A Rh(III)-Catalyzed Formal [4+1] Approach to Pyrrolidines from Unactivated Terminal Alkenes and Nitrene Sources

Article abstract of DOI:10.1021/jacs.9b07012

We have developed a formal [4+1] approach to pyrrolidines from readily available unactivated terminal alkenes as 4-carbon partners. The reaction provides a rapid construction of various pyrrolidine containing structures, especially for the diastereoselect

Full text of DOI:10.1021/jacs.9b07012

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Cite This: J. Am. Chem. Soc. XXXX, XXX, XXX−XXX
A Rh(III)-Catalyzed Formal [4+1] Approach to Pyrrolidines from
Unactivated Terminal Alkenes and Nitrene Sources
Sumin Lee,§ Honghui Lei,§ and Tomislav Rovis*
Department of Chemistry, Columbia University, New York, New York 10027, United States
S
* Supporting Information
Scheme 1. Intermolecular Synthetic Approaches for
Pyrrolidine Using Alkenes as Coupling Partners
ABSTRACT: We have developed a formal [4+1]
approach to pyrrolidines from readily available unac-
tivated terminal alkenes as 4-carbon partners. The
reaction provides a rapid construction of various
pyrrolidine containing structures, especially for the
diastereoselective synthesis of spiro-pyrrolidines. Mecha-
nistic investigation suggests a Rh(III)-catalyzed intermo-
lecular aziridination of the alkene and subsequent acid-
promoted ring expansion for the pyrrolidine formation.
yrrolidine is a prevalent structural unit in pharmaceuticals,
1
Pbiologically active natural products and materials.
Consequently, significant efforts have been devoted to the
development of efficient routes to pyrrolidines. Early examples
̈
can be traced back to the classical Hofmann−Loffler−Freytag
reaction in the 19th century.2 Given the ubiquity of the
heterocycle, a myriad of cyclization methods have been
developed for its assembly involving nearly every reaction
class.3
Convergent synthetic strategies involving two or three
unique components has also received great attention. Among
potential reaction partners, olefins are perhaps the most
abundant, general and desirable. The [3+2] cycloaddition
between azomethine ylides and alkenes represents a well-
studied method among them (Scheme 1).4 Other recent
examples also include the reaction of β-amino aldehydes,
protected cinnamyl amines and aziridines with various types of
alkenes as two-carbon sources.5 Strategies utilizing alkenes as
three-carbon coupling partners are relatively rare and often
require prefunctionalization. For example, 2-((trimethylsilyl)-
methyl) allyl acetate has been reported as a three-carbon
source for the formal [3+2] cycloaddition with imines
(Scheme 1).6 Most recently, a visible light-mediated photo-
redox catalyzed synthesis of spiropyrrolidines was reported
using homoallylic amines as 3-carbon/1-nitrogen sources with
aliphatic ketones as 1-carbon partners.7 The use of alkenes as
4-carbon partners is unknown. Herein, we report a Rh(III)-
catalyzed formal [4+1] approach to pyrrolidines from α-olefins
as 4-carbon sources and hydroxylamine derivatives as nitrogen
sources.
Inspired by this preliminary result and the rapid access to
pyrrolidines, we sought to optimize the transformation.
Although desired product could be formed by Rh(III) alone,
we found that the yield of pyrrolidine (3aa) is greatly
improved by prestirring the reaction mixture until full
consumption of 1-hexene (1a) and then subjecting the
reaction mixture with AgOTf at 80 °C (entry 2).
Systematic examination of acid additives revealed that
Sc(OTf)3 is more effective than AgOTf, promoting the
cyclization even at room temperature (entry 3; for detailed
information, see SI). Eventually, TfOH was chosen as optimal,
delivering 66% yield of desired 2-ethyl-1-tosylpyrrolidine (3aa)
(entry 4). The electron-deficient heptamethylindenyl (Ind*)
ligand on the Rh(III) catalyst is crucial with the more common
[Cp*RhCl2]2 providing product in a much lower yield (entry
5).10 Moreover, other nitrene precursors11 such as dioxazolone
Recently, we reported a branch-selective allylic amination of
simple α-olefins using Ir(III) catalysis.8 During the course of
this work, we noted that heptamethylindenyl (Ind*) Rh(III)
catalyst9 delivers the pyrrolidine side product (3aa) and linear
allylic amination product (4) in low yield from 1-hexene (1a)
and N-pivalolyloxy tosylamide (2a) (Table 1, entry 1).
Received: July 2, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.9b07012
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Journal of the American Chemical Society
Communication
are tolerated when located far from the reaction center,12
providing corresponding products (3fa−3ka) in moderate to
good yield.
a
Table 1. Reaction Optimization
In consideration of the importance of spirocyclic pyrroli-
dines among pharmaceuticals, we tested synthetic utility of this
method for the synthesis of spiro-pyrrolidines with a variety of
allyl cyclohexane substrates (Scheme 3). Allyl cyclohexane (1l)
Scheme 3. Allyl Cyclohexane Substrate Scope
yield of 3aa
yield of 4
b
b
entry
nitrene source
additive
(%)
(%)
c
l
Ts-NH-OPiv (2a)
Ts-NH-OPiv (2a)
Ts-NH-OPiv (2a)
Ts-NH-OPiv (2a)
Ts-NH-OPiv (2a)
3-Phenyl-1,4,2-dioxazol-
5-one
Ts-N3
−
15
0 (50)
45 (58)
66
15
0
15
−
−
−
−
−
d
2
3
4
AgOTf
Sc(OTf)3
TfOH
TfOH
TfOH
d
e
5
6
7
TfOH
0
−
a
Reactions were conducted on a 0.1 mmol scale using 1a (1.0 equiv).
b
Additive was added after 24 h. Determined by analysis of 1H nuclear
magnetic resonance (NMR) of the unpurified reaction mixture.
c
Reaction was conducted at 40 °C with 1 equiv of 2a, with
d
[Ind*RhCl2]2/AgOTf as the catalyst precursor. Temperature
e
increased to 80 °C after addition of the additive. [Cp*RhCl2]2 was
used.
or tosyl azide (entry 6, 7) lead to no pyrrolidine product
formation.
We next sought to examine the scope of this method with
various terminal alkenes (Scheme 2). The reaction proceeds
Scheme 2. Alkene Substrate Scope
a
b
c
From 1n (3.1:1 dr). From 1o (2.8:1 dr). From 1p (3.0:1 dr).
d
e
f
From 1q (3.8:1 dr). From 1s (1.6:1 dr). Reaction conducted at 4
°C.
was successfully converted to the 1-tosyl-1-azaspiro[4.5]decane
(3la) product in excellent yield. A conformational bias in the
cyclohexane ring (4-tert-butyl, 4-phenyl, 3-methyl and 3-
trifluoromethyl) produced corresponding spiro-pyrrolidine
products with excellent diastereoselectivity (3na, 3oa, 3pa
and 3qa). It is also worth noting that >20:1 diastereoselectiv-
ities are achieved regardless of trans/cis ratio of the starting
cyclohexane. The relative stereochemistry of 3na and 3pa was
unambiguously determined by X-ray crystallography. Interest-
ingly, the reaction with 2-allyl adamantane (1r) causes a 1,2-
hydride shift before cyclization, leading to the formation of an
unprecedented structure 3ra. A similar hydride shift event was
also observed with 1-allyl-2-methylcyclohexane (1s), giving rise
to 6,6-fused bicyclic, decahydroquinoline (3sa). Moreover,
naphthyl sulfonyl group was introduced as an alternative tosyl
protecting group due to its milder deprotection conditions
(3nb).13 Last, regiodivergent synthesis of pyrrolidine-based
a
Reaction conducted at 40 °C.
smoothly with alkenes containing substituents at C4 and C5
positions, giving desired products (3aa−3da) in good yield.
Interestingly, in the case of 4,4-dimethyl-1-pentene (1e) where
the C4 position is blocked, one of the methyl groups migrates
to the C3 position, forming 2,2,3-trimethyl-1-tosylpyrrolidine
(3ea) selectively. Additionally, a variety of functional groups
such as −Br, −OAc, −OTs, −NPhth, −CONR2 and −CO2R
B
DOI: 10.1021/jacs.9b07012
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Journal of the American Chemical Society
Communication
spirocycle (3la) and fused bicyclic compound (5la) was
achieved from allyl cyclohexane (1l) with exquisite selectivity
by simply changing reaction temperature.
Scheme 5. Proposed Mechanism
To obtain mechanistic insights, we first conducted the
reaction with 1-hexene (1a) using the standard reaction
conditions without the sequential treatment of TfOH. N-Tosyl
aziridine 6aa was isolated in quantitative yield. The
aziridination of unactivated alkenes catalyzed by Ind*Rh(III)
is unprecedented, although it is a well-explored research area.14
Further subjecting the resulting aziridine to TfOH leads to
pyrrolidine product in 75% yield (3aa) (Scheme 4a).5c,15
Scheme 4. Mechanistic Investigation
subsequently to form N-tosyl aziridine (6aa). It is also possible
that the aziridine (6aa) is formed through the alkene migratory
insertion of intermediate I, followed by a concerted C−N bond
formation and N−O bond cleavage. Upon treatment with
triflic acid, aziridine ring expansion is initiated by 1,2-hydride
shift, followed by a combination of 1,2-hydride shift and
elimination/protonation pathways, and eventually quenches
the carbocation at C4 position to form the pyrrolidine product
(3aa). The possible intervention of homoallylic amide VI
explains the modest loss of deuteration in the deuterium
labeling experiments noted above.
In summary, we have developed a Rh(III)-catalyzed formal
[4+1] synthesis of pyrrolidines from readily available
unactivated alkenes. Mechanistic studies show that the reaction
proceeds through a Rh(III)-catalyzed aziridination of the
alkene and subsequent ring expansion from aziridine to
pyrrolidine promoted by the acid. This method offers a new
strategy for pyrrolidine synthesis by employing a simple alkene
as a four-carbon source. With this method, various types of
pyrrolidines, especially spiro-pyrrolidines, were rapidly con-
structed. Further efforts at elucidating the mechanism and
expanding this chemistry are currently underway.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.9b07012.
■
S
These results suggest that the Rh(III)-catalyzed intermolecular
aziridination of the alkene and subsequent acid-promoted ring
expansion is likely responsible for the reaction mechanism.
In order to investigate the reaction mechanism, allylic and
homoallylic tosyl amides (4 and 7) were subjected to TfOH
(Scheme 4b). Allylic amine (4) does not lead to pyrrolidine
product, while a quantitative yield was achieved from
homoallylic amine (7).16 Furthermore, we continued to test
the mechanism with C1 to C4 deuterated alkenes (Scheme
4c). In the case of C3 deuterated aziridine (6ca-C3-d2),
extensive deuterium incorporation is observed at the C2
position. In addition, significant erosion of deuterium is
observed in the case of 6ca-C4-d2.
Crystallographic data for 3na, 3pa, 3ra and 5la (ZIP)
Experimental procedures, detailed optimization table,
characterization, copies of 1H, 13C and 19F NMR spectra
for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*tr2504@columbia.edu
ORCID
■
Tomislav Rovis: 0000-0001-6287-8669
Author Contributions
Taken together, these experiments suggest a plausible
reaction mechanism (Scheme 5). N-Pivalolyloxy tosylamide
(2a) first coordinates to the Rh(III) catalyst and undergoes
Rh-nitrene formation (II).17 Alkene aziridination proceeds
§S.L. and H.L. contributed equally to this work.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/jacs.9b07012
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Journal of the American Chemical Society
Communication
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ACKNOWLEDGMENTS
■
We gratefully acknowledge NIGMS (GM80442) for funding.
Single crystal X-ray diffraction was performed at the Shared
Materials Characterization Laboratory (SMCL) at Columbia
University. Use of the SMCL was made possible by funding
from Columbia University.
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