Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-Acylaziridines and Alkenes

Article abstract of DOI:10.1021/jacs.7b06723

We report Ti-catalyzed radical formal [3+2] cycloadditions of N-acylaziridines and alkenes. This method provides an efficient approach to the synthesis of pyrrolidines, structural units prevalent in bioactive compounds and organocatalysts, from readily available starting materials. The overall redox-neutral reaction was achieved via a redox-relay mechanism, which harnesses radical intermediates for selective C - N bond cleavage and formation.

Full text of DOI:10.1021/jacs.7b06723

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Communication
Radical Redox-Relay Catalysis: Formal [3+2]
Cycloaddition of N-Acylaziridines and Alkenes
Wei Hao, Xiangyu Wu, James Zhengmou Sun, Juno Castillo Siu, Samantha N. MacMillan, and Song Lin
J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b06723 • Publication Date (Web): 21 Aug 2017
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Radical Redox-Relay Catalysis: Formal [3+2] Cycloaddition of N-
Acylaziridines and Alkenes
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Wei Hao, Xiangyu Wu, James Z. Sun, Juno C. Siu, Samantha N. MacMillan, Song Lin*
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, United States
Supporting Information Placeholder
mations involving aziridines. Compared with their
closed-shell counterparts, radicals usually exhibit
exceptionally high reactivity and a distinct pattern of
selectivity.9 Owing to the enhanced stability of car-
bon radicals with higher degrees of substitution,
aziridine ring opening mediated by radical interme-
diates might display regioselectivity that differs from
that of conventional electrophilic or nucleophilic
activation. Therefore, a radical-mediated approach
will enable the preferential cleavage and subsequent
functionalization of the more substituted C–N bond
in the three-membered azacycle, thereby allowing
access to a broader array of N-containing molecules
with diverse structures starting from aziridines. In-
deed, recent advances have shown that Ni catalysts
enable aziridine-based cross-coupling reactions that
adopt a single-electron pathway favoring homolysis
and functionalization of the more sterically hindered
C–N bond.10 In these examples, however, suitable
substrates are primarily terminal and styrene-derived
aziridines. In this work, we report a redox-metal-
catalyzed radical [3+2] cycloaddition of N-
acylaziridines and alkenes that leads to substituted
pyrrolidines, structural motifs common in natural
products, synthetic therapeutics, and small-molecule
catalysts (Scheme 1C).
ABSTRACT: We report Ti-catalyzed radical formal
[3+2] cycloadditions of N-acylaziridines and alkenes.
This method provides an efficient approach to the
synthesis of pyrrolidines—structural units prevalent
in bioactive compounds and organocatalysts—from
readily available starting materials. The overall re-
dox-neutral reaction was achieved via a redox-relay
mechanism, which harnesses radical intermediates
for selective C–N bond cleavage and formation.
Owing to the presence of nitrogen-containing mo-
tifs in the vast majority of medicinally relevant syn-
thetic targets, the development of efficient, selective,
and sustainable technologies for constructing these
organic structures is of critical importance. The ring
opening of aziridines represents an attractive ap-
proach for the synthesis of novel nitrogenous mole-
cules. The tendency of these strained heterocycles to
rupture at two distinct reactive sites offers unique
opportunities for the efficiently introduction of new
functionalities.1 Classical methods and recent devel-
opments in alkene aziridination have rendered these
synthetic intermediates readily available from simple
and abundant feedstocks.2 Current strategies for
ring-opening functionalization of aziridines rely
primarily on closed-shell, two-electron mechanisms
mediated by acid, base, or transition metal catalysts
(Scheme 1A & 1B).2 These protocols are restricted
primarily to nucleophilic addition,3 insertion of un-
saturated molecules,4,5 isomerization,6 and cross-
coupling, however.7 Furthermore, the regioselectivity
of these reactions usually favors cleavage and func-
tionalization of the less substituted C–N bond.8 As
such, the N-containing structures accessible using
existing approaches are limited.
Scheme 1. Ring opening of aziridines: two-
electron versus radical redox-relay approach
Radical-mediated chemistry offers a unique plat-
form on which to expand the scope of transfor-
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R2
O
N
A. Existing approach: acid and/or base catalysis
R4
O
R3
R1
1
2
3
4
5
6
7
8
A
R2
R1
PG
A and/or B
(cat.)
N
PG
Mn+
PG
HN
N
N
R3
I
V
Nu
R
R
Nu
H
B
R
NuH
–
Nu = halide, Co(CO)4
N3–, CN–, etc.
,
(PG = protecting
group)
oxidative
ring closure
A = acid, B = base
M(n+1)+
PG
O
Mn+
PG
N
R1
R2
A (cat.)
R1
N
R4
O
N
N
R3
R3
Ar
N
Ar
alkene/yne
A = Lewis acid
Ar
R2
R1
R2
PG
IV
M———I
R2 R1
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B. Existing approach: transition-metal catalysis
M(n+1)+
O
PG
E
PG
PG
reductive
ring opening
PG
N
M
N
E
HN
M (cat.)
N
R3
N
or
R2
E
R
R
R4
R
R
E
II
R1
M = transition
III
E = aryl, alkyl, CO, alkene,
heterocumulene, etc.
metal
We drew inspiration from recent research demon-
strating that redox-active transition metals such as
TiIII complexes enable facile cleavage of strong N–H
bonds in carbamates.12,13 Density functional theory
calculations suggested that an analogous approach
would also be feasible in facilitating the homolysis of
the aziridine C–N bond, as its ab initio bond dissoci-
ation free energy (BDFE) decreases substantially
when bound to TiCl3 via the acyl O atom (ΔBDFE =
22.4 kcal/mol). Our scheme involved pyrrolidine
formation via the addition of a carbon radical to an
azaenolate (IV to V), a reaction step with no litera-
ture precedent. However, structurally analogous Ti-
enolates have been shown excellent radical acceptors
in C–C bond-forming transformations14,15. These
seminal advances served as the foundation for our
proposed redox-metal-catalyzed aziridine [3+2] cy-
cloaddition.
C. This work: radical redox-relay catalysis
R5
R1
R2
O
R1
O
R3
R3
R4
M (cat.)
N
O
N
R2
R1
N
R2
M
R3
R4
R5
We envisioned that the overall redox-neutral cy-
cloaddition of aziridines and alkenes could be
achieved in a tandem redox-relay sequence consist-
ing of single-electron reduction, radical addition,
and radical oxidation (Scheme 2). Specifically, a re-
dox-active metal complex could induce homolytic
cleavage of the more substituted C–N bond through
coordination to N-acylaziridine I and subsequent
spin transfer from the metal center to the organic
substrate. This process would yield a carbon radical
tethered to an azaenolate (II). Addition of the radical
intermediate to an alkene (III) would then result in
the formation of a new C–C bond. The incipient rad-
ical adduct IV would subsequently undergo cycliza-
tion to furnish a new C–N bond (V) and thus com-
plete the [3+2] cycloaddition. In this step, the metal
complex would be reduced and released from the
pyrrolidine product to regenerate the active catalyst.
This proposed strategy was reminiscent of atom-
transfer radical reactions in which a carbon–halogen
bond is homolyzed and the resultant radical equiva-
lents are added across an alkene C=C π-bond.11 In this
proposed redox-relay catalytic cycle, reductive aziri-
dine ring opening and oxidative ring closure are the
key steps that would likely determine the efficiency
of the radical chain process.
We first explored the ring opening of N-benzoyl-
2,2-dimethylaziridine (1) and its addition to t-butyl
acrylate (2) to construct 3,3-dimethylproline (3). A
series of redox-active complexes with oxophilic early
transition metal centers were surveyed, and lead re-
sults were obtained with Ti catalysts bearing cyclo-
pentadienyl ligands. Multiple iterations of optimiza-
tion resulted in a highly efficient reaction system
comprising Cp*TiCl3 (5 mol%) as the catalyst precur-
sor and Zn dust (10 mol%) as the reductant to gener-
ate the active TiIII species. In toluene at ambient
temperature, 3 was formed in 94% NMR yield with
complete regioselectivity with respect to both aziri-
dine ring opening and alkene addition (Table 1, entry
1).16
Scheme 2. Proposed catalytic cycle
Table 1. Ti-catalyzed [3+2] cycloaddition under vari-
ous reaction conditions
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(Scheme 3). A number of 2,2-disubstituted N-
1
2
3
4
5
6
7
8
acylaziridines were converted to the corresponding
prolines in good to excellent yield. Monosubstituted
N-acylaziridines were unreactive under identical
conditions, likely as a result of the substantially lower
stability of the corresponding secondary radical in-
termediates. Various alkenes proved suitable sub-
strates. In particular, acrylates with functionalities
that are reductively labile, such as alkyl chloride, or
strongly basic, such as tertiary amine, participated
smoothly in the cycloaddition (11 and 12). Notably,
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21
methyl
methacrylate
and
α-methylene-γ-
butyrolactone were also viable substrates, forming
two tetrasubstituted carbons in a single step in high
yields (13 and 14). Various other electron-deficient
alkenes, including N,N-dimethylacrylamide, acrylo-
nitrile, and phenyl vinyl sulfone, were transformed to
the corresponding product readily under the stand-
ard conditions (15–17). Styrenes also proved excellent
radical acceptors for the [3+2] cycloaddition, and the
reaction efficiency showed minimal sensitivity to the
electronic properties of the alkene (18–22). α-
Methylstyrene was converted to 2-methyl-2-
phenylpyrrolidine derivative 23 in high efficiency.
Finally, when an acrylamino acid was subjected to
the reaction, a dipeptide with an unnatural proline
residue was formed (24).
When less electron-rich CpTiCl3 (Ered = –0.82 V vs
Fc+/Fc) was used instead of Cp*TiCl3 (Ered = –1.10 V)
under identical conditions, the desired product was
isolated in markedly lower yield with the remaining
starting material largely intact (entry 2). This result
indicates that reductive ring opening may be in-
volved in the rate-limiting process. Titanocene17,18
and TiCl4 were inactive in the reaction, however (en-
tries 3 and 4). When Zn was removed from the reac-
tion, no cycloaddition was observed; instead, the
starting material 1 was fully converted to allylic am-
ide 4, presumably via Lewis acid activation by TiIV
(entry 5). The role of ZnCl2—a byproduct generated
from catalyst reduction—in the cycloaddition reac-
tion was excluded because Mn dust also furnished
the desired product in good yield (entry 6), and
without Ti, neither Zn dust nor ZnCl2 alone could
effect the formation of 3 (entry 7). The reaction re-
quires relatively non-coordinating solvents, such as
aromatic and chlorinated hydrocarbons (entry 8);
THF and MeCN completely suppressed the reactivity
(entry 9). The loading of alkene 2a can be reduced to
1.0 equiv with respect to 1a without decreasing the
yield of the reaction (entry 10). Finally, the corre-
sponding N-tosyl aziridine (5) did not furnish any
desired pyrrolidine product (entry 11), and the start-
ing material was fully recovered. This result is con-
sistent with the proposed spin relay mechanism of
aziridine C–N activation (see Scheme 2), as the lack
of conjugation precludes valence tautomerization in
5. Finally, the intermediacy of 4 on the catalytic cycle
was ruled out, as no proline 3 was detected when 4
was used as the starting material instead of 1.
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Preliminary mechanistic data supported the for-
mation of radical intermediates during the reaction.
Both dimethyl maleate [(Z)-25] and dimethyl
fumarate [(E)-25] were converted to trans-26 in near-
ly complete diastereoselectivity (Scheme 4A), which
is consistent with a stepwise cycloaddition process.
Moreover, competition experiments suggested that
the rate of reaction was positively correlated with the
electron-deficiency of the alkene (Scheme 4B). This
result also agreed with the proposed radical pathway,
as the tertiary carbon radical resulting from homo-
lytic ring opening of aziridine is highly nucleophilic.
We thus ruled out the possibility of Lewis acid acti-
vation of the aziridine to form a carbocation inter-
mediate followed by 1,2-dipolar cycloaddition. An
alternative mechanism of the cyclization step (IV to
V) involves electron transfer from the carbon-
centered radical to the TiIII-azaenolate to form the
corresponding carbon cation and TiIV-azaenolate
followed by polar addition. This scenario is, however,
unlikely to be operating on thermodynamic grounds
given the unmatched potential of two redox pairs.19
Finally, we conducted spin trapping experiments20
with 5,5-Dimethyl-1-pyrroline N-oxide (DMPO) and
observed persistent nitroxide radical 30 by ESR and
MS (Scheme 4C).
We then investigated the substrate scope of the
radical [3+2] cycloaddition under optimal conditions
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Scheme 3. Substrate scopea
overall redox-neutral reaction was achieved using a
1
2
3
4
5
6
redox-relay strategy, harnessing radical intermedi-
ates for selective C–N cleavage and formation. We
anticipate that this new strategy will be widely appli-
cable for overcoming other synthetic challenges in-
volving overall redox-neutral reactions.
7
8
ASSOCIATED CONTENT
9
Supporting Information. Experimental procedures
and characterization data. Crystallographic data were
deposited in the CCDC (compound 9: CCDC1555909;
compound 17: CCDC1555908; and compound 19:
CCDC1555907). Supporting information is available free
of charge on the ACS Publications website.
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AUTHOR INFORMATION
Corresponding Author
*songlin@cornell.edu
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support was provided by Cornell University
and the Atkinson Center for a Sustainable Future. This
study made use of the Cornell Center for Materials Re-
search Shared Facilities supported from NSF MRSEC
(DMR-1120296), NMR facility supported by the NSF
(CHE-1531632), and ESR facility supported by the
NIGMS (P41GM103521). We thank Jason Chari and
Keith Carpenter for experimental assistance, Dr. Ivan
Keresztes for help with NMR spectral analysis, Dr. Boris
Dzikovski for assistance with ESR data acquisition and
analysis.
Scheme 4. Mechanistic experiments in support
of the intermediacy of radical species
A. Stereochemical infidelity of the [3+2] cycloaddition
Bz
Ph
N
O
standard conditions
CO2Me
CO2Me
CO2Me
Me
Me
N
+
Me
Me
MeO2C
1
E- or Z-25 (1.2 equiv)
26, from Z-25: 36%, dr > 19:1
from E-25: 34%, dr > 19:1
B. Competition experiments using alkenes with different electronic properties
O
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+
Ph
OtBu
Bz
Bz
N
N
2 (1.2 equiv) 27 (1.2 equiv)
CO2tBu
Ph
+
Me
Me
Me
Me
standard conditions
3:18 = 4:1 (5% combined yield)
3
18
1
Bz
Bz
standard conditions
19:20 = 3:1 (30% combined yield)
N
N
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Ar1 = 4-Cl-C6H4 Ar2 = 4-MeO-C6H4
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NHBz
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1 + 27
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standard conditions
O
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In summary, we developed a Ti-catalyzed radical
formal [3+2] cycloaddition of N-acylaziridines with
alkenes in high yield and with complete regioselec-
tivity. This method offers an efficient approach to the
synthesis of pyrrolidines—structural motifs fre-
quently observed in bioactive natural products, syn-
thetic pharmaceuticals, and molecular catalysts. The
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137, 5638−5641. (c) Woods, B. P.; Orlandi, M.; Huang, C.-Y. Sig-
man, M. S.; Doyle, A. G. J. Am. Chem. Soc. 2017, 139, 5688-5691.
11. Matyjaszewski, K. Curr. Org. Chem. 2002, 6, 67-82.
14. Beaumont, S.; Ilardi, E. A.; Monroe, L. R.; Zakarian, A. J.
Am. Chem. Soc. 2010, 132, 1482-1483.
15. For a review on radical chemistry of Ti-enolates, see: Cież,
D; Pałasz, A.; Trzewik, B. Eur. J. Org. Chem. 2016, 1476-1493.
16. The majority of the pyrrolidine products exist as two slowly
interconverting stereoisomers with respect to the amide bond
geometry.
17. Titanocene and its analogues have been shown to promote
reductive coupling reactions involving epoxides, carbonyls,
imines, and nitriles: (a) Nugent, W. A.; RajanBabu, T. V. J. Am.
Chem. Soc. 1988, 110, 8561-8562. (b) RajanBabu, T. V.; Nugent, W.
A. J. Am. Chem. Soc. 1989, 111, 4525-4527. (c) Kablaoui, N. M.;
Buchwald, S. L. J. Am. Chem. Soc. 1995, 117, 6785-6786. (d)
Crowe, W. E.; Rachita, M. J. J. Am. Chem. Soc. 1995, 117, 6787-
6788. (e) Gansäuer, A.; Pierobon, M.; Bluhm, H. Angew. Chem.
Int. Ed. 1998, 37, 101-103. (f) Gansäuer, A.; Fleckhaus, A.; Lafont,
M. A.; Okkel, A.; Kotsis, K.; Anoop, A.; Neese, F. J. Am. Chem.
Soc. 2009, 131, 16989-16999. (g) Streuff, J.; Feurer, M.; Bichovski,
P.; Frey, G.; Gellrich, U. Angew. Chem., Int. Ed. 2012, 51,
8661−8664. (h) Gansäuer, A.; Kube, C.; Daasbjerg, K.; Sure, R.;
Grimme, S.; Fianu, G. D.; Sadasivam, D. V.; Flowers, R. A., II. J.
Am. Chem. Soc. 2014, 136, 1663-1671. (i) Morcillo, S. P.; Miguel, D.;
Resa, S.; Martín-Lasanta, A.; Millán, A.; Choquesillo-Lazarte, D.;
García-Ruiz, J. M.; Mota, A. J.; Justicia, J.; Cuerva, J. M. J. Am.
Chem. Soc. 2014, 136, 6943-6951. (j) Zhao Y.; Weix, D. J. J. Am.
Chem. Soc. 2015, 137, 3237−3240. (k) Gansäuer, A.; Hildebrandt,
S.; Vogelsang, E.; Flowers, R. A. II Dalton Trans. 2016, 45, 448-
452. (l) Leijendekker, L. H.; Weweler, J.; Leuther, T. M.; Streuff,
J. Angew. Chem. Int. Ed. 2017, 56, 6103-6106.
18. Substituted titanocene, Cp*2TiCl2, was also tested but re-
sults showed batch dependence. See supporting information.
19. Reduction of Cp*TiCl3: -1.1 V. Oxidation of a secondary
benzylic radical: 0 V; see: (a) Wayner, D. D. M.; McPhee, D. J.;
Griller, D. J. Am. Chem. Soc. 1988, 110, 132-137. Oxidation of an α-
carbonyl radical: ≥0.14 V; see: (b) Schmittel, M.; Lal, M.; Lal, R.;
Röck, M.; Langels, A.; Rappoport, Z.; Basheer, A.; Schlirf, J.;
Deiseroth, H.-J.; Flörke, U.; Gescheidt, G. Tetrahedron 2009, 65,
10842-10855.
12. Tarantino, K. T.; Miller, D. C.; Callon, T. A.; Knowles, R. R.
J. Am. Chem. Soc. 2015, 137, 6440-6443.
20. A variety of other spin trapping experiments were also car-
ried out. See SI.
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R2
R1
R5
O
catalytic TiIII
R4
R3
R4
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radical redox relay
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alkene
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