Diastereoselective C?H Bond Amination for Disubstituted Pyrrolidines

Article abstract of DOI:10.1002/anie.201708519

We report herein the improved diastereoselective synthesis of 2,5-disubstituted pyrrolidines from aliphatic azides. Experimental and theoretical studies of the C?H amination reaction mediated by the iron dipyrrinato complex (^AdL)FeCl(OEt₂) provided a model for diastereoinduction and allowed for systematic variation of the catalyst to enhance selectivity. Among the iron alkoxide and aryloxide catalysts evaluated, the iron phenoxide complex exhibited superior performance towards the generation of syn 2,5-disubstituted pyrrolidines with high diastereoselectivity.

Full text of DOI:10.1002/anie.201708519

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Accepted Article
Title: Diastereoselective C-H bond amination for disubstituted
pyrrolidines
Authors: Theodore Alexander Betley, Diana A Iovan, Matthew J. T.
Wilding, Elisabeth T. Hennessy, and Yunjung Baek
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.201708519
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10.1002/anie.201708519
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Diastereoselective C–H Bond Amination for Disubstituted
Pyrrolidines
Diana A. Iovan, Matthew J. T. Wilding, Yunjung Baek, Elisabeth T. Hennessy, and Theodore A. Betley*
Abstract: We report herein on the improved diastereoselective
synthesis of 2,5-disubstituted pyrrolidines from aliphatic azides.
Experimental and theoretical studies of the C–H amination reaction
mediated by the iron dipyrrinato complex (AdL)FeCl(OEt2) provided a
model for diastereoinduction and allowed for systematic variation of
the catalyst to enhance selectivity. Among the iron alkoxide and
aryloxide catalysts evaluated, the iron-phenoxide complex exhibited
superior performance towards the generation of syn 2,5-disubstituted
pyrrolidines with high diastereoselectivity.
The prevalence of 2,5-disubstituted pyrrolidines in natural
products,[1] pharmaceuticals,[2] and synthetic applications[3] has
Figure 1. Truncated solid-state structure[6] of (AdL)FeCl[2-(o-(F3C)C6H4)-5-
vinylpyrrolidine] (4) (a) and (AdL)Fe(OPh)(THF) (8) (b) at 100 K with 50%
probability ellipsoids.
inspired the emergence of numerous stereoselective
methodologies[4] for the synthesis of these N-heterocycles.
However, more atom-economical, efficient, and general
processes to access complex architectures featured in many of
these N-containing compounds are highly desirable. Towards this
goal, direct C–H amination methods could provide a streamlined
protocol and may serve to enhance the scope of conventional
syntheses.
To develop an understanding of the diastereocontrol of the
amination reaction, we investigated the diastereoselective
cyclization with catalyst 1a. A series of 1-azido-1-aryl-hex-5-ene
substrates were examined to establish the electronic and steric
contributions of the aryl-ring on the observed selectivity. Both
electron-donating and withdrawing substituents (e.g., Me, halides,
CF3) were amenable to cyclization (Table 1). Interstingly, para
(3b-3f) and meta (3g-3i) aryl functionality gave d.r. consistent with
our initial findings (3-4:1), whereas ortho-substitution (3j-3m)
afforded a single diastereomer. Increasing the steric bulk of the
R3 group (3p) or exchanging the positions of the phenyl and vinyl
functionalities (3q) does not affect diastereoselectivity. However,
the cyclization of 1-azido-2-phenyl-hex-5-ene (2r) yields the
corresponding 2,4-disubstituted pyrrolidine (3r) with a low (1.5:1)
Scheme 1. Diastereoselective iron-catalyzed cyclization.
[5]
d.r. 1D NOESY experiments on the deprotected[7] pyrrolidines
Our group has recently reported a catalytic C–H amination
process for the conversion of aliphatic azides to N-heterocycles
using a high-spin iron dipyrrin complex (AdL)FeCl(OEt2) (AdL = 1,9-
adamantyl-5-Ar-dipyrrin, Ar = 2,6-Cl2C6H3 (1a), mesityl (1b)).[5]
During our studies, we found that exposure of 1-azido-1-phenyl-
hex-5-ene to catalytic quantities of 1a in the presence of di-tert-
along with X-ray diffraction studies on single crystals of the Fe-2-
(o-(F3C)C6H4)-5-vinylpyrrolidine adduct (4) (Figure 1a) identified a
major syn diastereomer in all instances.
Prompted by these results, DFT studies were undertaken to
evaluate the factors leading to the diastereoselectivity manifest by
1a. Starting from crystalographic parameters for 1b and 4, the
reaction trajectory for cyclization of 2a was calculated to locate
ferric iminyl and amido intermediates (Figure 2a) with metrics
matching those for analogous isolated dipyrrin iron species.[8] The
C–H bond activation transition state (TS) identified displays an
elongated Fe–Nim bond (1.835 Å) and a nearly linear Nim–H–C4
vector (155°) in line with a hydrogen atom abstraction (HAA)
mechanism.[9] Scanning the potential energy surface to locate a
TS for the subsequent radical rebound step resulted in immediate
convergence to the Fe-pyrrolidine adduct. This finding suggests a
barrier-less recombination event, consistent with our
butyldicarbonate
(Boc2O)
afforded
Boc-2-phenyl-5-
vinylpyrrolidine as a 3.9:1 syn:anti mixture of diastereomers
(Scheme 1).[5] The inherent stereocontrol of the iron-catalyzed
cyclization, albeit modest, encouraged us to establish whether
diastereoselectivity could be enhanced via catalyst modification.
Herein we present a dipyrrinato-iron phenoxide complex that
furnishes 2,5-disubstituted pyrrolidines with > 20:1 syn:anti
diastereoselectivity (d.r.).
[*]
Diana A. Iovan, Matthew J. T. Wilding, Elisabeth T. Hennessy,
Yunjung Baek, Prof. Theodore A. Betley
Department of Chemistry and Chemical Biology
Harvard University
experimental observations using
a radical-clock probe to
establish a short-lived (< 10–11 s) carboradical intermediate.[5]
A
similar energetic profile was reported for the di-ruthenium nitrene
mediated allylic intramolecular C–H amination.[10]
The fast recombination rate identified experimentally and
theoretically establishes HAA as the selectivity determining step.
As such, TS for the HAA of each of the two diastereotopic H-
12 Oxford Street, Cambridge MA 02138
E-mail: betley@chemistry.harvard.edu
Supporting information for this article is given via a link at the end of
the document.
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10.1002/anie.201708519
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Table 1. Diastereoselective C–H amination.
[a] 1H NMR yield (isolated yields in parentheses). [b] syn:anti. [c] Catalyst 1a. [d] Catalyst 8. [e] 10 mol% catalyst.
atoms were investigated. Calculations revealed that formation of
between productive reactivity and diastereoinduction and cannot
be altered without compromising the desired chemistry. However,
the ancillary anionic ligand can affect the steric profile. To this end,
we sought to examine if a series of electronically and sterically
modular alkoxide and aryloxide complexes afforded superior
catalysis and diastereoselectivity.
kcal
the syn pyrrolidine product is favored by 0.93
/mol. The energy
difference is subtle; however, it predicts a 4.6:1 ratio of
diastereomers, corroborating the experimental 3.9:1 d.r.[5] The
optimized pro-anti TS (Figure S-11a) shows unfavorable
interactions of the substrate with both the dipyrrin bridgehead
position and the cleft comprised of the adamantyl groups and the
Cl ligand. Rotation about the C4–C5 bond reduces the steric
interference between the vinyl substituent and the mesityl group
(Figures 2b,S-11b) and allows for a decrease in the Cmeso–Fe–Nim
angle from 112.1° (anti) to 106.9° (syn), pulling the iminyl
fragment away from the cleft. The steric pressure between the α-
azido aryl unit and the cleft components is thus minimized,
affording
experimentally
a
lower energy pro-syn TS, in line with the
favored syn diastereomer. Ortho-aryl
functionalities induce additional strain to furnish the syn product
exclusively, whereas the remote meta and para substitutions
have no effect on d.r. assuming no change in TS organization.
The modest d.r. found for substrates 2p-2q can also be explained:
the planar phenyl ring interacts similarly with the mesityl unit,
while a vinyl group does not project far into the cleft to enhance
diastereocontrol.
The insight gained from DFT allowed us to systematically
modify our catalyst so as to improve diastereoselectivity. Among
the features proposed to dictate selectivity, the larger Taft steric
parameter[11] of Me versus Cl suggests that the bridgehead
mesityl group may be beneficial over the 2,6-Cl2-C6H3 in 1a. With
respect to the cleft, the adamantyl moieties provide a balance
Scheme 2. Synthesis of catalyst variants.
Addition of KOR reagents to 1b did not cleanly produce mono-
substituted complexes, as the anionic species (AdL)Fe(OR)2(μ2-K)
were readily formed. Alternatively, metathesis from the triflate
complex (AdL)Fe(OTf)(THF)2 (5; Supporting Information) provided
the alkoxide or aryloxide solvento-adducts (AdL)Fe(OR)(THF)
(Scheme 2, 6-13). All paramagnetic complexes 5–13 were
1
analyzed by H NMR and combustion analysis to assess purity
and single crystal X-ray diffraction to establish a coordination
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Figure 2. (a) Calculated[12] reaction coordinate for cyclization of 1-azido-1-phenyl-hex-5-ene (2a) mediated by 1b; (b) Geometry optimized TS for the HAA step in
the pro-syn (blue) and pro-anti (red) configuration.
sphere typical of high-spin ferrous dipyrrin complexes. While
individual bond metrics are unremarkable, the size of the OR
group changes the geometry at the Fe center from trigonal
monopyramidal for iron-phenoxide complexes 8-13 (Figure 1b) to
distorted tetrahedral for the alkoxide variants 6-7 (Figures S3–
S4), where the large alkoxide ligand resides outside the cleft
created by the two adamantyl units.
With catalysts 6–13 in hand, we began canvassing the
respective performance for the cyclization of test substrates 1-
azido-1-(4-chlorophenyl)-hex-5-ene (2b) (6-8) or 1-azido-1-
phenyl-hex-5-ene (2a) (9-13) (Table 2). While 1a yielded modest
d.r. (3:1), employing the OC(CF3)(Me)Ph alkoxide variant (6)
improved the selectivity to 13:1; however, introduction of the
larger alkoxide OC(CF3)Ph2 (7) resulted in both diminished
conversion and d.r. In fact, paring back the steric demands of 6 to
a phenoxide (8) provided the highest diastereoselectivity (> 20:1)
for the syn diastereomer. Ortho-substitution on the aryl unit does
not alter the observed d.r., but the yield diminishes with increased
steric bulk of the ortho position. Finally, para-substituted
phenoxide complexes preserve d.r. relative to 8, consistently
offering the best yields (66–82%).
As the highly performant catalysts 8 and 13 afforded similar
yields with problematic substrates (Table S-1), the more readily
accessible complex 8 was used to further explore the scope of
stereoinduction. Compared to 1a, catalyst 8 displays uniformly
elevated isolated yields and remarkable selectivity for the syn
diastereomer (> 20:1) regardless of the aryl substitution (Table 1).
Unlike the alkoxide variants, the OPh unit can engage in π-
interactions with the Fe, which may lock the OPh ligand within the
Fe-dipyrrin plane and induce more steric clashes with the
substrate. Further, given our recent study on the role of ancillary
ligands in ferric dipyrrin complexes,[13] we propose that the
enhanced Fe–OPh covalency stabilizes the Fe-iminyl
intermediate, improving cyclization yields. The only exceptions for
this substrate class are entries 2n (d.r. 11:1) and 2o (d.r. 10:1).
The benzylic C–H bond proximal to the iminyl moiety (2n) may
promote other reactions, decreasing both the d.r. and pyrrolidine
yield. The reason for the diminished selectivity of the naphthyl-
containing substrate remains unclear. In the absence of sterically
demanding α-azido groups (2q–2r), d.r. are low, corroborating the
proposed steric role of the anionic ligand.
Table 2. Catalyst screening as a function of ancillary ligand.
R
Complex
Yield (%)
54[a]
d.r.[c]
13:1
C(CF3)(Me)Ph
C(CF3)Ph2
Ph
6
7
26[a]
6:1
8
67[a]
> 20:1
16:1
o-C6H3Cl2
o-C6H3Br2
9
42[b]
10
11
12
13
42[b]
> 20:1
> 20:1
> 20:1
> 20:1
i
o-C6H3 Pr2
49[b]
p-C6H4F
66[a]
p-C6H4OMe
82[a]
Catalysts 6-8: reaction with 1-azido-1-(4-chlorophenyl)-hex-5-ene (2b); 9-13:
reaction with 1-azido-1-phenyl-hex-5-ene (2a); [a] Isolated yields. [b] 1H NMR
yields. [c] syn:anti.
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[10] M. E. Harvey, D. G. Musaev, J. Du Bois, J. Am. Chem. Soc. 2011, 133,
17207.
[11] C. Hansch, A. Leo, Substituent Constants for Correlation Analysis in
Chemistry and Biology, Wiley-Interscience, NY, 1979.
[12] M. J. Frisch, et al., Gaussian, Inc., Wallingford, CT, USA, 2009.
[13] C. Kleinlein, S.-L. Zheng, T. A. Betley, Inorg. Chem. 2017, 56, 5892.
The foregoing results demonstrate the viability of rendering
the catalytic N-heterocycle synthesis via direct C–H amination
diastereoselective. DFT studies guided a systematic catalyst
design leading to an optimized diastereoselective cyclization
using a phenoxide ancillary ligand. This ligand is likely involved in
π-bonding with the Fe and resides in the Fe-dipyrrin plane, thus
creating a more directional steric profile than the Cl or alkoxide
variants examined. The Fe–OPh interaction may also contribute
to the improved catalytic performance and highlights the interplay
of electronic and steric factors required for robust catalysts.
Acknowledgements
Authors are grateful for the assistance of Dr. Shao-Liang Zheng
with X-ray analysis.
This work was supported by the NSF (CHE-0955885) and NIH
(GM-115815), and Harvard University. M.W. would like to thank
the NSF and E.H. the DOE for Predoctoral Graduate
Fellowships.
Keywords: C–H activation • diastereoselectivity • iron dipyrrin•
phenoxide •pyrrolidine
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Entry for the Table of Contents (Please choose one layout)
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COMMUNICATION
Iron dipyrrin complexes catalyze the
conversion of aliphatic azides to 2,5-
disubstituted pyrrolidines
Diana A. Iovan, Matthew J. T. Wilding,
Yunjung Baek, Elisabeth T. Hennessy,
Theodore A. Betley*
diastereoselectively. A combination of
experimental and theoretical
Page No. – Page No.
investigations unveiled features
relevant for diastereocontrol. The
insight gained led to the synthesis of
the phenoxide substituted
Diastereoselective C–H Bond
Amination for Disubstituted
Pyrrolidines
(AdL)Fe(OPh)(THF) catalyst which
accesses syn 2,5-disubstituted
pyrrolidines with high diastereocontrol.
Layout 2:
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Author(s), Corresponding Author(s)*
((Insert TOC Graphic here))
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Title
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