Nitrone and Alkyne Cascade Reactions for Regio- and Diastereoselective 1-Pyrroline Synthesis

Article abstract of DOI:10.1002/anie.202101511

The synthesis of 1-pyrrolines from N-alkenylnitrones and alkynes has been explored as a retrosynthetic alternative to traditional approaches. These cascade reactions are formal [4+1] cycloadditions that proceed through a proposed dipolar cycloaddition and N-alkenylisoxazoline [3,3′]-sigmatropic rearrangement. A variety of cyclic alkynes and terminal alkynes have been shown to undergo the transformation with N-alkenylnitrones under mild conditions to provide the corresponding spirocyclic and densely substituted 1-pyrrolines with high regio- and diastereoselectivity. Mechanistic studies provide insight into the balance of steric and electronic effects that promote the cascade process and control the diastereo- and regioisomeric preferences of the 1-pyrroline products. Diastereoselective derivatization of the 1-pyrrolines prepared by the cascade reaction demonstrate the divergent synthetic utility of the new method.

Full text of DOI:10.1002/anie.202101511

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How to cite:
International Edition: doi.org/10.1002/anie.202101511
German Edition: doi.org/10.1002/ange.202101511
Synthetic Methods
Nitrone and Alkyne Cascade Reactions for Regio- and Diastereo-
selective 1-Pyrroline Synthesis
Guanqun Zhang+, Abdullah S. Alshreimi+, Laura Alonso, Alan Antar, Hsien-Cheng Yu,
Shahidul M. Islam, and Laura L. Anderson*
Abstract: The synthesis of 1-pyrrolines from N-alkenyl-
nitrones and alkynes has been explored as a retrosynthetic
alternative to traditional approaches. These cascade reactions
are formal [4 + 1] cycloadditions that proceed through a pro-
posed dipolar cycloaddition and N-alkenylisoxazoline [3,3’]-
sigmatropic rearrangement. A variety of cyclic alkynes and
terminal alkynes have been shown to undergo the transforma-
tion with N-alkenylnitrones under mild conditions to provide
the corresponding spirocyclic and densely substituted 1-pyrro-
lines with high regio- and diastereoselectivity. Mechanistic
studies provide insight into the balance of steric and electronic
effects that promote the cascade process and control the
diastereo- and regioisomeric preferences of the 1-pyrroline
products. Diastereoselective derivatization of the 1-pyrrolines
prepared by the cascade reaction demonstrate the divergent
synthetic utility of the new method.
Introduction
Cascade reactions that pair two fragments to form
reactive intermediates and undergo subsequent transforma-
tions to form more complex products are important processes
in synthetic chemistry.[1] These reactions facilitate modular
access to sophisticated scaffolds from simple reagents. Peri-
cyclic reactions have featured prominently in a variety of
fragment coupling and domino processes.[2] While pyranyl and
furanyl substrates such as 1 and 3 are well-known to undergo
[3,3’]-sigmatropic rearrangements to carbocycles 2 and 4, the
analogous transformation of N-alkenylisoxazoline 5 to 1-
LG=leaving group. EWG=electron-withdrawing group.
Scheme 1. N-Alkenylisoxazoline approach to 1-pyrroline synthesis.
pyrroline 6 is underdeveloped due to the challenges involved
in accessing this heterocycle (Scheme 1A).[3–5] Identification
of new modular routes to N-alkenylisoxazoline 5 represent an
opportunity for the design of new cascade processes.
(Scheme 1B).[7–11] While several elegant catalytic systems
have been designed to control the reactivity and selectivity of
these reactions, they still have fundamental limitations due to
1-Pyrrolines are prominent scaffolds in a variety of
biologically active molecules.[6] Traditionally, these com-
pounds are prepared by Heck-type or imino radical cycliza-
tions, Michael addition and condensation processes, or
dipolar cycloadditions of nitrile ylides or munchnones
À
À
the specific C N and C C bond forming events involved in
each synthetic approach. We were curious if 1-pyrrolines 6
could be constructed from readily accessible N-alkenylni-
trone 7 and an alkyne through the [3,3’]-sigmatropic rear-
rangement of N-alkenylisoxazoline 5 (Scheme 1C). If suc-
cessful, this approach would enable access to this important
heterocyclic scaffold through a formal [4 + 1] process and
[*] G. Zhang,[+] A. S. Alshreimi,[+] L. Alonso, A. Antar, H.-C. Yu,
Dr. S. M. Islam, Prof. L. L. Anderson
Department of Chemistry, University of Illinois at Chicago
845 W Taylor St. MC 111, Chicago, IL 60607 (USA)
E-mail: lauralin@uic.edu
À
assembly of the two sterically congested C C bonds tethering
the carbon atom at the 4-position of the ring. This trans-
formation would facilitate the incorporation of a ring-fusion
at the 2- and 3-positions, which is challenging to achieve with
dipolar cycloadditions of nitrile ylides and munchnones. In
addition, when paired with an N-alkenylisoxazoline synthesis
[+] These authors contributed equally to this work.
Supporting information and the ORCID identification number(s) for
the author(s) of this article can be found under:
https://doi.org/10.1002/anie.202101511.
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via dipolar cycloaddition, this approach achieves the benefit Results and Discussion
of modularity that is lacking from many cyclization strategies.
Recently, we communicated a dipolar cycloaddition and
dearomative rearrangement cascade reaction for the syn-
thesis of spirocyclic 1-pyrrolines (Scheme 2A).[12] This trans-
Cascade Synthesis of Spirocyclic 1-Pyrrolines from N-
Alkenylnitrones and Cyclic Alkynes
To initially explore the tolerance of the cascade reaction
for spirocyclic 1-pyrroline formation beyond aryne reagents,
the reactivity of cyclohexyne was investigated with N-
alkenylnitrone 7a (Table 1).[16,17] As shown in Table 1, when
Table 1: Optimization of cascade synthesis of 1-pyrroline 12a from
nitrone 7a and cyclohexyne precursor 11a.
Entry[a] Solvent 11a [equiv] 18-crown-6 [equiv] 7a [M] Yield [%][b]
1
2
3
4
5
6
7
8
i-PrOAc
DCE
PhMe
THF
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
2
2
2
2
2
2
2
1
2
2
2
2
2
2
2
2
2
0
1
2
2
2
2
2
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.1
0.05
0.5
64
66
22
78
84[c]
12
78
77
74
87
86
69
Scheme 2. 1-Pyrroline synthesis via fragment coupling of N-alkenylni-
trones and alkynes.
9[d]
10[e]
11
12
1
[a] Conditions: 7a (0.05 mmol). [b] Yield determined by H NMR
spectroscopy using CH2Br2 as an internal reference. [c] Isolated yield.
[d] Reaction performed at 08C. [e] Reaction run for 48 h. DCE=1,2-
dichloroethane, i-PrOAc=isopropyl acetate.
formation is proposed to proceed via a [3 + 2]-dipolar cyclo-
addition of an N-alkenylnitrone and an aryne to give N-
alkenylbenzisoxazoline intermediate 9, which spontaneously
undergoes a formal dearomative [3,3’]-sigmatropic rearrange-
ment to give the corresponding spirocyclic 1-pyrrolines 10.[13]
These studies provided proof of principle for the utility of N-
alkenylisoxazoline cascade intermediates as retrosynthetic
alternatives for 1-pyrroline synthesis and were facilitated by
our previous discovery of the use of the Chan-Lam reaction
for preparing N-alkenylnitrones from oximes.[14] We surmised
that this reactivity pattern could be advanced beyond highly
reactive benzyne reagents and that further investigation
would improve our understanding of the generation and
reactivity of N-alkenylisoxazolines. Herein we describe the
development of dipolar cycloaddition and [3,3’]-sigmatropic
rearrangement cascade reactions of N-alkenylnitrones with
cycloalkynes and terminal alkynes to give a broad range of
spirocyclic and densely substituted 1-pyrrolines (Scheme 2B).
These transformations are regioselective, diastereoselective,
and access 1-pyrrolines through an unusual formal [4 + 1]-
process, which allows for consideration of alternative retro-
synthetic strategies in comparison to traditional approaches
(Scheme 1B). Mechanistic studies are included, which de-
scribe the regiochemical preferences of the initial dipolar
cycloaddition, consider the relationship between cycloaddi-
tion synchronicity and reaction scope, and explore the
diastereomeric preference of the products. Functionalization
studies further showcase the utility of this method for
synthetic applications.[15]
cyclohexyne was generated in the presence of nitrone 7a
under the optimal conditions reported for the formation of 10,
pyrroline 12a was observed in 64% yield (entry 1). Further
screening indicated that this transformation is sensitive to
solvent effects and increased yields of 12a were obtained in
THF and MeCN (entries 1–5). While the polarity of MeCN
could mediate the need for a crown-ether additive, it was
observed that at least one equivalent of 18-crown-6 increases
the yield of the desired product (entries 5–7). This require-
ment is likely associated with the activation of 11a. The ratio
of 7a to 11a could be reduced to 1:1 but a slight reduction in
yield was observed under these conditions (entry 8). Variation
of the reaction time and decreasing the reaction temperature
to 08C showed little effect on the yield of 12a and concen-
tration studies indicated cleaner reactivity with less concen-
trated mixtures (entries 9–12). With the optimal conditions of
Table 1, entry 5 in hand, the scope of the cycloalkyne and N-
alkenylnitrone cascade reaction was explored for the syn-
thesis of 1-pyrroline spirocycles.
Investigation of the scope of the dipolar cycloaddition and
rearrangement reaction for the synthesis of spirocyclic 1-
pyrrolines 12 included variation of both the N-alkenylnitrone
and cycloalkyne components as illustrated in Scheme 3. When
cyclohexyne was generated in the presence of malonate-
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also be combined with a deprotection process to give 12q over
two steps (Scheme 3B). Investigation of nitrones derived
from unsymmetrical ketones introduced a third stereocenter
to the 1-pyrroline ring with consistently high diastereoselec-
tivity (see 12h–12m). The stereochemical relationship of the
three stereocenters was confirmed by an X-ray crystal
structure of 12i and is consistent with the cascade reaction
being a stereospecific process dependent on the stereochem-
istry of 7.[18] The isolation of 12h–12j are noteworthy since
analogous cascade reactions between N-alkenylnitrones de-
rived from benzoylformate esters and benzyne give dihydro-
benzofurans through a proposed spontaneous rearomatiza-
tion process.[12] Further attempts at controlling stereochem-
ical information using a chiral non-racemic ester substituent
on the nitrone showed only moderate selectivity (12k)
suggesting that the stereochemical information is likely too
À
far removed from the initial C C bond forming event to be
influential. To the best of our knowledge, spirocyclic 1-
pyrrolines 12 are new compounds that have not previously
been reported in the literature. The only exception is 12b,
which was reported by our group via the hydrogenation of
10.[12] These novel 1-pyrroline scaffolds highlight the expand-
ed chemical space can be accessed by moving beyond the
retrosynthetic limitations of traditional methods.
A survey of biologically active spirocyclic pyrrolidines
encouraged us to further explore 1-pyrroline scaffolds that
incorporate isatin- and acenapthylenedione-derived function-
alities.[20–23] Conversion of N-methyl isatin and acenapthyle-
nedione to N-cyclohexenylnitrones and treatment with 11a or
11c under the optimized cascade reaction conditions showed
that these compounds are well-tolerated for the synthesis of 1-
pyrrolines 12n–12p (Scheme 3A). These new heterocycles
contain two adjacent spirocyclic functionalities and are
consistently formed in high diastereoselectivity. Due to the
importance of cyclooctyne cycloadditions in biorthogonal
transformations, cyclooctyne 15 was also prepared and tested
in the cascade process.[24] As shown in Scheme 3C, the
reaction tolerated this less strained cyclic alkyne and the
remote cyclopropyl functional group resulted in the forma-
tion of a (5:1) mixture of diastereomeric products. Subse-
quent crystallization gave the major isomer 12r in 61% yield.
The results illustrated in Scheme 3 show the breadth of the
cascade reaction for the synthesis of a range of new spirocyclic
1-pyrrolines through a unique retrosynthetic disconnection.
Scheme 3. Scope of the synthesis of spirocyclic 1-pyrrolines from
nitrones 7 and cycloalkynes (R=Et for 11a and 11b, R=Me for 11c).
derived nitrones with cyclic, styrenyl, linear, and heterocyclic
N-alkenyl substituents, pyrrolines 12a–12e were formed in
good yield with high diastereoselectivity. The cis-relationship
between the alkyl substituent at the 3-position and the ketone
at the 4-position was initially assumed in analogy to benzyne
cascade products 10 but later confirmed by X-ray crystallog-
raphy (see 12i).[18] Similarly, when the cyclohexyne precursor
was exchanged for pyranyne precursor 11b and piperidyne
precusor 11c, spirocyclic pyrrolines 12 f and 12g were
generated smoothly. These single regioisomeric products
corresponded to the preferred dipolar cycloaddition regiose-
lectivity predicted by the torsion-distortion model previously
reported by Garg and Houk.[19] The synthesis of 12g could
Cascade Reaction of Nitrones and Terminal Alkynes
Having established that N-alkenylnitrones 7 undergo the
addition and rearrangement cascade process with minimally
strained cycloalkynes such as cyclooctyne 15, the transforma-
tion was tested with terminal alkynes.[25] Gratifyingly, when
nitrone 7a was treated with phenylacetylene 13a at 708C in
MeCN, formation of pyrroline 14a was observed in 59% yield
as a single regioisomer with moderate diastereoselectivity
(Table 2, entry 1).[17] Further optimization showed that this
reaction is sensitive to solvent effects and an increase in yield
was observed for i-PrOAc, toluene, and THF, with THF
giving the highest yield of 1-pyrroline 14a with excellent
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Table 2: Optimization of cascade synthesis of 1-pyrroline 14a from
nitrone 7a and phenylacetylene.
conditions in hand for the conversion of nitrone 7a to 1-
pyrroline 14a (Table 2, entry 6), a broader survey of terminal
alkyne reaction partners was undertaken.
Investigation of the scope of the cascade reaction for the
synthesis of 1-pyrrolines 14 included variation of both the N-
alkenylnitrone and terminal alkyne components as illustrated
in Scheme 4A. When nitrone 7a was treated with aryl,
heteroaryl, or alkyl alkynes, pyrrolines 14a–14e were formed
in good yield with high regio- and diastereoselectivity
corresponding to a sterically controlled dipolar cycloaddition
and favoring a trans-relationship between the substituents at
the 3- and 4-positions of the 1-pyrroline. While pyrrolines
14a–14c converted to diastereomeric mixtures when left in
solution, no isomerization was observed for pyrrolines 14d
and 14e under analogous conditions. Nitrones with substi-
tuted N-cyclohexenyl, N-cyclooctenyl, and N-heterocyclic
functionalities were also shown to be tolerant of the addition
and rearrangement cascade process (see 14 f–14h); however,
nitrones with linear N-alkenyl substituents underwent com-
Entry[a]
Solvent
7a [M]
T [8C]
dr (trans:cis)
Yield [%][b]
1
2
3
4
5
6
7
MeCN
i-PrOAc
DCE
PhMe
THF
THF
THF
THF
THF
0.1
0.1
0.1
0.1
0.1
0.2
0.2
0.2
0.2
0.2
70
70
70
70
70
70
25
70
70
70
7:1
14:1
5:1
15:1
20:1
20:1
20:1
20:1
14:1
13:1
59
71
49
78
80
87
25
79
71
60
8[c]
9[d]
10[e]
THF
[a] Conditions: 7a (0.05 mmol), 13a (3 equiv). [b] Yield determined by
1H NMR spectroscopy using CH2Br2 as an internal reference.
[c] Time=9 h. [d] Time=36 h. [e] 13a (1 equiv). DCE=1,2-dichloro-
ethane, i-PrOAc=isopropyl acetate.
diastereoselectivity (entries 2–5). Increasing the concentra-
tion of the reaction mixture further increased the yield of 14a
and decreasing the reaction temperature and time inhibited
the conversion (entries 6–8). Increasing the reaction time led
to a decrease in diastereoselectivity (entry 9). The major
diastereomer of the product was identified by X-ray crystal-
lography and has a trans-relationship between the substitu-
ents at the 3- and 4-positions of the 1-pyrroline ring.[18] The
trans/cis-diastereomeric ratio between these two positions
was shown to be dependent on the selection of the reaction
medium as well as the concentration of phenylacetylene
(entries 1–5 and 10). While 14a can be purified by column
chromatography, isolated as a single trans-diastereomer, and
crystallized as a single trans-diastereomer, solutions of 14a in
CDCl3 and [D4]MeOH isomerize over time to mixtures of
trans-14a and cis-14a as illustrated in Table 3.[26] With optimal
Table 3: Isomerization of 1-pyrroline trans-14a in CDCl3 and [D4]MeOH.
Entry[a]
Solvent
T [8C]
t [h]
dr
1
2
3
4
5
6
7
8
CDCl3
CDCl3
CDCl3
CDCl3
CD3OD
CD3OD
CD3OD
CD3OD
25
25
60
70
25
25
60
70
0
12
8
18
0
12
8
18
>50:1
13:1
10:1
10:1
>50:1
>50:1
>50:1
11:1
[a] Conditions: trans-14a (0.07 mmol), 0.2 M. [b] Yield determined by
1H NMR spectroscopy using 1,4-dimethoxybenzene as an internal
standard. No deuterium incorporation was observed at the 3- or 4-
positions of 14a.
Scheme 4. Scope of cascade synthesis of 1-pyrrolines from nitrones 7
and terminal alkynes 13. [a] 258C.
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petitive intramolecular 4p-electrocyclization at the elevated
reaction temperature to give azetidine nitrones such as 17
(Scheme 4B).[14a,17,27] Nitrones derived from unsymmetrical
carbonyl precursors were also shown to participate in the
cascade process with alkyl- and aryl-substituted terminal
alkynes to give 14i–14l. The pyrrolines formed in these
reactions incorporated an additional tertiary carbon stereo-
center with analogous high regio- and diastereoselectivity.
The relative stereochemistry of these compounds was con-
firmed by X-ray crystallographic analysis of 14j.[18] In contrast
to 14c, 1-pyrroline 14l was resistant to isomerization in
solution. Nitrones prepared from N-methylisatin and acenap-
thylenedione were unreactive with terminal alkynes suggest-
ing that some amount of strain release is required to initiate
the cascade reaction for these substrates.[25] Activated internal
alkynes such as 13j were observed to undergo analogous
reactivity to give pyrrolines such as 14n with a quaternary
stereocenter at the 4-position of the pyrroline
(Scheme 4C).[17,28] This survey of reaction scope showcased
the tolerance of the cascade process beyond strained alkynes,
while also highlighting a need for increased reaction temper-
ature, a preference for the trans-pyrroline diastereomer, and
competition with alternative reaction pathways. In analogy to
the spirocyclic compounds presented in Scheme 3, it is worth
noting that the 1-pyrrolines illustrated in Scheme 4 are also
new compounds that are more easily accessed through the
cascade approach than traditional cycloaddition and cycliza-
tion methods.
Mechanistic Considerations
Previously, we proposed that the cascade reaction of N-
alkenylnitrones and arynes proceeds via an initial dipolar
cycloaddition to form 9 followed by a [3,3]-sigmatropic
rearrangement to form 10 (Scheme 2A). This reaction path-
way is consistent with the stereochemistry observed for the
dearomatized spirocyclic pyrroline products and was also
supported by the isolation of a dipolar cycloaddition adduct
that was deactivated towards the subsequent [3,3’]-sigma-
tropic rearrangement.[12] We initially proposed that cascade
reactions of N-alkenylnitrones with cyclic and terminal
alkynes likely proceed by an analogous mechanism (see
Scheme 5A) but decided to further interrogate this conjec-
ture.
The regioselectivity observed for the cascade synthesis of
1-pyrrolines 12 and 14 supports our mechanistic proposal of
a dipolar cycloaddition followed by a [3,3’]-sigmatropic
rearrangement. The regioselectivity observed for 12 f–12i is
consistent with the torsion-distortion regiochemical model
proposed by Garg and Houk but does not rule out an
alternative stepwise addition, rearrangement, and cyclization
mechanism (Scheme 5B).[19,29,30] The regioselectivity ob-
served for the cascade synthesis of 1-pyrrolines 14 is
consistent with a sterically controlled dipolar cycloaddition
(Scheme 4 and Scheme 5A). To determine if electronically
activated alkynes could reverse this selectivity or indicate an
alternative operative mechanism such as the one shown in
Scheme 5B, propiolate 13k was subjected to reaction con-
Scheme 5. Correlation of observed regioselectivity and proposed mech-
anism.
ditions with nitrone 7a. As shown in Scheme 5C, pyrroline
14o was observed as the major product and supports
a mechanistic pathway that proceeds through a dipolar
cycloaddition instead of a conjugate addition. A computa-
tional study was also initiated to interrogate the transition
states for the dipolar cycloadditions of nitrone 7a with methyl
propiolate, 1-octyne, and phenylacetylene.[17] As shown in
Scheme 5D, all of these transformations kinetically favor the
sterically controlled transition state that leads to the observed
regiochemically favored product. Therefore, although we
have not been able to experimentally observe N-alkenylisox-
azoline intermediates converting to 1-pyrrolines in these
transformations, the above regiochemical data supports the
proposed mechanism illustrated in Scheme 5A.[31]
While investigating the tolerance of the cascade reaction
for different nitrone substitution patterns, we observed that
nitrone 7r does not form the corresponding 1-pyrroline 12s or
intermediate 18s when treated with cyclohexyne precursor
11a.[32] Only starting material decomposition was observed
for these reaction mixtures (Scheme 6A). Considering the
steric and electronic differences between benzaldehyde-
derived nitrone 7r and the other electron-deficient keto-
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Scheme 6. Dipolar cycloaddition transition-state comparisons.
nitrones 7 that successfully form 1-pyrrolines when treated
with cyclic and terminal alkynes (Scheme 3 and Scheme 4),
we wondered if comparison of these substrates could inform
on the mechanism of the cascade process. As shown in
Scheme 6B, transition states TS-5a, TS-5b, and TS-5c
correspond to substrate mixtures that form spirocyclic pyrro-
lines 12a, 12l, and 12j, respectively, when subjected to
reaction conditions. A computational study indicated that all
of three of these dipolar cycloaddition transition states have
Scheme 7. Isomerization of 1-pyrrolines 14.
the observed isolation of trans-14. The data in Tables 2 and 3
provide evidence of isomerization of 14a after completion of
the cascade reaction. Ground state computational studies
indicated that the trans-isomers of 14a and 14d are thermo-
dynamically favored over the cis-isomers; in contrast, spiro-
cyclic 1-pyrrolines 12a and 12t thermodynamically favor their
cis-isomers (Scheme 7B).[17] As described in Table 3, while
the isomerization of 14a was monitored in [D4]MeOH at
elevated temperature, no incorporation of deuterium was
observed at any of the acidic hydrogens. This observation
suggests that the isomerization of 14a is unlikely to be
occurring by epimerization.[26] Alternatively, isomerization
could be occurring via the mechanism illustrated in
Scheme 7C. This type of 1-pyrroline ring-opening was
previously proposed to explain rearomatization pathways
observed for 10.[12]
À
bond length differences between the forming C C bond and
[17,33]
À
the forming C O bond that are less than 0.7 ꢀ.
In
comparison, transition state TS-5d corresponds to the exper-
imentally failed conversion of 7r to 12s and has a bond length
distance difference greater than 1 ꢀ between the two forming
bonds. This distinction suggests that reagents that favor more
synchronous bond-forming events in the dipolar cycloaddi-
tion may be more likely to proceed via the cascade process to
form spirocyclic pyrrolines and avoid alternative decomposi-
tion pathways.[34]
1-Pyrroline Isomers
1-Pyrroline Functionalization Studies
Upon isolation of pyrrolines 14, we were initially sur-
prised to observe a trans-relationship between the substitu-
ents at the 3- and 4-positions of the ring because an analogous
cascade reaction mechanism to the one proposed for the
aryne and cycloalkyne cascade processes would kinetically
Opportunities for derivatization of 1-pyrrolines 12 and 14
were explored to assess the synthetic utility of the modular
cascade method presented above (Scheme 8). Simple acidic
hydrolysis of 14d gave the dione ammonium salt 22. Although
this compound readily cyclizes back to the corresponding 1-
pyrroline when subjected to mild base, the salt can be isolated
cleanly.[35] Decarboalkoxylation and hydrogenation were also
tested to determine if the relative stereochemistry installed by
the cascade reaction could further direct the formation of new
favor
a
cis-relationship between these substituents
(Scheme 5A and Scheme 7A). We surmised that isomeriza-
tion of 14 under the elevated reaction temperatures of the
cascade reaction for terminal alkynes could be responsible for
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Conclusion
1-Pyrrolines are common motifs in synthetic targets. Due
to the demand for these molecules, a variety of methods have
been developed for their synthesis; however, even with these
advances, there are still examples of 1-pyrrolines that are
difficult to access due to the limitations of retrosynthetic
approaches using known transformations. The new cascade
route to 1-pyrrolines described above broadens the chemical
space around these important heterocycles and includes the
opportunity to consider retrosynthetic disconnections that
formally involve a [4 + 1] process via insertion of the carbon
atom at the 4-position using an alkyne. This transformation is
enabled by access to unusual N-alkenylisoxazolines via the
dipolar cycloadditions of N-alkenylnitrones, which are acces-
sible via the Chan-Lam N-alkenylation of oximes. Not only
does this modular method provide access to spirocyclic and
densely functionalized 1-pyrrolines but it also supports
opportunities for the divergent derivatization of these new
heterocyclic structures. Ongoing efforts are focused on using
the mechanistic lessons learned in the above studies to
leverage this reactivity in new directions.
Scheme 8. Functionalization of 1-pyrrolines 12 and 14. Conditions:
[a] TFA, MeOH:H2O (1:1); [b] H2 (1 atm), cat. Pd/C, MeOH; [c] KI,
Py:MeOH (1:1), 1108C; [d] m-CPBA, CH2Cl2, 08C. TFA=trifluoroacetic
acid. m-CPBA=meta-chloroperbenzoic acid.
Acknowledgements
We acknowledge generous funding from the National Science
Foundation (NSF-CHE 1855833) and the University of
Illinois at Chicago. We thank Mr. Furong Sun (UIUC) for
high resolution mass spectroscopy data and Professor Do-
nald J. Wink (UIC) for X-ray crystallographic data prepara-
tion. X-Ray crystallography data was obtained by H.-C. Yu on
an instrument purchased with partial funding from NIH-R01
GM116820 (PI: Professor Neal P. Mankad, UIC).
stereocenters. As shown in Scheme 8A, when 14d was
subjected to Krapcho decarboxylation conditions 1-pyrroline
23 was isolated in good yield and high selectivity with three
contiguous stereocenters at the 3-, 4-, and 5-positions of the 1-
pyrroline ring.[36] Similarly, when 14d was reduced with H2 in
the presence of Pd/C, pyrrolidine 24 was isolated in good yield
and high diastereoselectivity with three contiguous stereo-
centers at the 2-, 3-, and 4-positions of the heterocycle.
Pyrrolidine 24 was subsequently subjected to decarboxylation
conditions and pyrrolidine 25 was obtained with high
selectivity and 4-contiguous stereocenters at each carbon of
the pyrrolidine ring. Beyond, hydrolysis, decarboalkoxyla-
tion, and hydrogenation, oxidation with m-chloroperbenzoic
acid was tested with 14a and 14d, and gave the unusual
strained oxaziridines 26 and 27, respectively.[37] This reactivity
pattern was not accessible for 12a. The connectivity and
stereochemistry of 26 and 27 were confirmed by X-ray
crystallographic analysis of 27.[18] Finally, an interesting
transformation was observed with extended reaction times
for the formation of 12b. As shown in Scheme 8B, lactone 28
is formed in good yield and high diastereoselectivity. Further
experimentation showed that 28 could also be obtained
directly from 12b by treatment with K2CO3 under the cascade
reaction conditions. The transformations illustrated in
Scheme 8 showcase the utility of cascade reaction for access-
ing highly substituted and stereodefined pyrrolines that can
be easily converted into a variety of molecules with increased
complexity using simple procedures.
Conflict of interest
The authors declare no conflict of interest.
Keywords: 1-pyrroline · cycloalkynes · dipolar cycloaddition ·
nitrones · sigmatropic rearrangement cascade
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Manuscript received: January 31, 2021
Revised manuscript received: March 6, 2021
Accepted manuscript online: March 24, 2021
Version of record online: && &&
,
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Angewandte
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Research Articles
Synthetic Methods
G. Zhang, A. S. Alshreimi, L. Alonso,
A. Antar, H.-C. Yu, S. M. Islam,
L. L. Anderson*
&&&& — &&&&
Nitrone and Alkyne Cascade Reactions for
Regio- and Diastereo-
selective 1-Pyrroline Synthesis
A formal [4+1] cascade reaction of N-
alkenylnitrones and alkynes has been
developed for the regio- and stereoselec-
tive synthesis of densely substituted 1-
pyrrolines. This transformation provides
a distinct disconnection strategy to
access these heterocycles in comparison
to traditional approaches. The scope,
tolerance, and utility of the method are
discussed, and mechanistic studies are
examined to better understand reactivity
and selectivity.
Angew. Chem. Int. Ed. 2021, 60, 2 – 11
ꢀ 2021 Wiley-VCH GmbH
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&&&&
These are not the final page numbers!