Superacid-promoted synthesis of indolizidine derivatives

Article abstract of DOI:10.1016/j.tetlet.2018.03.094

A series of amido-acetals were reacted with the Br?nsted superacid, CF₃SO₃H, to provides indolizidine derives by a cyclization cascade. A mechanism is proposed involving formation of a vinylogous enol which undergoes a 6π-electrocycl

Full text of DOI:10.1016/j.tetlet.2018.03.094

Accepted Manuscript
Superacid-Promoted Synthesis of Indolizidine Derivatives
Sean Kennedy, Anila Kethe, Ahmad Qarah, Douglas A. Klumpp
PII:
S0040-4039(18)30431-3
https://doi.org/10.1016/j.tetlet.2018.03.094
TETL 49863
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Tetrahedron Letters
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30 March 2018
31 March 2018
Please cite this article as: Kennedy, S., Kethe, A., Qarah, A., Klumpp, D.A., Superacid-Promoted Synthesis of
Indolizidine Derivatives, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.03.094
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Superacid-Promoted Synthesis of
Indolizidine Derivatives
Sean H. Kennedy, Anila Kethe, Ahmad Qarah, and Douglas A. Klumpp

1
Tetrahedron Letters
Superacid-Promoted Synthesis of Indolizidine Derivatives
Sean Kennedy, Anila Kethe, Ahmad Qarah, and Douglas A. Klumpp*
aDepartment of Chemistry and Biochemistry, Northern Illinois University, DeKalb, IL 60115
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of amido-acetals were reacted with the Brønsted superacid, CF3SO3H, to provides
indolizidine derives by a cyclization cascade. A mechanism is proposed involving formation of
a vinylogous enol which undergoes a 6-electrocyclization reaction with an adjacent N-acyl
iminium ion group. With aryl substituents, there is a strong tendency for the N-acyl iminium ion
group to undergo Friedel-Crafts type cyclizations with the aryl group. The synthetic
methodology was used to prepare the alkaloid natural product, ilpadine.
Available online
Keywords:
heterocycles
alkaloid
2009 Elsevier Ltd. All rights reserved.
superacid
electrocyclization
acyliminium ions
Introduction
During the course of studies related to the aza-Nazarov
reaction, we observed an unexpected transformation involving an
amido-acetal (1, Scheme 1).1 The superacid-promoted chemistry
In the following manuscript, we describe our studies of
cyclization cascades with amido-acetals providing a series of
indolizidine derivatives. The scope of the transformation is
explored and the mechanism is examined through the use of
theoretical calculations. Several unexpected Friedel-Crafts-type
cyclizations were observed with aryl-substituted amido-acetals.
The new synthetic method has been used to prepare the
indolizidine natural product, ipalbidine (6).
Scheme 1.
leads to the tetracyclic compound (2) in reasonably good yield.
This conversion may be understood to be the result of two
cyclizations. First, the amido-acetal undergoes cyclization to the
N-acyliminium ion (3) by well-known acid-catalyzed
condensation chemistry.2 Second, ion 3 exists in equilibrium with
the vinylogous enol 4 and this species may undergo a 6-
Results and Discussion
Our studies began with the preparation of amido-acetals from
appropriate unsaturated carboxylic acids or derivatives. Thus,
amido-acetals 9 and 10 were prepared from crotonoyl chloride
and 3,3-dimethylacryloyl chloride, respectively, and the 4-
aminobutyraldehyde acetals. When these substrates are reacted
in superacid, compound 9 provides only the amide product 11,
while compound 10 gives the expected indolizidine 12 in nearly
quantitative yield (eqs 1-2). The conversion to indolizidine 12
prompted further studies of the scope of this chemistry. A series
of amido-acetals were prepared and reacted with superacid,
providing several novel indolizidine derivatives (Table 1). This
includes the 2-pentenoic acid derivative 13 to
electrocyclization to give the final product (after
a
deprotonation). Interestingly, this cyclization cascade gives the
indolizidine ring-system. The indolizidines are a well-known
class of alkaloids, many of which exhibit biological activities.3
Examples of indolizidine natural products include, swainsonine
(5), ipalbidine (6), gephyrotoxin (7), and lepadiformine (8). This
class of alkaloids is a frequent target in synthetic studies due to
its diverse structures and useful biological activities.4 Thus, new
synthetic routes to the indolizidines are potentially valuable.

2
Tetrahedron
Table 1. Products and yields from the reactions of amido-acetals
(13-20).
Scheme 2.
provide the desired indolizidine (eq 1), the observed product 11
is consistent with the proposed mechanism. This product likely
arises by formation of an N-acyl iminium ion without the
accompanying tautomerization to the vinylogous enol.
Consequently, cyclization does not occur and product 11 is
formed by deprotonation.
For products 20-23, there exists the possibility of two
stereoisomers, the cis and trans ring junction products. Likewise,
compound 19 has a similar potential for stereoisomerism. Both
NMR and GC analysis suggest that a single stereoisomer is
formed in the cyclization cascades. If the proposed mechanism is
correct, then the final cyclization step should occur by a thermal,
6 electrocyclization. According to the Woodward-Hoffman
rules of orbital symmetry, this would require a disrotatory ring
closure and this produces the cis ring junction for compounds 20-
23. Analysis of compound 23 was done by correlated NMR
spectroscopic methods and the multiplet analysis method
described by Hoye and coworkers.5 The results indicate the
coupling constant between the ring junction protons is 10.3 Hz –
a value consistent with the trans ring junction rather than the cis
ring junction. Both stereoisomers of 23 were modelled with DFT
calculations (gas-phase B3LYP 6-311G (d,p) level, Scheme 3)
provide the methyl-substituted indolizidine 19. Ring-fused
products may also be generated from this chemistry. For
example, the cyclopentane derivative (14) gives ring-fused
product 20, while the aza-steroidal ring system is prepared in
good yield from the cyclization of acetals 15 and 16. A similar
product (23) is prepared in 47% yield from the indanyl derivative
17. Product 24 is formed in good yield by a cyclization cascade
involving 18 (for a mechanistic explanation, see equation 4).
Scheme 3.
and the trans stereoisomer (23t) is found to be significantly more
stable than the cis stereoisomer (23c).6 Upon examination of the
optimized structures, the trans stereoisomer 23t has a H-C-C-H
dihedral angle of 175° at the ring junction carbons while the cis
stereoisomer (23c) has a H-C-C-H dihedral angle of 77°.
Whereas a dihedral angle of 175° would be expected to give a
coupling constant in the range of 10.3 Hz, a dihedral angle of 77°
would not give such a coupling constant (based on the Karplus
equation).7 These data clearly suggest the trans stereoisomer 23t
is formed in the superacid-promoted cyclization. How could this
occur when a Woodward-Hoffman 6 electrocyclization gives
the cis stereoisomer? There are two possibilities. First,
cyclization may not be a formal Woodward-Hoffman-type
pericyclic reaction. The cyclization may be an electrophilic
reaction involving an iminium ion with neighboring -bonds, one
that forms the trans stereoisomer directly. Alternatively, a
Woodward-Hoffman-type electrocyclization could provide the
cis stereoisomer but then it isomerizes quickly to the more stable
trans stereoisomer. This chemistry can be considered to occur
through the vinylogous enol (30) and reprotonation steps (eq 3).
All of the above transformations may be explained by
formation of the respective N-acyliminium ions and subsequent
cyclization via the vinylogous enol (Scheme 2). For example,
amido-acetal 10 is initially ionized in the superacid to give the
carboxonium ion 25. This species undergoes cyclization to 26
and elimination of methanol to provide the N-acyl iminium ion
27. Since N-acyl iminium ions are not sufficiently electrophilic
to insert directly into a C-H -bond, the conversion likely
involves tautomerization to the vinylogous enol 28 followed by a
6 electrocyclization to give 29. The conversions are best done
in excess superacid, suggesting that the tautomerization occurs
through
a
dicationic intermediate.
This would involve
protonation of the carbonyl oxygen and subsequent deprotonation
of the -carbon to give intermediate 28. Intermediate 28 is then
favorably disposed to undergo a 6 electrocyclization reaction.
Although the amido-acetal from crotonoyl chloride (9) did not

3
Since this type of tautomerization is likely involved in the
cyclization, it seems reasonable to expect similar chemistry with
compound 23 and other indolizidine products.
In order to access the desired aryl-substituted indolizidine
(36), an alternative approach was developed. The amido-acetal
(39) was prepared from the known 2-bromo-3,3-dimethylacrylic
acid and this substrate provides the brominated indolizidine (40)
in nearly quantitative yield (Scheme 5). The same substance may
be prepared by bromination of the indolizidine 12. Using Suzuki
coupling, the aryl-substituted indolizidine 36 is obtained.
A
similar Stille coupling with 4-methoxyphenyltributyl tin was not
In the case of acetal 18, three independent cyclizations occur
to give product 24 (eq 4). The initial stages of the reaction
provide the dihydronaphthalene ring by cyclization of the -
ketoamide (18). This process involves 6 reaction steps to
complete the cyclodehydration chemistry (including proton
transfers and the Friedel-Crafts reaction).8 Similarly, the iminium
ion formation requires 6 reaction steps. Product 24 likely arises
from cyclization of the vinylogous enol 32 – a process that adds 4
more reaction steps from 31 to 24. Thus, the conversion of acetal
18 to product 24 occurs by a sixteen-step process and it leads to
three new rings.
Scheme 5.
successful. Indolizidine 36 was then converted to the natural
product ipalbidine (6) by carbonyl reduction and demethylation
of the aryl ether.9
Other aryl-substituted amido-acetals did not provide good
yields of the expected indolizidines, but rather cyclizations
occurred from Friedel-Crafts type reactions. We prepared the 4-
methoxyphenyl derivative (33) in an approach to the synthesis of
the indolizidine natural product, ipalbidine (6, Scheme 4). Rather
than providing the indolizidine product 36, cyclization of
When the aryl group is installed at the 3-position of the
acrylamide, both the Friedel-Crafts and indolizidine products
may be obtained. Thus, the 4-fluorophenyl derivative 41 gives
the products 42 and 43 from the electrocyclization and Friedel-
Crafts reactions, respectively. The indolizidine product (43) is
the major product – isolated in 66% yield. With phenyl and 4-
Scheme 4
the N-acyliminium ion 34 leads to product 35 in excellent yield.
This product clearly arises from reaction of the N-acyliminium
ion at the para-methoxy phenyl group. When a less nucleophilic
aryl group is used - the 3,4-dichlorophenyl group - the same type
of cyclization products is obtained (eq 5). Evidently, the Friedel-
Crafts-type reaction is rapid even with a mildly deactivated aryl
group, as the cyclization product (38) is obtained in 82% yield as
a mixture of regioisomers.
Scheme 6.
methoxyphenyl derivatives, the Friedel-Crafts-type products (44-
45) are isolated as the major products. Amido-acetal 46 gives
two major products from reaction in superacid. The Friedel-
Crafts-type reaction leads to the unusual tricyclic product 47,
isolated in 38% yield. The indolizidine 48 is also isolated as a
minor product in 25% yield. Product 48 evidently arises from the
vinylogous enol (50). Interestingly, product 49 is not observed –
suggesting the other potential vinylogous enol (51) does not

4
Tetrahedron
References and notes
1. Sai, K. K. S.; O’Connor, M. J.; Klumpp, D. A. Tetrahedron Lett.
2011, 52, 2195-2198.
2. (a) Wu, L.; Aliev, A. E.; Caddick, S.; Fitzmaurice, R. J.; Tocher,
D. A.; King, F. D. Chem. Commun. 2010, 46, 318; (b) King, F. D.;
Aliev, A. E.; Caddick, S.; Copley, R. C. B. Org. Biomol. Chem.
2009, 7, 3561; (c) King, F. D.; Aliev, A. E.; Caddick, S.; Tocher,
D. A.; Courtier-Murias, D. Org. Biomol. Chem. 2009, 7, 167.
3. Michael, J. P. Nat. Prod. Rep. 2008, 25, 139.
4. (a) Pansare, S. V.; Thorat, R. G. Targ.Hetero. Sys. 2013, 17, 57.
(b) Chakraborty, I.; Jana, S. Synthesis 2013, 45, 3325. (c) Bhat, C.;
Tilve, S. G. RSC Adv. 2014, 4, 5405.
5. Hoye, T. R.; Zhao, H. J. Org. Chem. 2002, 67, 4014.
6. Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.;Cheeseman, J. R.; Scalmani, G.; Barone, V.;
Mennucci, B.; Petersson, G. A.;Nakatsuji, H.; Caricato, M.; Li, X.;
Hratchian, H. P.; Izmaylov, A. F.; Bloino, J.; Zheng, G.;
Sonnenberg, J. L.; Hada, M.; Ehara, M.; Toyota, K.; Fukuda, R.;
Hasegawa, J.; Ishida, M.; Nakajima, T.; Honda, Y.; Kitao, O.;
Nakai, H.; Vreven,T., ; Montgomery, J. A., Jr.; Peralta, J. E.;
Ogliaro, F.; Bearpark, M.; Heyd, J. J.;Brothers, E.; Kudin, K. N.;
Staroverov, V. N.; Kobayashi, R.; Normand, J.;Raghavachari, K.;
Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.; Cossi,
M.;Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R.
E.; Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski,
J. W.; Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G.
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Gaussian 09, Revision E.01; Gaussian Inc: Wallingford, CT, 2009.
7. Karplus, M. J. Am. Chem. Soc. 1963, 85, 2870.
Scheme 7.
form. Formation of intermediate 50 may be favored somewhat
by conjugation available with the phenyl group.
In summary, we have found that indolizidine derivatives may
be prepared in fair to excellent yields by cyclization cascades
involving amido-acetals. A mechanism is proposed in which an
N-acyliminium ion is in equilibrium with a vinylogous enol
intermediate. The vinylogous enol undergoes cyclization, perhaps
through a 6-electrocyclization, and the indolizidine framework
is produced. Although aryl substituent groups are tolerated in
some cases, we have found several examples in which
cyclizations occur at the aryl group by Friedel-Crafts chemistry.
Aryl-substituted indolizidines can also be accessed by Suzuki
coupling with a brominated indolizidine - a strategy which was
used to prepare the natural product, ipalbidine.
8. Kurouchi, H.; Sugimoto, H.; Otani, Y.; Ohwada, T. J. Am. Chem.
Soc. 2010, 132, 807.
9. Danishefsky, S. J.; Vogel, C. J. Org. Chem. 1986, 51, 3915.
Supplementary Material
Acknowledgments
Experimental procedures and analytical data. This
supplementary data can be found in the online version, at
The support of the National Science Foundation is gratefully
acknowledged (1300878).

5
Bullet Points:
•Cascade reaction leading to the indolizidine ring
system
•Superacid-promoted condensation and
electrocyclization
•Synthesis of the alkaloid natural product,
ipalbidine