Synthesis of Spirocyclic 1-Pyrrolines from Nitrones and Arynes through a Dearomative [3,3′]-Sigmatropic Rearrangement

Article abstract of DOI:10.1002/anie.202004652

A dearomative [3,3′]-sigmatropic rearrangement that converts N-alkenylbenzisoxazolines into spirocyclic pyrroline cyclohexadienones has been developed by using the dipolar cycloaddition of an N-alkenylnitrone and an aryne to access these unusual transient rearrangement precursors. This cascade reaction affords spirocyclic pyrrolines that are inaccessible through dipolar cycloadditions of exocyclic cyclohexenones and provides a fundamentally new approach to novel spirocyclic pyrroline and pyrrolidine motifs that are common scaffolds in biologically-active molecules. Diastereoselective functionalization processes have also been explored to demonstrate the divergent synthetic utility of the unsaturated spirocyclic products.

Full text of DOI:10.1002/anie.202004652

A Journal of the Gesellschaft Deutscher Chemiker
Angewandte
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Accepted Article
Title: Synthesis of Spirocyclic 1-Pyrrolines from Nitrones and Arynes
via a Dearomative [3,3']-Sigmatropic Rearrangement
Authors: Abdullah S Alshreimi, Guanqun Zhang, Tyler W Reidl,
Ricardo L Pena, Nicholas-George Koto, Shahidul M Islam,
Donald J Wink, and Laura L Anderson
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202004652
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10.1002/anie.202004652
Angewandte Chemie International Edition
COMMUNICATION
Synthesis of Spirocyclic 1-Pyrrolines from Nitrones and Arynes
via a Dearomative [3,3’]-Sigmatropic Rearrangement
Abdullah S. Alshreimi‡, Guanqun Zhang‡, Tyler W. Reidl, Ricardo L. Peña, Nicholas-George Koto,
Shahidul M. Islam, Donald J. Wink, and Laura L. Anderson*
Abstract:
A
dearomative [3,3’]-sigmatropic rearrangement that
to form spirocyclic pyrroline cyclohexadienones 4. This new
method provides access to spirocyclic pyrrolines that are
inaccessible via nitrile ylide dipolar cycloadditions due to
regiochemical preferences (Scheme 1C).[10-12] In addition, it
establishes the use of tethered heterocyclic substrates with weak
N–O bonds as a tool for accessing dearomatized spirocyclic
compounds through [3,3’]-sigmatropic rearrangements. The
scope and tolerance of this new cascade reaction are described
below in addition to opportunities for divergent derivatization of
the spirocyclic pyrroline cyclohexadienone products.
converts N-alkenylbenzisoxazolines to spirocyclic pyrroline
cyclohexadienones has been discovered using the dipolar
cycloaddition of an N-alkenylnitrone and an aryne to access these
unusual transient rearrangement precursors. This cascade reaction
affords spirocyclic pyrrolines that are inaccessible via dipolar
cycloadditions of exocyclic cyclohexenones and provides
a
fundamentally new approach to novel spirocyclic pyrroline and
pyrrolidine motifs that are common scaffolds in biologically-active
molecules. Diastereoselective functionalization processes have also
been explored to demonstrate the divergent synthetic utility of the
unsaturated spirocyclic products.
A) Dearomative allyl aryl ether rearrangement - Gagné and coworkers 2017[5a]
Me
Me
Dearomative functionalization reactions have inspired many
important advances in synthetic chemistry because they convert
planar feedstock reagents to value-added stereocomplex building
blocks.[1] In particular, dearomatizations of arenols and indoles
have provided important solutions to accessing challenging
biologically-active spirocyclic scaffolds.[2-4] Alleviation of the
enthalpic cost of the loss of aromatic stabilization is an important
consideration in these processes and has been achieved through
the use of oxidants, activated electrophiles, and extended
aromatic systems.[2,3] As a mild approach to dearomatization with
quaternary carbon stereocenter installation, several research
groups have explored the use of stereospecific [3,3’]-sigmatropic
rearrangements.[5] For example, Gagné and coworkers reported
that gold catalysis can be used to promote dearomative Claisen
rearrangements of allyl aryl ethers (Scheme 1A).[5a] Similarly, List
and coworkers discovered that Fischer-Indole reactions run with
ortho-substituted naphthyl hydrazines can be stalled after the
stereodetermining C–C bond formation to give enantioenriched
1,4-diones under mild conditions (Scheme 1B).[5b] We wondered
if a dearomative [3,3’]-sigmatropic rearrangement could be
achieved to directly form spirocyclic pyrrolines by exploiting the
weak N–O bond in an N-alkenylbenzisoxazoline (Scheme 1D).[6]
While isoxazolines such as 3 are difficult to prepare via
heterocyclic N-functionalization,[7] we surmised that N-
alkenylnitrones 1 could provide a versatile and facile route to
these key intermediates through dipolar cycloadditions with
arynes.[8,9] Herein we disclose that when arynes are generated in
the presence of nitrones 1, cycloaddition occurs to transiently
form isoxazoline 3, which triggers a dearomative rearrangement
O
cat. Ph3PAuNTf2
O
DCE, 50 °C
75%
Me
Me
B) Dearomative Fischer-Indole rearrangement - List and coworkers 2015[5b]
Ar
O
O
O
O
P
cat.
OH
Me
O
+
Ar
NH2
Amberlite CG50, H2O
HN
Me
PhCO2H, p-xylenes
40 °C, 3 - 7 d
81%
Me
O
>20:1 dr, 95:5 er
Me
C) Traditional approach to spirocyclic 1-pyrrolines - Xie and coworkers 2013[10a]
O
Ph
2)
Ph
O
N
Ph
Ph
dr = 75:25
O
Ph
1) SOCl2
Ph
N
Ph
N
Ph
KOt-Bu
65%
H
D) Dearomative rearrangement to spirocyclic 1-pyrrolines - This work
R1
R2
R1
N
R2
O
R3
CO2Me
N
1
N
[3,3’]
20 examples
[3+2]
CO2Me
R1
R3
MeO2C
SiMe3
O
R2
O
4
R3
2
3
OTf
Scheme 1. Dearomative Rearrangements and Spirocyclic Pyrrolines.
The conversion of nitrone 1a to pyrroline 4a was initially
observed in 1,2-dichloroethane (DCE) in the presence of benzyne,
generated from a mixture of 2a, CsF, and 18-crown-6 (Scheme
2A). The product was verified by X-ray crystal structure analysis
and both solution and solid-state characterization data were
consistent with the proposed formation of 4a via a boat-like [3,3’]-
sigmatropic rearrangement of dipolar cycloaddition intermediate
3a (Scheme 2B).[13,14] Computational studies suggest that the
transition state for the conversion of 3a to 4a is accessible at
ambient temperature and that formation of the new C–C and C=O
bonds exceeds the cost of the weak N–O bond and the loss of
[*]
A. S. Alshreimi, G. Zhang, T. W. Reidl, R. L. Peña, N.-G. Koto, Dr.
S. M. Islam, Dr. D. J. Wink, Prof. L. L. Anderson
Department of Chemistry, University of Illinois at Chicago
845 W Taylor Street, Chicago, IL (USA)
E-mail: lauralin@uic.edu
[‡]
These authors contributed equally to this work.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/anie.202004652
Angewandte Chemie International Edition
COMMUNICATION
aromaticity (Scheme 2B).[15] Optimization of reaction conditions
for the formation of 4a was achieved by examining solvent and
additive effects (Scheme 2A).[15] These studies indicated that the
cascade process is tolerant of a variety of solvents and yields
above 90% were observed in DCE, i-PrOAc, and MeCN with 2
equiv of CsF and 18-crown-6. No reactivity was observed in the
absence of the CsF and 18-crown-6 additives. The use of i-PrOAc
was selected as the optimal solvent for further screening because
it facilitated additive separation. With optimal conditions in hand,
the scope of the spirocyclic pyrroline synthesis was investigated.
Beyond investigation into the tolerance of the cascade reaction
in terms of the nitrone reagent, aryne and heteroaryne precursors
2b – 2d were tested to further examine reaction scope and to
R2
R3
SiMe3
R4
R3
R1
R1
N
2a
R2
O
R1
OTf
N
N
via
18-crown-6, CsF
i-PrOAc, 25 °C
2O
R3 R4
1
R
O
R4
4
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
N
N
N
N
Ar
Ph
Ph
Ph
SiMe3
A)
O
O
O
i-Pr
O
Me
4d (72%)
(dr = 2:1)
2a
OTf
18-crown-6, CsF
Et
Ph
CO2Me
CO2Me
Ph
Cl
N
4c (60%)
(dr = >20:1)
Ar = p-CF3(C6H4)
Et
O
4a (95%)
(dr = >20:1)
4b (86%)
(dr = >20:1)
Ph
N
=
solvent, 25 °C
O
Et
MeO2C
CO2Me
DCE = 91%
MeCN = 94%
i-PrOAc = 97%
CO2Me
CO2Me
CO2Me
N
CO2Me
CO2Me
CO2Me
CO2Me
1a
4a (dr = >20:1)
N
N
N
CO2Me
Me
n-Bu
B) DFT study (E = CO2Me)
Et
E
O
O
Me
O
O
n-Bu
O
CO2Me
CO2Me
Ph
Et
Ph
N
4e (90%)
(dr = >20:1)
4f (87%)
(dr = 1:1)
4g (76%)
(dr = >20:1)
4h (75%)
(dr = >20:1)
Ph
CO2Me
N
N
Et O
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
CO2Me
O
O
N
N
N
E
4a
ΔG° = -36.8 kcal/mol
CO2Me
3a
ΔG‡ = 25.07 kcal/mol
O
O
O
BocN
O
O
Scheme 2. Initial Results and Reaction Optimization.
4k (78%)
4i (55%)
4j (71%)
(dr = >20:1)
(dr = >20:1)
(dr = >20:1)
O
Ar
CO2Me
Ar
CO2Et
CO2Me
CO2Me
CO2Et
CF3
Ph
N
N
The scope of the formation of spirocyclic pyrrolines 4 from N-
alkenylnitrones and benzyne was tested using nitrones
N
N
Ph
1
prepared from a variety of oximes and alkenyl boronic acids
(Scheme 3).[9] As shown for 4a – 4d, malonate-derived nitrones
with N-styrenyl groups are well-tolerated for the pyrroline
synthesis with both primary and secondary alkyl groups at the β-
position. While the diastereoselectivity of C–C bond formation is
high for all N-styrenyl substrates lacking chiral substituents, the
defined stereochemistry of a 1-phenethyl group at the β-position
was shown to have little influence over the formation of 4d.
Nitrones with linear alkyl N-alkenyl substituents smoothly undergo
the cascade transformation to form pyrrolines 4e – 4f. While
isomerically pure N-alkenyl nitrones give pyrrolines such as 4e in
high diastereoselectivity, nitrones that are isolated as mixtures of
isomers, or prone to isomerization under reaction conditions, give
mixtures of products such as 4f. Both carbocyclic and heterocyclic
N-alkenyl groups are tolerated and diastereoselectively give 4g –
4l in good yields. Investigation of nitrones prepared from
unsymmetrical oximes established that malonate-derived
substrates are not required for the observed reactivity and that a
third carbon stereocenter can be set on the pyrroline ring during
the cascade process (4m – 4o). Both 4m and 4n are formed with
high diastereoselectivity corresponding to TS2, which puts the
larger R4-substituent in the least hindered position. The favored
diastereomer of 4n was verified by X-ray crystallography.[13] In
contrast, the aryl ketone and ester substituents of 4o
demonstrated competing preferences for controlling the facial
selectivity of C–C bond formation. These experiments established
the breadth of the new cascade process in terms of the nitrone
component for the preparation of spirocyclic pyrrolines 4.
O
O
Et
Et
O
O
4n (60%)
(dr = >20:1)
Ar = p-NO2(C6H4)
4o (76%)
(dr = 1:1)
Ar = p-OMe(C6H4)
4l (69%)
(dr = >20:1)
4m (55%)
(dr = >20:1)
Scheme 3. Scope of Dearomative Cascade Reaction for Pyrroline Synthesis.
R4
N
R1
R3
2
R1
R2
O
18-crown-6, CsF
N
i-PrOAc, 25 °C
2O
R
1
4
R3 R4
SiMe3
SiMe3
SiMe3
Me
N
O
O
OTf
2d
OTf
2b
2c
OTf
CO2Me
CO2Et
CF3
Ar
CO2Me
N
N
N
CO2Me
Ph
O
O
O
O
O
O
O
Et
O
O
4p (93%)
4q (66%)
(dr = >20:1)
4r (Ar = p-NO2(C6H4)
(63%, dr = >20:1)
(dr = >20:1)
CO2Me
CO2Me
X
CO2Me
CO2Me
N
N
CO2Me
CO2Me
N
+
O
O
O
4t (X = NMe)
(69%, dr = >20:1)
4s (62%)
2:1
dr = >20:1
dr = >20:1
Scheme 4. Dearomative Spirocyclic Pyrroline Synthesis with Arynes.
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10.1002/anie.202004652
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COMMUNICATION
determine regioselectivity preferences (Scheme 4). The
symmetrical aryne derived from benzdioxole 2b cleanly forms 4p
– 4r in good yields and high diastereoselectivities when treated
with N-alkenylnitrones 1g, 1m, and 1n, respectively.
Unsymmetrical 1,2-naphthylyne generated from 2c cleanly forms
a mixture of 4s and 4s’ when treated with 1g. In contrast, when
electronically biased 6,7-indolyne is generated from 2d in the
presence of N-alkenylnitrone 1g, 4t is formed in good yield with
high regioselectivity corresponding to the electronically-favored
dipolar cycloaddition.[16] While N-alkenylisoxazoline intermediates
3 were not observed during the synthesis of 4, the regioselectivity
observed for the formation of 4t supports the proposed
mechanism for the cascade formation of 4 from 1 through N-
alkenylbenzoisoxazoline intermediate 3.[15]
favored 5 for substrates generated from benzoylformate esters
and 6 for malonate-derived pyrrolines.[15,18]
Initial examination of the reactivity of spirocyclic pyrrolines 4
focused on testing transformations that would further increase the
stereochemical complexity of these unsaturated spirocyclic
scaffolds. As shown in Scheme 6, chemoselective reduction
conditions have been determined for the conversion of 4a to 7 –
10 in good yield and high diastereoselectivity. Further
decarboalkoxylation of these reduced spirocycles gave 11 – 14
with 3 – 4 contiguous stereocenters.[9a] When 4a was subjected
to decarboxylation conditions, only 6a was observed due the high
reaction
temperature.
Cyclopropanation,
epoxidation,
nucleophilic addition, and dipolar cycloaddition processes have
further been developed to derivatize spirocyclic scaffold 8 to give
17 – 19 in good yields and diastereoselectivities favoring
approach of the nucleophile or dipolarophile from the face of the
cyclohexanone opposite to the pyrroline ethyl group. Spirocyclic
pyrrolidines are privileged motifs in biologically active
molecules.[4] The transformations described above illustrate how
the new dearomative cascade process can be used to access
A) Alternative product formation
Ar
Ar
CO2Me
N
MeO2C
N
H
2a
O
N
O
18-crown-6, CsF
4u
i-PrOAc, 25 °C
64%
Ar = p-NO2(C6H4)
O
MeO2C
MeO
Ar
1p
5a
novel unsaturated intermediates
4 that undergo divergent
ΔGcalc = 26.0 kcal/mol
(dr = >20:1)
derivatization to stereocomplex examples of these important
heterocycles.
O
O
N
O
N
Ph
N
Ph
MeO2C
5c (80%, dr = >20:1)
Me
MeO2C
H
H
MeO2C
Me
E
N
E
5d (80%, dr = >20:1)
5b (82%, dr = >20:1)
Ph
B) Thermodynamically-favored rearrangement of 4a
4a
(E = CO2Me)
E
E
O
Et
E
E
O
N
E
E
N
70 °C
Ph
reduction
NH
Ph
THF
E = CO2Me
[b]
[a]
N
[c]
N
[d]
89%
91%
73%
72%
O
Et
Ph
Et
Et
O
E
E
H
N
E
E
E
E
E
4a
int1
6a (77%)
N
E
Ph
Ph
Ph
Ph
Scheme 5. Observation of Benzofuran Formation and Rearomatization.
O
O
Et
O
Et
O
Et
Et
8 (dr = >20:1)
[e]
7 (dr = >20:1)
9 (dr = >20:1)
10 (dr = >20:1)
[e]
N
[e]
N
[e]
- CO2Me
62%
E
52%
60%
E
64%
E
Surprisingly, when benzyne is generated in the presence of N-
cyclohexenylnitrones derived from benzoylformate esters (see
H
N
E
N
1p), spirocyclic pyrrolines
4
are not observed and
Ph
Ph
Ph
Ph
dihydrobenzofurans 5a – 5c are isolated in good yield (Scheme
5A).[13,17] This result is consistent for analogous nitrones with
linear alkyl-substituted N-alkenyl groups (see 5d), although
pyrroline formation is favored for malonate-derived nitrones and
N-styrenylnitrones (see Scheme 3: 4e, 4g and 4n). Evidence of
pyrroline 4u was not observed during reaction monitoring but
computational studies suggest that a transition state for the
rearrangement of 4u to 5a is accessible.[15] To determine if 5 were
thermodynamically-favored rearrangement products that could be
accessed from spirocyclic pyrrolines, 4a and 4r were heated to
70 °C. While no reaction was observed for 4r, 4a was converted
to benzoxazepine 6a through proposed intermediate int1
(Scheme 5B). The observed resistance of pyrroline 4r to undergo
rearomatization could be due to destabilization of the build-up of
negative charge on the phenoxide fragment. The formation of 6a
indicates that rearomatization of 4 can occur under mild heating
but 7-membered ring formation is preferred for malonate-derived
pyrrolines.[15] These results suggest that pyrrolines 4 are kinetic
products that are accessible due to the mild conditions of the
cycloaddition cascade but can convert to thermodynamically-
O
O
Et
Et
O
O
Et
Et
13 (dr = >20:1)
14 (dr = >20:1)
11 (dr = 9:1)
12 (dr =>20:1)
Me
Ph
Me
O
[f] to 15, 75%
[g] to 16, 64%
[h]
Ph
O
8
N
R
72%
N
E
X
E
E
18 [i], 90%
CN
15 (dr = >20:1)
17
Me
(X = CH2, R = H)
16 (dr = >20:1)
(X = O, R = E)
(dr = >20:1)
Ph
O
Ph
NH
H
H
N
E
18 =
Ph
N
E
E
19
E
(dr = >20:1)
Scheme 6. Selective Functionalization of Spirocyclic Pyrrolines. [a] L-Selectride,
THF, -78 °C, [b] Pd/alumina, H2 (1 atm), EtOAc, [c] Pd/alumina H2 (1 atm),
MeCN, [d] Pd/alumina, H2 (1 atm), MeOH, [e] KI, pyridine:MeOH (1:1), 110 °C,
[f] Me3SI, NaH, DMSO, [g] t-BuOOH, DBU, MeOH, [h] KCN, Et3N•HCl, MeOH,
[i]cat. Ag(CO2CF3), cat. dppp, NEt3, CHCl3 (DBU = 1,8-diazabicyclo[5.4.0]-
undec-7-ene, dppp = 1,3-bis(diphenylphosphino)propane)
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10.1002/anie.202004652
Angewandte Chemie International Edition
COMMUNICATION
10257; e) G. Periyasami, R. Raghunathan, G. Surendiran, N. Mathivanan,
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In conclusion, a cycloaddition and rearrangement cascade
reaction has been developed for the dearomative synthesis of 4
from nitrone and aryne precursors. This transformation provides
a route to spirocyclic pyrrolines that are inaccessible by nitrile
ylide cycloaddition mechanisms and that contain unsaturated
functionalities that can be further derivatized by stereoselective
functionalization. This cascade process is a new advance in the
use of [3,3’]-sigmatropic rearrangements for the dearomative
synthesis of spirocycles that was enabled through the generation
of N-alkenylbenzisoxazolines from nitrones and arynes.
[5]
For dearomative [3,3’]-rearrangements: a) M. T. Peruzzi, S. J. Lee, M. R.
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Acknowledgements
[6]
For an example of a dearomative Claisen rearrangement that forms a
quaternary carbon stereocenter and can be subsequently cyclized to a
spirocycle see reference [5c].
We acknowledge generous funding from the National Science
Foundation (NSF-CHE 1855833) and the University of Illinois at
Chicago. RLP thanks the UIC Summer Research Opportunities
Program (SROP 2019). We thank Mr. Furong Sun (UIUC) for high
resolution mass spectrometry data.
[7]
D. T. Ahneman, J. G. Estrada, S. Lin, S. D. Dreher, A. G. Doyle, Science,
2018, 360, 186.
[8]
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Anderson, Angew. Chem. Int. Ed. 2017, 56, 3059.
Keywords: spirocyclic pyrroline • nitrone • dearomatization •
[10] For dipolar cycloaddition approaches to spirocyclic cyclohexanone
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RSC Adv. 2013, 3, 25103; b) M. P. Balu, H. Ila, H. Junjappa, Tetrahedron,
1990, 46, 6771.
dipolar cycloaddition • [3,3’]-sigmatropic rearrangement
[1]
[2]
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contain the supplementary crystallographic data for this paper. These
data can be obtained free of charge from The Cambridge
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[15] See Supporting Information for a full optimization table, details regarding
computational studies, formation of 3 via the cycloaddition of a sterically-
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[4]
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[18] A 3:1 mixture of 5e:6b was observed after heating a solution of 4n. This
suggests that the formation of 5 is also dependent on the nitrone N-
alkenyl substitution pattern. See Supporting Information for details.
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10.1002/anie.202004652
Angewandte Chemie International Edition
COMMUNICATION
Entry for the Table of Contents
Ar
CO2Me
N
CO2Me
R2
N
CO2Me Ph
SiMe3
Me
R1
R1
R3
R4
Et O
O
O
O
R2
N
O
OTf
O
Me
N
18-crown-6, CsF
R3 R4
CO2Me
CO2Me
CO2Et
CF3
N
N
dearomative
[3,3’]-sigmatropic
rearrangement
O
O
BocN
A cascade reaction has been designed for the synthesis of spirocyclic pyrrolines from nitrones and arynes. A key feature of this
transformation is an unusual dearomative [3,3’]-sigmatropic rearrangement of a heterocyclic intermediate that results in a
spirocyclization. This modular route to new examples of spirocyclic pyrrolines further provides opportunities for accessing a variety of
three-dimensionally-defined pyrrolines and pyrrolidines through simple divergent methods for diastereoselective derivatization.
This article is protected by copyright. All rights reserved.