Amide and amine nucleophiles in polar radical crossover cycloadditions: Synthesis of γ-lactams and pyrrolidines

Article abstract of DOI:10.1021/acs.orglett.5b00316

In this work we present a direct catalytic synthesis of γ-lactams and pyrrolidines from alkenes and activated unsaturated amides or protected unsaturated amines, respectively. Using a mesityl acridinium single electron photooxidant and a thiophenol cocata

Full text of DOI:10.1021/acs.orglett.5b00316

Letter
pubs.acs.org/OrgLett
Amide and Amine Nucleophiles in Polar Radical Crossover
Cycloadditions: Synthesis of γ‑Lactams and Pyrrolidines
Nathan J. Gesmundo, Jean-Marc M. Grandjean, and David A. Nicewicz*
Department of Chemistry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290, United States
S
* Supporting Information
ABSTRACT: In this work we present a direct catalytic synthesis of γ-
lactams and pyrrolidines from alkenes and activated unsaturated amides or
protected unsaturated amines, respectively. Using a mesityl acridinium
single electron photooxidant and a thiophenol cocatalyst under irradiation,
we are able to directly forge these important classes of heterocycles with
complete regiocontrol.
eterocyclic γ-lactam and pyrrolidine motifs represent a
significant portion of chemical space present in natural
H
products, physiologically active synthetic entities, and cata-
lysts.1−7 Due to the ubiquity and importance of these structures,
particularly as pharmacophores, methods that enable the
generation of these heterocycles utilizing novel disconnections
have been a significant area of study. Many groups have
developed unique approaches to these structures that compli-
ment traditional γ-lactam/pyrrolidine forming strategies. Intra-
molecular strategies such as Rh-catalyzed C−H insertion,8 Pd-
catalyzed alkene functionalization,9,10 and halolactamiza-
tion11−16 have been developed for γ-lactam synthesis. In
addition, intermolecular strategies such as allylsilane annula-
tion,17 nitro-Mannich/lactamization cascades,18−20 N-hetero-
cyclic carbene-catalyzed imine/enal annulations,21 and tandem
Michael addition/elimination sequences have been explored.22,23
Regarding pyrrolidine synthesis, intramolecular strategies such as
alkene hydroamination24−34 and halocyclization35 have been
extensively studied and intermolecular approaches such as a
Michael addition/reductive cyclization36 and polar/radical redox
processes have been reported.37,38
Figure 1. Prior photoredox polar radical cyclization work and proposed
N-heterocycle synthesis.
labile protecting groups (Boc, trifluoroacetyl), or nucleophiles
lacking protecting groups, lead to decomposition or no reaction.
A catalyst system comprised of the mesityl acridinium photo-
oxidant (1a) and 4-methoxythiophenol as a H-atom donor was
employed to probe the effect of sulfonyl electronics (Ms, Ts, Ns,
Tf) on conversion and product distribution. In all cases, only
trace uncyclized products were observed. More electron-
deficient protecting groups resulted in higher conversion and
greater selectivity for γ-lactam formation, with N-Tf substrate 3d
producing the lactam 4a in a 58% yield and an N/O ratio of 5.8:1.
To confirm the product assignments and stereochemistry, the
lactam and imidate adducts were isolated and subjected to
epimerization/deprotection experiments (Figure 2B). We
presumed that the 3,4-trans/4,5-trans diastereomer would be
the most stable;44 therefore, DBU-catalyzed epimerization of a
3,4-cis/4,5-trans adduct would result in diastereomer inversion
while a 3,4-trans/4,5-trans adduct would be enriched. Subjecting
Our laboratory has developed a program focused on novel
redox-neutral transformations employing a dual catalyst system
comprised of an organic single electron photooxidant and a
redox-active H-atom donor to access the unique reactivity of
olefin cation radicals. We have demonstrated methods for anti-
Markovnikov olefin hydrofunctionalization39,32,40−42 as well as
O-containing heterocycle synthesis by polar radical crossover
cycloadditions (PRCC, Figure 1).43,44 Herein, we disclose our
efforts toward the direct synthesis of γ-lactam and pyrrolidine
heterocycles from alkenes and activated unsaturated N-
nucleophiles using an acridinium organic photoredox catalyst
(1) and redox active H atom donor cocatalyst.
We began our investigation into γ-lactam synthesis using β-
methylstyrene (2a) as the alkene partner and N-activated
cinnamamide nucleophiles (Figure 2A). A major hurdle for
this method was steering reactivity toward N-addition (lactam
formation, 4) over O-addition (imidate formation, 5), also a
challenge for halolactamization strategies.14,35 Sulfonyl-pro-
tected amides produced generally clean reactions, while more
Received: January 30, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00316
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Organic Letters
Letter
electron-deficient aryl thiols such as methyl thiosalicylate (entry
3) or thiophenol (entry 4) resulted in diminished yields relative
to 4-methoxythiophenol (entry 5).45 More electron-rich H-atom
donors such as 2,4-dimethoxythiophenol (entry 6) did not
increase reaction efficiency. We were however pleased to see that
H-atom donor loading could be lowered from 30 to 20 mol %
with no deleterious effect (entry 7). More polar solvents such as
acetone (entry 8) or acetonitrile (entry 9) resulted in diminished
or reversed lactam/imidate selectivity. A modest increase in yield
and, more importantly, crude reaction purity was observed with
CHCl3 relative to CH2Cl2 (entry 10). Control experiments
demonstrated the importance of each reaction component:
without base, light, H-atom donor, or 1b, little or none of 4a was
formed (entries 11−14).
We propose a mechanism analogous to the lactone-forming
PRCC (Scheme 1).44 Excitation of acridinium catalyst 1b
Scheme 1. Proposed Mechanism
Figure 2. Activating group optimization, product identification.
the major product 4a to DBU-catalyzed epimerization resulted in
diastereomeric inversion producing 4a′ in 10:1 dr. Subjecting
epimerized adduct 4a′ to TiCl3/Li0 deprotection revealed γ-
lactam 6, confirming the major product of the cyclization as the
desired 3,4-cis/4,5-trans lactam. Likewise, subjecting the minor
cyclization product, the presumed 3,4-cis/4,5-trans imidate 5a, to
DBU-catalyzed epimerization/hydrolysis in DMF/H2O pro-
duced 3,4-trans/4,5-trans lactone 7.
Continuing the optimization with β-methylstyrene and 3d, we
observed an increase in the yield of 4a by using N-Ph catalyst 1b
in place of N-Me catalyst 1a (Table 1, entries 1−2). A screen of
various thiophenols as H-atom donor cocatalysts revealed that
Table 1. Lactam Reaction Optimization
generates excited state species 1b* which oxidizes the alkene,
generating a cation radical and the reduced acridine radical.
Nucleophilic attack by the unsaturated amide nucleophile and
deprotonation produce C-centered radical A, which readily
undergoes 5-exo-trig cyclization to form exocyclic radical B. The
lactam product is formed by H-atom transfer from 4-(MeO)-
C6H4SH (BDE = 77 kcal/mol),46 and electron transfer between
the acridine radical and thiyl radical C reoxidizes the acridinium
catalyst.47,48 Protonation of the thiolate (pKa = 11.2 in DMSO)46
regenerates the H-atom donor. An alternative mechanism is also
ox
plausible, whereby the N-sulfonyl amide nucleophile (Ep/2
=
+1.88 V vs SCE) is deprotonated and oxidized to the amidyl
radical, in analogy to recent work by Moeller.49 This might allow
alkenes outside the range of the acridinium photooxidant to be
used; yet, 1,1-disubstituted/terminal aliphatic alkenes of higher
oxidation potential than 1b* were not competent reaction
partners.
With the ideal reaction parameters identified, we set out to
investigate the scope of the transformation with respect to the
unsaturated amide (Scheme 2). Model system product 4a was
produced in 64% isolated yield and 5.2:1 N/O ratio favoring the
lactam. Cinnamamide nucleophiles with varying aromatic
substitution afforded the expected lactams (4b, 4c) in similar
yields to 4a. We were pleased to find that β-aryl substitution is
not required for radical cyclization as β,β-dialkyl unsaturated
amides formed the anticipated cycloadducts (4d and 4e) in
a
Reactions run in N2-sparged solvents at 0.2 mmol scale under 2 ×
b
455 nm LED lamps for 22 h. Yield relative to (Me3Si)2O NMR
c
internal standard of crude reaction mixture. 2,6-Lutidine omitted.
d
Light excluded.
B
DOI: 10.1021/acs.orglett.5b00316
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Organic Letters
Letter
a
a
Scheme 2. Lactam Formation: Amide Scope
Scheme 3. Lactam Formation: Alkene Scope
a
Reactions were run in N2-sparged solvents on a 0.5 mmol scale under
2 × 455 nm LED lamps for 24 h. Yields represent average of two
1
isolated yields at 0.5 mmol scale. N/O ratio determined by H NMR
b
relative to (Me3Si)2O internal standard. Imidate characterization
provided in the Supporting Information for comparison.
higher yields (70% and 74%), dr (4.9:1 and 5.8:1), and N/O
ratios (9.2:1 and >20:1). Monosubstituted β-alkyl unsaturated
amides were also successful in this context, as N-Tf β-
isopropylacrylamide 3i afforded lactam 4f in 52% yield and
nearly complete regioselectivity (N/O > 20:1), albeit with no
diastereocontrol. Formation of an α-quaternary center was
possible using N-Tf α-methylcinnamamide 3j as the nucleophile
to give 4g in 59% yield and modest diastereoselectivity. We also
were successful in employing N-Tf propiolamide nucleophiles to
furnish lactams bearing substituted exocyclic olefins in high
yields (4h and 4i). Interestingly, alkene formation is Z-selective
for the Si-iPr3-substituted propiolamide, presumably due to rapid
equilibration of the fleeting vinyl radical species which partitions
the bulky silyl group away from the adjacent phenyl substituent.
Using nucleophile 3d, we examined the oxidizable alkene
scope of the transformation (Scheme 3). Both electron-deficient
(4j, 4k) and -rich (4l−4o) lactams could be readily accessed from
the corresponding β-methylstyrene derivatives in useful chemical
yields and with modest relative stereocontrol. Lactams 4m−4o
demonstrate that steric effects on the styrene derivatives do not
have a great impact on reaction efficiency. Furthermore, we
found that initial olefin geometry was inconsequential with
regards to product relative stereochemistry.50 Indene also
participated in the title reaction, producing fused tricyclic species
4p in 60% yield and 10:1 dr. The lactam derived from α-
methylstyrene was isolated in lower yields but still produced the
desired lactam 4q with a β-quaternary stereocenter in a 7:1 dr.
The reaction displayed a reasonable tolerance to functional
groups, as a TBS ether (4r), free alcohol (4s), ester (4t), and
phthalamide (4u) in the starting styrenes were all retained under
these reaction conditions. Though markedly less reactive,
trisubstituted alkenes did provide modest amounts of the
a
Reactions were run in N2-sparged solvents on a 0.5 mmol scale under
2 × 455 nm LED lamps for 24 h. Yields represent average of two
isolated yields at 0.5 mmol scale. N/O ratio determined by H NMR
relative to (Me3Si)2O internal standard. 3 equiv of anethole to 1
equiv of 3d. 2 equiv of alkene to 1 equiv of 3d. Isolation at 0.25
1
b
c
d
e
mmol scale. 1 equiv of diene to 1 equiv of 3d.
expected lactams 4v and 4w (35% and 37% yields, respectively).
Lastly, while noticeably less efficient, diene substrate 2,4-
dimethyl-1,3-pentadiene produced lactam 4x in 35% yield
(6.8:1 dr) as the exclusive regioisomer, retaining a trisubstituted
alkene in the final adduct.
Finally, we sought to employ this method to directly access
pyrrolidine heterocycles (Scheme 4). Using cinnamyl amine as a
a
Scheme 4. Pyrrolidine Formation: Scope
a
Reactions were run in N2-sparged solvents on a 0.5 mmol scale under
2 × 455 nm LED lamps for 24 h. Yields shown represent average of
two isolated yields after Boc removal/deprotection.
C
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Organic Letters
Letter
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found that the Boc protecting group offered the best balance
between reactivity and product purity/separation compared to
N-Ts and N-Tf alternatives. Phenyldisulfide, which partitions to
thiophenol during the course of the reaction,51 was the optimum
H-atom donor for the system and yields were highest when
excess alkene was employed. A brief examination of the reaction
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TFA deprotection of the initial crude mixture of Boc-protected
adducts. Efforts are underway to expand the scope of this
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synthesis.
In summary, we have developed mild, efficient synthetic
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a photoredox-mediated approach from simple oxidizable alkenes
and unsaturated nucleophiles. The reactions displayed good
functional group compatibility, and deprotection of the initial
adducts to the parent heterocycles was demonstrated. We believe
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medicinal chemistry and natural product synthesis.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures and spectroscopic data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
■
(35) Combettes, L. E.; Schuler, M.; Patel, R.; Bonillo, B.; Odell, B.;
Thompson, A. L.; Claridge, T. D. W.; Gouverneur, V. Chem.Eur. J.
2012, 18, 13126.
(36) Corbett, M. T.; Xu, Q.; Johnson, J. S. Org. Lett. 2014, 16, 2362.
(37) Jui, N. T.; Garber, J. A. O.; Finelli, F. G.; MacMillan, D. W. C. J.
Am. Chem. Soc. 2012, 134, 11400.
*E-mail: nicewicz@unc.edu.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This research was supported by an NSF-CAREER grant (CHE-
1352490) and the Packard Foundation.
(38) Kafka, F.; Holan, M.; Hidasova,
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