,
70.19; H, 6.43; N, 14.88. Found: C, 69.98; H, 6.36; N, 14.86.
ASSOCIATED CONTENT
■
S
* Supporting Information
1H and 13C NMR spectra of all the synthesized compounds and
X-ray structural data (CIF) of compound 28. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: tcchien@ntnu.edu.tw.
■
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by Research Grants 102-2113-M-003-
004- and 100-2113-M-003-007-MY2 from the National Science
Council, Taiwan, and NTNU100-D-06 from National Taiwan
Normal University. We also thank Mr. Ting-Shen Kuo for his
assistance with X-ray crystallogrphic analysis.
DEDICATION
■
Dedicated to Professor Hung-wen (Ben) Liu on the occasion of
his 60th birthday.
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