Synthetic and Computational Study of Tin-Free Reductive Tandem Cyclizations of Neutral Aminyl Radicals

Article abstract of DOI:10.1021/acs.orglett.8b02456

5-exo, 5-exo Cyclizations of conformationally unbiased propargylic aminyl radicals proceed with excellent yield, chemoselectivity, and diastereoselectivity under tin-free reductive cyclization conditions, regardless of the electronic environments and intermediate radical stabilization resulting from various olefin substituents. These conditions avoid the need for slow addition of initiator and reductant. By contrast, analogous 6-exo, 5-exo cyclizations require substituents capable of intermediate radical stabilization to avoid premature reduction products. These experimental results are corroborated by computations that further establish the reactivity of these aminyl radicals upon exposure to tin-free cyclization conditions.

Full text of DOI:10.1021/acs.orglett.8b02456

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthetic and Computational Study of Tin-Free Reductive Tandem
Cyclizations of Neutral Aminyl Radicals
Hansamali S. Sirinimal,‡ Sebastien P. Hebert,‡ Ganesh Samala, Heng Chen, Gregory J. Rosenhauer,
H. Bernhard Schlegel,* and Jennifer L. Stockdill*
Department of Chemistry, Wayne State University, Detroit, Michigan 48202, United States
S
* Supporting Information
ABSTRACT: 5-exo, 5-exo Cyclizations of conformationally
unbiased propargylic aminyl radicals proceed with excellent
yield, chemoselectivity, and diastereoselectivity under tin-free
reductive cyclization conditions, regardless of the electronic
environments and intermediate radical stabilization resulting
from various olefin substituents. These conditions avoid the
need for slow addition of initiator and reductant. By contrast,
analogous 6-exo, 5-exo cyclizations require substituents
capable of intermediate radical stabilization to avoid
premature reduction products. These experimental results
are corroborated by computations that further establish the reactivity of these aminyl radicals upon exposure to tin-free
cyclization conditions.
Scheme 1. Structural Features of Substrate for
Calyciphylline A Alkaloid Synthesis
ertiary amines are privileged structures in pharmaceutical
Tlead targets because they improve solubility and decrease
lipophilicity, while maintaining potency.1 Polycyclic molecules
bearing tertiary amines are of special interest because they
possess the rigid structural framework, high density of sp3
centers, and low molecular weight profile associated with
“drug-like” molecules.2 We were attracted to the potential
utility of neutral aminyl radicals to construct these frameworks
because radical cascades have well-established reactivity with
predictable bond construction outcomes. While amidyl,3
iminyl,4 and aminium5 radicals are more reactive and tend to
cyclize more efficiently6,7 than the more stable neutral aminyl
radicals,8,9 the latter are strategically appealing because their
cyclization reactions lead directly to aliphatic amine-containing
products.10 In this work, we demonstrate the utility of our
recently reported11 tin-free conditions for the cyclization of
neutral aminyl radicals. We obtained good yields of 5-exo-
initiated12 tandem cyclization products employing electroni-
cally differentiated olefins and demonstrated the electronic
dependence of 6-exo cyclizations of conformationally un-
biased13 substrates. Lastly, we computed the barrier heights
and thermodynamics of these cyclizations in the gas phase,
toluene, and tetrahydrofuran (THF).
Cl reduction products.14 Finally, our experiences indicated that
internal and terminal alkynes performed differently in
otherwise analogous tandem cyclizations. Because of the
unique features of this substrate relative to known cyclizations
of aminyl radicals, we sought to establish the utility of these
tin-free cyclization conditions, which also avoid slow
addition15 of initiator and H atom donor, in conformationally
unbiased systems.
We hypothesized that cascades beginning with cyclization of
the relatively nucleophilic16 aminyl radicals would have lower
barriers when cyclizing with electron-deficient olefins than with
nonactivated olefins.17 Findings that enones analogous to
substrate 1 cyclized efficiently while the corresponding allylic
alcohol14 led only to N−Cl reduction (R2N−Cl → R2N−H)
were consistent with our hypothesis but were insufficient to
provide insight into 5-exo and 6-exo cyclizations of conforma-
tionally unbiased substrates. Thus, we selected representative
unactivated and activated olefin substituents to investigate
We recently reported the development of tin-free conditions
to access the ABC core of the calyciphylline A alkaloids via
tandem cyclization of a neutral aminyl radical.11 In these
cyclizations, an existing six-membered ring (ring A) reduced
the conformational degrees of freedom in the substrate
(Scheme 1). The cyclization of N-chloroamine 1 is initiated
via 6-exo cyclization, which is a rare mode of reactivity for
aminyl radicals. An electron-deficient olefin was required in
these cyclizations as allylic alcohol derivatives led only to N−
Received: August 1, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b02456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
under these conditions. For convenience, we retained the
terminal alkyne in the second cyclization, thus minimizing
potential complications arising from the formation of multiple
diastereomers. We found that unactivated substrates 3a−3b18
afforded good to excellent yields of cyclized products 4a−4b
when treated with azobisisobutyronitrile (AIBN) and the weak
H-atom donor (iPr)3SiH at 100 °C in THF.14,19 Bicyclic amine
4b was formed as a single diastereomer. The relative
stereochemistry is consistent with previous stereochemical
studies of 5-exo, 5-exo tandem cyclizations.20 Enone substrate
3c also cyclized efficiently, and following thermal isomerization
of the exocyclic olefin, bicyclic amine 4c was isolated in 87%
yield. Cyclization of trans-3d led to a 69% yield of 4d with 95:5
dr (Scheme 2). The cis-isomer of the styrenyl substrate (cis-3d)
Table 1. Activation Barriers and Relative Energies of
Radical Intermediates in the 5-exo, 5-exo Pathway
a
int
5−8c
int
barrier 2 5−8d
b
c
R
solvent 5−8b barrier 1
H (5)
H
H
CH2OMe
(6)
(gas)
PhMe
THF
(gas)
0.0
0.5
0.9
2.3
13.2
13.9
14.2
11.8
−6.2
−4.2
−3.1
−6.3
12.4
11.6
10.8
6.5
−26.6
−24.5
−23.0
−26.4
Scheme 2. Tin-Free Cyclization of Unactivated and
Activated N-Chloro Propargylamines
CH2OMe
CH2OMe
COEt (7)
COEt
COEt
Ph (8)
Ph
PhMe
THF
(gas)
PhMe
THF
(gas)
PhMe
THF
2.4
3.1
−1.0
−0.3
0.8
−1.2
0.7
0.6
12.0
12.7
11.4
11.4
7.3
10.1
10.1
9.3
−5.8
−6.8
6.9
7.2
−24.8
−20.9
−25.6
−23.3
−21.5
−24.4
−21.7
−20.4
−12.6
−11.6
−10.4
−15.0
−17.5
−12.7
12.4
13.9
13.3
15.6
16.2
16.3
Ph
a
ωB97xD functional and Gibbs free energies were calculated at 100
b
°C. All values in kcal/mol. Barrier 1 is calculated from the
c
prearranged conformation (5−8b). All intermediate values are
relative to the energy of the fully elongated, staggered aminyl radical
(5−8a).
performed similarly to enone 3c with an isolated yield of 86%
and 91:9 dr. Isomerization of the exocyclic olefin was not
observed in either case, and the major product diastereomer
was trans for both cyclizations.21
15.4 to 26.9 kcal/mol depending on the substrate and solvent.
These data suggest that the first 5-exo cyclization event is likely
irreversible for most of these substrates. These results are
consistent with some7,27,28 previous experimental rate stud-
ies.29 For all evaluated substrates, the transformation of the N-
centered radical (5a−8a) to the vinylic radical (5d−8d) is
exothermic owing to the formation of two C−C bonds and a
fused bicyclic system.
As expected, barrier 1 tracks the stability of the intermediate
radicals 5c−8c. The barrier for the terminal olefin (5b) was
1.4−1.9 kcal/mol higher in energy than for methoxymethyl-
substituted 6b. The barrier for enone 7b was 1.8−2.5 kcal/mol
lower than for 5b in the gas phase or implicit toluene, while in
THF, the gap is larger than expected at 6.9 kcal/mol. The
barrier for styrenyl substrate 8b was 2.5−3.5 kcal/mol lower
than for 5b. While these energy differences follow the expected
trend, they are relatively small, and the high temperature for
cyclization is sufficient to enable cyclization even in the highest
barrier case (R = H). Interestingly, barrier 1 is higher in THF
than in toluene for 5b and 6b and lower for 7b and 8b. For
substrates capable of generating a stabilized C-centered radical
intermediate (i.e., 7c and 8c), the barrier height for the second
cyclization (barrier 2) is significantly larger than for radicals 5c
and 6c. α-Keto radical 7c is 7.3−7.4 kcal/mol more stabilized
than primary radical 5c in implicit THF and toluene solvent,
respectively. For styrenyl substrate 8c, these values increase to
9.6−13.3 kcal/mol, respectively.
Previously, we observed that cyclization of N-chloroenone 1
in THF with (iPr)3SiH as an H atom donor led to fewer
reduction products than did the same cyclization in toluene
with Bu3SnH.11 We presumed that the change in H atom
donor was the primary contributor to this reactivity; however,
both solvents can also donate hydrogen atoms. The calculated
energy barrier for intermolecular H atom transfer from the
solvent to radical 8a was 13.4 kcal/mol in implicit THF and
15.4 kcal/mol in implicit toluene (calculations were performed
using the Gaussian 09 software22 and the ωB97xD level of
theory and 6-31+G(d,p) basis set at 100 °C).23 The barrier to
hydrogen atom transfer from each reducing agent to radical 8a
was also calculated at 100 °C. For Et3SnH,24 the barrier is 4.8
kcal/mol in implicit THF and 5.0 kcal/mol in implicit toluene.
For (iPr)3SiH, the barrier is 13.7 kcal/mol in implicit THF and
14.4 kcal/mol in implicit toluene. Thus, the reduction products
observed in toluene/tin hydride conditions likely arise due to
H atom transfer from the stannane, not toluene. These labeling
experiments and computational data support our hypothesis
that a weaker H atom donor should favor tandem cyclization
products in preference to N−H bond formation.11
We next calculated the energetics of the cyclization pathway
from the aminyl radicals 5a−8a to vinylic radicals 5d−8d via
the Beckwith−Houk transition states of each substrate (Table
1).25,26 For 5-exo-initiated cyclizations, the initial cyclization
barriers (i.e., barrier 1 = ΔG⧧ for 5b−8b → 5c−8c) range
from 9.3 to 14.2 kcal/mol in implicit solvent, with the barrier
for 7b in THF as an apparent outlier. These data are consistent
with published computational results for aminyl radical
monocyclization.7a The reverse reaction barriers range from
On the basis of the computational results outlined above, we
hypothesized that 6-exo-initiated cyclizations would be more
sensitive to substitution changes because of the significantly
reduced reactivity of these substrates. We selected H and Ph
groups as representative electron-normal and electron-with-
drawing substituents. Attempted cyclization of N-hexenyl-N-
B
DOI: 10.1021/acs.orglett.8b02456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
propargyl chloroamine 9 with THF/(iPr)3SiH conditions led
to recovery of 77% reduced amine 11 (Scheme 3A). Bicycle 10
12.3 kcal/mol. It is thus expected to be competitive with
reduction, and a mixture of products (13 and 14) is observed.
As expected, the barrier 2 heights and overall thermodynamics
are similar to the 5,5-cyclization pathway. Overall, these
computational data suggest that the rate differences between
these 5-exo and 6-exo radical cyclizations are primarily derived
from entropic factors associated with substrate prearrangement
rather than an inherent decrease in reactivity for 6-exo
cyclization resulting from an issue with alignment of the
participating molecular orbitals.
Scheme 3. Sensitivity of 6-exo, 5-exo Initiated Cyclizations
to Olefin Electronics
We also investigated the applicability of these conditions to
the 5-exo, 6-exo substrate chloroamine 15 (Scheme 4). The
Scheme 4. Sensitivity of 6-exo, 5-exo Initiated Cyclizations
to Olefin Electronics
was not observed in the crude NMR. For the styrenyl analogue
of this substrate (12), cyclization product 13 was isolated in
40% yield after an acetic anhydride workup, which was
required to facilitate isolation of 14 (44% yield, Scheme 3B).
Presumably, formation of the reduced products (pre-11, pre-
14) in these cases occurs via both intramolecular and
intermolecular H-atom transfer. This is particularly true in
the styrenyl system where the allylic radical is highly
stabilized.20a
The computational analysis for these two cyclizations is
consistent with the drop in both overall reactivity for 6-exo
cyclizations and in the relative success of the two substrates
(Table 2). Interestingly, once the substrate (9a and 12a)
desired product was formed in 39% yield and 77:23 dr. The
lower dr here presumably arises from competitive rotation of
the Ph group to the pseudoequatorial position in the transition
state. Interestingly, despite the initial formation of a 5-
membered ring, significant amounts of reduction product
(isolated as the acetate, 17) were observed (35% yield). The
dependence of the formation of reduced amine on the size of
the second ring suggests reversibility in the first cyclization.
Meanwhile, our computational results from Table 1 support
irreversible cyclization of the N-centered radical with a reverse
barrier of ∼23 kcal/mol for 8c → 8b. The retention of
stereochemistry in reduction product 17 suggests that
intermolecular H-atom transfer to the aminyl radical is faster
than 5-exo cyclization in this substrate. By contrast, no
reduction is observed in any of our 5-exo, 5-exo tandem
cyclizations. Combining previous rate studies with these new
computational and experimental data, one can conclude that
the reversibility of neutral aminyl cyclizations is dependent on
the intermediate radical stability, the reaction conditions, and
the effects of impurities27 in the reaction.
In summary, kinetically favorable 5-exo, 5-exo cyclizations of
propargyl-appended aminyl radicals proceed efficiently in tin-
free conditions employing a weak H atom donor in THF,
regardless of the electronic nature of the substitution on the
olefin. Importantly, these conditions avoid kinetic tricks such
as slow addition of the radical initiator and reducing agent. By
contrast, a radical stabilizing group is essential to facilitate
cyclization in 6-exo, 5-exo cyclizations of propargylic aminyl
radicals. These results are supported by computational data.
Finally, application to a 5-exo, 6-exo cyclization reveals a
dependence on the size of the second ring in determining the
ratio of cyclization to reduction. Overall, the weak H atom
donating ability of (iPr)3SiH and THF results in an unusual, if
apparently synergistic, solvent/H atom donor combination
that is effective for a range of tandem cyclizations. We
anticipate that these experimental and computational data will
be useful for future synthetic design using neutral aminyl
radicals. Further investigation into the factors influencing
reversibility is ongoing in our laboratories.
Table 2. Activation Barriers and Relative Energies of
a
Radical Intermediates in the 6-exo, 5-exo Pathway
9b,
12b
int 9c,
c
int 9d,
c
b
R
solvent
barrier 1
12c
barrier 2
12d
H (9)
H
H
Ph (12) (gas)
Ph
(gas)
PhMe
THF
3.1
2.1
2.6
1.0
2.9
4.0
10.5
12.3
12.7
8.4
8.1
8.3
−8.3
−7.1
−5.8
−17.4
−16.2
−14.0
8.9
8.7
8.6
12.9
13.8
13.3
−29.2
−28.3
−26.8
−28.3
−25.2
−23.2
PhMe
THF
Ph
a
ωB97xD functional and Gibbs free energies were calculated at 100
b
°C. All values in kcal/mol. Barrier 1 is calculated from the
prearranged conformation (9b, 12b). All intermediate values are
c
relative to the energy of the fully elongated, staggered aminyl radical
(9a, 12a).
adopts the appropriate conformation for cyclization (9b and
12b), the barrier 1 values for 6-exo cyclization are not
significantly different from the 5-exo substrates. However, the
energy required to adopt these precyclization conformations is
significant. In THF, combining the uphill conformational
change with the activation barrier gives an overall transition
state energy (ΔG⧧) of 15.3 kcal/mol. Thus, it is unsurprising
that the reduction pathway, which had a barrier of 13.4 kcal/
mol for H atom transfer from THF to 8a, outcompetes the
cyclization. However, for the styrenyl substrate, the ΔG⧧ is
C
DOI: 10.1021/acs.orglett.8b02456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(6) (a) Le Tadic-Biadatti, M.-H. L.; Callier-Dublanchet, A.-C.;
Horner, J. H.; Quiclet-Sire, B.; Zard, S. Z.; Newcomb, M. Absolute
Rate Constants for Iminyl Radical Reactions. J. Org. Chem. 1997, 62,
559−563. (b) Horner, J. H.; Musa, O. M.; Bouvier, A.; Newcomb, M.
Absolute Kinetics of Amidyl Radical Reactions. J. Am. Chem. Soc.
1998, 120, 7738−7748. (c) Horner, J. H.; Martinez, F. N.; Musa, O.
M.; Newcomb, M.; Shahin, H. E. Kinetics of Dialkylaminium Cation
Radical Reactions: Radical Clocks, Solvent Effects, Acidity Constants,
and Rate Constants for Reactions with Hydrogen Atom Donors. J.
Am. Chem. Soc. 1995, 117, 11124−11133. (d) Musa, O. M.; Horner,
J. H.; Shahin, H.; Newcomb, M. A Kinetic Scale for Dialkylaminyl
Radical Reactions. J. Am. Chem. Soc. 1996, 118, 3862−3868.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b02456.
■
S
Experimental procedures and spectroscopic data (PDF)
Computational methodology and Cartesian coordinates
(PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(7) (a) Maxwel, B. J.; Tsanaktsidis, J. Cyclization of N-Butyl-4-
pentenylaminyl: Implications for the Cyclization of Alkenylaminyl
Radicals. J. Am. Chem. Soc. 1996, 118, 4276−4283. (b) Maxwell, B. J.;
Smith, B. J.; Tsanaktsidis, J. The Cyclization of N-Butylpent-4-
enylaminyl Revisited: A Combined Theoretical and Experimental
Study. J. Chem. Soc.; Perkin Trans. 2000, 2, 425−431.
*E-mail: stockdill@wayne.edu (J. L. Stockdill).
*E-mail: hbs@chem.wayne.edu (H. B. Schlegel).
ORCID
H. Bernhard Schlegel: 0000-0001-7114-2821
Jennifer L. Stockdill: 0000-0003-4238-6530
Author Contributions
‡H.S.S. and S.P.H. contributed equally.
Notes
̌
̌
(8) (a) Hioe, J.; Sakic, D.; Vrcek, V.; Zipse, H. The Stability of
Nitrogen-Centered Radicals. Org. Biomol. Chem. 2015, 13, 157−169.
(b) Stella, L. Homolytic Cyclizations of N-Chloroalkenylamines.
Angew. Chem., Int. Ed. Engl. 1983, 22, 337−350. (c) Boate, D.;
Fontaine, C.; Guittet, E.; Stella, L. Synthese Du Systeme Cyclique De
L’Aza-Triquinane Lineaire Par Trois Cyclisations Radicalaires En
Cascade. Tetrahedron 1993, 49, 8397−8406.
The authors declare no competing financial interest.
(9) (a) Quiclet-Sire, B.; Zard, S. Z. Some aspects of radical cascade
and relay reactions. Proc. R. Soc. London, Ser. A 2017, 473, 20160859.
(b) Chen, J.-R.; Hu, X.-Q.; Lu, L.-Q.; Xiao, W.-J. Visible light
photoredox-controlled reactions of N-radicals and radical ions. Chem.
Soc. Rev. 2016, 45, 2044−2056. (c) Zard, S. Z. Recent Progress in the
Generation and Use of Nitrogen-Centered Radicals. Chem. Soc. Rev.
2008, 37, 1603−1618.
(10) White, L. V.; Schwartz, B. D.; Banwell, M. G.; Willis, A. C. A. A
Chemoenzymatic Total Synthesis of (+)-Clividine. J. Org. Chem.
2011, 76, 6250−6257.
(11) Lopez, A. M.; Ibrahim, A. I.; Rosenhauer, G. J.; Sirinimal, H. S.;
Stockdill, J. L. Tin-Free Access to the ABC Core of the Calyciphylline
A Alkaloids and Unexpected Formation of a D-Ring-Contracted
Tetracyclic Core. Org. Lett. 2018, 20, 2216−2219.
(12) Baldwin, J. E. Rules of Ring Closure. J. Chem. Soc., Chem.
Commun. 1976, 734−736.
ACKNOWLEDGMENTS
■
The authors thank the National Institutes of Health (R00-
GM097095 for 5,5-cyclizations with R = H, R = Ph), the
National Science Foundation (CAREER Award to JLS: CHE-
1554752 for all remaining experiments, Grant to BHS: CHE-
1464450), and Wayne State University for generous financial
support (startup funds to JLS, Rumble-Schaap Fellowship to
HSS, and use of the computational grid). We thank Materia,
Inc. for the kind donation of all metathesis catalysts used in the
substrate syntheses. We are grateful to the staff of the WSU
Lumigen Instrument Center, especially Nicholas Peraino, for
spectroscopic support, and we thank Dr. Ahmad A. Ibrahim
(WSU) for helpful discussions.
(13) Beesley, R. M.; Ingold, C. K.; Thorpe, J. F. The Formation and
Stability of spiro-Compounds. Part I. Spiro-Compounds from
Cyclohexane. J. Chem. Soc., Trans. 1915, 107, 1080−1106.
(14) Ibrahim, A. A.; Golonka, A. N.; Lopez, A. M.; Stockdill, J. L.
Rapid Access to the Heterocyclic Core of the Calyciphylline A and
Daphnicyclidin A-Type Daphniphyllum Alkaloids via Tandem
Cyclization of a Neutral Aminyl Radical. Org. Lett. 2014, 16, 1072−
1075.
(15) Jasperse, C. P.; Curran, D. P.; Fevig, T. L. Radical Reactions In
Natural Product Synthesis. Chem. Rev. 1991, 91, 1237−1286.
(16) Kim, S.; Yoon, K. S.; et al. Kinetics of Intramolecular Additions
of the Aminyl Radicals to Carbonyl Groups and Subsequent Ring
Openings. Tetrahedron 1995, 51, 8437−8446.
(17) Roberts, B. P. Polarity-reversal catalysis of hydrogen-atom
abstraction reactions: concepts and applications in organic chemistry.
Chem. Soc. Rev. 1999, 28, 25−35.
(18) See the Supporting Information for experimental details and
substrate synthesis.
(19) The cyclization of 3a was performed on a 1.1 mmol scale,
resulting in 81% yield of 4a. See the Supporting Information for
details.
(20) (a) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Synthesis of
pyrrolizidines using aminyl radicals generated from sulfenamide
precursors. Tetrahedron 1994, 50, 1295−1310. (b) Hasegawa, H.;
Senboku, H.; Kajizuka, Y.; Orito, K.; Tokuda, M. Stereoselective
synthesis of 2-methylenepyrrolizidines by tandem cyclization of N-
propargylaminyl radicals. Tetrahedron 2003, 59, 827−832. (c) Tsuchi-
da, S.; Kaneshige, A.; Ogata, T.; Baba, H.; Yamamoto, Y.; Tomioka, K.
REFERENCES
■
(1) Ghose, A. K.; Viswanadhan, V. N.; Wendoloski, J. J. A
Knowledge-Based Approach in Designing Combinatorial or Medicinal
Chemistry Libraries for Drug Discovery. 1. A Qualitative and
Quantitative Characterization of Known Drug Databases. J. Comb.
Chem. 1999, 1, 55−68.
(2) Newman, D. J.; Cragg, G. M.; Snader, K. M. Natural Products as
Sources of New Drugs over the Period 1981−2002. J. Nat. Prod.
2003, 66, 1022−1037.
(3) (a) Sharp, L.; Zard, S. Z. A Short Total Synthesis of ( )
Aspidospermidine. Org. Lett. 2006, 8, 831−834. (b) Callier-
Dublanchet, A.-C.; Cassayre, J.; Gagosz, F.; Quiclet-Sire, B.; Sharp,
L. A.; Zard, S. Z. Amidyls in Radical Cascades. The Total Synthesis of
( )-Aspidospermidine and ( )-13-Deoxyserratine. Tetrahedron
2008, 64, 4803−4816. (c) Biechy, A.; Hachisu, S.; Quiclet-Sire, B.;
Ricard, L.; Zard, S. Z. The Total Synthesis of ( )-Fortucine and a
Revision of the Structure of Kirkine. Angew. Chem., Int. Ed. 2008, 47,
1436−1438.
(4) Bowman, W. R.; Cloonan, M. O.; Fletcher, A. J.; Stein, T.
Synthesis of Heteroarenes Using Cascade Radical Cyclization via
Iminyl Radicals. Org. Biomol. Chem. 2005, 3, 1460−1467.
(5) (a) Newcomb, M.; Marquardt, D. J.; Deeb, T. M. N-
Hydroxypyridine-2-thione Carbamates. V. Syntheses of Alkaloid
Skeletons by Aminium Cation Radical Cyclizations. Tetrahedron
1990, 46, 2329−2344. (b) Cosgrove, S. C.; Plane, J. M. C.; Marsden,
S. P. Radical-mediated direct C−H amination of arenes with
secondary amines. Chem. Sci. 2018, 9, 6647−6652.
D
DOI: 10.1021/acs.orglett.8b02456
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Consecutive Cyclization of Allylaminoalkene by Intramolecular
Aminolithiation− Carbolithiation. Org. Lett. 2008, 10, 3635−3638.
(21) Hasegawa, H.; Senboku, H.; Kajizuka, Y.; Orita, K.; Tokuda, M.
Stereoselective synthesis of 2-methylenepyrrolizidines by tandem
cyclization of N-propargylaminyl radicals. Tetrahedron 2003, 59, 827−
832.
(22) Frisch, M. J.; Trucks, G. W.; Schlegel, H. B.; Scuseria, G. E.;
Robb, M. A.; Cheeseman, J. R.; Scalmani, G.; Barone, V.; Petersson,
G. A.; Nakatsuji, H.; Caricato, M.; Li, X.; Hratchian, H. P.; Izmaylov,
A. F.; Bloino, J.; Zheng, G.; Sonnenberg, J. L.; Hada, M.; Ehara, M.;
Toyota, K.; Fukuda, R.; Hasegawa, J.; Ishida, M.; Nakajima, T.;
Honda, Y.; Kitao, O.; Nakai, H.; Vreven, T.; Montgomery, J. A.;
Peralta, J. E., Jr.; Ogliaro, F.; Bearpark, M.; Heyd, J. J.; Brothers, E.;
Kudin, K. N.; Staroverov, V. N.; Kobayashi, R.; Normand, J.;
Raghavachari, K.; Rendell, A.; Burant, J. C.; Iyengar, S. S.; Tomasi, J.;
Cossi, M.; Rega, N.; Millam, J. M.; Klene, M.; Knox, J. E.; Cross, J. B.;
Bakken, V.; Adamo, C.; Jaramillo, J.; Gomperts, R.; Stratmann, R. E.;
Yazyev, O.; Austin, A. J.; Cammi, R.; Pomelli, C.; Ochterski, J. W.;
Martin, R. L.; Morokuma, K.; Zakrzewski, V. G.; Voth, G. A.;
Salvador, P.; Dannenberg, J. J.; Dapprich, S.; Daniels, A. D.; Farkas,
̈
O.; Foresman, J. B.; Ortiz, J. V.; Cioslowski, J.; Fox, D. J. Gaussian 09,
Revision E.01; Gaussian, Inc.: Wallingford, CT, 2016.
(23) See the Supporting Information for computational details.
(24) Ethyl is employed to expedite the computation.
(25) (a) Gilmore, K.; Igor, V. A. Cyclizations of alkynes: revisiting
Baldwin’s rules for ring closure. Chem. Rev. 2011, 111, 6513−6556.
(b) Beckwith, A. L. J.; Easton, C. J.; Serelis, A. K. Some guidelines for
radical reactions. J. Chem. Soc., Chem. Commun. 1980, 11, 482−483.
(c) Julia, M. Free radical cyclizations. Pure Appl. Chem. 1967, 15,
167−184. (d) Baldwin, J. E. Rules for ring closure. J. Chem. Soc.,
Chem. Commun. 1976, 18, 734−736. (e) Beckwith, A. L. J.; Lawrence,
T.; Serelis, A. K. Stereoselectivity of ring closure of substituted hex-5-
enyl radicals. J. Chem. Soc., Chem. Commun. 1980, 11, 484−485.
(f) Beckwith, A. L. J.; Schiesser, C. H. Regio-and stereo-selectivity of
alkenyl radical ring closure: A theoretical study. Tetrahedron 1985, 41,
3925−3941. (g) Spellmeyer, D. C.; Houk, K. N. Force-field model for
intramolecular radical additions. J. Org. Chem. 1987, 52, 959−974.
(26) Clark, A. J.; Filik, R. P.; Thomas, G. H.; Sherringham, J. Anti-
Beckwith stereoselectivity in amidyl radical cyclisations: Bu3SnH-
mediated 5-exo-trig acyl mode cyclisation of 2-substituted pent-4-
enamide radicals. Tetrahedron Lett. 2013, 54, 4094−4097.
(27) Maxwell, B. J.; Tsanaktsidis, J. Influence of bis(tributyltin)
Oxide on Aminyl Radical Cyclizations. J. Chem. Soc., Chem. Commun.
1994, 533−534.
(28) (a) Musa, O. M.; Horner, J. H.; Shahin, H.; Newcomb, M. A
Kinetic Scale for Dialkylaminyl Radical Reactions. J. Am. Chem. Soc.
1996, 118, 3862−3868. (b) Newcomb, M.; Musa, O. M.; Martinez, F.
N.; Horner, J. H. Kinetics of 5-exo Cyclizations of N-Alkyl-4-
pentenaminyl Radicals and β-Fragmentations of β-(Dialkylamino)-
alkyl Radicals. J. Am. Chem. Soc. 1997, 119, 4569−4577. (c) New-
comb, M.; Horner, J. H.; Shahin, H. Rate Constants for Aminyl
Radical Reactions. Tetrahedron Lett. 1993, 34, 5523−5526.
(29) Bowman, W. R.; Clark, D. N.; Marmon, R. J. Generation of
Aminyl Radicals using Sulfenamides as Synthetic Precursors.
Tetrahedron 1994, 50, 1275−1294.
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DOI: 10.1021/acs.orglett.8b02456
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