Aluminum(III)-Catalyzed, Formal Homo-Nazarov-Type Ring-Opening Cyclizations toward the Synthesis of Functionalized Tetrahydroindolizines

Article abstract of DOI:10.1055/s-0035-1561621

A general approach to functionalized 5,6,7,8-tetrahydroindolizines (THIs) is disclosed. The THIs are directly formed from Al(OTf)₃-catalyzed, formal homo-Nazarov-type ring-opening cyclizations of N-pyrrolyl cyclopropyl malonamides. The THI products were stable to silica gel chromatography and isolated in up to 97% yield with diastereomeric ratios up to 4.0:1. The cyclization demonstrates good substrate scope as aryl, heteroaryl, gem-dialkyl, heteroatomic, and silylmethyl donor groups on the cyclopropane are tolerated. Moreover, the protocol is both pharmaceutically relevant and environmentally friendly as a cheap, earth-abundant metal catalyst is used along with acetonitrile as a greener solvent.

Full text of DOI:10.1055/s-0035-1561621

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
©
Georg Thieme Verlag Stuttgart · New York
2016, 48, A–J
A
special topic
Synthesis
M. A. Cavitt, S. France
Special Topic
Aluminum(III)-Catalyzed, Formal Homo-Nazarov-Type Ring-Open-
ing Cyclizations toward the Synthesis of Functionalized Tetrahy-
droindolizines
Marchello A. Cavitt1,a
Stefan France*a,b
(
OTf)3
Al
O
O
O
Al(OTf)3
20 mol %)
O
O
2
CO Me
(
a
N
OMe
R
N
School of Chemistry and Biochemistry, Georgia Institute
2
MeCN (0.1 M)
84 °C
up to 3 h
N
OMe
of Technology, 901 Atlantic Drive, Atlanta, GA 30332,
USA
Petit Institute for Bioenginering and Bioscience, Georgia
R1
R2
R1
b
H
R2 R3
11 examples
up to 97% yield
up to 4.0:1 dr
Institute of Technology, Atlanta, GA 30332, USA
Stefan.france@chemistry.gatech.edu
Received: 15.02.2016
Accepted after revision: 21.03.2016
Published online: 28.04.2016
N
N
N
DOI: 10.1055/s-0035-1561621; Art ID: ss-2016-c0115-st
5,6,7,8-tetrahydro-
octahydroindolizine (2)
indolizine (1)
indolizine (3)
Abstract A general approach to functionalized 5,6,7,8-tetrahydroin-
dolizines (THIs) is disclosed. The THIs are directly formed from Al(OTf)3-
catalyzed, formal homo-Nazarov-type ring-opening cyclizations of N-
pyrrolyl cyclopropyl malonamides. The THI products were stable to sili-
ca gel chromatography and isolated in up to 97% yield with diastereo-
meric ratios up to 4.0:1. The cyclization demonstrates good substrate
scope as aryl, heteroaryl, gem-dialkyl, heteroatomic, and silylmethyl
donor groups on the cyclopropane are tolerated. Moreover, the proto-
col is both pharmaceutically relevant and environmentally friendly as a
cheap, earth-abundant metal catalyst is used along with acetonitrile as
a greener solvent.
X
N
N
O
N
N
N
Et
Et
n-Pr
Cl
O
HN
R
NH2
O
rhazincine
myrmicarin 217 (5)
CMV423 (6)
polygonatine A
(R = H; 7a)
(X = O; 4a)
rhazinilam
X = H, H; 4b)
polygonatine B
(R = Et; 7b)
kinganone
(
Key words heterocycles, fused-ring systems, ring-opening cycliza-
tions, tetrahydroindolizines, formal homo-Nazarov cyclization, donor-
acceptor cyclopropanes
(R = n-Bu; 7c)
Scheme 1 5,6,7,8-Tetrahydroindolizine framework and representative
biologically active derivatives
The 5,6,7,8-tetrahydroindolizine (THI) skeleton 1 rep-
resents a key target and building block in organic synthesis
rolidine-mediated annulations10c of 1,3-dicarbonyl com-
pounds with 2-formylpiperidine HCl, Ru-catalyzed multi-
2
(
Scheme 1). Under reductive conditions, THI can be readily
3
10d
10i
converted to octahydroindolizine (2), a common molecular
component reactions,
and [3+3] cycloadditions. How-
architecture in natural products. In contrast, oxidation pro-
vides indolizine (3), a similarly recurrent structural class.
The THI motif is also central to the core of a variety of bio-
active natural products and therapeutically relevant com-
pounds. Examples include: rhazinicine (4a) and rhazinilam
ever, each method is limited in some fashion that has pre-
vented broader synthetic utility. Specific limitations in-
clude long reaction times, high pressure flammable gases,
expensive transition-metal catalysts, high loadings of cata-
lyst (or bases), high temperatures (>120 °C), and/or multi-
step precursor syntheses. Furthermore, poor functional
group tolerance, narrow substrate scope, limited substitu-
tion patterns, or low overall yields are common. Therefore,
a more generalized and synthetically versatile approach to-
wards functionalized THIs remains a worthwhile endeavor
for synthetic chemists.
4
(
4b), two members of a family of anticancer natural prod-
5
ucts; myrmicarin 217 (5), a member of a large family of al-
kaloids isolated from African ants; CMV423 (6), a promis-
ing human cytomegalovirus (HMCV) therapeutic; and an-
6
7
timicrobials polygonatine A (7a), polygonatine B (7b), and
8
kinganone (7c).
Several methods have been reported in the literature to
Over the last five years, we have exploited the utility of
the Lewis acid-catalyzed, formal homo-Nazarov cyclization
of donor-acceptor (D-A) cyclopropanes as a template for di-
9,10
access the THI framework.
Some recent representative
approaches include partial reduction of indolizines,1 pyr-
0b
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

B
Synthesis
M. A. Cavitt, S. France
Special Topic
O
O
previous work
N
OMe
Ln
M
R1
R2
R3
O
O
O
O
22 examples
up to 99% yield
MLn
N
OMe
R
2
N
OMe
R3
R1
O
O
1H
R2 R3
I
R
this work
N
OMe
R2 R3
Scheme 2 Cyclopropane ring-opening cyclization approach to 5,6,7,8-tetrahydrolindolizines
versity-oriented synthesis.11 In one pertinent example, we
reported that highly functionalized hydropyrido[1,2-a]in-
To investigate our hypothesis, N-pyrrolyl cyclopropane
malonamides 11 were synthesized using a four-step syn-
thetic sequence (Scheme 3). The known N-pyrrolyl
malonamide 913 was formed in two steps from pyrrole and
carbonyl diimidazole. Diazo transfer14 gave α-diazo
malonamide 10 in 90% yield. Alkene cyclopropanation cata-
lyzed by Rh esp [bis(rhodium(α,α,α′,α′-tetramethyl-1,3-
benzenedipropionic acid)] afforded cyclopropanes 11 in
moderate to good yields (up to 81%).
Methyl 2-phenyl-1-(1H-pyrrole-1-carbonyl)cyclopro-
pane-1-carboxylate (11a) was chosen as the model sub-
strate for reaction optimization (Table 1). As expected, no
cyclized product was formed without catalyst (Table 1, en-
doles could be formed efficiently from In(OTf) -catalyzed
3
intramolecular ring-opening cyclizations of N-indolyl cy-
clopropyl malonamides in both batch and continuous flow
12
(
Scheme 2). The reactions are highly modular, providing a
diverse set of hydropyridoindole products with broad func-
tional group tolerance. Mechanistically, cyclopropane ring-
opening precedes intramolecular Friedel–Crafts alkylation
by the indole. We postulate that the cyclization proceeds
through aza-cationic intermediate I, generating the lactam
ring. Given the modularity of this protocol, we envisioned
an analogous approach toward the tetrahydroindolizine
skeleton in which the indolyl moiety is replaced by a pyr-
role. From N-pyrrolyl cyclopropyl malonamides, ring-open-
ing cyclization would generate a similar aza-cationic inter-
2
2
15
try 1). In accordance with our previous reports, In(OTf) was
3
the first Lewis acid to be employed. Preliminary control re-
actions revealed that heat is required for ring-opening opti-
mediate to form
a
5-oxo-5,6,7,8-tetrahydroindolizine.
mization and, ultimately, established that In(OTf) (20 mol
3
Herein, we disclose our successful efforts toward an effi-
cient and general synthetic approach to these functional-
ized THIs.
%) in 1,2-dichloroethane (0.1 M) at reflux would serve as
the reaction benchmark to compare all further Lewis acid
screening.16 These conditions provided THI 12a in 51% yield
after one hour (entry 2). Given these results, typical Lewis
acid catalysts used for cyclopropane ring-opening were
subsequently screened. Sc(OTf) , Yb(OTf) , and Cu(OTf)
2
a. LDA, THF
O
O
O
–78 °C; then
3
3
2
NH 1. CDI
MeOAc
N
OMe
generated lowered yields of 12a (entries 3–5), while other
N
N
DMSO
2b. DBU
Lewis acids (La(OTf) , Mg(OTf) , Ni(OTf) , and Zn(OTf) )
3
2
2
2
showed no desired product formation (entries 6–9). Given
8
(75%)
9 (70%)
R1
the results with In(OTf) , we compared the performance of
3
4.
other Group III triflate salts. Ga(OTf) gave a modest 38%
R2
3
O
O
3
. TsN3, Et3N
MeCN
O
O
yield while Al(OTf) outperformed In(OTf) , affording 56%
Rh2esp2
3
3
N
O2Me
N
OMe
of THI 12a (entries 10 and 11). With Al(OTf) as the newly
3
R
CH2Cl2
N2
selected catalyst, we performed a new solvent screen (en-
tries 12–15). We determined that the reaction occurs most
efficiently in acetonitrile to afford 12a in 64% yield (entry
R1
1
0 (90%)
11
up to 81% yield
O
O
15). The reaction presumably proceeds better in acetoni-
N
OMe
trile due to a synergistic combination of catalyst solubility
and stabilization of charged intermediates formed. Further
attempts to reduce the catalyst loading or change reaction
concentration failed to provide better yields.16 Hence, the
optimized conditions that were carried forward was
Ph
model precursor (11a)
Scheme 3 Preparation of methyl 1-(1H-pyrrole-1-carbonyl)cyclopro-
pane-1-carboxylates 11
Al(OTf) (20 mol%) in acetonitrile (0.1 M) at reflux.
3
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

C
Synthesis
M. A. Cavitt, S. France
Special Topic
Table 1 Reaction Optimizationa
cyclopropane 11g (entry 8). We were pleased to find that
no degradation was observed with either the 2-furyl cyclo-
propane 11h or its product 12h, which was isolated in 78%
yield with a 1.2:1 dr.
O
O
O
Lewis acid
20 mol%)
CO2Me
(
N
N
OMe
Ph
solvent (0.1 M)
temperature
Table 2 Al(OTf) -Catalyzed Ring-Opening Cyclizationsa
Ph
3
11a
12a
Entry Cyclopropane 11
Product 12
Yield drc
(%)
Temp (°C) Time (h) Yield of 12a (%)b
b
Entry Lewis acid
Solvent
1
2
3
4
5
6
7
8
9
none
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
1,2-DCE
toluene
EtOAc
84
84
84
84
84
84
84
84
84
84
84
110
77
80
84
24
1.0
1.75
21.0
–c
O
N
O
O
CO2Me
In(OTf)
3
51
42
28
22
N
OMe
Ph
1
2
64
97
1.5:1
Sc(OTf)
Yb(OTf)
Cu(OTf)
La(OTf)
Mg(OTf)
Ni(OTf)
Zn(OTf)
Ga(OTf)
3
Ph
3
11a
11b
1
2a
2
1.5
23.0
21.0
21.0
21.0
0.5
O
–d
O
O
3
CO2Me
–d
N
2
N
OMe
1.3:1
1.5:1
1.8:1
–d
2
C6H4-4-OMe
4
1
-MeO-C6H4
–d
2
2b
1
0
1
2
3
4
5
3
38
56
48
40
29
64
O
O
O
1
1
1
1
Al(OTf)
Al(OTf)
Al(OTf)
Al(OTf)
3
4.0
2
CO Me
N
N
OMe
3
3
3
2.0
3
4
71
54
C6H4-4-F
17.5
18.0
2.0
4
-F-C6H4
1
1c
benzene
MeCN
12c
1
Al(OTf)
3
O
O
O
a
CO2Me
Reactions run with 20 mol% Lewis acid and 1.0 equiv of cyclopropane 11a
in indicated solvent (0.1 M) at reflux.
Isolated yields after column chromatography.
Starting material recovered.
N
N
OMe
b
c
C6H4-4-Cl
4
1
-Cl-C6H4
d
11d
11e
No desired product obtained.
2d
O
O
O
To demonstrate the generality of the reaction, the donor
substituents on the cyclopropane were changed (Table 2).
In order to explore an electronic effect of aryl substituents,
differing para-substituted electron-donating and electron-
withdrawing groups were investigated. Phenyl cyclopro-
pane 11a afforded THI 12a in 64% yield with a 1.5:1
trans/cis dr (Table 2, entry 1). The addition of a p-OMe do-
nating group, as in 11b, gave increased yield (97%) for 12b
with a dr = 1.3:1 (entry 2). 4-Fluorophenyl cyclopropane
1c provided its product 12c in 71% yield with a 1.5:1 dr
entry 3). Longer reaction times and decreased yields (54%
and 51%) were observed for the cyclizations of 4-chloro-
phenyl (11d) and 4-bromophenyl (11e) cyclopropanes, re-
spectively (entries 4 and 5). In terms of the mechanism,
these product outcomes are in accordance with expected
CO2Me
N
N
OMe
5
6
7
51
95
69
1.8:1
4.0:1
1.3:1
6 4
C H -4-Br
4
1
-Br-C6H4
2e
O
O
O
CO2Me
CO2Me
N
N
OMe
Me
Ph
Me
N
Ph
1
1
1f
1
2f
1
(
O
O
O
N
OMe
2-Np
2-Np
1g
12g
17
Hammett predictions based on electronic effects.
O
O
O
By adding another donor group, product outcome was
better due to formation of a more stabilized carbocationic
intermediate upon ring-opening. The geminal methyl-phe-
nyl cyclopropane 11f gave THI 12f in 95% yield with a 4.0:1
dr (Table 2, entry 6), affording a quaternary center directly,
and increasing product complexity. Tetrahydroindolizine
CO2Me
N
N
OMe
8
78
1.2:1
2-furyl
2-furyl
11h
1
2h
12g was obtained in 69% with a 1.3:1 dr from 2-naphthyl
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

D
Synthesis
M. A. Cavitt, S. France
Special Topic
Table 2 (continued)
O
O
O
O
Entry Cyclopropane 11
Product 12
Yield drc
CO2Me
N
b
N
(
%)
N
OMe In(OTf)3
Et
(30 mol%)
O
Et
Et
CH2Cl2
50 °C
O
O
2
CO Me
N
O
HN
O
N
OMe
TBDPS
9
72
1.5:1
MeO
11l
MeO
O
rhazinicine (4a)
12l
1
1i
TBDPS
6
1
5% yield
.1:1 dr
1
1
1
2i
O
Scheme 4 Initial efforts toward the rhazinicine framework
O
O
O
CO2Me
N
N
OMe
SPh
–d
–e
1
0
gem-dialkyl donor groups were tolerated on the cyclopro-
pane as the hydropindolizine products were formed in up
to 97% yield. Moreover, the reaction proceeds in acetoni-
trile, a pharmaceutically acceptable solvent. Next steps in-
clude the transfer of the reaction from batch to continuous
flow and the biological evaluation of the synthesized hy-
droindolizines. Lastly, application of the method toward a
concise synthesis of rhazinicine will be reported in due
course.
SPh
O
1
1
1j
2j
O
CO2Me
N
N
OMe
OPh
–f
–e
11
OPh
1k
2k
a
3
Reactions run with 1.0 equiv. of cyclopropane 11 and 20 mol % Al(OTf) in
MeCN at 84 °C.
Isolated yields after column chromatography.
trans/cis diastereometic ratios (dr) determined from H NMR of crude re-
b
c
1
action mixture.
All reactions were carried out in predried glassware from the oven
and any additional moisture was removed by flame-drying the reac-
d
Product obtained as an inseparable mixture with unidentified impurities.
Not determined.
e
f
tion vessel. Each reaction proceeded under a N atmosphere with an-
2
No desired products formed.
hyd solvents, unless stated otherwise. THF was distilled from Na/ben-
zophenone ketyl under N and stored in a Schlenk flask. Benzene, tol-
2
In accordance with Yadav’s studies using methylsilyl
groups for β-cation stability, cyclopropane 11i readily re-
acted to form 12i in 72% yield with a 1.5:1 dr (Table 2, entry
uene, 1,2-dichloroethane (DCE) and CH Cl were purified by
2
2
18
distillation from CaH . All other reagents were purchased from Acros,
2
Sigma-Aldrich, Fluka, VWR, Merck, Alfa Aesar, TCI, and Strem (for
metal catalysts) and used without further purification. Compounds 9
7
). The TBDPS group offers a useful handle for further
13
and 10 were synthesized according to previous report.
chemical derivatization. Heteroatom donors were also ex-
amined under the reaction conditions. With phenyl thio-
ether cyclopropane 11j, the desired THI 12j was formed as
an inseparable mixture with impurities. We anticipate that
heating is the cause of the degradation of 12j as elimination
of PhSH, and other side reactions, are possible. Unfortu-
nately, phenyl ether cyclopropane 11k did not give any ap-
preciable product and only degradation was observed.
With a working reaction in hand, we turned our atten-
tion towards potential applications in natural product syn-
thesis. With a 7,8-dihydroindolizin-5(6H)-one unit at its
core, rhazinicine (4a) was chosen as an initial target. Rhazi-
nicine has a gem-dialkyl substitution at C8. As a proof of
concept, we sought to demonstrate that gem-dialkyl N-pyr-
rolyl cyclopropane malonamide 11l, bearing the appropri-
ate substituents, would cyclize as anticipated. After some
optimization, tetrahydroindolizinone 12l was cleanly
formed in 65% yield as a 1.1:1 mixture of diastereomers us-
ing In(OTf) (30 mol %) in refluxing CH Cl (Scheme 4).
Chromatographic purification was performed as flash chromatogra-
phy with Silicycle silica gel (40–65 μm). For quantitative flash chro-
matography, technical grades solvents were utilized. Analytical TLC
was performed on Silicycle silica gel F254 TLC glass plates. Visualiza-
tion was accomplished with UV light, aq basic KMnO solution, I , aq
acidic dinitrophenylhydrazine (DNP) solution, aq acidic p-anisalde-
hyde (PAA) solution, and an EtOH solution of phosphomolybdic acid
(PMA) followed by heating. Each yield refers to an isolated, analytical-
ly pure material.
4
2
1H and 13C NMR spectra were recorded on a Varian Mercury Vx 300
MHz, Varian Mercury Vx 400 MHz, Bruker 400 MHz, or Bruker 500
MHz spectrometer with solvent resonances as the internal standard
1
13
1
(
H NMR: CDCl at 7.26 ppm; C NMR: CDCl at 77.0 ppm). H NMR
3
3
data are reported as follows: chemical shift (ppm), multiplicity (stan-
dard abbreviations), coupling constants (Hz), and integration. Diaste-
1
reomeric ratios for the cyclized products were determined by H NMR
based on a comparison of the signal ratios of the benzylic protons
(~4.0–5.0 ppm) for the two diastereomeric protons or other signals
displaying clear separation. These assignments are based on the cou-
pling constants. A single observable diastereomer corresponds to
3
2
2
>
99:1 dr.
In conclusion, we have developed a general and efficient
approach to functionalized hydroindolizines using
Mass spectra were obtained using a MicroMass Autospec M. The ac-
curate mass analyses were run in EI mode at a mass resolution of 10
Al(OTf) -catalyzed ring-opening cyclizations of N-pyrrolyl
3
000 using PFK (perfluorokerosene) as an internal calibrant.
cyclopropyl malonamides. Aryl, heteroaryl, silylmethyl, and
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

E
Synthesis
M. A. Cavitt, S. France
Special Topic
Cyclopropanation; N-Pyrrolyl Cyclopropane Malonamides 11;
tion was quenched, and silica gel column chromatography rendered
General Procedure
11c; yield: 131.8 mg (56%); white solid; mp 88–90 °C; R = 0.71 (30%
f
EtOAc/hexane).
The cyclopropanes 11 were prepared using a modified version of Sou-
19
meillant’s protocol. A round bottom flask was charged with Rh esp2
IR (film): 2954.3 (w), 1735.3 (m), 1710.0 (s), 1604.5 (w), 1512.7 (m),
1463.7 (m), 1311.8 (s), 1223.4 (s), 1156.4 (s), 1102.3 (m), 933.0 (w),
907.7 (w), 837.4 (s), 733.6 cm (s).
2
and a magnetic stir bar. CH Cl2 (2.0 mL) was added to the flask. The
2
–1
reaction vessel was cooled to 0 °C, and the corresponding alkene (1.0–
3
.0 equiv) was added. After 10 min, methyl 2-diazo-3-oxo-3-(1H-pyr-
1
H NMR (300 MHz, CDCl ): δ = 7.37–7.26 (m, 4 H), 7.09–6.88 (m, 2 H),
.32 (dd, J = 2.7, 2.0 Hz, 2 H), 3.45–3.36 (m, 4 H), 2.38 (dd, J = 8.3, 5.4
3
rol-1-yl)propanoate (10; 1.0–2.0 equiv) was dissolved in CH Cl (5
2
2
6
mL) and syringed into the reaction mixture. After 10 min, the ice bath
was removed and the reaction was allowed to proceed at r.t. Upon
completion (monitored by TLC) or 12 h of reactivity, the solution was
quenched with sat. aq thiourea and stirred for 5 min. The organic lay-
er was separated, and the aqueous layer was extracted with CH Cl (3
Hz, 1 H), 1.80 (dd, J = 9.3, 5.4 Hz, 1 H).
13
C NMR (75 MHz, CDCl ): δ = 167.4, 165.4, 163.7, 160.5, 130.7 and
3
1
1
30.6 (JC,F = 8.1 Hz), 129.7 and 129.6 (JC,F = 3.4 Hz), 119.4, 115.2, 114.9,
13.4, 52.8, 38.3, 30.3, 18.7.
2
2
×
). The combined organic layers were washed with brine, dried (an-
HRMS (ESI): m/z [M]+ calcd for C16H14FNO3: 287.0958; found:
hyd Na SO ), filtered, and concentrated under reduced pressure. The
287.0967.
2
4
residue was purified by silica gel flash chromatography.
Methyl 2-(4-Chlorophenyl)-1-(1H-pyrrole-1-carbonyl)cyclopro-
Methyl 2-Phenyl-1-(1H-pyrrole-1-carbonyl)cyclopropanecarbox-
panecarboxylate (11d)
ylate (11a)
The general procedure was followed using 1-chloro-4-vinylbenzene
(88 μL, 0.726 mmol), the diazo reagent 10 (187.6 mg, 0.971 mmol),
Rh esp (1.2 mg, 1.519 μmol), and CH Cl (7 mL). After 8 h, the reac-
The general cyclopropanation procedure was followed using styrene
(650 μL, 5.67 mmol), methyl 2-diazo-3-oxo-3-(1H-pyrrol-1-yl)propa-
2
2
2
2
noate (10; 538.8 mg, 2.79 mmol), Rh esp (4 mg, 5.06 μmol), and
tion was quenched, and silica gel column chromatography furnished
2
2
CH Cl (12.5 mL). After 7 h, the reaction was quenched, and silica gel
11d; yield: 105.3 mg (48%); white solid; mp 108–110 °C; R = 0.71
2
2
f
column chromatography afforded 11a; yield: 605.7 mg (81%); white
(30% EtOAc/hexane).
solid; mp 120–122 °C; R = 0.73 (30% EtOAc/hexane).
f
IR (film): 2922.4 (w), 1707.3 (s), 1464.4 (m), 1305.3 (s), 1155.8 (s),
1091.7 (s), 834.0 (s), 739.2 cm (s).
–1
IR (film): 2955.6 (w), 1706.5 (s), 1463.3 (m), 1320.6 (s), 1157.7 (s),
–1
1087.1 (s), 931.5 (m), 831.5 (w), 797.2 (w), 743.4 (s), 701.6 cm (s).
1
H NMR (300 MHz, CDCl ): δ = 7.32–7.27 (m, 2 H), 7.28–7.20 (m, 4 H),
3
1
H NMR (500 MHz, CDCl ): δ = 7.35–7.30 (m, 6 H), 7.29–7.26 (m, 1 H),
6.29 (dd, J = 2.7, 2.0 Hz, 2 H), 3.41–3.33 (m, 4 H), 2.35 (dd, J = 8.3, 5.4
3
6.33–6.29 (m, 2 H), 3.44 (dd, J1 = J2 = 9.5 Hz, 1 H), 3.39 (s, 3 H), 2.41
Hz, 1 H), 1.79 (dd, J = 9.3, 5.4 Hz, 1 H).
(
1
dd, J = 8.3, 5.3 Hz, 1 H), 1.80 (dd, J = 9.3, 5.3 Hz, 1 H).
13
C NMR (75 MHz, CDCl ): δ = 167.3, 165.3, 133.4, 132.4, 130.4, 128.4,
3
3
C NMR (75 MHz, CDCl ): δ = 167.6, 165.6, 133.9, 129.1, 128.2, 127.5,
119.4, 113.5, 52.8, 38.4, 30.4, 18.6.
3
1
19.5, 113.4, 52.7, 38.4, 31.2, 18.6.
HRMS (ESI): m/z [M]+ calcd for C16H15NO3: 269.1052; found:
69.1043.
HRMS (ESI): m/z [M]+ calcd for C16H14ClNO : 303.0662; found:
303.0674.
3
2
Methyl 2-(4-Bromophenyl)-1-(1H-pyrrole-1-carbonyl)cyclopro-
Methyl 2-(4-Methoxyphenyl)-1-(1H-pyrrole-1-carbonyl)cyclopro-
panecarboxylate (11e)
panecarboxylate (11b)
The general procedure was followed using 1-bromo-4-vinylbenzene
(105 mg, 0.574 mmol), the diazo reagent 10 (159.8 mg, 0.827 mmol),
Rh esp (1.0 mg, 1.266 μmol), and CH Cl (5.5 mL). After 7 h, the reac-
The general procedure was followed using 1-methoxy-4-vinylben-
zene (104 μL, 0.742 mmol), the diazo reagent 10 (192.7 mg, 0.998
mmol), Rh esp (1.1 mg, 1.392 μmol), and CH Cl (7.5 mL). After 12 h,
2
2
2
2
tion was quenched, and silica gel column chromatography gave 11e;
2
2
2
2
the reaction was quenched, and silica gel column chromatography af-
yield: 87.8 mg (44%); white solid; mp 110–112 °C; R = 0.66 (30%
f
forded 11b; yield: 134 mg (61%); white solid; mp 103–105 °C; R =
EtOAc/hexane).
f
0
.71 (30% EtOAc/hexane).
IR (film): 2923.4 (w), 1735.9 (m), 1706.9 (s), 1463.5 (m), 1305.3 (s),
1195.6 (m), 1155.6 (m), 1101.9 (m), 1074.8 (m), 1011.8 (w), 833.0 (s),
740.8 (s), 711.3 cm (s).
IR (film): 2951.7 (w), 1711.1 (s), 1612.9 (w), 1514.5 (w), 1326.5 (m),
–1
1
7
1
301.6 (s), 1244.9 (m), 1152.4 (m), 1084.7 (m), 1028.2 (m), 833.3 (m),
–1
58.0 cm (s).
1
H NMR (300 MHz, CDCl ): δ = 7.50–7.39 (m, 2 H), 7.31 (t, J = 2.4 Hz, 2
3
H NMR (300 MHz, CDCl ): δ = 7.37–7.30 (m, 2 H), 7.30–7.20 (m, 2 H),
H), 7.24–7.16 (m, 2 H), 6.35–6.28 (m, 2 H), 3.43 (s, 3 H), 3.36 (dd, J =
3
1
6.91–6.80 (m, 2 H), 6.35–6.27 (m, 2 H), 3.79 (s, 3 H), 3.46–3.32 (m, 4
J2 = 8.8 Hz, 1 H), 2.37 (dd, J = 8.3, 5.4 Hz, 1 H), 1.81 (dd, J = 9.3, 5.4 Hz,
H), 2.36 (dd, J = 8.3, 5.3 Hz, 1 H), 1.78 (dd, J = 9.4, 5.2 Hz, 1 H).
1 H).
13
13
C NMR (75 MHz, CDCl ): δ = 167.6, 165.7, 158.9, 130.1, 125.7, 119.4,
C NMR (75 MHz, CDCl ): δ = 167.4, 165.3, 133.0, 131.3, 130.8, 121.6,
3
3
113.5, 113.3, 104.9, 55.1, 52.7, 38.3, 30.7, 18.7.
119.5, 113.6, 52.9, 38.4, 30.5, 18.6.
HRMS (ESI): m/z [M]+ calcd for C17H17NO4: 299.1158; found:
99.1154.
HRMS (ESI): m/z [M]+ calcd for C16H14BrNO : 347.0157; found:
347.0169.
3
2
Methyl 2-(4-Fluorophenyl)-1-(1H-pyrrole-1-carbonyl)cyclopro-
Methyl 2-Methyl-2-phenyl-1-(1H-pyrrole-1-carbonyl)cyclopro-
panecarboxylate (11c)
panecarboxylate (11f)
The general procedure was followed using 1-fluoro-4-vinylbenzene
The general procedure was followed using prop-1-en-2-ylbenzene
(110 μL, 0.838 mmol), the diazo reagent 10 (247.5 mg, 1.281 mmol),
Rh esp (1.2 mg, 1.519 μmol), and CH Cl (6 mL). After 12 h, the reac-
(100 μL, 0.822 mmol), the diazo reagent 10 (216.4 mg, 1.120 mmol),
Rh esp (1.2 mg, 1.519 μmol), and CH Cl (8.2 mL). After 7 h, the reac-
2
2
2
2
2
2
2
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

F
Synthesis
M. A. Cavitt, S. France
Special Topic
tion was quenched, and silica gel column chromatography gave 11f;
Methyl 2-[(tert-Butyldiphenylsilyl)methyl]-1-(1H-pyrrole-1-car-
yield: 176 mg (74%); mp 110–112 °C; R = 0.68 (30% EtOAc/hexane);
bonyl)cyclopropanecarboxylate (11i)
f
diastereomeric ratio: 14.7:1.
The general procedure was followed using allyl(tert-butyl)diphenylsi-
lane (1.17 g, 4.17 mmol), the diazo reagent 10 (399.2 mg, 2.067
IR (film): 2924.6 (w), 1713.0 (vs), 1464.9 (m), 1435.8 (m), 1347.8 (s),
–1
1298.4 (s), 1235.7 (s), 1089.3 (s), 916.6 (m), 739.9 (s), 698 cm (s).
mmol), Rh esp (3.4 mg, 4.30 μmol), and CH Cl (10 mL). After 12 h,
2
2
2
2
1
the reaction was quenched, and silica gel column chromatography
H NMR (300 MHz, CDCl ): δ = 7.46–7.27 (m, 7.25), 7.21–7.11 (m,
.56), 7.09–7.03 (m, 0.16), 6.34 (dd, J = 2.7, 2.1 Hz, 1.91), 6.15–6.12
3
furnished 11i; yield: 129.7 mg (14%); clear oil; R = 0.71, 0.64 (20%
f
0
EtOAc/hexane); diastereomeric ratio: 1.02:1.
(m, 0.14), 3.71 (s, 0.18), 3.41 (s, 2.94), 2.60 (d, J = 5.5 Hz, 0.07), 2.42 (d,
J = 5.1 Hz, 1.03), 1.91–1.86 (m, 0.30), 1.81 (d, J = 5.2 Hz, 1.00), 1.49 (s,
IR (film): 2953.0 (m), 2859.0 (m), 1710.9 (vs), 1466.9 (m), 1333.4 (vs),
1197.0 (m), 1166.0 (m), 1102.2 (m), 914.5 (m), 822.4 (m), 731.2 (vs),
701.1 cm (vs).
3.11).
–1
13
C NMR (125 MHz, CDCl ): δ = 168.0, 164.8, 140.4, 128.4, 128.1,
3
1H NMR (500 MHz, CDCl
): δ = 7.66–7.63 (m, 4.02), 7.63–7.59 (m,
127.3, 119.9, 113.3, 52.6, 40.8, 38.1, 25.9, 25.5.
3
HRMS (ESI): m/z [M]+ calcd for C17H17NO3: 283.1208; found:
83.1208.
0.85), 7.60–7.56 (m, 4.52), 7.45–7.31 (m, 14.58), 7.21–7.17 (m, 2.30),
6.32 (t, J = 2.3 Hz, 2.21), 6.24 (t, J = 2.4 Hz, 2.13), 3.67 (s, 2.74), 3.59 (s,
3.00), 2.21–2.16 (m, 0.40), 2.13–1.96 (m, 2.42), 1.63–1.57 (m, 2.28),
1.45–1.32 (m, 2.41), 1.30–1.16 (m, 4.20), 1.11–1.05 (m, 11.53), 1.00 (s,
11.29), 0.50 (dd, J = 14.7, 12.5 Hz, 1.41).
2
Methyl 2-(Naphthalen-2-yl)-1-(1H-pyrrole-1-carbonyl)cyclopro-
panecarboxylate (11g)
13
C NMR (125 MHz, CDCl ): δ = 170.9, 169.3, 166.2, 165.2, 136.1,
3
The general procedure was followed using 2-vinylnaphthalene
1
1
3
1
36.0, 135.9 (2 C), 134.1, 133.7 (2 C), 133.6, 129.4, 129.3 (2 C), 129.0,
27.8, 127.7 (2 C), 127.6, 127.5, 119.6, 119.4, 113.3, 113.0, 52.8, 52.8,
6.2, 35.9, 27.8 (2 C), 27.7, 26.2, 25.4, 23.8, 22.98, 18.7, 18.1, 18.0,
0.61, 7.87.
(
0.5824 g, 3.66 mmol), the diazo reagent 10 (402.0 mg, 2.081 mmol),
Rh esp (3.8 mg, 4.81 μmol), and CH Cl (11 mL). After 15 h, the reac-
2
2
2
2
tion was quenched, and silica gel column chromatography rendered
1g; yield: 412 mg (62%); light yellow solid; mp 78–80 °C; R = 0.66
1
f
+
HRMS (ESI): [M] calcd for C27H NO Si: 445.2073; found: 445.2063.
(20% EtOAc/hexane); diastereomeric ratio: 4.7:1.
31
3
IR (film): 2950.8 (w), 1705.8 (vs), 1598.8 (w), 1465.2 (m), 1436.4 (m),
Methyl 2-(Phenylthio)-1-(1H-pyrrole-1-carbonyl)cyclopropane-
carboxylate (11j)
1
9
1
306.5 (s), 1195.9 (s), 1152.8 (s), 1099.8 (s), 1070.3 (m), 955.9 (m),
07.5 (m), 821.2 (s), 740.7 cm (vs).
–1
The general procedure was followed using phenyl(vinyl)sulfane (97
μL, 0.720 mmol), the diazo reagent 10 (214.1 mg, 1.108 mmol),
Rh esp (1.1 mg, 1.392 μmol), and CH Cl (7.3 mL). After 12 h, the re-
H NMR (500 MHz, CDCl ): δ = 7.86–7.77 (m, 4.12), 7.74–7.69 (m,
3
0.48), 7.65–7.61 (m, 0.34), 7.57–7.55 (m, 0.29), 7.52–7.43 (m, 3.14),
2
2
2
2
7.44–7.39 (m, 0.51), 7.38 (s, 1.85), 7.20 (dd, J = 8.5, 1.9 Hz, 0.25), 7.05
action was quenched, and silica gel column chromatography afforded
1j; yield: 14 mg (7%); brown solid; mp 61–63 °C; R = 0.69 (30%
(s, 0.39), 6.35–6.28 (m, 1.98), 6.04–5.98 (m, 0.42), 3.73 (s, 0.61), 3.60
1
f
(
dd, J = J = 8.8 Hz, 0.97), 3.54 (dd, J = J = 8.7 Hz, 0.25), 3.35 (s, 2.91),
1
2
1
2
EtOAc/hexane).
2.56 (dd, J = 8.3, 5.3 Hz, 1.00), 2.50 (dd, J = 8.0, 5.4 Hz, 0.26), 2.00 (dd,
J = 9.3, 5.4 Hz, 0.22), 1.89 (dd, J = 9.3, 5.3 Hz, 1.01).
IR (film): 2951.0 (w), 2848.5 (w), 1736.0 (m), 1705.3 (s), 1580.2 (w),
1467.7 (m), 1399.3 (w), 1334.5 (s), 1294.8 (s), 1158.0 (m), 1085.2 (m),
13
C NMR (125 MHz, CDCl ): δ = 167.5, 165.6, 133.1, 133.0, 132.7,
3
–1
907.4 (m), 738.4 (vs), 687.2 cm (vs).
131.4, 128.1, 128.0, 127.8 (2 C), 127.7, 127.6, 127.5, 126.9, 126.5,
126.2, 126.0, 125.9, 119.5, 119.4, 113.5, 112.9, 53.1, 52.8, 38.9, 38.6,
33.5, 31.4, 19.9, 18.8.
1H NMR (400 MHz, CDCl
): δ = 7.48–7.43 (m, 2 H), 7.34–7.27 (m, 4 H),
3
7.21–7.16 (m, 1 H), 6.31–6.29 (m, 2 H), 3.55–3.50 (m, 4 H), 2.13 (dd,
HRMS (ESI): m/z [M]+ calcd for C20H17NO3: 319.1208; found:
19.1215.
J = 7.4, 5.8 Hz, 1 H), 1.88 (dd, J = 9.3, 5.8 Hz, 1 H).
13C NMR (100 MHz, CDCl
26.0, 119.4, 113.8, 53.1, 38.8, 27.8, 20.0.
): δ = 166.9, 164.7, 135.3, 128.9, 127.6,
3
3
1
Methyl 2-(Furan-2-yl)-1-(1H-pyrrole-1-carbonyl)cyclopropanecar-
HRMS (ESI): m/z [M]+ calcd for C16H15NO S: 301.0773; found:
3
boxylate (11h)
301.0784.
The general procedure was followed using 2-vinylfuran (1.79 g, 9.51
mmol), the diazo reagent 10 (600 mg, 3.11 mmol), Rh esp (11.2 mg,
Methyl 2-Phenoxy-1-(1H-pyrrole-1-carbonyl)cyclopropanecar-
2
2
0
.014 mmol), and CH Cl2 (10 mL). After 15 h, the reaction was
boxylate (11k)
2
quenched, and silica gel column chromatography afforded 11h; yield:
82 mg (48%); yellow solid; mp 68–70 °C; R = 0.52 (20% EtOAc/hex-
ane); diastereomeric ratio: 9.09:1.
The general procedure was followed using phenyl vinyl ether (150 μL,
3
f
1.221 mmol), the diazo reagent 10 (0.3604 g, 1.866 mmol), Rh esp2
2
(
3.0 mg, 3.80 μmol), and CH Cl (8.5 mL). After 7.5 h, the reaction was
2 2
IR (film): 2952.6 (s), 2867.8 (m), 1735.3 (m), 1698.8 (vs), 1463.8 (m),
quenched, and column chromatography formed 11k; yield: 249.3 mg
(72%); light brown oil; R = 0.43 (20% EtOAc/hexane).
1
9
1
402.6 (m), 1312.7 (vs), 1201.2 (m), 1159.9 (s), 1062.0 (vs), 1012.0 (s),
17.5 (m), 731.5 cm (vs).
f
–1
IR (film): 2953.5 (w), 1706.8 (vs), 1593.2 (m), 1467.9 (m), 1404.2 (m),
1332.5 (s), 1305.3 (s), 1247.9 (s), 1219.6 (s), 1159.4 (s), 1075.5 (s),
H NMR (500 MHz, CDCl ): δ (major) = 7.42–7.35 (m, 3 H), 6.36–6.30
3
–1
(
m, 3 H), 6.27–6.25 (m, 1 H), 3.53 (s, 3 H), 3.21 (dd, J = J = 8.8 Hz, 1
916.5 (s), 744.4 (vs), 693.7 cm (s).
1
2
H), 2.28 (dd, J = 8.0, 5.3 Hz, 1 H), 1.90 (dd, J = 9.5, 5.3 Hz, 1 H).
1
H NMR (500 MHz, CDCl ): δ = 7.28–7.33 (m, 4 H), 7.16–7.21 (m, 2 H),
3
13
C NMR (125 MHz, CDCl ): δ (major) = 167.3, 165.0, 148.8, 142.4,
6.99–7.03 (m, 1 H), 6.30–6.33 (m, 2 H), 4.67 (dd, J = 7.13, 5.38 Hz, 1 H),
3
119.7, 113.5, 110.5, 108.8, 52.9, 37.2, 24.4, 18.6.
3.45 (s, 3 H), 2.53 (dd, J = 6.64, 5.34 Hz, 1 H), 1.80 (dd, J = J = 6.90 Hz,
1 2
HRMS (ESI): m/z [M]+ calcd for C14H13NO4: 259.0845; found:
59.0844.
1 H).
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

G
Synthesis
M. A. Cavitt, S. France
Special Topic
1
3
C NMR (125 MHz, CDCl ): δ = 166.0, 164.6, 157.22, 129.5, 122.1,
Methyl 8-(4-Methoxyphenyl)-5-oxo-5,6,7,8-tetrahydroindolizine-
6-carboxylate (12b)
3
1
19.2, 115.0, 113.8, 59.6, 53.0, 36.8, 20.6.
HRMS (ESI): m/z [M]+ calcd for C16H15NO4: 285.1001; found:
85.1004.
Methyl
panecarboxylate (11b; 50.1 mg, 0.167 mmol), Al(OTf)
.033 mmol), and MeCN (1.8 mL) were combined according to the
2-(4-methoxyphenyl)-1-(1H-pyrrole-1-carbonyl)cyclopro-
2
3
(16.0 mg,
0
general method to afford 12b after 20 min; yield: 48.6 mg (97%);
Methyl 2-Ethyl-2-(3-methoxy-3-oxopropyl)-1-(1H-pyrrole-1-car-
bonyl)cyclopropanecarboxylate (11l)
green oil; R = 0.54 (20% EtOAc/hexane); diastereomeric ratio: 1.75:1.
f
IR (film): 2946.6 (w), 2834.6 (w), 1712.0 (s), 1611.6 (w), 1511.9 (m),
The general procedure was followed. Rh esp (1.9 mg, 2.405 μmol)
2
2
–1
1404.8 (m), 1248.2 (s), 1176.3 (m), 830.9 (m), 730.9 cm (m).
was added to a dry flask equipped with a stir bar under N . CH Cl (2
2
2
2
1
mL) was added. Methyl 2-diazo-3-oxo-3-(1H-pyrrol-1-yl)propanoate
H NMR (500 MHz, CDCl ): δ = 7.44–7.41 (m, 0.99), 7.40–7.38 (m,
3
(
10; 124.7 mg, 0.646 mmol) was dissolved in CH Cl (4.0 mL). Methyl
1.05), 7.24–7.19 (m, 2.21), 7.12–7.07 (m, 1.93), 6.92–6.83 (m, 4.51),
2
2
4-methylenehexanoate (298.5 mg, 2.099 mmol) was added to the re-
6.25 (t, J = 3.3 Hz, 1.00), 6.22 (t, J = 3.3 Hz, 1.08), 5.78–5.75 (m, 0.87),
action pot followed by slow addition of the diazo compound 10 at 0.5
mL/h (2 mL/4 h). After 12 h, the reaction was quenched, and silica gel
column chromatography afforded 11l; yield: 59.8 mg (30%); yellow
5.64–5.62 (m, 1.00), 4.22 (dd, J = 9.4, 4.4 Hz, 0.97), 4.02 (dd, J = 12.6,
3.7 Hz, 1.14), 3.85–3.74 (m, 16.87), 2.71–2.52 (m, 2.17), 2.45–2.30 (m,
2.23).
oil; R = 0.53 (30% EtOAc/hexane); diastereomeric ratio: 1.74:1.
13
f
C NMR (125 MHz, CDCl ): δ = 169.2, 169.1, 164.4, 163.9, 158.9,
3
IR (film): 2956.8 (m), 2679.3 (w), 1733.2 (vs), 1465.9 (m), 1437.9 (m),
158.8, 136.5, 135.5, 133.3, 132.9, 129.1, 128.8, 116.9, 116.8, 114.1,
114.0, 113.4,113.3, 111.2, 55.2, 52.9, 52.7, 50.8, 48.2, 39.7, 36.8, 34.6,
34.1.
HRMS (ESI): m/z [M]+ calcd for C17H17NO4: 299.1158; found:
–1
1333.0 (s), 1267.4 (m), 1223.6 (m), 1094.0 (m), 746.4 cm (m).
1
H NMR (500 MHz, CDCl ): δ = 7.35–7.26 (m, 1.63), 6.28–6.25 (m,
3
1
1
1
.85), 3.69 (s, 1.01), 3.68–3.65 (m, 2.68), 3.63 (s, 1.60), 2.58–2.45 (m,
.00), 2.41–2.23 (m, 1.41), 2.17–2.03 (m, 1.01), 1.87–1.76 (m, 1.26),
.76–1.65 (m, 1.46), 1.57–1.49 (m, 1.00), 1.35–1.21 (m, 0.93), 1.00 (t,
299.1165.
J = 7.5 Hz, 1.92), 0.95 (t, J = 7.0 Hz, 1.11), 0.92–0.86 (m, 0.48).
Methyl 8-(4-Fluorophenyl)-5-oxo-5,6,7,8-tetrahydroindolizine-6-
carboxylate (12c)
13
C NMR (125 MHz, CDCl ): δ = 173.2, 173.1, 169.2, 169.1, 165.0,
3
1
64.9, 119.8, 119.7, 113.2, 113.1, 53.0, 52.9, 51.7 (2 C), 40.3, 40.0, 37.7
Methyl 2-(4-fluorophenyl)-1-(1H-pyrrole-1-carbonyl)cyclopropane-
carboxylate (11c; 50.2 mg, 0.175 mmol), Al(OTf)3 (16.8 mg, 0.035
mmol), and MeCN (1.9 mL) were combined according to the general
(
2 C), 31.2, 31.1, 28.4, 27.1, 27.0, 26.7, 24.0, 21.9, 10.6, 10.5.
HRMS (ESI): m/z [M]+ calcd for C16H21NO5: 307.1420; found:
07.1419.
3
method to render 12c after 1 h; yield: 35.6 mg (71%); oil; R
20% EtOAc/hexane); diastereomeric ratio: 1.47:1.0.
f
= 0.44
(
Ring-Opening Cyclization of Cyclopropyl β-Amide Esters 11; Gen-
eral Procedure
IR (film): 2954.0 (m), 1713.4 (vs), 1604.0 (m), 1509.4 (s), 1405.6 (s),
1357.0 (s), 1279.1 (s), 1220.4 (s), 1157.0 (s), 1087.7 (m), 911.8 (m),
–1
836.8 (s), 731.0 cm (s).
Al(OTf) , cyclopropyl β-amide ester 11 (1.0 equiv), and MeCN needed
3
1
for 0.1 M at r.t. were combined in a round bottom flask and heated to
reflux. Upon completion, the reaction mixture was purified directly
by silica gel flash column chromatography. Products were shown by
H NMR (500 MHz, CDCl ): δ = 7.45–7.42 (m, 1.00), 7.42–7.39 (m,
3
0.96), 7.29–7.26 (m, 1.56), 7.18–7.14 (m, 2.06), 7.08–6.99 (m, 4.21),
6.26 (dd, J1 = J2 = 3.3 Hz, 0.92), 6.23 (dd, J1 = J2 = 3.3 Hz, 0.94), 5.80–
5.72 (m, 0.88), 5.66–5.58 (m, 0.90), 4.25 (dd, J = 10.2, 4.5 Hz, 1.09),
2-D TLC to be stable on silica gel.
4.07 (dd, J = 12.5, 4.4 Hz, 1.04), 3.85–3.74 (m, 9.14), 2.72–2.56 (m,
Methyl 5-Oxo-8-phenyl-5,6,7,8-tetrahydroindolizine-6-carboxyl-
ate (12a)
2.13), 2.46–2.32 (m, 2.07).
13
C NMR (125 MHz, CDCl ): δ = 169.1, 169.0, 164.3, 163.8, 162.8,
3
Methyl 2-phenyl-1-(1H-pyrrole-1-carbonyl)cyclopropanecarboxyl-
ate (11a; 50.1 mg, 0.186 mmol), Al(OTf)3 (17.6 mg, 0.037 mmol),
MeCN (2.0 mL) were combined according to the general method to
161.1, 161.0, 137.0, 136.7, 136.6, 135.9, 134.9, 129.7, 129.6, 129.5,
129.4, 128.2, 117.2, 117.0, 116.6, 115.7, 115.6, 115.4, 113.4, 113.3,
113.2, 111.4, 111.3, 53.0, 52.8, 50.6, 48.2, 39.8, 37.0, 34.6, 34.1, which
13
19
give 12a after 3 h; yield: 32 mg (64%); green oil; R = 0.42 (20%
includes C- F coupled peaks.
f
EtOAc/hexane); diastereomeric ratio: 1.54:1.
HRMS (ESI): m/z [M]+ calcd for C16H14FNO3: 287.0958; found:
IR (film): 2951.8 (w), 1710.9 (vs), 1488.0 (m), 1443.1 (m), 1405.1 (s),
287.0949.
1
7
1
355.7 (s), 1275.0 (s), 1154.2 (s), 1085.4 (m), 1029.0 (m), 971.9 (m),
35.6 (s), 699.7 cm (s).
–1
Methyl 8-(4-Chlorophenyl)-5-oxo-5,6,7,8-tetrahydroindolizine-6-
carboxylate (12d)
H NMR (500 MHz, CDCl ): δ = 7.47–7.43 (m, 0.89), 7.41 (dt, J = 3.5,
3
1
.3 Hz, 1.13), 7.39–7.27 (m, 8.68), 7.20–7.15 (m, 1.98), 6.27 (dd, J1
=
Methyl 2-(4-chlorophenyl)-1-(1H-pyrrole-1-carbonyl)cyclopropane-
carboxylate (11d; 50.5 mg, 0.166 mmol), Al(OTf)3 (17.3 mg, 0.036
mmol), and MeCN (1.8 mL) were combined according to the general
J = 3.3 Hz, 0.88), 6.23 (dd, J = J = 3.3 Hz, 1.07), 5.79 (m, 0.90), 5.64
2
1
2
(m, 1.04), 4.28 (dd, J = 9.4, 4.5 Hz, 1.00), 4.08 (dd, J = 12.5, 4.5 Hz,
1.16), 3.89–3.68 (m, 8.30), 2.76–2.60 (m, 2.05), 2.49–2.36 (m, 2.12).
method to furnish 12d after 3 h; yield: 27.3 mg (54%); green oil; R =
f
13
0.43 (20% EtOAc/hexane); diastereomeric ratio: 1.75:1.
C NMR (125 MHz, CDCl ): δ = 169.62, 169.27, 165.03, 164.92,
3
1
1
1
5
58.58, 158.53, 134.50, 134.44, 133.73, 133.49, 132.80, 132.26,
31.36, 131.09, 128.95, 128.27, 124.82, 124.79, 124.14, 124.04,
18.15, 117.96, 116.52, 115.21, 114.84, 114.15, 113.90, 55.15, 52.56,
2.39, 49.77, 47.10, 43.40, 37.91, 35.24, 33.87, 33.00, 8.72, 8.34.
IR (film): 2951.9 (w), 1711.4 (vs), 1487.8 (m), 1404.7 (m), 1356.6 (m),
1273.1 (m), 1157.3 (m), 1087.3 (m), 1016.6 (m), 821.0 (m), 732.5
cm (m).
–
1
1
H NMR (500 MHz, CDCl ): δ = 7.46–7.43 (m, 0.87), 7.42–7.39 (m,
3
HRMS (ESI): m/z [M]+ calcd for C16H15NO3: 269.1052; found:
69.1058.
1.09), 7.36–7.29 (m, 4.34), 7.27–7.22 (m, 2.93), 7.15–7.11 (m, 2.13),
2
6.26 (dd, J = J = 3.3 Hz, 0.96), 6.23 (d, J = J = 3.3 Hz, 1.05), 5.77–5.74
1
2
1
2
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

H
Synthesis
M. A. Cavitt, S. France
Special Topic
(
m, 0.83), 5.65–5.61 (m, 1.00), 4.25 (dd, J = 9.3, 4.4 Hz, 0.94), 4.06 (dd,
Methyl 8-(Naphthalen-2-yl)-5-oxo-5,6,7,8-tetrahydroindolizine-6-
carboxylate (12g)
J = 12.5, 4.4 Hz, 1.10), 3.85–3.74 (m, 9.01), 2.72–2.52 (m, 2.13), 2.47–
2
.34 (m, 2.14).
Methyl 2-(naphthalen-2-yl)-1-(1H-pyrrole-1-carbonyl)cyclopropan-
13
C NMR (125 MHz, CDCl ): δ = 169.0, 168.9, 164.1, 163.7, 139.9,
ecarboxylate (11g; 49.9 mg, 0.156 mmol), Al(OTf) (14.8 mg, 0.031
3
3
1
1
39.4, 135.5, 134.6, 133.4, 133.2, 129.5, 129.3, 128.9, 117.2, 117.1,
13.4, 113.3, 111.5, 111.4, 53.0, 52.8, 50.6, 48.1, 39.9, 37.1, 34.3, 33.9.
mmol), and MeCN (1.7 mL) were mixed according to the general
method to render 12g after 30 min; yield: 34.6 mg (69%); light green
HRMS (ESI): m/z [M]+ calcd for C16H14ClNO : 303.0662; found:
solid; mp 130–132 °C; R
ratio: 1.31:1.
f
= 0.50 (20% EtOAc/hexane); diastereomeric
3
303.0671.
IR (film): 2955.9 (s), 1712.2 (s), 1570.6 (w), 1401.6 (s), 1358.1 (s),
1
7
1
250.1 (s), 1156.4 (m), 1085.7 (m), 964.5 (m), 866.4 (m), 818.5 (s),
40.2 cm (vs).
Methyl 8-(4-Bromophenyl)-5-oxo-5,6,7,8-tetrahydroindolizine-6-
carboxylate (12e)
–1
H NMR (500 MHz, CDCl ): δ = 7.90–7.73 (m, 7.19), 7.61 (s, 0.82),
Methyl 2-(4-bromophenyl)-1-(1H-pyrrole-1-carbonyl)cyclopropane-
carboxylate (11e; 50.0 mg, 0.144 mmol), Al(OTf)3 (13.8 mg, 0.029
mmol), and MeCN (1.5 mL) were combined according to the general
3
7
.54–7.46 (m, 5.96), 7.46–7.38 (m, 1.09), 7.34 (dd, J = 8.5, 1.8 Hz,
.80), 6.29 (dd, J1 = J2 = 3.3 Hz, 0.74), 6.24 (dd, J1 = J2 = 3.3 Hz, 0.97),
.83–5.80 (m, 0.78), 5.67–5.64 (m, 1.00), 4.46 (dd, J = 9.2, 4.0 Hz,
.81), 4.25 (dd, J = 12.3, 4.3 Hz, 1.04), 3.88 (dd, J = 12.7, 4.6 Hz, 1.19),
.85–3.73 (m, 6.69), 2.83–2.72 (m, 1.89), 2.60–2.51 (m, 0.85), 2.52–
.43 (m, 1.11).
0
5
0
3
2
method to furnish 12e after 3 h; yield: 25.6 mg (51%); green oil; R =
f
0.45 (20% EtOAc/hexane); diastereomeric ratio: 1.79:1.
IR (film): 2950.8 (w), 1711.3 (vs), 1486.1 (m), 1404.7 (m), 1356.9 (m),
–1
1
272.4 (m), 1012.6 (m), 818.9 (m), 732.5 cm (m).
13
C NMR (125 MHz, CDCl ): δ = 169.2, 169.1, 164.4, 163.9, 138.7,
1
3
H NMR (500 MHz, CDCl ): δ = 7.52–7.45 (m, 4.22), 7.44 (ddd, J = 3.4,
3
138.2, 135.9, 135.0, 133.4, 133.3, 132.8, 132.6, 128.6, 128.5, 127.7 (2
1.6, 0.7 Hz, 0.91), 7.41 (dt, J = 3.4, 1.3 Hz, 1.02), 7.21–7.16 (m, 2.25),
C), 127.6, 127.1, 126.8, 126.3 (2 C), 126.0 (2 C), 125.9, 125.7, 117.1,
16.9, 113.4, 111.5, 111.5, 52.9, 52.7, 50.7, 48.1, 40.6, 37.8, 34.3, 33.9.
HRMS (ESI): m/z [M]+ calcd for C20H17NO3: 319.1208; found:
19.1201.
7
3
9
3
.10–7.05 (m, 1.83), 6.26 (dd, J = J = 3.3 Hz, 0.89), 6.23 (dd, J = J =
1
2
1
2
1
.3 Hz, 1.01), 5.77–5.74 (m, 0.83), 5.65–5.61 (m, 1.00), 4.24 (dd, J =
.5, 4.3 Hz, 0.88), 4.05 (dd, J = 12.5, 4.4 Hz, 1.04), 3.84–3.78 (m, 7.30),
.76 (t, J = 5.5 Hz, 1.12), 2.70–2.56 (m, 2.00), 2.44–2.34 (m, 1.97).
3
13
C NMR (125 MHz, CDCl ): δ = 169.0, 168.9, 164.2, 163.6, 140.4,
3
Methyl 8-(Furan-2-yl)-5-oxo-5,6,7,8-tetrahydroindolizine-6-car-
boxylate (12h)
1
1
3
39.9, 135.4, 134.5, 131.9, 131.7, 129.9, 129.6, 121.5, 121.3, 117.2,
17.1, 113.4, 1113.3, 111.5, 111.4, 53.0, 52.8, 50.6, 48.1, 39.9, 37.2,
4.3, 33.9.
Methyl
2-(furan-2-yl)-1-(1H-pyrrole-1-carbonyl)cyclopropanecar-
(18.5 mg, 0.039
HRMS (ESI): m/z [M]+ calcd for C16H14BrNO : 347.0157; found:
boxylate (11h; 50.0 mg, 0.193 mmol), Al(OTf)
3
3
mmol), and MeCN (2.0 mL) were combined according to the general
method to give 12h after 30 min; yield: 39.2 mg (78%); light brown
347.0165.
oil; R = 0.44 (20% EtOAc/hexane); diastereomeric ratio: 1.15:1.
f
Methyl 8-Methyl-5-oxo-8-phenyl-5,6,7,8-tetrahydroindolizine-6-
carboxylate (12f)
IR (film): 2952.6 (s), 2867.8 (m), 1735.3 (m), 1698.8 (vs), 1463.8 (m),
1
9
1
402.6 (m), 1312.7 (vs), 1201.2 (m), 1159.9 (s), 1062.0 (vs), 1012.0 (s),
17.5 (m), 731.5 cm (vs).
Methyl 2-methyl-2-phenyl-1-(1H-pyrrole-1-carbonyl)cyclopropane-
carboxylate (11f; 49.8 mg, 0.176 mmol), Al(OTf)3 (16.7 mg, 0.035
mmol), and MeCN (1.9 mL) were combined according to the general
method to give 12f after 30 min; yield: 47 mg (95%); light yellow sol-
–1
H NMR (500 MHz, CDCl ): δ = 7.43–7.39 (m, 2.72), 7.37 (dd, J = 1.9,
3
0
.9 Hz, 0.90), 6.35 (dd, J = 3.2, 1.8 Hz, 0.97), 6.31 (dd, J = 3.2, 1.9 Hz,
.94), 6.27 (m, 1.86), 6.18–6.16 (m, 0.92), 6.04–6.01 (m, 1.81), 5.98–
.95 (m, 0.90), 4.45–4.41 (m, 0.95), 4.29 (dd, J = 10.3, 4.4 Hz, 1.00),
.83–3.73 (m, 7.54), 2.80–2.66 (m, 2.04), 2.60 (ddd, J = 13.5, 7.4, 5.0
0
5
3
id; mp 83–85 °C; R = 0.76 (30% EtOAc/hexane); diastereomeric ratio:
f
4.0:1.
IR (film): 2957.3 (w), 1744.5 (s), 1711.8 (vs), 1489.3 (w), 1402.4 (s),
Hz, 0.99), 2.54–2.46 (m, 1.00).
1
7
1
355.4 (s), 1272.9 (s), 1160.3 (s), 1087.8 (m), 963.6 (m), 765.3 (m),
34.7 (s), 700.4 cm (s).
13
–1
C NMR (75 MHz, CDCl ): δ = 169.1, 168.8, 164.0, 163.8, 153.6, 153.4,
3
1
1
42.2, 142.1, 132.5, 131.9, 117.2, 117.1, 113.4, 113.3, 111.2, 111.1,
10.3, 107.0, 106.8, 52.9, 52.8, 49.8, 47.8, 33.4, 31.5, 31.1, 30.4.
H NMR (500 MHz, CDCl ): δ = 7.50 (dd, J = 3.4, 1.6 Hz, 0.15), 7.44 (dd,
3
J = 3.4, 1.6 Hz, 0.97), 7.31–7.26 (m, 2.26), 7.24–7.19 (m, 1.27), 7.16–
HRMS (ESI): m/z [M]+ calcd for C14H13NO4: 259.0845; found:
59.0844.
7
.12 (m, 0.36), 6.99–6.95 (m, 2.11), 6.38 (dd, J = J = 3.3 Hz, 0.97), 6.35
1 2
2
(
dd, J = J = 3.3 Hz, 0.18), 6.21 (dd, J = 3.2, 1.5 Hz, 0.99), 6.04 (dd, J =
1 2
3
0
.2, 1.6 Hz, 0.17), 3.76 (s, 2.67), 3.32 (dd, J = 13.2, 4.6 Hz, 1.04), 3.22 (s,
.49), 2.97 (dd, J = 13.9, 5.3 Hz, 0.20), 2.64 (t, J = 13.2 Hz, 1.10), 2.56
Methyl 8-[(tert-Butyldiphenylsilyl)methyl]-5-oxo-5,6,7,8-tetrahy-
(dd, J = 13.2, 4.7 Hz, 1.11), 2.41 (dd, J = 13.9, 6.2 Hz, 0.22), 1.74 (s,
droindolizine-6-carboxylate (12i)
3
.00), 1.71 (s, 0.53).
Methyl 2-[(tert-butyldiphenylsilyl)methyl]-1-(1H-pyrrole-1-carbon-
13
C NMR (125 MHz, CDCl ): δ = 169.4, 164.5, 144.9, 138.3, 128.7,
yl)cyclopropanecarboxylate (11i; 49.8 mg, 0.112 mmol), Al(OTf)
3
3
1
5
28.0, 127.0, 126.9, 125.9, 117.2, 117.1, 113.3, 113.2, 110.9, 110.7,
2.6, 52.3, 47.9, 40.1, 39.9, 39.7, 29.3, 29.1.
(10.8 mg, 0.023 mmol), and MeCN (1.2 mL) were combined according
to the general method to furnish 12i after 30 min; yield: 35.7 mg
HRMS (ESI): m/z [M]+ calcd for C17H17NO3: 283.1208; found:
83.1206.
(72%);
EtOAc/hexane); diastereomeric ratio: 1.45:1.
IR (film): 2931.6 (m), 2855.2 (m), 1742.4 (s), 1713.3 (vs), 1566.0 (w),
light green solid; mp 153–155 °C;
R
f
= 0.52 (20%
2
1
468.2 (m), 1402.7 (s), 1358.1 (s), 1271.8 (s), 1170.3 (s), 1100.5 (s),
–1
987.6 (m), 871.7 (m), 731.0 (vs), 696.5 cm (vs).
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

I
Synthesis
M. A. Cavitt, S. France
Special Topic
1
H NMR (500 MHz, CDCl ): δ = 7.74–7.70 (m, 0.84), 7.69–7.64 (m,
References
3
7
.77), 7.46–7.35 (m, 13.33), 7.33–7.27 (m, 1.99), 6.24 (dd, J = J = 3.3
1 2
(
1) Present Address: Division of Chemistry and Chemical Engineer-
ing, California Institute of Technology, Pasadena, CA 91125,
USA.
Hz, 0.86), 6.21 (dd, J1 = J2 = 3.3 Hz, 1.01), 6.13–6.09 (m, 0.84), 6.00–
5
3
1
.97 (m, 1.00), 3.68 (s, 2.54), 3.58 (t, J = 5.0 Hz, 1.02), 3.47 (s, 3.09),
.23 (dd, J = 13.0, 4.6 Hz, 0.85), 3.02–2.92 (m, 1.06), 2.85–2.75 (m,
.03), 2.10–2.01 (m, 1.14), 1.93 (dd, J = 15.4, 3.1 Hz, 0.91), 1.89–1.81
(2) (a) Ahmed, S. A.; Khairou, K. S.; Asghar, B. H.; Muathen, H. A.;
Nahas, N. M. A.; Alshareef, H. F. Tetrahedron Lett. 2014, 55, 2190.
(m, 1.86), 1.81–1.71 (m, 1.36), 1.69–1.62 (m, 1.04), 1.47–1.31 (m,
(b) Bertin, L.; Mailliet, P.; Minoux, H.; Ruxer, J.-M. PCT Int. Appl
2
.25), 1.10–1.06 (m, 10.01), 1.05 (s, 9.59).
WO 2011027081 A2, 2011. (c) Bao, J.; Lu, H.; Morriello, G. J.;
Carlson, E. J.; Wheeldon, A.; Chicchi, G. G.; Kurtz, M. M.; Tsao,
K.-L. C.; Zheng, S.; Tong, X.; Mills, S. G.; De Vita, R. J. Bioorg. Med.
Chem. Lett. 2010, 20, 2354. (d) Payne, L. J.; Downham, R.; Sibley,
G. E. M.; Edwards, P.; Davies, G. M. PCT Int. Appl.
WO 2008145963 A1, 2008.
1
3
C NMR (75 MHz, CDCl ): δ = 169.1, 169.0, 164.6, 164.0, 139.0, 138.9,
3
1
1
1
36.0 (2 C), 135.9, 135.8, 134.8, 134.2, 133.5, 133.3, 129.6, 129.5 (2 C),
29.4, 129.3, 127.9 (2 C), 127.8, 127.7 (2 C), 116.8 (2 C), 113.0, 108.9,
08.8, 52.6, 52.5, 50.8, 48.8, 34.0, 33.4, 29.9, 27.8, 27.7, 27.4, 26.5, 18.2
(2 C), 14.4, 13.8.
HRMS (ESI): m/z [M]+ calcd for C27H31NO Si: 445.2073; found:
4
3
(3) For representative articles on the synthesis and biological eval-
uation of octahydroindolizines, see: (a) Hu, Y.; Zhang, C.; Zhao,
X.; Wang, Y.; Feng, D.; Zhang, M.; Xie, H. J. Nat. Prod. 2016, 79,
252. (b) Davies, S. G.; Hughes, D. G.; Price, P. D.; Roberts, P. M.;
Russell, A. J.; Smith, A. D.; Thomson, J. E.; Williams, O. M. H.
Synlett 2010, 567. (c) Pandey, G.; Dumbre, S. G.; Pal, S.; Khan, M.
I.; Shabab, M. Tetrahedron 2007, 63, 4756. (d) Apodaca, R.;
Carruthers, N. I.; Carson, J. R.; Chai, W.; Kwok, A. K.; Li, X.;
Lovenberg, T. W.; Rudolph, D. A.; Shah, C. R. PCT Int. Appl.
WO 2002024695 A2, 2002.
45.2075.
Methyl 8-Ethyl-8-(3-methoxy-3-oxopropyl)-5-oxo-5,6,7,8-tetrahy-
droindolizine-6-carboxylate (12l)
In(OTf)3 (84.1 mg, 0.150 mmol) was charged to a flame-dried flask.
Methyl 2-ethyl-2-(3-methoxy-3-oxopropyl)-1-(1H-pyrrole-1-carbon-
yl)cyclopropanecarboxylate (11l; 153.3 mg, 0.499 mmol) was dis-
solved in CH Cl (3 mL) and added to the flask. CH Cl (2 mL) was used
to rinse the flask containing the starting material and syringed into
the reaction pot at 50 °C. The reaction mixture was heated at reflux
for 50 min and cooled to r.t. The crude was purified directly to obtain
2
2
2
2
(
4) For some representative reviews on indolizines, see:
(
(
a) Sharma, V.; Kumar, V. Med. Chem. Res. 2014, 23, 3593.
b) Vemula, V. R.; Vurukonda, S.; Bairi, C. K. Int. J. Pharm. Sci. Rev.
1
2l; yield: 95.8 mg (65%); light brown oil; R = 0.34 (20% EtOAc/hex-
f
ane); diastereomeric ratio: 1.10:1.
Res. 2011, 11, 159. (c) Singh, G. S.; Mmatli, E. E. Eur. J. Med.
Chem. 2011, 46, 5237. (d) Michael, J. P. Nat. Prod. Rep. 2007, 24,
IR (film): 2953.4 (m), 1712.5 (vs), 1564.5 (w), 1439.1 (m), 1404.8 (s),
1
7
1
354.4 (s), 1277.9 (s), 1169.4 (s), 1088.6 (m), 971.5 (m), 873.3 (m),
33.6 cm (s).
191.
–1
(
5) (a) David, B.; Sevenet, T.; Thoison, O.; Awang, K.; Pais, M.;
Wright, M.; Guenard, D. Bioorg. Med. Chem. Lett. 1997, 7, 2155.
(b) Kam, T. S.; Subramaniam, G. Nat. Prod. Lett. 1998, 11, 131.
(c) Subramaniam, G.; Hiraku, O.; Hayashi, M.; Koyano, T.;
Komiyama, K.; Kam, T.-S. J. Nat. Prod. 2007, 70, 1783. (d) Gan, C.-
Y.; Low, Y.-Y.; Thomas, N. F.; Kam, T.-S. J. Nat. Prod. 2013, 76,
957.
H NMR (500 MHz, CDCl ): δ = 7.33–7.30 (m, 1.90), 6.22 (dd, J = J =
.3 Hz, 0.91), 6.20 (dd, J = J = 3.3 Hz, 0.99), 5.97 (dd, J = 3.3, 1.5 Hz,
.93), 5.94 (dd, J = 3.3, 1.5 Hz, 1.00), 3.93 (dd, J = 13.0, 5.1 Hz, 1.07),
.85 (dd, J = 12.8, 5.1 Hz, 1.13), 3.81–3.77 (m, 6.10), 3.64 (s, 2.94), 3.57
3
1
2
3
0
3
1 2
(s, 3.05), 2.44–2.26 (m, 5.23), 2.25–2.17 (m, 1.25), 2.11–1.88 (m, 5.58),
1
.83–1.74 (m, 1.47), 1.71 (q, J = 7.5 Hz, 2.17), 1.65–1.46 (m, 2.20),
0
.91–0.82 (m, 6.50).
(6) (a) Schroder, F.; Francke, W. Tetrahedron 1998, 54, 5259.
(b) Schroeder, F.; Franke, S.; Francke, W.; Baumann, H.; Kaib, M.;
Pasteels, J. M.; Daloze, D. Tetrahedron 1996, 52, 13539.
13
C NMR (125 MHz, CDCl ): δ = 173.7, 173.4, 169.8, 169.7, 164.0,
3
1
5
2
63.9, 137.0, 136.9, 117.1, 117.0, 113.1, 112.9, 109.9, 109.7, 52.7 (2 C),
1.6 (2 C), 46.9, 46.8, 36.8, 36.5, 34.8, 34.2, 31.7, 31.3, 31.1, 29.7, 28.9,
8.7, 8.12, 7.7.
(
7) (a) Bournique, B.; Lambert, N.; Boukaiba, R.; Martinet, M. Br. J.
Clin. Pharmacol. 2001, 52, 53. (b) Snoeck, R.; Andrei, G.; Bodaghi,
B.; Lagneaux, L.; Daelemans, D.; de Clercq, E.; Neyts, J.; Schols,
D.; Naesens, L.; Michelson, S.; Bron, D.; Otto, M. J.; Bousseau, A.;
Nemecek, C.; Roy, C. Antiviral Res. 2002, 55, 413.
HRMS (ESI): m/z [M]+ calcd for C16H21NO5: 307.1420; found:
07.1427.
3
(8) (a) Sun, L.-R.; Li, X.; Wang, S.-X. J. Asian Nat. Prod. Res. 2005, 7,
1
27. (b) Dinsmore, A.; Mandy, K.; Michael, J. P. Org. Biomol.
Acknowledgment
Chem. 2006, 4, 1032. (c) Wang, Y.-F.; Lu, C.-H.; Lai, G.-F.; Cao, J.-
X.; Luo, S.-D. Planta Med. 2003, 69, 1066.
S.F. gratefully acknowledges financial support from the National Sci-
ence Foundation (CAREER Award CHE-1056687). M.A.C. thanks the
Ford Foundation, NSF (DGE-1148903), and Georgia Tech for generous
support.
(
9) For seminal contributions for the synthesis of 5,6,7,8-tetrahy-
droindolizines, see: (a) Dalla Croce, P.; La Rosa, C. Heterocycles
2
001, 55, 1843. (b) Dallemagne, P.; Sonnet, P.; Enguehard, C.;
Rault, S. J. Heterocycl. Chem. 1996, 33, 1689. (c) Raussou, S.;
Urbain, N.; Mangeney, P.; Alexakis, A.; Platzer, N. Tetrahedron
Lett. 1996, 37, 1599. (d) Katritzky, A. R.; Grzeskowiak, N. E.;
Alvarez-Builla, J. J. Chem. Soc., Perkin Trans. 1 1981, 1180.
Supporting Information
(
(
e) Pizzorno, M. T.; Albonico, S. M. J. Org. Chem. 1977, 42, 909.
f) Uchida, T.; Tsubokawa, S.; Harihara, K.; Matsumoto, K. J. Het-
erocycl. Chem. 1978, 15, 1303.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1561621.
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u
p
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10) For recent examples for the syntheses of tetrahydroindolizines
and their derivatives, see: (a) Zhou, Y.; Liu, X.-W.; Gu, Q.; You,
S.-L. Synlett 2016, 27, 586. (b) Teodoro, B. V. M.; Correia, J. T. M.;
Coelho, F. J. Org. Chem. 2015, 80, 2529. (c) Capomolla, S. S.; Lim,
©
Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J

J
Synthesis
M. A. Cavitt, S. France
Special Topic
N.-K.; Zhang, H. Org. Lett. 2015, 17, 3564. (d) Biletzki, T.; Imhof,
W. Eur. J. Org. Chem. 2012, 6513. (e) Magerramov, A. M.; Aliev, I.
A.; Farzaliev, S. F.; Sadykhova, N. D.; Akhmedov, I. M. Russ. J. Org.
Chem. 2010, 46, 1101. (f) Chiurato, M.; Boulahjar, R.; Routier, S.;
Troin, Y.; Guillaumet, G. Tetrahedron 2010, 66, 4647. (g) Gracia,
S.; Cazorla, C.; Metay, E.; Pellet-Rostaing, S.; Lemaire, M. J. Org.
Chem. 2009, 74, 3160. (h) Gracia, S.; Metay, E.; Pellet-Rostaing,
S.; Lemaire, M. Synlett 2009, 2617. (i) Ghosh, S. K.; Buchanan, G.
S.; Long, Q. A.; Wei, Y.; Al-Rashid, Z. F.; Sklenicka, H. M.; Hsung,
R. P. Tetrahedron 2008, 64, 883. (j) Kimball, F. S.; Himes, R. H.;
Georg, G. I. Bioorg. Med. Chem. Lett. 2008, 18, 3248.
(12) (a) Aponte-Guzmán, J.; Shenje, R.; Huang, Y.; Woodham, W. H.;
Saunders, S. R.; Mostaghimi, S. M.; Flack, K. R.; Pollet, P.; Eckert,
C. A.; Liotta, C. L.; France, S. Ind. Eng. Chem. Res. 2015, 54, 9550.
(b) Patil, D. V.; Cavitt, M. A.; Grzybowski, P.; France, S. Chem.
Commun. 2011, 47, 10278.
(13) Patil, D. V.; Cavitt, M. A.; France, S. Org. Lett. 2011, 13, 5820.
(14) Presset, M.; Mailhol, D.; Coquerel, Y.; Rodriguez, J. Synthesis
2011, 2549.
(15) Espino, C. G.; Fiori, K. W.; Kim, M.; Du Bois, J. J. Am. Chem. Soc.
2004, 126, 15378.
(16) See Supporting Information for optimization details.
(17) Hansch, C.; Leo, A.; Taft, R. W. Chem. Rev. 1991, 91, 165.
(18) Yadav, V. K.; Sriramurthy, V. Angew. Chem. Int. Ed. 2004, 43,
2669.
(k) Rocchiccioli, S.; Guazzelli, G.; Lazzaroni, R.; Settambolo, R.
J. Heterocycl. Chem. 2007, 44, 479. (l) Dalla Croce, P.; La Rosa, C.
Heterocycles 2001, 55, 1843. (m) Marchalin, S.; Cvopova, K.;
Pham-Huu, D. P.; Chudik, M.; Kozisek, J.; Svoboda, I.; Daich, A.
Tetrahedron Lett. 2001, 42, 5663.
(19) Gonzalez-Bobes, F.; Fenster, M. D. B.; Kiau, S.; Kolla, L.;
Kolotuchin, S.; Soumeillant, M. Adv. Synth. Catal. 2008, 350, 813.
(11) Martin, M. C.; Shenje, R.; France, S. Isr. J. Chem. 2016, 56, in
press; DOI: 10.1002/ijch.201500099.
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Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–J