Unsymmetrical tetra-Acceptor-Substituted alkenes as polyfunctionalized building blocks: A divergent synthesis of densely functionalized pyrrolizines

Article abstract of DOI:10.1246/bcsj.20180213

Various tetra-acceptor-substituted alkenes possessing unsymmetrical substituents have been effectively synthesized from vicinal tricarbonyl compounds. The alkenes have polyfunctionality and high electron deficiency. In addition, they easily react with pyrroles to give divergent pyrrolizine derivatives via the conjugate addition of pyrroles followed by intramolecular cyclization. We successfully controlled the chemoselectivity of the intramolecular cyclization (ester/ketone attack) to afford a wide range of valuable pyrrolizine derivatives.

Full text of DOI:10.1246/bcsj.20180213

Advance Publication Cover Page
Unsymmetrical Tetra-acceptor-substituted Alkenes as Polyfunctionalized Building Blocks:
A Divergent Synthesis of Densely Functionalized Pyrrolizines
Haruyasu Asahara,* Shu Kawakami, Kotaro Yoshioka, Shinki Tani,
Kazuto Umezu, and Nagatoshi Nishiwaki*
Advance Publication on the web October 10, 2018
doi:10.1246/bcsj.20180213
©
2018 The Chemical Society of Japan
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Publication manuscripts.

Unsymmetrical Tetra-acceptor-substituted Alkenes as Polyfunctionalized Building
Blocks: A Divergent Synthesis of Densely Functionalized Pyrrolizines
Haruyasu Asahara,*1,2 Shu Kawakami, Kotaro Yoshioka, Shinki Tani, Kazuto Umezu, and Nagatoshi Nishiwaki*
2
3
3
3
2,4
1
Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Yamadaoka 2-1, Suita, Osaka 565-0871
2
School of Environmental Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502
3
Kumiai Chemical Industry Co., Ltd. Fujikawa-cho, Ihara-gun, Shizuoka 421-3306
4
Research Center for Material Science and Engineering, Kochi University of Technology, Tosayamada, Kami, Kochi 782-8502
E-mail: <asahara@chem.eng.osaka-u.ac.jp (H. Asahara). nishiwaki.nagatoshi@kochi-tech.ac.jp (N. Nishiwaki)>
Haruyasu Asahara
Haruyasu Asahara received his Ph. D. degree in 2010 from Osaka University. After completion of his degree he was
appointed as a Postdoctoral Fellow at the Minakata’s group in Osaka University. From 2010, he joined the Herbert Mayr’s
group at LMU in Germany as a Humboldt Fellow. And then he moved to a postdoctoral position at the Akashi’s group in
Osaka University. He worked at Professor Nishiwaki’s group in Kochi University of Technology, as assistant professor
(2013-2015) and as designated associate professor (2016). In 2017, he returned to the Osaka University as a designated
associate professor (the group of Inoue/Ohkubo).
Nagatoshi Nishiwaki
Nagatoshi Nishiwaki received his Ph.D. in 1991 from Osaka University. He worked in Professor Ariga’s group in the
Department of Chemistry, Osaka Kyoiku University as assistant professor (1991–2000) and as associate professor (2001–
2008). From 2000 to 2001, he joined Karl Anker Jørgensen’s group at Århus University in Denmark. He worked at the
Center for Collaborative Research, Anan National College of Technology as associate professor from 2008 to 2009. Then,
he moved to Kochi University of Technology in 2009, and he has been a professor since 2011. His research interests
comprise synthetic organic chemistry using nitro compounds and heterocycles.
Abstract
Various tetra-acceptor-substituted alkenes possessing
pyrrolizine derivatives using tetra-acceptor-substituted alkenes.
6
The pyrrolizine scaffold is exemplified as one of the most
7
unsymmetrical substituents have been effectively synthesized
from vicinal tricarbonyl compounds. The alkenes have
polyfunctionality and high electron deficiency. In addition, they
easily react with pyrroles to give divergent pyrrolizine
derivatives via the conjugate addition of pyrroles followed by
intramolecular cyclization. We successfully controlled the
chemoselectivity of the intramolecular cyclization (ester/ketone
attack) to afford a wide range of valuable pyrrolizine derivatives.
significant structural subunits in natural products and especially
pharmaceutical products. They possess important activities9
such as antiviral, antimicrobial, herbicidal, and antitumor agents.
Owing to increased interest in this class of compound, we
envisage that the development of a synthetic method for
preparing divergent pyrrolizine structures would be valuable for
drug discovery. There have been few literature reports to date for
the synthesis of pyrrolizine derivatives.
8
2
. Results and Discussion
Keywords:
tricarbonyl compound, Pyrrolizine
Electron-deficient
alkene,
Vicinal
First, we hypothesized that the Knovenagel condensation
reaction of vicinal tricarbonyl compounds with 1,3-dicarbonyl
compounds would yield the desired tetra-acceptor-substituted
alkenes by simply changing the starting material. At the outset,
the reaction of diethyl mesoxalate (1) with ethyl (4-
methoxybenzoyl)acetate (2a) was studied under dehydrative
conditions, such as in the presence of acid or under azeotrope
conditions. However, all attempts to obtain the alkene in a single
step failed. To our delight, the O-mesylation of the intermediate
alcohol 3a followed by elimination yielded the tetra-acceptor-
substituted alkene 4a in 67% isolated yield over the two steps
(Scheme 1). By employing this method, various alkenes
possessing the desired carbonyl groups were obtained in
moderate to good yields. A somewhat lower yield was obtained
from the reaction of a substrate possessing a strong electron-
withdrawing nitro group, likely due to instability of the product
(4c). Aliphatic keto esters were tolerated under the optimized
reaction conditions and were converted into the alkenes 4d and
4e in moderate yields. However, when a keto amide was used,
only a 32% yield of 4f was afforded due to the formation of an
1. Introduction
Electron-deficient alkenes are important substrates for
Diels-Alder reactions, Michael additions, and polymerizations.
In particular, tetra-acceptor-substituted alkenes such as
tetracyanoethylene (TCNE) or ethylenetetracarboxylates have
been shown to serve as efficient building blocks for the synthesis
of densely functionalized compounds due to their high reactivity
and polyfunctionality. Although there are many examples of the
synthesis of symmetrically substituted electron-deficient alkenes,
only a few synthetic methods have been reported for tetra-
acceptor-substituted
substituents.5
This fact prompted us to study the development of a more
efficient and concise method for the construction of tetra-
acceptor-substituted alkenes having different functional groups.
In addition, we describe a novel synthetic method for divergent
1
2
3
4
alkenes
having
unsymmetrical

unidentified by-product. The reactions of acetylacetone and
diethyl malonate proceeded smoothly, even with the use of a
investigated (Table 1). When 4a was subjected to the reaction
with pyrrole 5a and then two equivalents of K CO , the cyclized
2
3
smaller amount of NEt
3
and MsCl, to afford the corresponding
3-hydroxypyrrolizine product 7aa was obtained in 67% yield
(entry 1). Here, the use of excess amount of pyrroles gave a
shorter reaction time. When 1.2 equiv of pyrrole was applied,
longer reaction time was required to complete the reaction (more
than 60 h). The 3-hydroxypyrrolizine 7aa was formed via
regioselective addition of pyrrole to the more electrophilic
carbon of the alkene followed by intramolecular cyclization. A
control experiment indicated that no cyclized product was
obtained in the absence of base (entry 2). An organic base, tert-
BuOK, was also effective in the cyclization reaction to afford
pyrrolizine 7aa in a similar yield (entry 3). When the reaction
was carried out in the presence of pyridine, only the conjugate
adduct 6aa was obtained and no cyclized product was formed,
presumably due to the low basicity of pyridine. Indeed, stronger
products 4g and 4h in 87% and 93% yields, respectively.
However, nitriles 2i and 2j did not give alcohol intermediates 3
under the same reaction conditions. The issue was resolved by
the addition of a base, and the corresponding alkenes 4i and 4j
were synthesized directly from mesoxalate and nitrile
compounds in the presence of a catalytic amount of K CO .
2 3
Meanwhile, nitro-substituted alkene 4k showed reduced
reactivity that resulted in a low yield. Indeed, the isolated alkene
4
k easily decomposed in air at room temperature. Other isolated
alkenes 4a–j also decomposed when stored at room temperature
for one month. This problem was addressed by storing the
products at -20 °C or as a dilute solution. This result indicates
that tetra-acceptor-substituted alkenes are highly reactive.
organic bases, such as NEt
3
and diisopropylethylamine (i-
Pr NEt), provided pyrrolizine 7aa in 67% and 66% yields,
2
respectively (entries 5 and 10). It is noted that there is no
significant difference in the product ratio (6aa/7aa) even at a
higher reaction temperature, longer reaction time, or increased
amount of base (entries 6–8). These results indicate the existence
of an equilibrium between conjugate adduct 6aa and 3-
hydroxypyrrolizine 7aa in the presence of an amine. In fact, 35%
1
of 6aa was observed by H NMR when isolated 7aa was
subjected to the same reaction conditions as the cyclization
reaction, i.e., heated to 60 °C in chloroform in the presence of
two equivalents of NEt (Scheme 3(a)). Surprisingly, when 1,8-
3
diazabicycloundec-7-ene (DBU) was used as the base,
Table 1. Conjugate Addition of Pyrrole with Tetra-acceptor-
substituted Alkenes
Scheme 1. Synthesis of Tetra-acceptor-substituted Alkenes
Yielda),b) (%)
Next, we tried to demonstrate the synthetic utility of the
obtained tetra-acceptor-substituted alkenes. Based on structural
features of the alkenes that possess high electrophilicity and
multiple functionality, we reasoned that they can undergo
conjugate addition with low-reactive dinucleophiles, such as
pyrrole derivatives. Namely, the conjugate addition/cyclization
cascade reaction of pyrrole and alkenes could be achieved
pKa of
Base
equiv)
Entry
conjugate
acid
(
6aa
7aa
8aa
67
(97 : 3)
0
63
(97 : 3)
1
2
3
K
2
CO
none
t-BuOK
2)
Pyridine
2)
3
(2)
10.3
29
99
29
1
0
3
(Scheme 2).
17.0
5.3
(
4
99
30
0
0
0
(
6
7
5
NEt
3
(2)
10.6
(96 : 4)
6 c)
NEt
NEt
NEt
(2)
(2)
(2)
30
31
30
30
69
65
68
67
66
(98 : 2)
0
0
0
0
0
3
3
3
d)
7
Scheme 2. Reaction of Alkenes with Pyrrole and Two
8 e)
9
NEt
3
(10)
Intramolecular Cyclization Paths
i-Pr
2
NEt
1
0 f)
10.9
13.2
31
0
0
(2)
In addition, there are two possible cyclization paths when
unsymmetrical alkenes are used as substrates, namely,
intramolecular attack of the pyrrole nitrogen on the ester carbon
11
DBU (1)
85
a) Determined by 1H NMR measurement using 1,1,2,2-
tetrachloroethane as the internal standard. b) The numbers in
(path (a)) or on the ketone/nitrile carbon (path (b)) (Scheme 2).
1
parentheses are diastereoisomeric ratio determined by H NMR.
Here, we succeeded in controlling the chemoselectivity of the
cyclization, affording a divergent synthesis of pyrrolizine
derivatives. The two cyclization paths were controlled by
changing the additives.
c) Reaction was performed at 100 °C. d) Reaction was performed
at 120 °C. e) Reaction was performed over 24 h. f) Reaction was
performed over 18 h.
Initially, the cascade reaction of pyrrole with 4a was

The reaction of selected substrates, triester or tetraester (4b, 4d,
e, 4h, 4i, 4k), with various pyrrole derivatives (5a–d), gave the
4
corresponding products 8 in moderate to high yields. Both aryl
and alkyl ketone substituents of alkenes could furnish the
corresponding pyrrolizinone 8ba and 8da in 82% and 75%
yields, respectively. Gratifyingly, this cyclization proceeded well
with good efficiency even with a bulky t-butyl group (8ea, 69%).
Additionally, alkenes possessing electron-withdrawing
substituents, such as ester, cyano, and nitro, were efficiently
converted to pyrrolizinones (8ha, 8ia, and 8ka) in high yields
(64–85%). The reaction of alkyl-substituted pyrroles 5b–5d
Scheme 3. Control Experiments
gave a complicated/complex product mixture under the
optimized reaction conditions. This is probably due to the higher
pyrrolizinone 8aa was selectively obtained without any
detectable amount of 7aa (entry 11). This product was formed
by the nucleophilic attack of the pyrrole nitrogen on the ester
carbonyl carbon.
To obtain further mechanistic insight about the dependence
of the cyclization path on the base, the time course of the reaction
of conjugate adduct 6aa with the base was studied (Figure 1).
11
nucleophilicity of alkyl substituted pyrroles than that of
unsubstituted pyrrole. In these cases, it was necessary to conduct
the reaction with a lower amount of pyrrole and a shorter
reaction time. Under these mild reaction conditions, the desired
pyrrolizinones 8bb–8bd were obtained in moderate to high
yields.
With the addition of NEt
proceeded smoothly and reached equilibrium within 90 min
Figure 1(a)). On the other hand, when DBU was used,
3
to 6aa, the cyclization reaction
(
pyrrolizine 7aa was immediately formed, following which the
conversion of 7aa into pyrrolizinone 8aa was observed. In
addition, DBU treatment of isolated pyrrolizine 7aa yielded 8aa
as the sole product (Scheme 3(b)). Based on these results, a
plausible reaction mechanism is proposed in Scheme 4.
Intramolecular cyclization proceeds at the acyl group prior to the
ester group due to its higher electron deficiency and yields 3-
hydroxypyrrolizine. This nucleophilic addition reaction is
reversible process. On the other hand, DBU effectively activates
the intramolecular attack of the pyrrole nitrogen on the ester
carbonyl carbon, including DBU-assisted proton transfer
transition states I and II (Scheme 4).10 This nucleophilic
substitution reaction is irreversible process. As a result, the
intramolecular cyclization of intermediate 6 gives pyrrolizinone
8
as sole product.
1
00
100
80
60
40
20
0
8
6
4
2
0
0
0
0
0
a)
STEP 1: 1.2 equiv of pyrrole for 1 h.
Scheme 5. Scope of the Cyclization Reaction for the Formation
of Pyrrolizinone Derivatives
Next, we investigated the reaction of alkenes with pyrroles
in the presence of acid (Scheme 6). Surprisingly, switching the
additive from base to acid gave a distinctly different product.
Namely, neither 3-hydroxypyrrolizine nor 3-oxopyrrolizine
were detected, but dehydrated pyrrolizine derivative 9aa was
obtained as the sole product (65% yield) via dehydration of 7aa.
0
30
60
90
120
150
180
0
30
60
90
120
150
180
Figure 1. Time course of the reaction of 6 in the presence of (a)
triethylamine, and (b) DBU
Scheme 4. A Plausible Mechanism for Intramolecular
Scheme 6. Conjugate Addition and Cyclization of Pyrrole 5a
with Tetra-acceptor-substituted Alkene 4a
Cyclization
With the optimal reaction conditions in hand, we set out to
construct a pyrrolizine library with additive-dependent divergent
cyclizations. As shown in Scheme 5, the formation of 3-
oxopyrrolizines (pyrrolizinone) induced by DBU was studied.
The scope of this acid-mediated reaction was studied in
detail (Scheme 7). Alkenes 4b and 4d showed similar reactivity
to 4a to afford the corresponding pyrrolizine 9 in high yields. On

the other hand, the reaction of sterically hindered 4e gave an
inseparable complex mixture. When the intramolecular
cyclization reaction of isolated pyrrole adduct 6ea was
performed in the presence of p-TsOH, only a trace amount of 9ea
was obtained along with 11% of water adduct intermediate 7ea.
This may be due to the steric repulsion of the t-butyl group.
Figure 2. Molecular structure of pyrrolizine 11 with a 50%
probability level
3
. Conclusion
We have demonstrated the synthesis of various tetra-
acceptor-substituted alkenes possessing unsymmetrical
substituents. The alkenes have a high electron-deficient
character and easily react with pyrroles without any additives.
Moreover, we have also developed an efficient method for the
construction of divergent pyrrolizine derivatives. The reaction
occurs via the regioselective nucleophilic addition of pyrroles to
alkenes followed by intramolecular cyclization. Importantly, the
selective cyclization to form different types of pyrrolizine
derivatives from the same starting materials was accomplished
by using different additives.
a
Two step method, from isolated 6ea
Scheme 7. Scope of the Cyclization Reaction for the
Formation of Pyrrolizine Derivatives
Interestingly, the reaction of 2-ethylpyrrole 5b gave not
only 9bb (46% yield), but also 28% of 10bb (Scheme 8). The
0bb product was formed via intramolecular nucleophilic attack
of the pyrrole ring C3 to ketone carbonyl carbon. This is
probably due to the slightly higher electron density at the pyrrole
ring from the electron-donating alkyl substituent. Pyrroles
possessing several alkyl substituents also underwent the
addition/cyclization reaction to give only N-cyclized products
1
4. Experimental
General Procedure for the Synthesis of Tetra-acceptor-
substituted Alkenes
9
bc and 9bd, both in 84% yield.
–
1,3-dicarbonyl compounds as substrate
To a chloroform solution (1.0 mL) of diethyl mesoxalate (209
mg, 1.2 mmol) in a screw capped tube, 1,3-dicarbonyl
compounds 2 (1.0 mmol) was added, and the resultant mixture
was heated at 60 °C for 24 h. Upon completion of the reaction,
the mixture was added 5 mL of water, and was extracted with
4
chloroform (3 × 3 mL). The extract was dried over MgSO and
concentrated in vacuo to afford the oily product. The crude
product without purification was directly used in the next step.
The crude material was dissolved in dichloromethane (1.0 mL)
at -0 °C and then triethylamine (830 μL, 6.0 mmol) and a
solution of methanesulfonyl chloride (573 mg, 5.0 mmol) in
dichloromethane (2.0 mL) were added slowly. After 3 h, the
mixture was quenched with 10% HCl aq. (6 mL) and the
Scheme 8. Conjugate Addition and Cyclization Reaction of
Alkene 4b with various Pyrrole Derivatives
combined organic phases were washed with a saturated NaHCO
aq. (30 mL × 3) and brine (30 mL). After drying with MgSO
and concentration under reduced pressure, the residue was
purified by column chromatography (8 : 2 = hexane/ethyl
acetate) to afford the product.
3
When the reaction of dicyano-substituted alkene 4j with
pyrrole was performed in the presence of NEt , pyrrolizine 11
3
was obtained in 92% yield (Scheme 9). The structure of 11 was
further confirmed by single crystal X-ray analysis (Figure 2).
4
–
Cyano substituted active methylene compounds as substrate
To a dichloromethane solution (20 mL) of diethyl mesoxalate
455 mg, 2.6 mmol) in a round bottom flask, cyano compounds
(2.1 mmol) and potassium carbonate (0.2 mmol) were added,
(
2
and the resultant mixture was heated at 40 °C for 2 h. Upon
completion of the reaction, the mixture was added 20 mL of
dichloro methane, and was washed with water (2 × 20 mL). The
Scheme 9. Conjugate Addition and Cyclization Reaction of
Alkene 4j with Pyrrole 5a
4
residue was dried over MgSO and concentrated in vacuo to
afford the oily product. The crude product was purified by
column chromatography (8 : 2 = hexane/ethyl acetate) to afford
the product.
–
Nitro ester as substrate
To a dichloromethane solution (5 mL) of diethyl mesoxalate (119
mg, 0.68 mmol) in a round bottom flask, ethyl nitroacetate 2k
(102 mg, 0.53 mmol) and potassium carbonate (0.05 mmol) were
added, and the resultant mixture was heated at 40 °C for 3 h.

Upon completion of the reaction, the mixture was added 5 mL of
water, and was extracted with dichloromethane (5 mL). The
(CH
(CH
3
2
), 13.8(CH
3 3 2 2
), 14.0 (CH ), 62.7 (CH ), 63.2 (CH ), 63.3
), 124.2 (CH), 129.7 (CH), 136.6 (C), 140.0 (C), 141.1 (C),
extract was dried over MgSO
4
and concentrated in vacuo. The
150.8 (C), 161.7 (C), 163.2 (C), 189.0 (C); IR (ATR)1724, 1689,
-1
+
crude product without purification was directly used in the next
step. The dehydration step was same as the case of 1,3-
dicarbonyl compounds.
General Procedure for the Reaction of Tetra-acceptor-
substituted Alkenes
Formation of pyrrolizine 7: A 5 mL test tube was charged with
alkene 4 (1.2 mmol) with pyrrole (6.4 mmol) and ethanol (2.5
mL). The reaction mixture was heated to 60 °C for 24 h. After
the solvent was removed under vacuum, chloroform (5 mL) and
1529, 1346 cm ; HRMS (ESI) m/z [M + Na] Calcd for
+
C
18
H
19NO
9
Na :416.0952, Found: m/z 416.0971.
Triethyl 3-oxobut-1-ene-1,1,2-tricarboxylate (4d): Yellow oil
1
(160 mg, 56% yield); H NMR (400 MHz, CDCl
3
) δ 1.25–1.37
(m, 9H), 2.43 (s, 3H), 4.24–4.40 (m, 6H); C NMR (100 MHz,
CDCl ) δ 13.7 (CH ), 13.8(CH ), 13.8 (CH ), 29.7 (CH ), 62.4
(CH ), 62.7 (CH ), 62.8 (CH ), 133.4 (C), 142.9 (C), 162.3 (C),
162.3 (C), 163.2 (C), 196.9 (C); IR (ATR) 1724, 1713, 1710 cm
1
3
3
3
3
3
3
2
2
2
-
1
+
+
; HRMS (ESI) m/z [M + Na] Calcd for C13
Found: 309.0946.
1,1-Diethyl 2-methyl 3-oxo-4,4-dimethylpent-1-ene-1,1,2-
tricarboxylate (4e): Colorless oil (189 mg, 60% yield); 1
NMR (400 MHz, CDCl ) δ 1.24 (s, 9H), 1.28 (t, J = 7.2 Hz, 3H),
1.32 (t, J = 7.2 Hz, 3H), 3.81 (s, 3H), 4.29 (q, J = 7.2, Hz, 2H),
7
H19NaO : 309.0945,
3
NEt (2.4 mmol) were added. The mixture was stirred at 60 °C
for 3 h. After completion of reaction, the solvent was removed
under reduced pressure. The residue was purified by silica gel
column chromatography (9 : 1 = hexane/ethyl acetate).
Formation of pyrrolizinone 8: A5 mL test tube was charged with
alkene 4 (1.0 mmol) with pyrrole (5.0 mmol) and ethanol (2 mL).
The reaction mixture was heated to 60 °C for 24 h. Then, DBU
H
3
1
3
4.32 (q, J = 7.2, Hz, 2H); C NMR (100 MHz) δ 13.9 (CH
13.9 (CH ), 27.4 (CH ), 45.0 (C), 53.2 (CH ), 62.3 (CH ), 62.8
(CH ), 133.4 (C), 145.3 (C), 162.3 (C), 163.0 (C), 163.4 (C),
206.8 (C); IR (NaCl) 1737, 1732, 1703 cm ; HRMS (ESI) m/z
3
),
3
3
3
2
(1.0 mmol) was added, and the reaction mixture was stirred for
2
-1
3
h at 60 °C. The reaction was quenched with 1 M HCl aq. (1
+
+
mL) and the solvent was evaporated under reduced pressure. The
residue was extracted three times with chloroform (3 × 5 mL).
The combined organic layers were dried over MgSO
7
[M + Na] Calcd for C15H22NaO : 337.1258, Found: 337.1248.
1,1-Diethyl 2-methyl 3-(dimethylamino)-3-oxoprop-1-ene-
1
4
and
1,1,2-tricarboxylate (4f): Yellow oil (96 mg, 32% yield); H
filtered, and the filtrate was concentrated under reduced pressure.
The residue was purified by silica gel column chromatography
NMR (400 MHz, CDCl
7.2 Hz, 3H), 2.43 (s, 3H), 3.01 (s, 3H), 3.02 (s, 3H),4.25 (q, J =
3
) δ 1.28 (t, J = 7.2 Hz, 3H), 1.30 (t, J =
13
(95 : 5 = hexane/ethyl acetate).
7.2, Hz, 2H), 4.28 (q, J = 7.2, Hz, 2H); C NMR (100 MHz) δ
13.9 (CH ), 14.0 (CH ), 29.2 (CH ), 34.7 (CH ), 38.0 (CH ), 62.4
(CH ), 126.9 (C), 151.4 (C), 162.7 (C), 163.5 (C), 164.0 (C),
Formation of pyrrolizine 9: A 5 mL test tube was charged with
alkene 4 (1.0 mmol) with pyrrole (5.0 mmol) and ethanol (2 mL).
The reaction mixture was heated to 60 °C for 24 h. After the
solvent was removed under vacuum, chloroform (5 mL) and p-
TsOH (1.1 mmol) were added, and the reaction mixture was
stirred for 3 h at 60 °C. The reaction was quenched with saturated
3
3
3
3
3
2
-
1
197.6 (C); IR (NaCl) 1734, 1715, 1707, 1653 cm ; HRMS (ESI)
+
+
m/z [M + H] Calcd for C13
H20NO
6
: 286.1285, Found:
286.1274.
Diethyl 2-(2,4-dioxopentan-3-ylidene)malonate (4g): Yellow
1
NaHCO
3
aq. (2 × 5 mL) and organic layer was dried over MgSO
4
oil (223 mg, 87% yield); H NMR (400 MHz, CDCl
J = 7.2 Hz, 6H), 2.40 (s, 6H), 4.29 (q, J = 7.2, Hz, 4H), C NMR
(100 MHz) δ 13.8 (CH ), 29.7 (CH ), 62.6 (CH ), 127.8 (C),
154.7 (C), 163.0 (C), 197.3 (C); IR (NaCl) 1735, 1711 cm ;
HRMS (ESI) m/z [M + Na] Calcd for C12
3
); δ 1.31 (t,
1
3
and filtered, and the filtrate was concentrated. The residue was
purified by silica gel column chromatography (9 : 1 =
hexane/ethyl acetate).
3
3
2
-1
+
+
Triethyl
tricarboxylate (4a): Yellow oil (253 mg, 67% yield); H NMR
400 MHz, CDCl ) δ 1.07 (t, J = 6.8 Hz, 3H), 1.17 (t, J = 7.2 Hz,
H), 1.37 (t, J = 7.2 Hz, 3H), 3.87 (s, 3H), 4.08 (q, J = 6.8 Hz,
H), 4.21 (q, J = 7.2 Hz, 2H), 4.38 (q, J = 7.2 Hz, 2H), 6.95 (d,
3-oxo-3-(4-methoxyphenyl)prop-1-ene-1,1,2-
H16NaO
6
: 279.0839,
1
Found: 279.0839.
4
c
(
3
Tetraethyl ethene-1,1,2,2-tetracarboxylate (4h) : Yellow oil
1
3
2
3
(294 mg, 93% yield); H NMR (400 MHz, CDCl ) δ 1.32 (t, J =
7.2 Hz, 12H), 4.32 (q, J = 7.2 Hz, 8H).
1
3
J = 8.0 Hz, 2H), 7.89 (d, J = 8.0 Hz, 2H); C NMR (100 MHz,
CDCl ) δ 13.6 (CH ), 13.8 (CH ), 14.0 (CH ), 55.6 (CH ), 62.4
), 62.7 (CH ), 63.8 (CH ), 114.2 (CH), 128.8(C), 131.3
CH), 134.7 (C), 142.7 (C), 162.0 (C), 162.7 (C), 163.7 (C),
1,1-Diethyl 2-methyl 2-cyanoethene-1,1,2-tricarboxylate
5
d
1
3
3
3
3
3
(4i) : Yellow oil (176 mg, 69% yield); H NMR (400 MHz,
CDCl ) δ 1.36 (t, J = 7.2 Hz, 3H), 1.37 (t, J = 7.2 Hz, 3H), 3.92
(s, 3H), 4.40 (q, J = 7.2 Hz, 2H), 4.41 (q, J = 7.2 Hz, 2H);
NMR (100 MHz, CDCl ) δ 13.8 (CH ), 13.9 (CH ), 54.4 (CH
63.3 (CH ), 64.0 (CH ), 112.0 (C), 114.0 (C), 147.6 (C), 159.8
(C), 159.8 (C), 161.9 (C); IR (NaCl) 2260, 1764, 1755, 1745,
(CH
2
2
2
3
13
(
C
-
1
164.4 (C), 188.7 (C); IR (ATR) 1724, 1670 cm ; HRMS (ESI)
3
3
3
3
),
+
+
m/z [M + Na] calcd for C19
01.1213
Triethyl 3-oxo-3-phenylprop-1-ene-1,1,2-tricarboxylate (4b):
H
22NaO
8
: 401.1207, Found:
2
2
4
-1
1625 cm .
Diethyl 2,2-dicyanoethene-1,1-dicarboxylate (4j) : Yellow
1
5d
Yellow oil (209 mg, 60% yield); H NMR (400 MHz, CDCl
.05 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz, 3H), 1.38 (t, J = 7.2
Hz, 3H), 4.07 (q, J = 7.2 Hz, 2H), 4.21 (q, J = 7.2 Hz, 2H), 4.40
q, J = 7.2 Hz, 2H), 7.48 (dd, J = 7.2, 8.0 Hz, 2H), 7.60 (t, J =
.2 Hz, 1H), 7.92 (d, J = 8.0 Hz, 2H); 13C NMR (100 MHz,
CDCl ) δ 13.5 (CH ), 13.8 (CH ), 14.0 (CH ), 62.5 (CH ), 62.8
), 62.8 (CH ), 128.9 (CH), 128.9 (CH), 134.0 (CH), 135.3
C), 135.6 (C), 142.3 (C), 161.9 (C), 162.4 (C), 163.6 (C), 190.3
3
) δ
1
1
oil (167 mg, 75% yield); H NMR (400 MHz, CDCl
J = 7.2 Hz, 6H), 4.45 (q, J = 7.2 Hz, 4H); 13C NMR (100 MHz,
CDCl ) δ 13.9 (CH ), 64.6 (CH ), 96.7 (C), 109.5 (C), 151.1 (C),
3
) δ 1.39 (t,
(
7
3
3
2
-1
159.2(C); IR (NaCl) 2237, 1755, 1745, 1732, 1608 cm .
3
3
3
3
2
Triethyl 2-nitroethene-1,1,2-tricarboxylate (4k): Yellow oil
1
(
(
(
[
CH
2
2
(69 mg, 24% yield); H NMR (400 MHz, CDCl
3
) δ 1.32 (t, J =
6.8 Hz, 3H), 1.35 (t, J = 7.2 Hz, 3H), 1.36 (t, J = 7.2 Hz, 3H),
-1
C); IR (NaCl) 1737, 1726, 1681, 1597 cm ; HRMS (ESI) m/z
M+Na] Calcd for C18
4.35 (q, J = 7.2, Hz, 2H), 4.38 (q, J = 6.8, Hz, 2H), 4.39 (q, J =
+
+
13
H
20NaO
7
: 371.1101, Found: 371.1110.
7.2, Hz, 2H); C NMR (100 MHz) δ 13.7 (CH
3
), 13.8 (CH
), 129.3 (C), 146.1
(C), 157.3 (C), 159.4 (C), 160.5 (C); IR (ATR) 1739, 1558, 1369
3
),
Triethyl
tricarboxylate (4c): Yellow oil (122 mg, 31% yield); H NMR
400 MHz, CDCl ) δ 1.14 (t, J = 7.2 Hz, 3H), 1.16 (t, J = 7.2 Hz,
H), 1.39 (t, J = 7.2 Hz, 3H), 4.12 (q, J = 7.2 Hz, 2H), 4.22 (q, J
3-oxo-3-(4-nitrophenyl)prop-1-ene-1,1,2-
3 2 2 2
13.9 (CH ), 63.6 (CH ), 63.9 (CH ), 64.4(CH
1
-1
+
+
(
3
cm ; HRMS (ESI) m/z [M + Na] Calcd for C11
312.0690, Found: 312.0675.
8
H15NNaO :
3
=
8
7.2 Hz, 2H), 4.42 (q, J = 7.2 Hz, 2H), 8.07 (d, J = 8.4 Hz, 2H),
) δ 13.7
Triethyl
3-oxo-3-(4-methoxyphenyl)-(1H-pyrrol-2-yl)
.34 (d, J = 8.4 Hz, 2H); 13C NMR (100 MHz, CDCl
propane-1,1,2-tricarboxylate (6aa): White solid (441 mg, 99%
3

1
yield); mp 116.5–117.4 °C (decomposite); H NMR (400 MHz,
CDCl ) δ 1.08 (dd, J = 7.2, 7.2 Hz, 3H), 1.21 (dd, J = 7.2, 7.2
Hz, 3H), 1.30 (t, J = 7.2 Hz, 3H), 3.85 (s, 3H), 4.02 (dq, J = 7.2,
1
1
3 2 2
(CH ), 59.4 (C), 61.7 (CH), 62.5 (CH ), 63.4 (CH ), 109.2 (CH),
3
113.2 (CH), 120.0 (CH), 128.9 (CH), 129.7 (CH), 134.4 (CH),
134.4 (C), 136.0 (C), 164.6 (C), 166.0 (C), 167.2 (C), 192.6 (C);
-1
0.8 Hz, 1H), 4.09 (dq, J = 7.2, 10.8 Hz, 1H), 4.19 (dq, J = 7.2,
0.8 Hz, 1H), 4.24 (dq, J = 7.2, 10.8 Hz, 1H), 4.36 (q, J = 7.2
IR (NaCl) 1768, 1737, 1687, 1681 cm ; HRMS (ESI) m/z [M +
+
+
Na] Calcd for C20
Diethyl 2-acetyl-3-oxo-2,3-dihydro-1H-pyrolizine-1,1-
dicarboxylate (8da): Brown oil (230 mg, 75% yield (Keto :
6
H19NNaO : 392.1105, Found: 392.1105.
Hz, 2H), 5.58 (s, 1H), 5.90–6.01 (m, 2H), 6.71 (dd, J = 2.4, 4.0
Hz, 1H), 6.91 (d, J = 8.8 Hz, 2H), 7.90 (d, J = 8.8 Hz, 2H), 9.60–
.70 (br s, 1H); 13C NMR (100 MHz, CDCl
) δ 13.8 (CH
), 58.0 (CH), 59.5 (C), 61.7 (CH ), 62.4 (CH
), 107.8 (CH), 108.4 (CH), 113.9 (CH), 118.4 (CH),
), 13.9
1
9
3
3
3
Enol = 28 : 72)); H NMR (400 MHz, CDCl ) keto δ 1.24 (dd, J
(CH
3
), 55.6 (CH
3
2
2
),
= 6.8, 7.2 Hz, 6H), 2.51 (s, 3H), 4.20–4.28 (m, 4H), 4.96 (s, 1H),
6.42 (dd, J = 0.8, 3.2 Hz, 1H), 6.50 (dd, J = 3.2, 3.2 Hz, 1H),
7.05 (dd, J = 0.8, 3.2 Hz, 1H). Enol δ 1.27 (dd, J = 7.2, 7.2 Hz,
6H), 2.17 (s, 3H), 4.20–4.28 (m, 4H), 6.29 (dd, J = 1.2, 3.2 Hz,
1H), 6.47 (dd, J = 2.8, 3.2 Hz, 1H), 7.11 (dd, J = 1.2, 2.8 Hz, 1H),
62.5 (CH
2
1
(
24.9 (C), 130.0 (C), 130.9 (CH), 163.9 (C), 167.5 (C), 168.5
C), 169.1 (C), 192.2 (C); IR (NaCl) 3425, 1737, 1681 cm ;
HRMS (ESI) m/z [M + H] Calcd for C23H28NO : 446.1809,
8
-1
+
+
-1
Found: m/z 446.1803.
12.21 (s, 1H); IR (ATR) 1736, 1689 cm ; HRMS (ESI) m/z [M
+
+
Triethyl 3-hydroxy-3-(4-methoxyphenyl)-2,3-dihydro-1H-
6
+ Na] Calcd for C15H17NNaO : 330.0948, Found: 330.0961.
pyrolizine-1,1,2-tricarboxylate (7aa): White Solid (294 mg,
Diethyl 3-oxo-2,3-dihydro-2-(2,2-dimethylpropanoyl)-1H-
1
66% yield (dr = 98 : 2)); mp 105.6–106.5 °C (decomposite); H
pyrolizine-1,1-tricarboxylate (8ea): Brown oil (241 mg, 69%
1
NMR (400 MHz, CDCl
3
) δ 1.14 (dd, J = 7.2, 7.2 Hz, 3H), 1.34
yield); H NMR (400 MHz, CDCl
3
) δ 1.26 (dd, J = 6.8, 7.2 Hz,
(
dd, J = 6.8, 7.2 Hz, 3H), 1.36 (dd, J = 7.2, 6.8 Hz, 3H), 3.83 (s,
3H), 1.27 (dd, J = 7.2, 7.2 Hz, 3H), 1.30 (s, 1H), 4.14 (dq, J =
6.8, 10.8 Hz, 1H), 4.22 (dq, J = 7.2, 10.8 Hz, 1H), 4.24 (dq, J =
7.2, 10.8 Hz, 1H), 4.26 (dq, J = 7.2, 10.8 Hz, 1H), 5.52 (s, 1H),
3
1
1
1
H), 4.03 (dq, J = 7.2, 10.8 Hz, 1H), 4.22 (dq, J = 7.2, 10.8 Hz,
H), 4.25-4.37 (m, 5H), 6.00 (s, 1H), 6.23 (dd, J = 1.2, 3.6 Hz,
H), 6.28 (dd, J = 2.8, 3.6 Hz, 1H), 6.45 (dd, J = 1.2, 2.8 Hz,
H), 6.88 (d, J = 8.8 Hz, 2H), 7.40 (d, J = 8.8 Hz, 2H); 13C NMR
6.39 (dd, J = 1.2, 3.2 Hz, 2H), 6.50 (dd, J = 3.2, 3.2 Hz, 2H),
13
7.03 (dd, J = 1.2, 3.2 Hz, 2H); C NMR (100 MHz, CDCl
3
) δ
), 46.2 (C), 60.0 (C), 60.4
), 109.2 (CH), 113.0 (CH), 119.8
(
(
8
(
100 MHz, CDCl
CH ), 59.6 (C), 61.4 (CH
9.7 (C), 103.5 (CH), 113.3 (CH), 114.0 (CH), 114.4 (CH), 128.2
CH), 130.1 (C), 132.2 (C), 159.9 (C), 167.3 (C), 167.8 (C),
3
) δ 13.8 (CH
3
), 14.0 (CH
3
), 14.1 (CH
3
), 55.4
13.9 (CH
3
), 14.0 (CH
3
), 26.2 (CH
3
3
2
), 62.4 (CH
2
), 63.7 (CH
2
), 66.9 (CH),
(CH), 62.7 (CH
2
), 63.4 (CH
2
(CH), 134.6 (C), 165.2 (C), 166.5 (C), 167.2 (C), 208.3 (C); IR
-
1
+
(ATR) 1761, 1743, 1707 cm ; HRMS (ESI) m/z [M + H] Calcd
-1
+
1
70.0 (C); IR (NaCl) 3373, 1745, 1713 cm ; HRMS (ESI) m/z
for C18
H24NO
6
: 350.1598, Found: 350.1609.
+
+
[M + Na] Calcd for C23
H
27NaO
8
: 468.1629, Found: 468.1619.
Triethyl
3-oxo-2,3-dihydro-1H-pyrrolizine-1,1,2-
1
1
,1-Diethyl 2-methyl 2,3-dihydro-3-hydroxy-3-(2-methyl-2-
tricarboxylate (8ha). Brown oil (216 mg, 64% yield); H NMR
propyl)-1H-pyrrolizine-1,1,2-tricarboxylate (7ea): Colorless
3
(400 MHz, CDCl ) δ 1.26 (dd, J = 6.8, 7.2 Hz, 3H), 1.27 (t, J =
1
oil (42 mg, 11% yield); H NMR (400 MHz, CDCl
3
) δ 1.10 (s,
7.2 Hz, 3H), 1.28 (t, J = 7.2 Hz, 3H), 4.16–4.31 (m, 6H), 4.81 (s,
1H), 6.41 (dd, J = 1.2, 3.2 Hz, 1H), 6.52 (dd, J = 3.2, 3.2 Hz,
9
3
6
7
3
H), 1.23 (dd, J = 7.2, 7.2 Hz, 3H), 1.31 (dd, J = 6.8, 7.2 Hz,
1
3
H), 3.77 (s, 3H), 4.12 (dq, J = 7.2, 10.8 Hz, 1H), 4.22 (dq, J =
.8, 10.8 Hz, 1H), 4.28 (dq, J = 7.2, 10.8 Hz, 1H), 4.30 (dq, J =
.2, 10.8 Hz, 1H), 4.78 (s, 1H), 4.84 (s, 1H), 6.09 (dd, J = 1.2,
.6 Hz, 1H), 6.29 (dd, J = 2.8, 3.6 Hz, 1H), 6.89 (dd, J = 1.2, 2.8
3
1H), 7.09 (dd, J = 1.2, 3.2 Hz, 1H); C NMR (100 MHz, CDCl )
δ 13.9 (CH
3
), 13.9 (CH
3
), 14.0 (CH
3
), 58.6 (C), 59.9 (CH), 62.6
(CH ), 62.7 (CH
2
2
), 63.4 (CH
2
), 109.2 (CH), 113.9 (CH), 120.0
(CH), 133.9 (C), 163.9 (C), 165.5 (C), 166.0 (C), 166.7 (C); IR
1
3
-1
+
Hz, 1H); C NMR (100 MHz, CDCl
5.5 (CH ), 40.7 (C), 52.7 (CH), 56.9 (CH), 61.3 (CH
CH ), 94.8 (C), 103.1 (CH), 114.2 (CH), 115.1 (CH), 130.4 (C),
3
) δ 13.9 (CH
3
), 14.1 (CH
3
),
(NaCl) 1776, 1732 cm ; HRMS (ESI) m/z [M + Na] Calcd for
+
2
(
3
2
), 62.7
C
16
H
19NNaO
7
: 360.1054, Found: 360.1038.
2
Diethyl
2-cyano-3-oxo-2,3-dihydro-1H-pyrrolizine-1,1-
-1
1
167.7 (C), 169.0 (C), 171.9 (C); IR (ATR) 3482, 1740 cm ;
dicarboxylate (8ia): Yellow oil (229 mg, 79% yield); H NMR
+
+
HRMS (ESI) m/z [M + Na] Calcd for C19
Found: 404.1675.
H
27NNaO
7
: 404.1680,
3
(400 MHz, CDCl ) δ 1.30 (dd, J = 7.2, 7.2 Hz, 3H), 1.35 (dd, J
= 7.2, 7.2 Hz, 3H), 4.26–4.43 (m, 4H), 4.94 (s, 1H), 6.43 (dd, J
= 0.8, 3.2 Hz, 1H), 6.56 (dd, J = 3.2, 3.2 Hz, 1H), 7.13 (dd, J =
Diethyl
2-(4-methoxybenzoyl)-3-oxo-2,3-dihydro-1H-
1
3
pyrrolizine-1,1-dicarboxylate (8aa): Brown oil (339 mg, 85%
0.8, 3.2 Hz, 1H); C NMR (100 MHz, CDCl
13.9 (CH ), 44.5 (CH), 58.5 (C), 63.8 (CH ), 64.1 (CH
(CH), 112.3 (C), 114.2 (CH), 120.3 (C), 131.1 (C), 159.9 (C),
3
) δ 13.8 (CH
3
),
1
yield); H NMR (400 MHz, CDCl
3
) δ 1.07 (t, J = 7.2 Hz, 3H),
3
2
2
), 110.0
1
2
1
3
.25 (dd, J = 6.8, 7.2 Hz, 3H), 3.90 (s, 3H), 4.12 (q, J = 7.2 Hz,
-
1
H), 4.23 (dq, J = 6.8, 10.8 Hz, 1H), 4.26 (dq, J = 7.2, 10.8 Hz,
H), 5.89 (s, 1H), 6.48 (dd, J = 1.2, 3.2 Hz, 1H), 6.53 (dd, J =
.2, 3.2 Hz, 1H), ,6.99 (d, J = 8.8 Hz, 2H), 7.06 (dd, J = 1.2, 3.2
165.4 (C); IR (NaCl) 2256, 1768, 1732, 1371 cm ; HRMS (ESI)
m/z [M + Na] Calcd for C14
+
+
14
H N
2
NaO
5
: 313.0795, Found:
313.0795.
1
3
Hz, 1H), 8.10 (d, J = 8.8 Hz, 2H); C NMR (100 MHz, CDCl
δ 13.7 (CH ), 13.9 (CH ), 55.7 (CH ), 59.4 (C), 61.6 (CH), 62.4
), 63.3 (CH ), 109.2 (CH), 113.2 (CH), 114.2 (CH), 119.9
CH), 129.0 (C), 132.2 (CH), 134.6 (C), 164.7 (C), 164.9 (C),
3
)
Diethyl
tricarboxylate (8ka): Yellow oil (264 mg, 85% yield); H NMR
(400 MHz, CDCl ) δ 1.26 (t, J = 7.2 Hz, 3H), 1.29 (dd, J = 7.2,
2-nitro-3-oxo-2,3-dihydro-1H-pyrolizine-1,1-
1
3
3
3
(CH
2
2
3
(
7.2 Hz, 3H), 4.25 (dq, J = 7.2, 10.8 Hz, 2H), 4.26 (t, J = 7.2 Hz,
2H), 4.32 (dq, J = 7.2, 10.8 Hz, 2H), 6.36 (s, 1H), 6.53 (dd, J =
1.2, 3.2 Hz, 1H), 6.15 (dd, J = 3.2, 3.2 Hz, 1H), 7.16 (dd, J = 1.2,
-
1
66.1 (C), 167.4 (C), 190.6 (C); IR (NaCl) 1766, 1755, 1681 cm
1
+
+
;
HRMS (ESI) m/s [M + H] Calcd for C21
Found: 400.1386.
Diethyl 2-benzoyl-3-oxo-2,3-dihydro-1H-pyrrolizine-1,1-
dicarboxylate (8ba): Brown oil (303 mg, 82% yield); H NMR
400 MHz, CDCl ) δ 1.06 (dd, J = 7.2, 7.2 Hz, 3H), 1.25 (dd, J
7.2, 7.2 Hz, 3H), 4.11 (dq, J = 7.2, 10.8 Hz, 1H), 4.12 (dq, J =
7
H22NO : 400.1391,
1
3
3.2 Hz, 1H); C NMR (100 MHz, CDCl
(CH ), 59.6 (C), 63.8 (CH ), 64.3 (CH ), 92.2 (CH), 110.8 (CH),
114.4 (CH), 121.5 (CH), 132.3 (C), 158.0 (C), 163.4 (C), 165.0
3 3
) δ 13.7 (CH ), 13.9
3
2
2
1
-1
(
=
3
(C); IR (NaCl) 1771, 1742, 1568, 1355 cm ; HRMS (ESI) m/z
[M + Na] Calcd for C13
+
+
H
14
N
2
NaO
7
: 333.0693, Found:
7
7
6
7
.2, 10.8 Hz, 1H), 4.25 (dq, J = 7.2, 10.8 Hz, 1H), 4.26 (dq, J =
.2, 10.8 Hz, 1H), 5.95 (s, 1H), 6.49 (dd, J = 0.8, 3.2 Hz, 1H),
.54 (dd, J = 3.2, 3.2 Hz, 1H), 7.07 (dd, J = 0.8, 3.2 Hz, 1H),
.53 (dd, J = 7.6, 8.0 Hz, 2H), 7.64 (t, J = 7.6 Hz, 1H), 8.11 (d,
333.0703.
Diethyl 3-oxo-2,3-dihydro-2-benzoyl-1H-5-ethylpyrolizine-
1,1-dicarboxylate (8bb): Brown oil (282 mg, 71% yield); H
NMR (400 MHz, CDCl
(t, J = 7.6 Hz, 3H), 1.26 (dd, J = 6.8, 7.2 Hz, 3H), 2.81 (dq, J =
1
3
) δ 1.06 (dd, J = 6.8, 7.2 Hz, 3H), 1.20
1
3
3 3
J = 8.0 Hz, 2H); C NMR (100 MHz, CDCl ) δ 13.7 (CH ), 13.9

0
6
6
6
.8, 7.6 Hz, 2H), 4.10 (dq, J = 7.2, 10.8 Hz, 1H), 4.12 (dq, J =
.8, 10.8 Hz, 1H), 4.22 (dq, J = 7.2, 10.8 Hz, 1H), 4.25 (dq, J =
.8, 10.8 Hz, 1H), 5.92 (s, 1H), 6.18 (dt, J = 0.8, 3.2 Hz, 1H),
.35 (d, J = 3.2 Hz, 1H),7.52 (dd, J = 7.6, 8.0 Hz, 2H), 7.62 (t, J
Triethyl 3-methyl-1H-pyrolizine-1,1,2-tricarboxylate (9da):
Yellow solid (268 mg, 80% yield); mp 67.9–68.2°C
1
(decomposite); H NMR (400 MHz, CDCl
3
) δ 1.24 (dd, J = 7.2,
7.2 Hz, 6H), 1.29 (t, J = 7.2 Hz, 3H), 2.61 (s, 3H), 4.16 (dq, J =
7.2, 10.8 Hz, 2H), 4.23 (dq, J = 7.2, 10.8 Hz, 2H), 4.25 (q, J =
7.2 Hz, 2H), 6.30 (dd, J = 0.8, 3.2 Hz, 1H), 6.35 (dd, J = 3.2, 3.2
=
7.6 Hz, 1H), 8.12 (dd, J = 0.8, 8.0 Hz, 2H); 13C NMR (100
MHz, CDCl ) δ 12.9 (CH ), 13.7 (CH ), 14.0 (CH ), 19.7 (CH ),
8.9 (C), 62.0 (CH), 62.4 (CH ), 63.3 (CH ), 108.7 (CH), 116.1
CH), 128.9 (CH), 129.8 (CH), 133.1 (C), 133.7 (C), 134.3 (CH),
3
3
3
3
3
1
3
5
(
2
2
Hz, 1H), 6.83 (dd, J = 0.8, 3.2 Hz, 1H); C NMR (100 MHz,
CDCl ) δ 11.9 (CH ), 13.9 (CH ), 14.2 (CH ), 60.2 (CH ), 62.1
(CH ), 62.5 (C), 105.9 (CH), 111.9 (CH), 114.7 (CH), 116.9 (C),
132.8 (C), 149.7 (C), 164.0 (C), 167.2 (C); IR (NaCl) 1741, 1730,
3
3
3
3
2
1
1
36.2 (C), 165.4 (C), 166.4 (C), 167.5 (C), 192.9 (C) IR (NaCl)
755, 1737, 1681 cm ; HRMS (ESI) m/z [M + Na] Calcd for
2
-1
+
+
-1
+
C
22
H
23NNaO
Diethyl
dimethylpyrolizine-1,1-dicarboxylate (8bc): Brown solid (326
6
: 420.1418, Found: 420.1420.
1693, 1394, 1363 cm ; HRMS (ESI) m/z [M + Na] Calcd for
+
3-oxo-2,3-dihydro-2-benzoyl-1H-5,7-
C
17
H
21NNaO
Triethyl-3-phenyl-5-ethyl-1H-pyrrolizine-1,1,2-
tricarboxylate (9bb): Brown oil (196 mg, 46% yield); H NMR
(400 MHz, CDCl ) δ 0.91 (t, J = 7.2 Hz, 3H), 1.00 (t, J = 7.2 Hz,
6
: 358.1261, Found: 358.1244.
1
1
mg, 82% yield); H NMR (400 MHz, CDCl
.2 Hz, 3H), 1.28 (dd, J = 6.8, 7.2 Hz, 3H), 2.17 (s, 3H), 2.34 (d,
J = 1.2 Hz, 3H), 4.06 (dq, J = 6.8, 10.8 Hz, 1H), 4.09 (dq, J =
3
) δ 1.05 (dd, J = 6.8,
7
3
3H), 1.28 (dd, J = 6.8, 7.2 Hz, 6H), 1.92 (dq, J = 1.2, 7.2 Hz,
2H), 4.02 (q, J = 7.2 Hz, 2H), 4.21 (dq, J = 7.2, 10.8 Hz, 2H),
4.27 (dq, J = 6.8, 10.8 Hz, 2H), 6.00 (dt, J = 1.2, 3.6 Hz, 1H),
7
7
.2, 10.8 Hz, 1H), 4.24 (dq, J = 6.8, 10.8 Hz, 1H), 4.27 (dq, J =
.2, 10.8 Hz, 1H), 5.98 (s, 1H), 5.99 (d, J = 1.2 Hz, 3H), 7.52
1
3
(
8
(
6
dd, J = 7.2, 8.0 Hz, 2H), 7.63 (t, J = 7.2 Hz, 1H), 8.11 (d, J =
.0 Hz, 1H); 13C NMR (100 MHz, CDCl
) δ 11.7 (CH ), 11.8
CH ), 13.8 (CH ), 14.1 (CH ), 58.9 (C), 62.1 (CH), 62.3 (CH ),
3.2 (CH ), 119.8 (C), 121.5 (CH), 126.7 (C), 127.2 (C), 128.9
6.29 (d, J = 3.6 Hz, 1H), 7.46–7.48 (m, 5H); C NMR (100 MHz,
CDCl ) δ 12.5 (CH ), 13.8 (CH ), 14.0 (CH ), 20.0 (CH ), 60.1
(CH ), 62.2 (CH ), 105.4 (CH), 111.7 (CH), 118.5 (C), 128.2
3
3
3
3
3
3
2
3
3
3
2
2
2
2
(CH), 129.1 (CH), 129.9 (CH), 130.0 (C), 132.2 (C), 132.6 (C),
151.4 (C), 163.2 (C), 167.4 (C); IR (NaCl) 1755, 1745, 1732,
(CH), 129.8 (CH), 134.3 (CH), 136.3 (C), 165.2 (C), 166.4 (C),
-1
-1
+
1
(
67.6 (C), 193.3 (C); IR (NaCl) 1745, 1739, 1683 cm ; HRMS
1595 cm ; HRMS (ESI) m/z [M
+
Na] Calcd for
ESI) m/z [M + Na]+ Calcd for C22
H23NNaO
+
: 420.1418,
C
27NNaO
Triethyl
tricarboxylate (9bc): Brown oil (357 mg, 84% yield); H NMR
(400 MHz, CDCl ) δ 0.99 (t, J = 7.2 Hz, 3H), 1.30 (dd, J = 7.2,
+
: 448.1731, Found: 448.1722.
6
24
H
6
Found: 420.1421.
Diethyl
dimethylpyrolizine-1,1-dicarboxylate (8bd): Brown solid
3-phenyl-1H-5,7-dimethylpyrrolizine-1,1,2-
1
3-oxo-2,3-dihydro-2-benzoyl-1H-6-ethyl-5,7-
3
1
(
=
170 mg, 40% yield); H NMR (400 MHz, CDCl
6.8, 7.2 Hz, 3H), 1.08 (t, J = 7.6 Hz, 3H), 1.28 (dd, J = 7.2, 7.2
Hz, 3H), 2.14 (s, 3H), 2.31 (s, 3H), 2.36 (q, J = 7.6 Hz, 2H), 4.06
3
) δ 1.05 (dd, J
7.2 Hz, 6H), 1.58 (d, J = 0.4 Hz, 3H), 2.12 (s, 3H), 4.01 (q, J =
7.2 Hz, 2H), 4.25 (dq, J = 7.2, 10.8 Hz, 2H), 4.27 (dq, J = 7.2,
1
3
10.8 Hz, 2H), 5.78 (br, 1H), 7.42–7.47 (m, 5H); C NMR (100
MHz, CDCl ) δ 11.1 (CH ), 12.7 (CH ), 13.9 (CH ), 14.2 (CH ),
60.0 (CH ), 62.1 (CH ), 116.5 (CH), 117.0 (C), 117.6 (C), 125.4
(
(
(
dq, J = 7.2, 10.8 Hz, 1H), 4.08 (dq, J = 6.8, 10.8 Hz, 1H), 4.24
dq, J = 7.2, 10.8 Hz, 1H), 4.26 (dq, J = 7.2, 10.8 Hz, 1H), 5.96
s, 1H), 7.56 (dd, J = 7.2, 8.0 Hz, 2H), 7.62 (t, J = 7.2 Hz, 1H),
3
3
3
3
3
2
2
(C), 128.0 (C), 128.3 (CH), 129.1 (CH), 129.7 (CH), 130.0 (C),
151.1 (C), 163.4 (C), 167.5 (C); IR (NaCl) 1741, 1732, 1712,
7
.11 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, CDCl
3
) δ 9.7
-
1
+
(
(
CH
CH
3
), 9.9 (CH
3
), 13.8 (CH
3
), 14.1 (CH
3
), 14.6 (CH
3
), 17.6
1589 cm ; HRMS (ESI) m/z [M + Na] Calcd for
+
2
), 59.0 (C), 62.1 (CH), 62.2 (CH
2
), 63.1 (CH
2
), 119.7 (C),
24 6
C H27NNaO : 448.1731, Found: 448.1739.
1
22.1 (C), 126.7 (C), 128.9 (CH), 129.8 (CH), 134.1 (CH), 134.2
Triethyl 3-phenyl-1H-6-ethyl-5,7-dimethylpyrrolizine-1,1,2-
tricarboxylate (9bd): Brown oil (381 mg, 84% yield); H NMR
(400 MHz, CDCl ) δ 0.99 (dd, J = 7.2, 7.2 Hz, 3H), 1.02 (t, J =
3
1
(
(
C), 136.4 (C), 165.0 (C), 166.5 (C), 167.7 (C), 193.5 (C); IR
NaCl) 1742, 1739, 1683 cm ; HRMS (ESI) m/z [M + Na]
-1
+
+
Calcd for C24
Triethyl
H
27NNaO
6
: 448.1731, Found: 448.1724.
7.6 Hz, 3H), 1.29 (t, J = 7.2 Hz, 6H), 1.53 (s, 3H), 2.10 (s, 3H),
2.31 (q, J = 7.6 Hz, 2H), 4.00 (q, J = 7.6 Hz, 2H), 4.25 (dq, J =
7.2, 10.8 Hz, 2H), 4.28 (dq, J = 7.2, 10.8 Hz, 2H), 7.43–7.47 (m,
3-(4-methoxyphenyl)-1H-pyrrolizine-1,1,2-
1
tricarboxylate (9aa): Brown oil (278 mg, 65% yield); H NMR
400 MHz, CDCl ) δ 1.16 (t, J = 7.2 Hz, 3H), 1.27 (dd, J = 7.2,
.2 Hz, 3H), 3.87 (s, 3H), 4.14 (q, J = 7.2 Hz, 2H), 4.20 (dq, J =
1
3
(
3
5H); C NMR (100 MHz, CDCl
3
) δ 9.5 (CH
), 17.7 (CH ), 59.8 (CH
), 116.5 (C), 116.5 (C), 120.9 (C), 127.5 (C), 128.2 (CH),
3
), 10.3 (CH
3
), 13.8
), 62.0
7
7
3
3
(CH
(CH
3
), 14.1 (CH
3
), 15.2 (CH
3
2
2
.2, 10.8 Hz, 2H), 4.27 (dq, J = 7.2, 10.8 Hz, 2H), 6.33 (dd, J =
.2, 3.2 Hz, 1H), 6.38 (dd, J = 1.2, 3.2 Hz, 1H), 6.68 (dd, J = 1.2,
.2 Hz, 1H), 7.01 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 8.8 Hz, 2H);
2
128.9 (CH), 129.0 (C), 129.6 (CH), 130.4 (C), 151.3 (C), 163.4
-1
(C), 167.6 (C), 167.6 (C); IR (NaCl) 1738, 1713, 1635 cm ;
1
3
+
+
C NMR (100 MHz, CDCl
CH ), 60.4 (CH ), 62.3 (CH
13.8 (CH), 114.6 (CH), 116.7 (CH), 120.2 (C), 131.5 (CH),
3
) δ 14.0 (CH
3
), 14.1 (CH
3
), 55.5
HRMS (ESI) m/z [M + Na] Calcd for C26
H
31NNaO
6
: 476.2044,
(
3
2
2
), 63.2 (C), 106.2 (CH), 113.7 (CH),
Found: 476.2035.
Triethyl 2-ethyl-4-phenyl-6H-pyrrole[b]cyclopentaediene-
1
1
1
32.7 (C), 150.0 (C), 161.5 (C), 163.4 (C), 167.3 (C); IR (NaCl)
5,5,6-tricarboxylate (10bb): Brown oil (106 mg, 28% yield);
-1
+
1
737, 1714 cm ; HRMS (ESI) m/z [M + Na] Calcd for
3
H NMR (400 MHz, CDCl ) δ 1.16 (t, J = 7.2 Hz, 3H), 1.24 (t,
+
C
23
H
25NNaO
7
: 450.1523, Found: 450.1503.
J = 7.6 Hz, 3H), 1.25 (dd, J = 7.2, 7.2 Hz, 6H), 2.65 (dq, J = 7.2,
7.6 Hz, 2H) 4.13 (q, J = 7.2, 7.6 Hz, 2H), 4.16 (dq, J = 7.2, 10.8
Hz, 2H), 4.29 (dq, J = 7.2, 10.8 Hz, 2H), 5.86 (dt, J = 1.2, 3.6
Hz, 1H), 7.38–7.41 (m, 3H), 7.66 (dd, J = 1.6, 7.2 Hz, 2H), 8.50–
Triethyl-3-phenyl-1H-pyrrolizine-1,1,2-tricarboxylate (9ba):
1
Yellow oil (362 mg, 81% yield); H NMR (400 MHz, CDCl
.12 (t, J = 7.2 Hz, 3H), 1.27 (dd, J = 7.2, 7.2 Hz, 6H), 4.13 (q,
J = 7.2 Hz, 2H), 4.22 (dq, J = 7.2, 10.8 Hz, 2H), 4.28 (dq, J =
3
) δ
1
1
3
8.60 (br, 1H); C NMR (100 MHz, CDCl
3
) δ 13.4 (CH
3
), 14.1
7
1
3
.2, 10.8 Hz, 2H), 6.33 (dd, J = 2.8, 3.6 Hz, 1H), 6.39 (dd, J =
.2, 3.6 Hz, 1H), 6.63 (dd, J = 1.2, 2.8 Hz, 1H), 7.49–7.52 (m,
(CH ), 14.2 (CH ), 21.6 (CH ), 60.0 (CH ), 62.3 (CH
3
3
2
2
2
), 65.6 (C),
99.4 (CH), 124.1 (C), 127.8 (CH), 129.0 (CH), 131.4 (C), 134.4
(C), 135.0 (C), 140.3 (C), 154.4 (C), 164.3 (C), 167.2 (C); IR
H), 7.62–7.64 (m, 2H); 13C NMR (100 MHz, CDCl
) δ 14.0
), 63. 2(C), 106.3 (CH),
13.6 (CH), 114.6 (CH), 117.6 (C), 128.2 (CH), 128.3 (C), 129.7
CH), 130.6 (CH), 132.7 (C), 150.0 (C), 163.2 (C); IR (NaCl)
3
-1
(CH
3
), 14.0 (CH
3
), 60.4 (CH
2
), 62.3 (CH
2
(NaCl) 3338, 1741, 1721, 1693 cm ; HRMS (ESI) m/z [M +
+
+
1
(
6
Na] Calcd for C24H27NNaO : 448.1731, Found: 448.1749.
Diethyl 3-amino-2-cyano-1H-pyrrolizine-1,1-dicarboxylate
(11): White solid (266 mg, 92% yield); mp 176.5–178.3 °C; H
NMR (400 MHz, CDCl ) δ 1.31 (t, J = 7.2 Hz, 6H), 4.29 (q, J =
3
-1
+
1
1745, 1714, 1344 cm ; HRMS (ESI) m/z [M + Na] Calcd for
+
C
22
H
23NNaO
6
: 420.1418, Found: 420.1434.

7
.2 Hz, 4H), 5.37 (s, 2H), 6.36 (dd, J = 0.8, 3.2 Hz, 1H), 6.44
Liang, J. Ye, Angew, Chem. Int. Ed. 2011, 50, 3232. (h) D.
I. Tasgin, C. Unaleroglu, Synthesis, 2013, 193.
13
(dd, J = 3.2, 3.2 Hz, 1H), 6.81 (dd, J = 0.8, 3.2 Hz, 1H);
C
NMR (100 MHz, CDCl
3
) δ 14.1 (CH
3
), 60.7 (C), 63.0 (CH
2
),
7.
Recent examples, see: (a) K. Savaspun, C. W. G. Au, S. G.
Pyne, J. Org. Chem. 2014, 79, 4569. (b) L. M. Petersen, J.
C. Frisvad, P. B. Knudsen, M. Rohlfs, C. H. Gotfredsen, T.
O. Larsen, J. Antibiot. 2015, 68, 603. (c) T. Khan, V.
Kumar, O. Das, Bull. Chem. Soc. Jpn. 2016, 89, 1331.
Recent examples, see: (a) J.-P. Jourdan, M. Since, L. E.
Kihel, C. Lecoutey, S. Corvaisier, R. Legay, J. S. O. Santos,
T. Cresteil, A. Mal zert-Fréon, C. Rochais, P. Dallemagne,
ChemMedChem 2017, 12, 913. (b) S. Haidar, Z. Bouaziz,
C. Marminon, T. Laitinen, A. Poso, M. L. Borgne, J. Jose,
Pharmaceuticals, 2017, 10, 8. (c) B. A. Trofimov, E. F.
Sagitova, O. V. Petrova, L. N. Sobenina, I. A. Ushakov, A.
V. Vashchenko, Tetrahedron Lett. 2017, 58, 2209. (d) K.
S. Mani, W. Kaminsky, S. P. Rajendran, New J. Chem.
2018, 42, 301.
66.0 (C), 108.0 (CH), 111.1 (CH), 116.5 (CH), 116.9 (C), 131.7
-
1
(C), 153.4 (C), 166.9 (C); IR (ATR) 2193, 1724, 1628 cm ;
+
+
HRMS (ESI) m/z [M + H] Calcd for C1
Found: 290.1140.
4 16 3 4
H N O : 290.1135,
8
.
Acknowledgement
This work has received funding from the Ajinomoto Award
in Synthetic Organic Chemistry, Japan.
#Dedicated to my daughter Mari on the occasion of her birth (H.
A.).
References
1
2
3
.
.
.
Selected examples about enantioselective Diels-Alder
reaction, see: (a) H. Xie, G. M. Sammis, E. M. Flamme, C.
M. Kraml, E. J. Sorensen, Chem. Eur. J. 2011, 17, 11131.
9.
For review on pyrrolizine alkaloids, see: (a) A.-F. M. Rizk,
Natural Occurring Pyrrolizidine Alkaloid, CRC, Boston,
1991. (b) T. Hartmann, L. Witte in Alkaloids: Chemical
and Biological Perspectives, Vol. 9 (Ed.: S. W. Pelletier),
Elsevier Science, Oxford, 1995, Chapter 4. (c) J. R. Liddell,
Nat. Prod. Rep. 2002, 19, 773. (d) J. Robertson, K. Stevens,
Nat. Prod. Rep., 2014, 31, 1721.
(b) S. Harada, T. Morikawa, A. Nishida, Org. Lett. 2013,
15, 5314. (c) R. Mose, M. E. Jensen, G. Preegel, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2015, 54, 13630.
Selected reviews about enantioselective Michael addition,
see: (a) D. Enders, C. Wang, J. X. Liebich, Chem. Eur. J.
10. DBU is known as good catalyst for the nucleophilic attack
of N-H moiety to ester group. [explained by the
nucleophilic catalysis mechanism] (a) K. E. Price, C.
Larrivée-Aboussafy, B. M. Lillie, R. W. McLaughlin, J.
Mustakis, K. W. Hettenbach, J. M. Hawkins, R.
Vaidyanathan Org. Lett. 2009, 11, 2003. [explained by the
stabilization of proton transfer transition state] (b) E. C. de
Lima, C. C. de Souza, R. de O. Soares, B. G. Vaz, M. N.
Eberlin, A. G. Dias, P. R. R. Costa, J. Braz. Chem. Soc.
2011, 22, 2186. (c) H. W. Horn, G. O. Jones, D. S. Wei, K.
Fukushima, J. M. Lecuyer, D. J. Coady, J. L. Hendrick, J.
E. Rice, J. Phys. Chem. A 2012, 116, 12389.
2009, 15, 11058. (b) M. M. Heravi, P. Hajiabbasi, H.
Hamidi, Curr. Org. Chem. 2014, 18, 489. (c) M. Sánchez-
Roselló, J. L. Aceña, A. Simón-Fuentes, C. del Pozo,
Chem. Soc. Rev. 2014, 43, 7430.
(a) X. Wu, J. Wu, Y. Liu, A. K.-Y. Jen, J. Am. Chem. Soc.,
1
999, 121, 472. (b) H. Quast, M. Seefelder, S. Ivanova, M.
Heubes, E.-M. Peters, K. Peters, Eur. J. Org. Chem. 1999,
343. (c) T. Mochida, S. Yamazaki, J. Chem. Soc., Dalton
3
Trans., 2002, 3559. (d) J. Luo, H. Ma, M. Haller, A. K.-Y.
Jen, R. R. Barto, Chem. Commun., 2002, 888. (e) T.
Michinobu, J. C. May, J. H. Lim, C. Boudon, J.-P.
Gisselbrecht, P. Seiler, M. Gross, I. Biaggio, F. Diederich,
Chem. Commun. 2005, 737.
11. T. A. Nigst, M. Westermaier, A. R. Ofial, H. Mayr, Eur. J.
Org. Chem. 2008, 2369.
4
5
.
.
(a) G. Adembri, C. Anselmi, A. M. Celli, L. R.
Lampariello, M. Scotton, J. Heterocyclic Chem. 1984, 569.
(
(
b) J. Skarżewski, J. Zoń, Synth. Commun. 1995, 25, 2953.
c) T. Linker, U. Linker, Angew. Chem. Int. Ed. 2000, 39,
902.
(a) T. Gotoh, A. B. Padias, H. K. Hall Jr., J. Am. Chem.
Soc, 1986, 108, 4920. (b) L. Y. Cao, J. R. Romero,
Tetrahedron Lett. 1995, 36, 8757. (c) C. Batsila, G.
Kostakis, L. P. Hadjiarapoglou, Tetrahedron Lett. 2002, 43,
5997. (d) A. N. Pillai, C. H. Suresh, V. Nair, Chem. Eur. J.
2008, 14, 5851. (e) T. A. Reekie, E. J. Donckele, L.
Ruhlmann, C. Boudon, N. Trapp, F. Diederich, Eur. J. Org.
Chem. 2015, 2015, 7264. (f) E. J. Donckele, T. A. Reekie,
N. Trapp, F. Diederich, Eur. J. Org. Chem. 2016, 2016,
716. (g) A. Whitehead, Y. Zhang, J. McCabe Dunn, E. C.
Sherer, Y.-H. Lam, J. Stelmach, A. Sun, M. Shiroda, R. K.
Orr, S. T. Waddell, S. Raghavan, Org. Lett. 2017, 19, 4448.
Recent reviews see: a) E. I. Martínez-Mora, M. A. Caracas,
C. H. Escalante, C. Espinoza-Hicks, H. Quiroz-Florentino,
F. Delgado, J. Tamariz, Synthesis, 2016, 48, 1055.
Selected examples, see: (b) J. H. Byers, A. DeWitt, C. G.
Nasveschuk, J. E. Swigor, Tetrahedron Lett, 2004, 45,
6.
6
5
587. (c) C. Unaleroglu, A. Yazici, Tetrahedron, 2007, 63,
608. (d) X. L. M. Despinoy, H. McNab, Org. Biomol.
Chem. 2009, 7, 4502. (e) C. Unaleroglu, D. I. Tasgin, S.
Aytac, B. Temelli, Synthesis, 2009, 3243. (f) H. McNab, J.
Montgomery, S. Parsons, D. G. Tredgett, Org. Biomol.
Chem. 2010, 8, 4383. (g) H. Huang, Z. Jin, K. Zhu, X.