A new flow methodology for the expedient synthesis of drug-like 3-aminoindolizines

Article abstract of DOI:10.1002/adsc.201200316

A flow-based synthesis of diversely functionalized indolizines and their aza-analogues is described. These drug-like heterocycles were generated via a tandem Sonogashira/cycloisomerization sequence, starting from widely available 2-bromopyridines and alkynes, employing a simple catalyst system together with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) as base. The use of flow technology allows a straightforward and rapid access to a variety of novel compounds, and enables linear scale-up from milligram- to gram-scales without a decrease in yield. Copyright

Full text of DOI:10.1002/adsc.201200316

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DOI: 10.1002/adsc.201200316
A New Flow Methodology for the Expedient Synthesis of Drug-
Like 3-Aminoindolizines
Paul P. Lange,a Andrew R. Bogdan,a and Keith Jamesa,*
a
Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037,
USA
Fax : (+1)-858-784-7550; phone: (+1)-858-784-2507; e-mail: kjames@scripps.edu
Received: April 15, 2012; Revised: May 5, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200316.
Abstract: A flow-based synthesis of diversely func-
tionalized indolizines and their aza-analogues is de-
scribed. These drug-like heterocycles were generat-
ed via a tandem Sonogashira/cycloisomerization se-
quence, starting from widely available 2-bromopyri-
dines and alkynes, employing a simple catalyst
nent reactions[9,10] which complicate macrocyclization
processes. Consequently, we set out to develop a syn-
thetic protocol that allowed efficient access to indoli-
zines bearing a range of synthetically useful functional
groups.
Recently, it has been shown that indolizines can be
accessed by a copper-mediated, intramolecular cyclo-
system together with 1,8-diazabicycloACHTNUTRGNEUNG[5.4.0]undec-7-
ene (DBU) as base. The use of flow technology
allows a straightforward and rapid access to a varie-
ty of novel compounds, and enables linear scale-up
from milligram- to gram-scales without a decrease
in yield.
isomerization of preformed 2-alkynylpyridines.[13] Sub-
ACHTUNGTRENNUNG
sequently, Liu et al. developed a one-pot sequential
cross-coupling/cycloisomerization reaction for the syn-
thesis of 3-aminoindolizines from aryl bromides and
alkynes in the presence of catalytic amounts of
copper.[14] Although the range of synthetically useful
functional groups compatible with this procedure was
limited, this elegant strategy offered an attractive
starting point for our purposes, since diversely func-
tionalized heteroaryl bromides and alkynes are widely
available, Sonogashira cross-couplings are a feasible
strategy for the construction of macrocycles[15] and the
Keywords: cross-coupling; cycloisomerization; flow
technology; heterocycles; homogenous catalysis
The pharmaceutical importance of compounds con- intramolecular cycloisomerization is copper-cata-
taining an indolizine substructure has been well docu- lyzed.[13,14]
mented. Thus, indolizines have found use as anti-
We have recently shown that copper-catalyzed mac-
HIV[1] and anti-inflammatory agents,[2] CNS depres- rocyclizations can effectively be performed in flow,
sants,[3] calcium entry blockers,[4] and in the treatment where a copper reactor surface serves as the cata-
of cancer.[5] A number of synthetic approaches to this lyst.[16] Moreover, multiple other reports have ap-
heterocyclic system has been reported and reviewed.[6] peared in the recent literature describing the success-
The most widely used strategies are the Tschitschiba- ful application of a copper tube flow reactor to effect
bin reaction,[7] the Scholtz reaction,[8] and the cycload- copper-catalyzed transformations.[17] As a result, we
dition of alkenes[9] or alkynes[10] to N-alkylpyridinium sought to investigate a similar approach for the syn-
salts.
thesis of indolizines and herein present the develop-
As part of an ongoing program to develop macro- ment of a novel flow-based protocol granting synthet-
cyclization reactions which generate drug-like scaf- ic access to diversely functionalized indolizines.
folds upon ring closure,[11] we were intrigued by the
We began by investigating the feasibility of employ-
possibility of using an indolizine formation in this ing a catalytically active copper reactor surface[16] to
way. To date, reports of macrocycles containing indo- facilitate the intramolecular cyclization of model sub-
lizines are surprisingly scarce,[12] presumably due to strate 1a which would be accessible via a Sonogashira
the fact that traditional syntheses often do not pro- reaction (Table 1, see the Supporting Information for
vide access to indolizines with suitable linking groups additional experiments). We found that most soluble
on both rings. Moreover, these synthetic approaches organic bases showed low activity for the desired
either require harsh conditions[8] or are multicompo- transformation (entries 1–3). However, upon employ-
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Table 1. Optimization of the intramolecular cyclization in
Table 2. Optimization of the Sonogashira coupling in flow.[a]
flow.[a]
Entry
Catalyst
Base[b]
Time
[min]
1a[c]
[%]
N
Entry Reactor Base[b]
material
Temp. Time 2a
[8C]
[min] [%][c]
ACHTUNGTRENNUNG
1
2
3
4
5
6
7
5% Pd
5% Pd
5% Pd
10% Pd
5% Pd
5% PdAHCTNUGTRENNNUG
N
TBAA (1.0)
TBAA (1.0)
TBAA (2.0)
TBAA (2.0)
TBAA (1.0)
TBAA (1.0)
NEt3 (1.5)
30
60
30
30
30
30
20
42
40
41
1
2
3
4
5
6
7
8
9
10
copper
copper
copper
copper
copper
copper
copper
Hast.
NEt3 (3.0)
TBAA (3.0) 120
120
5
2
5
0
G
41
DBN (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
–
120
120
150
180
180
180
180
180
5
5
5
5
10
10
5
0
19
34
61
39[d]
37[e]
94[f]
3% PdCl
10% CuI
2ACHTUNGTERN(NUNG PPh3)2/
93 (73)[d]
95
[a]
Reaction conditions: Accendo Conjure Flow Reactor in-
cubation chamber, 808C.
Number in parentheses corresponds to equivalents of
base.
Percent UV from LC-MS analysis.
With 5 mol% PPh3.
With 5 mol% P
Hast.
Hast.
95 (72)[d]
14
[b]
5
[a]
Reaction conditions: Accendo Conjure Flow Reactor. Cu
tubing (0.75 mm i. d., 1.6 mL internal volume), Hastelloy
tubing (0.75 mm i. d., 2.0 mL internal volume).
Number in parentheses corresponds to equivalents of
base.
Percent UV from LC-MS analysis.
Isolated yield. TBAA: tetrabutylammonium acetate.
Hast.: Hastelloy.
[c]
[d]
[e]
[f]
ACHTNUGRTNE(NGNU C6H4OMe)3.
[b]
DMSO as solvent. TBAA: tetrabutyl ammonium acetate.
[c]
[d]
the intermediates. The component stock solutions for
the first step are premixed and the segment is heated
in a sample loop. Upon completion of the reaction,
ing an excess of DBU in DMF at a temperature of other reagents can be added to the segment contain-
1208C and a residence time of merely 5 min, we de- ing the first-step product and subjected to the flow re-
tected the desired bis-functionalized indolizine 2a in actor for the second step. For the optimization of the
19% yield. Increasing the reactor temperature to first-step Sonogashira coupling the segment was
1808C and prolonging the residence time to 10 min quickly passed through the reactor at room tempera-
led to full consumption of 2-alkynylpyridine 1a and ture and analyzed by LC-MS (Table 2, see the Sup-
formation of indolizine 2a in an isolated yield of 73% porting Information for additional experiments).
(entry 7). A control experiment was performed to an-
Initially, we envisaged a Cu-free protocol for the
alyze the catalytic activity of the copper reactor sur- Sonogashira coupling of the model substrates 6-bro-
face, by replacing it with a reactor coil made from momethyl nicotinate 3a and N-methyl-N-propargyl-
Hastelloy, a chemically inert nickel alloy. When con- benzylamine 4a. However, when employing 5 mol%
ducting the reaction under otherwise identical condi- PdACTHNUTRGENUG(N OAc)2 and 1 equiv. TBAA in DMF, only low
tions, we found that the cyclization also took place yields were obtained for the desired product when
with complete conversion, within 5 min residence heated to 808C for 30 or 60 min (entries 1 and 2).
time, to afford the product 2a in 72% isolated yield Higher loadings of the catalyst system (entries 3 and
(entry 9). Thus, a copper catalyst is not required for 4) or the addition of phosphine ligands (entries 5 and
the cycloisomerization of substrate 1a under the de- 6) had no effect on the outcome of the reaction. How-
veloped flow conditions. The transformation is rapidly ever, we were delighted to find that under standard
effected by employing an excess of DBU base Sonogashira conditions [3 mol% PdCl2ACTHNUTRGEN(UNG PPh3)2,
(3 equiv.) at a reaction temperature of 1808C, which 10 mol% CuI, 1.5 equiv. NEt3) the reaction was com-
can be safely achieved and maintained in the flow re- plete within 20 min at 808C. DMSO proved to be the
actor.
optimal solvent, since the catalyst system is not suffi-
Next, we focused on the realization of the initial ciently soluble in DMF, THF or dioxane. An excess of
Sonogashira coupling step within the flow reactor. NEt3 base was required to avoid precipitation of pal-
The Conjure flow reactor[18] used for this project is ladium black from the stock solution upon standing.
equipped with an incubation chamber that enables 2-
With optimized protocols for both reaction steps in
step reaction sequences to be performed within the hand, we sought to combine them for the first flow-
reactor without the need for isolation or handling of based synthesis of multifunctionalized indolizines
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A New Flow Methodology for the Expedient Synthesis of Drug-Like 3-Aminoindolizines
Table 3. Synthetic scope of the flow indolizine synthesis in
regard to the heteroaryl bromide coupling partner.[a]
Scheme 1. Comparison of incubation vs. direct injection.
Entry
1
Product Entry
2
Product
from heteroaryl bromides and alkynes. Heating a seg-
ment (300 mL) containing the heteroaryl bromide 3a,
alkyne 4a and catalyst system to 808C for 20 min, fol-
lowed by the addition of a solution of DBU in DMF
(150 mL) and passing the resulting mixture through
the Hastelloy reactor (1808C, 5 min) afforded indoli-
zine 2a in 70% isolated yield. We then investigated
the option of directly injecting a segment (450 mL)
containing all reaction components into the flow reac-
tor and were delighted to find that the use of an incu-
bation chamber was not required. A direct injection
of the segment (450 mL) into the flow reactor (1808C,
5 min) gave clean conversion to the indolizine product
in 71% isolated yield (Scheme 1).
3
5
4
6
Thus, the high reaction concentrations and flow
conditions allow the rapid synthesis of indolizines in
mere minutes (5–10 min).[19] In contrast, earlier batch
protocols[14] require many hours (2–20 h) for comple-
tion of the reaction.[20]
Using these optimized conditions we next evaluated
the scope of this novel flow protocol. A variety of
functionalized heteroaryl bromides, featuring nitriles,
aldehydes, esters, amides, ethers and phenols, can be
employed for this synthesis (Table 3).
7
8
9
10
12
11
The optimal residence time for the reaction of het-
eroaryl bromide 3a was sufficient for full conversion
to the desired product in most cases. For some sub-
strates the residence time had to be slightly increased
to achieve full cycloisomerization of the Sonogashira
intermediate to the desired indolizine.
Particularly promising are the ester and amide moi-
eties on the heteroarene ring which exemplify versa-
tile points of diversification (entries 1–6). Notably, N-
Boc-protected amines are tolerated, allowing straight-
forward synthetic modification of the products (en-
tries 5, 6, and 8).
Furthermore, several alternative heterocyclic bro-
mides were successfully reacted. Pyrimidines give
much better yields than have previously been report-
ed for the procedure in batch[14] (79%, 5 min vs. 47%,
2 h, entry 7) and for the first time 2-bromopyrazine
13
14
16
15
[a]
Reaction conditions: Accendo Conjure Flow Reactor,
Hastelloy tubing (0.75 mm i. d., 2.0 mL internal volume).
20 Segments (450 mL, 0.05 mmol). Isolated yields and res-
idence times.
has been employed to generate a novel pyrroloACHTNUTRGNEUNG[1,2- The reaction of 2-bromo-6-formylpyridine is sluggish
a]pyrazine (entry 9). The limit of this methodology is and the corresponding product could only be obtained
the cycloisomerization of indolizine substrates with in low yields, as compound 2l showed deterioration
substituents in both the 3- and 5-positions (entry 12). during the purification step.
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Table 4. Synthetic scope of the flow indolizine synthesis in
Notably, cyclic amines (entries 11–13) undergo the re-
action in very good yields, in contrast to the batch
protocol,[14] in which such aliphatic propargylic
amines reacted only sluggishly and afforded low
yields (compound 5k: 74%, 5 min vs. 46%, 20 h).
Yields for amide and anilide substrates were generally
lower (entries 4 and 7). In these cases, complex mix-
tures were often obtained. However, we were delight-
ed to find that N-propargylic benzamides 4f and 4i re-
acted in good yields to afford the corresponding bis-
functionalized indolizines in 50% and 75% isolated
yield (entries 5 and 8). These substrates bear an ideal
substitution pattern for future incorporation in library
syntheses and in macrocycle construction. Overall,
the best results were obtained using propargylic
amines or amides. However, we were able to show for
the first time that propargylic ethers undergo the
transformation, albeit only in 16% isolated yield
(entry 15). Further optimization of the reaction condi-
tions regarding these substrates could therefore pro-
vide access to an entirely novel series of indolizines.
Aliphatic alkynes do not undergo the desired transfor-
mation (entry 16). For the synthesis of such 3-alkylin-
dolizines previously reported batch protocols are
clearly favored.[13]
regard to the alkyne coupling partner.[a]
Entry
1
Product Entry
2
Product
3
5
7
4
6
8
At this point in our investigations, it became clear
that our model alkyne substrate 4a was a poor choice
for the transformation of neutral or electron-rich het-
eroaryl bromides. In these cases, full conversion to
the Sonogashira intermediate was observed, but no
indolizine could be detected.
Upon further investigation we found that the
parent 2-bromopyridine, as well as several electron-
rich 2-bromopyridines, could be coupled in good
yields with propargylic amines 4b and 4j, thus extend-
ing the scope of the protocol even further (Table 5).
It appears therefore that a fine balance in the elec-
tronic properties on both coupling partners must be
maintained in order to achieve a successful cycloiso-
merization.
9
10
12
11
13
14
16
15
Scale-up of the synthesis using this new flow proto-
col is both linear and operationally simple, since the
scale of the reaction is simply determined by the
number of segments that are passed through the reac-
tor.[21] As a result, milligram-scale and gram-scale re-
actions to produce 2a could be performed with no di-
minution in yield (Scheme 2). The isolation and pu-
rification of the final products is straightforward and
[a]
Reaction conditions: Accendo Conjure Flow Reactor,
Hastelloy tubing (0.75 mm i. d., 2.0 mL internal volume).
20 Segments (450 mL, 0.05 mmol). Isolated yields.
Next, we investigated the scope with regard to the fast on all reaction scales.[22]
alkyne coupling partner using the model substrate 6-
bromomethyl nicotinate 3a.
It is noteworthy that the production of material on
a multi-gram scale is feasible using segmented flow in
A broad range of propargylic amines and amides the Conjure system; however, for the production of
was successfully reacted to yield the corresponding in- even larger amounts of material (>2 g) in shorter
dolizines (Table 4). Optimal results were obtained times we would recommend the use of an alternative
using amines with aryl and alkyl substituents (en- reactor system that provides true continuous flow
tries 1–3). Carbamates derived from propargylic conditions. Several such benchtop systems are com-
amines also undergo the reaction (entries 9 and 13). mercially available.[24]
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A New Flow Methodology for the Expedient Synthesis of Drug-Like 3-Aminoindolizines
Table 5. Indolizine synthesis with neutral and electron-rich
heteroaryl bromides.[a]
Entry
1
Product
Entry
2
Product
Scheme 3. Multi-step indolizine synthesis in flow.
to isolate or handle any of the intermediates. This
opens the way to the automated construction of com-
binatorial libraries using this procedure.
3
4
6
Experimental Section
General Procedure for the Synthesis of Indolizines
using a Conjure Flow Reactor
5
The aryl bromide (0.50M in DMSO, 100 mL, 0.05 mmol),
alkyne (2.00M in DMSO, 50.0 mL, 0.10 mmol), catalyst stock
solution [1.5 mmol PdCl2ACHTUNGTRENUNG(PPh3)2, 5 mmol CuI, 75 mmol NEt3
[a]
Reaction conditions: Accendo Conjure Flow Reactor,
Hastelloy tubing (0.75 mm i. d., 2.0 mL internal vol.). 20
Segments (450 mL, 0.05 mmol). Isolated yields and resi-
dence times.
in DMSO, 150 mL] and DBU (1.00M in DMF, 150 mL,
0.15 mmol) were aspirated from their respective source
vials, mixed through a PFA mixing tube (0.2 mm inner diam-
eter), and loaded into an injection loop. The reaction seg-
ment (450 mL) was injected into the flow reactor (Hastelloy
coil, 0.75 mm i. d., 2.0 mL internal volume) set at 1808C and
passed through the reactor at the respective flow-rate (200–
400 mLminÀ1 10–5 min residence time). A total of 20 reac-
tion segments prepared in this manner were collected in
a round-bottom flask.
Upon completion, the volatile reaction components were
removed from the collected reaction mixture under reduced
pressure (5–10 mbar) in a water bath (508C). The crude oily
residue was purified using a Biotage Isolera One automated
flash column chromatography system (silica gel or KP-NH,
gradient hexanes/ethyl acetate or hexanes/DCM).
Scheme 2. Linear scale-up of the indolizine synthesis.[23]
3-(N-Benzyl-N-methylamino)-6-methoxycarbonyl-
indolizine 2a
In conclusion, we have developed a novel flow-
based methodology for the synthesis of multifunction-
alized indolizines from readily available starting mate-
rials. The use of flow technology enables a rapid syn-
thesis of drug-like heterocycles on milligram- to
gram-scales. Our current efforts are focused on the
Compound 2a was synthesized according to the general flow
procedure using 20 segments (450 mL each) containing aryl
bromide 3a (0.50M in DMSO, 100 mL, 0.05 mmol), alkyne
4a (2.00M in DMSO, 50.0 mL, 0.10 mmol), catalyst stock so-
application of this new methodology to the synthesis lution [1.5 mmol PdCl2ACHTNUGTRNE(UNG PPh3)2, 5 mmol CuI, 75 mmol NEt3 in
DMSO, 150 mL] and DBU (1.00M in DMF, 150 mL,
0.15 mmol) and a flow-rate of 400 mLminÀ1 (5 min residence
time). Upon completion of the reaction, the volatile reaction
components (mainly DMF, NEt3, and fluorous spacer) were
removed under reduced pressure (5–10 mbar) in a water
bath (508C). The oily residue containing the product and re-
sidual DMSO was directly subjected to column chromatog-
raphy (silica gel, gradient hexanes/ethyl acetate 4:1) to
afford a yellow oil; yield: 206 mg (70%). Compound 2a was
also prepared in this manner using 1 segment (450 mL) to
of indolizine libraries and drug-like indolizine-based
macrocycles. In a preliminary investigation we were
able to exploit the full potential of the new protocol
in the Conjure reactor for the synthesis of libraries
(Scheme 3).
Conditions have been found that allow a fully auto-
mated modification of amine salt 7, incorporating two
orthogonal components, to generate drug-like indoli-
zine 9 in 43% isolated yield. All operations are con-
ducted automatically in the reactor without the need afford a yellow oil after preparative TLC (silica gel, hex-
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Paul P. Lange et al.
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anes/ethyl acetate 4:1); yield: 10.4 mg (71%) and using 120
segments (450 mL each) to afford a yellow oil after column
chromatography (silica gel, gradient hexanes/ethyl acetate
Hu, Synthesis 2000, 1733; c) U. Bora, A. Saikia, R. C.
Boruah, Org. Lett. 2003, 5, 435.
[11] a) A. R. Bogdan, N. L. Davies, K. James, Org. Biomol.
Chem. 2011, 9, 7727; b) G. Chouhan, K. James, Org.
Lett. 2011, 13, 2754; c) A. R. Bogdan, S. V. Jerome,
K. N. Houk, K. James, J. Am. Chem. Soc. 2012, 134,
2127.
[12] a) A. Baladina, V. Mamedov, S. Latypov, J. Mol. Struct.
2008, 889, 89; b) G. Surpateanu, P. I. Dron, D. Landy, S.
Fourmentin, M. Bria, Tetrahedron 2008, 64, 721.
[13] a) A. V. Kel’in, A. W. Sromek, V. Gevorgyan, J. Am.
Chem. Soc. 2001, 123, 2074; b) T. Schwier, A. W.
Sromek, D. M. L. Yap, D. Chernyak, V. Gevorgyan, J.
Am. Chem. Soc. 2007, 129, 9868; c) D. Chernyak, S. B.
Gadamsetty, V. Gevorgyan, Org. Lett. 2008, 10, 2307.
[14] Y. Liu, Z. Song, B. Yan, Org. Lett. 2007, 9, 409.
[15] For recent examples, see: a) A. C. Spivey, J. McKen-
drick, R. Srikaran, B. A. Helm, J. Org. Chem. 2003, 68,
1843; b) V. Balraju, D. S. Reddy, M. Periasamy, J. Iqbal,
J. Org. Chem. 2005, 70, 9626; c) H. T. ten Brink, D. T. S.
Rijkers, R. M. J. Liskamp, J. Org. Chem. 2006, 71, 1817.
[16] a) A. R. Bogdan, K. James, Chem. Eur. J. 2010, 16,
14506; b) A. R. Bogdan, K. James, Org. Lett. 2011, 13,
4060.
[17] a) S. Ceylan, T. Klande, C. Vogt, C. Friese, A. Kirschn-
ing Synlett 2010, 2009; b) L. Kupracz, J. Hartwig, J.
Wegner, S. Ceylan, A Kirschning, Beilstein J. Org.
Chem. 2011, 7, 1441; c) Y. Zhang, T. F. Jamison, S.
Patel, N. Mainolfi, Org. Lett. 2011, 13, 280.
[18] a) http://www.accendocorporation.com; b) for seminal
work on the application of the Conjure flow reactor,
see: A. R. Bogdan, N. W. Sach, Adv. Synth. Catal. 2009,
351, 849.
1
4:1); yield: 1.31 g (74%). H NMR (400 MHz, CDCl3): d=
ppm 2.72 (s, 3H) 3.93 (s, 3H) 4.10 (s, 2H) 6.39 (d, J=
3.90 Hz, 1H) 6.52 (d, J=3.90 Hz, 1H) 7.11 (dd, J=9.37,
1.56 Hz, 1H) 7.27–7.32 (m, 2H) 7.32–7.36 (m, 4H) 8.78–8.84
(m, 1H); 13C NMR (101 MHz, CDCl3): d=41.6, 51.9, 60.7,
98.3, 105.4, 113.45, 114.6, 118.4, 126.4, 127.3, 128.3, 128.4,
128.7, 136.0, 137.6, 166.7; HR-MS (ESI-TOF): m/z=
295.1442, calcd. for C18H18N2O2: [M+H]+: 295.1441.
The compounds in Table 3, Table 4 and Table 5 were pre-
pared accordingly. For full experimental procedures and an-
alytical data, see the Supporting Information.
Acknowledgements
The authors would like to thank Pfizer Worldwide R&D for
funding and generous donation of chemicals.
References
[1] M. V. R. Reddy, M. R. Rao, D. Rhodes, M. S. T.
Hansen, K. Rubins, F. D. Bushman, Y. Venkateswarlu,
D. J. Faulkner, J. Med. Chem. 1999, 42, 1901.
[2] a) S. Hagishita, M. Yamada, K. Shirahase, T. Okada, Y.
Murakami, Y. Ito, T. Matsuura, M. Wada, T. Kato, M.
Ueno, Y. Chikazawa, K. Yamada, T. Ono, I. Teshirogi,
M. Ohtani, J. Med. Chem. 1996, 39, 3636; b) R. C.
Oslund, N. Cermak, M. H. Gelb, J. Med. Chem. 2008,
51, 4708.
[3] a) W. B. Harrell, J. Pharm. Sci. 1970, 59, 275; b) I. An-
tonini, F. Claudi, U. Gulini, L. Micossi, F. Venturi, J.
Pharm. Sci. 1979, 68, 321.
[4] J. Gubin, H. de Vogelaer, H. Inion, C. Houben, J. Luc-
chetti, J. Mahaux, G. Rosseels, M. Peiren, M. Clinet, P.
Polster, P. Chatelain, J. Med. Chem. 1993, 36, 1425.
[5] M. Facomprꢁ, C. Tardy, C. Bal-Mahieu, P. Colson, C.
Perez, I. Manzanares, C. Cuevas, C. Bailly, Cancer Res.
2003, 63, 7392.
[6] For reviews, see: a) T. Uchida, K. Matsumoto, Synthesis
1976, 209; b) A. Behnisch, P. Behnisch M. Eggenweiler,
T. Wallenhorst, Indolizine: in Houben-Weyl, Methoden
der organischen Chemie, Vol. E6b/1, 2a, Thieme: Stutt-
gart, 1994, p 323.
[7] a) A. E. Tschitschibabin, Ber. Dtsch. Chem. Ges. 1927,
60, 1607; b) D. R. Bragg, D. G. Wibberley, J. Chem.
Soc. 1962, 2627; c) G. Jones; J. Stanyer, J. Chem. Soc.
1969, 901; d) R. I. Kostik, A. Abiko, A. Oku, J. Org.
Chem. 2001, 66, 2618.
[8] a) M. Scholtz, Ber. Dtsch. Chem. Ges. 1912, 45, 734;
b) V. Boekelheide, R. J. Windgassen Jr, J. Am. Chem.
Soc. 1959, 81, 1456.
[9] a) A. R. Katritzky, G. Qiu, B. Yang, H.-Y. He, J. Org.
Chem. 1999, 64, 7618; b) X. Zhang, W. Huang, Synthe-
sis 1999, 51; c) X. Fang, Y.-M. Wu, J. Denga, S.-W.
Wang, Tetrahedron 2004, 60, 5487.
[19] We found that this protocol can also be used in a micro-
wave reactor in which the required temperature of
1808C can easily be achieved. Under otherwise identi-
cal conditions, excellent conversions (>90%) were ob-
tained for the cycloisomerization of compound 1a (re-
action in Table 1, entry 9) and the tandem indolizine
synthesis (Scheme 1). We are unable to comment on
the scalability of such a microwave process.
[20] The residence time (5 min, set flow-rate: 400 mLminÀ1,
internal reactor volume: 2 mL) is determined via
a UV-detector that is integrated within the Conjure
system, allowing the flow stream to be continuously
monitored at the exit of the reactor. Thus, each seg-
ment is detected as soon as it exits the reactor and the
residence time is determined for each segment individ-
ually and logged by the Conjure software.
[21] Every segment (450 mL) that is prepared in the fluid
preparation unit of the Conjure reactor is preceded
and followed by an immiscible liquid spacer [perfluoro
(methyldecalin), 50 mL] and is then introduced into the
flow stream and passed through the reactor as an iso-
lated reaction. Thus, scale-up is linear, as each individu-
al segment is not altered in its composition or volume,
but simply multiple such identical segments are pre-
pared and individually passed through the reactor.
[22] The volatile components are removed from the collect-
ed reaction mixture under reduced pressure (5–
10 mbar) and the dark oily residue is subjected to
column chromatography from which the pure products
[10] a) Y. Miki, H. Hachiken, S. Takemura, Heterocycles
1984, 22, 701; b) L. Zhang, F. Liang, L. Sun, Y. Hu, H.
6
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
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A New Flow Methodology for the Expedient Synthesis of Drug-Like 3-Aminoindolizines
quickly elute due to their non-polar properties using
either hexanes/EtOAc (4:1) or hexanes/DCM (1:1).
1 segment, 10 min; 20 segments, 60 min; 120 segments,
5 h 30 min.
[23] Overall time required for the preparation of the respec-
tive amount of segments using the Conjure reactor in-
cluding segment preparation and complete collection:
[24] For examples see: a) Propel system, http://www.accen-
docorporation.com; b) R series: http://www.vapourtec.-
co.uk; c) FlowSyn system, http://www.uniqsis.com.
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
7
ÞÞ
These are not the final page numbers!

COMMUNICATIONS
8 A New Flow Methodology for the Expedient Synthesis of
Drug-Like 3-Aminoindolizines
Adv. Synth. Catal. 2012, 354, 1 – 8
Paul P. Lange, Andrew R. Bogdan, Keith James*
8
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!