Aminoketyl Radicals in Organic Synthesis: Stereoselective Cyclization of Five- and Six-Membered Cyclic Imides to 2-Azabicycles Using SmI2-H2O

Article abstract of DOI:10.1021/acs.orglett.5b02732

Synthetic application of aminoketyl radicals [R-C^?(O^-)NR′R″] formed by a direct electron capture into the amide bond is limited. Herein, we demonstrate addition of aminoketyl radicals to unactivated alkenes using SmI₂-H₂O as a crucial promoter based on the generic five- and six-membered imide template. Notably, this method enables direct access to aminoketyl radicals with wide-ranging applications in synthesis for the formation of C-C bonds adjacent to nitrogen via polarity reversal.

Full text of DOI:10.1021/acs.orglett.5b02732

Letter
pubs.acs.org/OrgLett
Aminoketyl Radicals in Organic Synthesis: Stereoselective Cyclization
of Five- and Six-Membered Cyclic Imides to 2‑Azabicycles Using
SmI2−H2O
Shicheng Shi and Michal Szostak*
Department of Chemistry, Rutgers University, 73 Warren Street, Newark, New Jersey 07102, United States
S
* Supporting Information
ABSTRACT: Synthetic application of aminoketyl radicals
[R−C•(O−)NR′R″] formed by a direct electron capture into
the amide bond is limited. Herein, we demonstrate addition of
aminoketyl radicals to unactivated alkenes using SmI2−H2O as
a crucial promoter based on the generic five- and six-
membered imide template. Notably, this method enables
direct access to aminoketyl radicals with wide-ranging
applications in synthesis for the formation of C−C bonds
adjacent to nitrogen via polarity reversal.
minoketyl radicals are versatile intermediates that have
been invoked in degradation of nucleobases1 and play a
be found in a variety of biologically active molecules;11
however, few methods for the stereoselective construction
have been reported.14
A
central role in electron capture dissociation (ECD) of peptides
and proteins.2 However, the use of aminoketyl radicals in
organic synthesis is limited due to the difficulty of a direct
electron transfer into the antibonding π* orbital of the amide
function due to nN → π*CO conjugation.3 Moreover, the
utility of carbon-centered aminoketyl radicals has been
hampered by the undesirable fragmentation of the N−Cα
bond, generating a new C-centered radical and an enolimine
intermediate with a formal negative charge at the nitrogen
atom.4 The facility of this fragmentation has been correlated
with the charge density at carbon of the aminoketyl group,5
restricting the range of acceptors that are amenable to cross-
coupling protocols. Aminoketyl radicals can be regarded as a
formal merger of the highly nucleophilic and predominantly
planar ketyl radicals6 with the highly stabilized and partially
pyramidalized α-aminyl radicals.7 However, in contrast to
widespread applications of ketyl and α-aminyl radicals to forge
new C−C bonds for the functionalization of α-C−O8 and α-
C−N bonds,9 respectively, often proceeding with exquisite
control of selectivity,8,9 the development of practical and
general coupling protocols for the addition of aminoketyl
radicals to unactivated π-acceptors in a stereoselective manner
remains a formidable challenge (Figure 1A,B).10
The 2-azabicyclic motif appears in a large number of
bioactive natural products and top-selling pharmaceuticals and
has been shown to impart novel properties in ligands and small-
molecule catalysts (Figure 1C).11 Moreover, 2-azabicycles serve
as key precursors for the synthesis of biologically active
heterocycles, such as indoles, pyrroles, and quinolines.12 New
selective methods for the preparation of 2-azabicycles are an
important focus of research.13 In particular, modular entries to
2-azabicycles featuring angular substituents adjacent to the
nitrogen atom are highly desirable because this ring system can
Herein, we report a general strategy to develop synthetically
useful, stereoselective, and modular cyclizations of aminoketyl
radicals with unactivated π-acceptors using SmI2−H2O15 as a
crucial promoter based on the generic five- and six-membered
imide template. The reaction provides direct access to 2-
azabicyclic motifs featuring three contiguous stereocenters (two
quaternary) in excellent selectivity (>95:5 in all cases
examined). A direct electron transfer from the activated
lanthanide(II) reagent into the antibonding π* orbital of the
amide group to generate an aminoketyl radical anion is the key
step.15 Notably, this process constitutes the first general
method for the synthesis of aminoketyl radicals under mild
electron transfer conditions.1−10,16 Considering the versatile
role of aminoketyl radicals and the prominence of 2-azabicyclic
motifs in organic synthesis, we expect that this strategy will find
widespread use for the synthesis of N-containing molecules via
open-shell reaction pathways.
Our strategy to achieve a modular, broadly useful generation
of aminoketyl radicals16 to access 2-azabicyclic motifs is based
on the following design features: (i) directing-group-controlled
activation of the functional group toward electron transfer,17a
and stabilization of the resulting aminoketyl intermediate by
chelation;17b,c (ii) pseudoanomeric stabilization of the amino-
ketyl radical anion intermediate;17d,e (iii) lower energy
antibonding π*orbital in the imide template;17f (iv) nN→
π*CO delocalization into the remaining carbonyl in a conforma-
tionally locked system to prevent N−Cα fragmentation;17g (v)
coordination of the oxophilic Ln(II) reagent to the carbonyl
group to lower the redox potential of the precursor.17h Suitable
Received: September 22, 2015
© XXXX American Chemical Society
A
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Scheme 1. Cyclization of Five-Membered Cyclic Imides via
a
Aminoketyl Radicals Using SmI2−H2O
a
b
Conditions: SmI2 (3 equiv), THF, H2O, 23 °C. SmI2 (8 equiv),
THF, H2O, 23 °C. See SI for full experimental details.
Figure 1. (a) General strategies for polarity reversal of carbonyl
groups. (b) This work: the first general chemoselective generation of
aminoketyl radicals. (c) 2-Azabicylic motif.
Importantly, reduction of the aminoketyl radical16a or over-
reduction of the amide group18a was not observed under these
conditions.
ligands activate the lanthanide(II) reagent and favor electron
transfer under thermodynamic control of the reaction path-
way.18 Importantly, the generic imide scaffold can be used as a
platform to access a wide range of functionalized 2-azabicycles
via postcyclization functionalizations.11−13
The following gram scale procedure is representative: a
mixture of 1a (1.0 g, 2.68 mmol), H2O (19.3 mL, 1.1 mol), and
SmI2 (5.36 mmol, 2.0 equiv) was stirred in THF at 23 °C for 5
min to afford 0.93 g of 2-azabicycle 2a (93% yield, >98:2 dr)
after direct recrystallization from the reaction mixture (eq 1).
Having identified optimal conditions for the coupling of
aminoketyl radicals, we next investigated the scope of the
transformation. As revealed in Scheme 1, the reaction
accommodates an array of functional groups. Electronically
diverse functional groups (2a−2c) as well as functions sensitive
to other electron transfer conditions,8,15b such as bromides
(2d), esters, and amides, are readily tolerated, providing
handles for further synthetic manipulations. Importantly, the
mild SmI2−H2O system tolerates functional groups that are
incompatible with Sm(II)-Lewis bases,18a such as electron-
deficient arenes (2e) and polyarenes (2f). Moreover, the less
activated terminal alkenes undergo the desired cross-coupling
with good efficiency (2g−2h).22 Furthermore, we were pleased
to find that the directing group is not required for efficient
coupling (2i−2j).17a The resulting 2-azabicyclic adducts bearing
quaternary aryl moieties are versatile precursors to a wide range
of biologically active natural products and pharmaceuticals.11f
In all cases the reaction was fully stereoselective with respect to
all three stereocenters.22c Moreover, the protocol can be
applied to alkynes as radical acceptors (2k). Interestingly, anti
addition of the aminoketyl radical gives the vinyl radical
intermediate, which isomerizes under SmI2−H2O conditions.23
We note that this process sets the stage for cascade reductive
transformations on the imide template.15f
We started our investigation by evaluating the addition of a
challenging five-membered imide19 bearing an unactivated
alkene tether and an ester directing group17a using SmI2 as a
promoter in the presence of various alcohols as ligands (see
Table 1-SI, Supporting Information (SI)).18 The proposed R−
C•(O−)NR′R″/C−C cross-coupling was indeed feasible in the
presence of ligands that have been shown to coordinate to the
inner coordination sphere of Sm(II) [MeOH, H2O, HO-
(CH2)2OH].20 Employing H2O as a ligand provided the
desired pyrrolidine adduct in the highest yield and
selectivity.18b,c Notably, in all productive cases examined, the
cross-coupling product was obtained with excellent stereo-
selectivity (>95:5 dr), highlighting the stability of aminoketyl
radicals by the nN → SOMO conjugation21 (vide infra).
Next, we focused our attention on the coupling of six-
membered precursors (Scheme 2). These substrates are
particularly challenging because of the facile reduction of the
aminoketyl radical to the anion.19 Moreover, literature data
indicate that ketyl-type radicals in six-membered rings are more
than two orders of magnitude more reactive than in five-
membered rings,17a increasing the potential for side reactions.
We were pleased to find that a variety of six-membered
B
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Letter
of the reactions involving aminoketyl radicals is a valuable
advantage of this coupling manifold.
Scheme 2. Cyclization of Six-Membered Cyclic Imides via
Aminoketyl Radicals Using SmI2−H2O
a
We conducted several experiments to gain insight into the
reaction mechanism (see SI). (1) The reductive cyclization of
imides 1a, 1m, and 1h with SmI2/D2O (1a: >98% D1; kH/kD =
1.49 0.1; 1m: >98% D1; kH/kD = 1.54 0.1; 1h: >98% D1;
kH/kD = 1.10
0.1) suggests that proton transfer is not
involved in the rate-determining step of the reaction,
irrespective of the ring size, directing group, and the π-system.
(2) The reaction of 1a with D2O (1:1 dr at the benzylic
position) demonstrates that the alkylsamarium(III) intermedi-
ate is not coordinated to the ring oxygen.17e (3) Intermolecular
competition experiments reveal that six-membered precursors
are inherently more reactive, consistent with the anomeric
stabilization of the aminoketyl radical intermediate.17d (4) Fully
chemoselective cyclization of substrates bearing a directing
group is observed, consistent with coordination of Sm(II).17a
(5) Hammett study with 4-substituted arylalkene radical
acceptors showed a large positive ρ-value of 0.89, R2 = 0.99,
consistent with the addition of a nucleophilic aminoketyl radical
onto the alkene. (6) The rate of cyclization of 1g with a fixed
amount of water26 is consistent with a stabilizing effect of water
on the cyclization.27 Notably, full chemoselectivity over the
reduction of a model lactone, 5-decanolide,17a,27 is observed,
suggesting that myriad reductive transformations of aminoketyl
radicals should be readily accomplished.15 Importantly, the
SmI2−H2O system can be used at varying concentrations of
water to fine-tune the lanthanide(II) reductant, which is not
possible with ester-derived radicals, which require a large
concentration of water to promote the reduction.
In conclusion, we have developed a general and versatile
method for the stereoselective synthesis of complex 2-
azabicycles, which relies on the efficient utilization of
aminoketyl radicals generated via a direct electron transfer to
five- and six-membered cyclic imides using SmI2−H2O.
Mechanistic data are consistent with the addition of an
aminoketyl radical to alkenes as the rate-determining step.
Most importantly, these studies advance the electron transfer
platform of ketyl radicals to aminoketyl radicals to afford
versatile motifs functionalized at the C atom adjacent to
nitrogen via an umpolung R−C•(O−)NR′R′ synthon. Further
investigations into related processes of aminoketyl radicals are
underway in our laboratory, and these results will be reported
shortly.
a
See Scheme 1. See SI for full experimental details.
precursors participate in the coupling. The reaction tolerates a
broad range of functional groups, including bromides (2o),
chlorides (2p), fluorides (2q), ethers (2m), trifluoromethyl
groups (2n), heterocycles (2t), and electron-deficient arenes
(2p).15b Steric hindrance is not a significant factor in these
reactions (2r).16b Ortho-coordinating groups on the arene (2s)
have no effect on the product selectivity.24 Cleavage of the
methylene bridge in 1,3-benzodioxole (2t) was not observed,
attesting to the mild conditions of the coupling.18 Sterically
demanding disubstituted olefin acceptors can be employed
without loss in overall yield and stereoselectivity (2v).17e
Moreover, dienyl precursors can be readily employed to give
vinyl-substituted 2-azabicycles after radical isomerization (2w).
To expand the scope of the synthesis of 2-azabicycles,
substrates containing activated π-acceptors have been exam-
ined, resulting in efficient coupling (eq 2). Interestingly, the
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b02732.
Experimental procedures and characterization data
(PDF)
AUTHOR INFORMATION
■
Corresponding Author
products were formed as mixtures of diastereoisomers as a
result of the “olefin-first” coupling mechanism (cf. “carbonyl-
first”).25 The latter mechanism gives the stabilized aminoketyl
radical, which permits the acceptor tether to adopt the lowest
energy conformation.21 Undoubtedly, the high stereoselectivity
*E-mail: michal.szostak@rutgers.edu.
Notes
The authors declare no competing financial interest.
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Letter
(c) Maity, S.; Zhu, M.; Shinabery, R. S.; Zheng, N. Angew. Chem., Int.
Ed. 2012, 51, 222. (d) Shaw, M. H.; Melikhova, E. Y.; Kloer, D. P.;
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(14) (a) Ito, T.; Overman, L. E.; Wang, J. J. Am. Chem. Soc. 2010,
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ACKNOWLEDGMENTS
■
Financial support was provided by Rutgers University. The
Bruker 500 MHz spectrometer used in this study was
supported by the NSF-MRI grant (CHE-1229030).
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