Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer and Radical-Polar Crossover

Article abstract of DOI:10.1021/acscatal.0c05359

Cyclic guanidines are found in many biologically active compounds and natural products. Further, the formation of the atypical seven-membered ring of cyclic guanidine remains challenging because of a lack of efficient preparation strategies and low yield. Herein, a catalytic synthetic method for cyclic guanidines was developed via transition-metal hydrogen atom transfer and radical-polar crossover. This mild and functional-group-tolerant process enabled the cyclization of alkenyl guanidines bearing common protective groups, such as Cbz and Boc groups. This powerful method provided not only typical five- and six-membered rings but also the atypical seven-membered ring. The derivatization of the products afforded various heterocycles. We also investigated the selective cyclization of monoprotected or heteroprotected (TFA and Boc) alkenyl guanidines and their further derivatizations.

Full text of DOI:10.1021/acscatal.0c05359

pubs.acs.org/acscatalysis
Letter
Catalytic Synthesis of Cyclic Guanidines via Hydrogen Atom Transfer
and Radical-Polar Crossover
Shunya Ohuchi, Hiroki Koyama, and Hiroki Shigehisa*
Cite This: ACS Catal. 2021, 11, 900−906
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: Cyclic guanidines are found in many biologically active
compounds and natural products. Further, the formation of the
atypical seven-membered ring of cyclic guanidine remains challenging
because of a lack of efficient preparation strategies and low yield.
Herein, a catalytic synthetic method for cyclic guanidines was
developed via transition-metal hydrogen atom transfer and radical-
polar crossover. This mild and functional-group-tolerant process
enabled the cyclization of alkenyl guanidines bearing common
protective groups, such as Cbz and Boc groups. This powerful
method provided not only typical five- and six-membered rings but
also the atypical seven-membered ring. The derivatization of the products afforded various heterocycles. We also investigated the
selective cyclization of monoprotected or heteroprotected (TFA and Boc) alkenyl guanidines and their further derivatizations.
KEYWORDS: hydrogen atom transfer, radical-polar crossover, cyclic guanidine, heterocycles, cobalt catalysis
transition-metal hydrogen atom transfer (TM-HAT) and
uanidine is an inherently effective basic motif. For
Ginstance, arginine contains the guanidine motif and radical-polar crossover (RPC).
contributes to the expression of biological functions.1 More-
over, its cyclic form is present in potent bioactive compounds
and natural products,2 such as saxitoxin3 (blocker of voltage-
gated sodium channels) and teixobactin4 (an antibiotic for
resistant bacteria) (Scheme 1). Because of these chemical and
medicinal properties of cyclic guanidines, the development of a
useful method for their synthesis has been of long-standing
interest in organic synthesis.2,5 There are various methods for
synthesizing cyclic guanidines, such as intramolecular displace-
ment,6 halocyclization,7 and others.8 Metal-catalyzed processes
were developed, including alkene hydroamination (Ag),9
alkene carboamination (Pd),10 alkene diamination (Pd),11
alkyne hydroamination (Ag, Rh),12 alkyne carboamination
(Pd),13 C−H amination (Rh),14 cyclization via (π-allyl)
palladium intermediate,15 and carbenylative amination
(Pd).16 Both traditional and metal-catalyzed methods have
been used in the synthesis of complex natural products.17
Despite numerous examples of cyclic guanidine formation, the
atypical and more challenging seven-membered ring, which is
an undeveloped chemical space, has not been prepared
efficiently. It is also noteworthy that potent drug candidates
containing seven-membered ring have been reported in recent
years.18 Dodd and co-workers reported two examples of seven-
membered ring guanidines synthesized via halocyclization;
however, to the best of our knowledge, there is significant
potential to improve the yields (23% and 21%).7e Herein, we
demonstrate a powerful, catalytic, Markovnikov-selective, and
scalable hydroamination that affords cyclic guanidines via the
Recently, TM-HAT catalytic systems have been used by
many groups to facilitate various transformations of alkenes
with excellent functional group tolerance.19 We have
previously reported the unique effect of N-fluorocollidinium
salt on the TM-HAT system that enables the ionic process via
the RPC mechanism, which led to further transformations
developed by us20 and other groups.21 Encouraged by these
reports, we envisioned that an alkenyl guanidine bearing a
common and easily removable protective groups (carbox-
ybenzyl (Cbz) and or tert-butoxycarbonyl (Boc)) could be
cyclized via the TM-HAT and RPC approach. The use of these
common protective groups was not successful for hydro-
aminations nor similar transformations with different cata-
lysis.9,10,11c Moreover, we assumed that the high reactivity
based on the TM-HAT/RPC mechanism could efficiently form
an unusual ring size of cyclic guanidines.
We initially chose to examine the five-membered ring
formation of alkenyl guanidine 1a bearing two Cbz groups and
obtained the desired cyclic guanidine 2a in 88% yield using
previously developed reaction conditions: cobalt catalyst C1,
N-fluoro-2,4,6-collidinium trifluoromethanesulfonate
Received: December 7, 2020
Revised: December 29, 2020
Published: January 5, 2021
https://dx.doi.org/10.1021/acscatal.0c05359
© 2021 American Chemical Society
ACS Catal. 2021, 11, 900−906
900

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
†
Scheme 1. (a) Representative Examples of Natural Products
bearing Cyclic Guanidine, (b) Representative Methods
Affording Cyclic Guanidine, and (c) This Work: Synthesis
of Cyclic Guanidine by the TM-HAT and RPC Concept
Scheme 2. Optimization of Reaction Condition
†
Conditions: alkenyl guanidine (0.1 mmol), catalyst (0.003 mmol),
Me3NFPY·X (0.2 mmol), silane (0.2 mmol), CH3Ph (1.0 mL), room
a
temperature, 20 h. NMR yield using 1,4-bis(trifluoromethyl)benzene
b
c
as the internal standard. isolation yield 2.30 mmol scale
Scheme 3. Scope of Alkenyl Guanidines Affording Five-
a
Membered Ring Products
(Me3NFPY·OTf), and 1,1,3,3-tetramethyldisiloxane (Scheme
2, entry 1). When phenylsilane was used, the yield of 2a
decreased because of the formation of cyclic urea 3a (entry 2).
Screening of various cobalt complexes (C1−C3) revealed that
the four tert-butyl groups were essential for acceptable
conversion (entries 1, 3, 4). We found that the previously
developed complex C4 provided slightly better conversion
than that of C1 (entry 5). Replacing the counteranion of
Me3NFPY salt with tetrafluoroborate (BF4) or hexafluoro-
phosphate (PF6) did not improve the efficiency of the reaction
(entries 6 and 7). Moreover, 841 mg (2.30 mmol) of 2a could
be synthesized from 1.02 g of 1a (82%).
a
Conditions: alkenyl guanidine (0.1 mmol), catalyst (0.003 mmol),
N-fluorocollidinium trifluoromethanesulfonate (0.2 mmol), 1,1,3,3-
tetramethyldisiloxane (0.2 mmol), CH3Ph (1.0 mL), room temper-
ature, 20 h; isolation yield
bearing the electron-withdrawing chloro (1b) or electron-
donating methoxy (1c) in the p-position of the aniline unit
gave 2b and 2c in good yields, respectively. The gem-
dimethylated product 2d was also synthesized from the
disubstituted alkenyl guanidine 1d in 80% yield together
With the optimal conditions, we next briefly examined the
scope of the substituted alkenyl guanidine forming five-
membered ring products (2b−2g) (Scheme 3). The substrates
901
https://dx.doi.org/10.1021/acscatal.0c05359
ACS Catal. 2021, 11, 900−906

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
a
Scheme 4. Scope of Alkenyl Guanidines Affording Six- and Seven-Membered Ring Products
a
Conditions: alkenyl guanidine (0.1 mmol), C4 (0.003 mmol), N-fluorocollidinium trifluoromethanesulfonate (0.2 mmol), 1,1,3,3-
b
c
tetramethyldisiloxane (0.2 mmol), CH3Ph (1.0 mL), room temperature, 20 h; isolation yield 3.00 mmol scale Nine mol % of C4 was used.
d
4.13 mmol scale
Scheme 5. Cyclization of Trisubstituted Alkenyl Guanidines
Scheme 6. Cyclization of Alkenyl Guanidines Bearing Boc
group
a
a
Conditions: alkenyl guanidine (0.5 mmol), catalyst (0.015 mmol),
N-fluorocollidinium trifluoromethanesulfonate (1.0 mmol), 1,1,3,3-
tetramethyldisiloxane (1.0 mmol), CH3Ph (5.0 mL), room temper-
ature, 20 h; isolation yield
possible under the same reaction conditions (2h and 2i)
(Scheme 4). The yields of 2h using C4 and C1 were identical,
but C4 proved to be advantageous for producing 2i. Although
this method was ineffective for the formation of eight-
membered guanidine 2j, we focused on the preparation of
various seven-membered guanidines.
We next examined the electronic and steric effects using
substrates with aniline units bearing electron-donating or
electron-withdrawing groups in different positions on the
with a hydroxylated compound (9%, see Supporting
Information). The yields were also excellent for these
substrates, including methylamine (1e), benzylamine (1f),
and phenethylamine (1g).
Encouraged by these results, we next applied the same
concept to form rings other than those with five members. We
discovered that six- and seven-membered ring formations were
902
https://dx.doi.org/10.1021/acscatal.0c05359
ACS Catal. 2021, 11, 900−906

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
a
Scheme 7. Derivatization of Cyclic Guanidines
Scheme 8. Selective Cyclization of Mono-protected or
Hetero-protected (TFA (Trifluoroacetyl) and Boc) Alkenyl
a
Guanidine and Further Derivatizations
a
Conditions: (A) Pd/C, H2, MeOH, rt, 1 h. (B) oxalyl chloride (2.0
equiv), NEt3 (5.0 equiv), CH2Cl2 (0.03 M), rt, 12 h. (C)
dimethylmalonyl dichloride (2.0 equiv), NEt3 (5.0 equiv), CH2Cl2
(0.03 M), rt, 12 h. (D) 1,2-benzenedisulfonyl dichloride (2.0 equiv),
NEt3 (5.0 equiv), CH2Cl2 (0.03 M), rt, 12 h.
aniline ring. We found no significant differences when using
substrates 1k−1n that gave the corresponding 4-methoxy (2k),
3-methoxy (2l), 2-methoxy (2m), and 4-chloro (2n) products.
Again, replacing the aniline unit with an aliphatic amine such
as methylamine, benzylamine, and phenethylamine, resulted in
comparable yields (2o−2q). The products bearing more
hindered amine such as cyclohexylamine (2r), cyclopentyl-
amine (2s), and tert-butylamine (2v), were prepared in 72−
90% yields. Strained carbocycles such as the cyclobutyl (2t)
and cyclopropylmethyl groups (2u) were tolerated in this
reaction condition. Moreover, we could prepare benzocyclic
guanidines (2w − 2y) in 73−90% yields using the same
method. We reinvestigated the scalability of this reaction using
1.42 g (3.00 mmol) of 1i and obtained 2i in 90% isolation
yield. This scale-up experiment enabled the isolation and
structural determination of a small amount of byproduct 2i′
(6%), probably produced via the 1,2-H shift of the alkylCo(IV)
intermediate. We also prepared 1.80 g of benzocyclic 2y in
90% yield, together with a small amount of complex byproduct
mixtures, from 2.00 g (4.13 mmol) of 1y.
We also examined cyclizations using trisubstituted alkenyl
guanidines (Scheme 5). Although the formation of the six-
membered cyclic guanidine 5a was possible, the yield was less
than moderate due to a side reaction (hydroarylation)
affording 5b, which had also been reported by our group.20d
The use of C1 did not improve the yield of 5a (14%). A seven-
membered cyclic guanidine 7a was also obtained; however, the
byproducts 7b and 7c were also formed in small amounts.22
Replacing the two Cbz groups of 1a with the Boc groups,
another common protective group, resulted in a 90% yield of
a
Conditions: (a) C4, Me3NFPY·OTf, (Me2SiH)2O, CH3Ph, rt, 20 h.
(b) HCO2H, Ac2O, NEt3, CH2Cl2, rt 3 h. (c) N-Boc-N’-TFA-
pyrazole-1-carboxamidine, THF, rt, 3 h. (d) NaH, 3-bromo-2-
methylpropene, DMF, rt, 1 h. (e) trifluoroacetic acid, CH2Cl2, rt 3 h.
the five-membered cyclic guanidine 9a (Scheme 6). The
products containing methylamine 9e and benzylamine 9f were
also synthesized in good yields. It should be noted that 9e
could not be synthesized by the previously reported hydro-
amination method.9 A seven-membered cyclic guanidine 9i
was obtained in 75% yield together with the alkene-isomerized
byproduct and six-membered cyclic guanidine similar to 2i′.
Moreover, the product 9p bearing a benzylamine unit was
obtained in comparable yield.
In order to demonstrate the synthetic potential of the cyclic
guanidines prepared by this method, five-membered cyclic
guanidine 2a was subjected to deprotection and diversification
(Scheme 7). The conventional palladium-catalyzed hydro-
genation of 2a produced free cyclic guanidine 10 almost
quantitatively, which was further transformed into bicyclic
guanidines 11a and 11b and tricyclic guanidine 11c in
moderate yields. We also derivatized seven-membered
guanidine 2y in the same manner to produce tricyclic
guanidines 13a and 13b and tetracyclic 13c in moderate yields.
For comparison, we performed cobalt catalysis with mono-
Ts guanidine 14, which had been successfully used in
hydroamination reactions (Scheme 8). To our surprise, we
found that the product selectivity was clearly complementary.
It was reported that 15 was selectively obtained under Wolfe’s
903
https://dx.doi.org/10.1021/acscatal.0c05359
ACS Catal. 2021, 11, 900−906

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
conditions, whereas we observed a high-polar compound
(assumed as 16INT), which could not be purified by silica gel
chromatography.9 The formylation of this crude mixture
enabled the isolation and structural determination as 16.
Thus, this result indicates that our reactive nitrogen atom of
the guanidine moiety is different than that of Wolfe’s.
ACKNOWLEDGMENTS
■
This work was supported by JSPS KAKENHI Grant number
17K15426, the Takeda Science Foundation, and the research
foundation for pharmaceutical sciences. We thank Prof. Kou
Hiroya (Musashino University) for our liberal research
environment.
Toward further examination of the scope of guanidine, we
prepared alkenyl guanidines 18 and 22 by Baran’s method.17h
The cyclization of Boc-TFA (trifluoroacetyl) guanidine 18,
followed by treatment with potassium carbonate (to remove
remaining TFA group), selectively produced 19 in 64% yield.
This yield was not improved using C1 instead of C4. The
alkylation of cyclic guanidine 19 and its Boc deprotection
affording 21 were both possible by conventional methods. On
the other hand, the cyclization of mono-Boc guanidine 22
yielded a high-polar compound (assumed as 23INT). This
structure was clearly elucidated by the formylation to be 23.
Unfortunately, the yield of Boc-guanidine 23 was much lower
than that of Ts-guanidine 16. This cyclization/formylation
sequence also afforded 25 in 61% yield, although the
cyclization of the corresponding Boc-TFA guanidine resulted
in a complex product mixture.
In summary, we developed a catalytic, Markovnikov-
selective, scalable method for synthesizing cyclic guanidines
using a TM-HAT/RPC approach. We efficiently constructed
five-, six-, and seven-membered cyclic guanidines bearing
common and easily removable Cbz or Boc under mild
conditions. This unique and powerful method enabled the
expansion of the chemical space of atypical seven-membered
cyclic guanidines. Further diversifications of the products
through cobalt catalysis led to various heterocycles. The
investigations using alkenyl guanidines bearing the mono-Boc
or Boc-TFA protective groups revealed the selective product
formation and expansion of accessible cyclic guanidines by
further transformations. We are currently investigating
enantioselective variants using a chiral cobalt catalyst.
REFERENCES
■
(1) (a) Adina-Zada, A.; Sereeruk, C.; Jitrapakdee, S.; Zeczycki, T.
N.; St. Maurice, M.; Cleland, W. W.; Wallace, J. C.; Attwood, P. V.
Roles of Arg427 and Arg472 in the Binding and Allosteric Effects of
Acetyl CoA in Pyruvate Carboxylase. Biochemistry 2012, 51, 8208−
8217. (b) Derbel, N.; Clarot, I.; Mourer, M.; Regnouf-de-Vains, J. B.;
Ruiz-Lopez, M. F. Intramolecular Interactions Versus Hydration
Effects on p-guanidinoethyl-phenol Structure and pKa Values. J. Phys.
Chem. A 2012, 116, 9404−9411. (c) Chen, X.; Guo, Y.; Jia, G.; Zhao,
H.; Liu, G.; Huang, Z. Arginine Promotes Slow Myosin Heavy Chain
Expression via Akirin2 and the AMP-Activated Protein Kinase
Signaling Pathway in Porcine Skeletal Muscle Satellite Cells. J.
Agric. Food Chem. 2018, 66, 4734−4740. (d) Brezina, K.; Duboue-
Dijon, E.; Palivec, V.; Jiracek, J.; Krizek, T.; Viola, C. M.; Ganderton,
T. R.; Brzozowski, A. M.; Jungwirth, P. Can Arginine Inhibit Insulin
Aggregation? A Combined Protein Crystallography, Capillary Electro-
phoresis, and Molecular Simulation Study. J. Phys. Chem. B 2018, 122,
10069−10076.
(2) Berlinck, R. G. S.; Bertonha, A. F.; Takaki, M.; Rodriguez, J. P.
G. The Chemistry and Biology of Guanidine Natural Products. Nat.
Prod. Rep. 2017, 34, 1264−1301.
(3) Thottumkara, A. P.; Parsons, W. H.; Du Bois, J. Saxitoxin. Angew.
Chem., Int. Ed. 2014, 53, 5760−5784.
(4) Ling, L. L.; Schneider, T.; Peoples, A. J.; Spoering, A. L.; Engels,
̈
I.; Conlon, B. P.; Mueller, A.; Schaberle, T. F.; Hughes, D. E.; Epstein,
S.; Jones, M.; Lazarides, L.; Steadman, V. A.; Cohen, D. R.; Felix, C.
R.; Fetterman, K. A.; Millett, W. P.; Nitti, A. G.; Zullo, A. M.; Chen,
C.; Lewis, K. A New Antibiotic Kills Pathogens Without Detectable
Resistance. Nature 2015, 517, 455−459.
(5) (a) Zhang, W.-X.; Xu, L.; Xi, Z. Recent Development of
Synthetic Preparation Methods for Guanidines via Transition Metal
́
Catalysis. Chem. Commun. 2015, 51, 254−265. (b) Lemrova, B.;
Soural, M. Synthetic Strategies for Preparing Bicyclic Guanidines. Eur.
J. Org. Chem. 2015, 2015, 1869−1886.
ASSOCIATED CONTENT
■
sı
* Supporting Information
(6) (a) Kim, H.-O.; Mathew, F.; Ogbu, C. A Convenient Synthesis
of Disubstituted Guanidines via the Mitsunobu Protocol. Synlett
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acscatal.0c05359.
̀
1999, 1999, 193−194. (b) Saniere, L.; Leman, L. c.; Bourguignon, J.-
J.; Dauban, P.; Dodd, R. H. Iminoiodane Mediated Aziridination of α-
allylglycine: Access to a Novel Rigid Arginine Derivative and to the
Natural Amino Acid Enduracididine. Tetrahedron 2004, 60, 5889−
5897. (c) Benohoud, M.; Leman, L.; Cardoso, S. H.; Retailleau, P.;
Dauban, P.; Thierry, J.; Dodd, R. H. Total Synthesis and Absolute
Configuration of the Natural Amino Acid Tetrahydrolathyrine. J. Org.
Chem. 2009, 74, 5331−5336. (d) O’Donovan, D. H.; Rozas, I. New
Methods for the Preparation of Aryl 2-iminoimidazolidines.
Tetrahedron Lett. 2012, 53, 4532−4535. (e) Buck, M. L.; Evans, D.
M.; Evans, V. A.; Herkt, D.; Sharp, H.; Hollinshead, J.; Mitschang, F.;
Murphy, P. J.; Nash, R. J.; Wenbourne, J. A Synthesis of
Tiruchanduramine and a Reinvestigation of Its Glycosidase Inhibitory
Activity. Tetrahedron 2017, 73, 4545−4548. (f) Imaoka, T.; Iwata, M.;
Nagasawa, K. Synthesis of a Quaternary N,N′-Aminal-Containing A-E
Ring System of Palau′amine via an Enamide-Type Overman
Rearrangement Reaction. Eur. J. Org. Chem. 2018, 2018, 2572−2578.
(7) (a) Watanabe, M.; Okada, H.; Teshima, T.; Noguchi, M.;
Kakehi, A. A facile and Regio- and Stereo-selective Preparation of
Bicyclic Guanidines by Iodocyclization of 3-(alk-2-enyl)-2-(substi-
tuted amino)-1-imidazolin-4-ones. Tetrahedron 1996, 52, 2827−2838.
(b) Chern, J. W.; Tao, P. L.; Wang, K. C.; Gutcait, A.; Liu, S. W.; Yen,
M. H.; Chien, S. L.; Rong, J. K. Studies on Quinazolines and 1,2,4-
benzothiadiazine 1,1-dioxides. 8.1, 2 synthesis and Pharmacological
Evaluation of Tricyclic Fused Quinazolines and 1,2,4-benzothiadia-
Experimental procedures and analytical data for all new
1
compounds, H and 13C NMR (PDF)
AUTHOR INFORMATION
■
Corresponding Author
Hiroki Shigehisa − Faculty of Pharmacy, Musashino
University, Nishitokyo-shi, Tokyo 202-8585, Japan;
orcid.org/0000-0003-3034-1159; Email: cgehisa@
musashino-u.ac.jp
Authors
Shunya Ohuchi − Faculty of Pharmacy, Musashino University,
Nishitokyo-shi, Tokyo 202-8585, Japan
Hiroki Koyama − Faculty of Pharmacy, Musashino University,
Nishitokyo-shi, Tokyo 202-8585, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acscatal.0c05359
Notes
The authors declare no competing financial interest.
904
https://dx.doi.org/10.1021/acscatal.0c05359
ACS Catal. 2021, 11, 900−906

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
zine 1,1-dioxides as Potential a1-adrenoceptor Antagonists. J. Med.
Chem. 1998, 41, 3128−3141. (c) Hirota, S.; Kato, R.; Suzuki, M.;
Soneta, Y.; Otani, T.; Saito, T. Synthesis of Diazaheterocyclic Ring-
Fused 1,2,4-Benzothiadiazine 1,1-Dioxides by a Sequential Aza-
Wittig/NH-Addition Cyclization/Nucleophilic Ring-Closure Meth-
odology with N-Alkenyl-2-carbodiimidobenzenesulfonamides as Key
Intermediates. Eur. J. Org. Chem. 2008, 2008, 2075−2083. (d) Al
Shuhaib, Z.; Davies, D. H.; Dennis, M.; Evans, D. M.; Fletcher, M. D.;
4494−4496. (b) Butler, D. C.; Inman, G. A.; Alper, H. Room
Temperature Ring-opening Cyclization Reactions of 2-vinylaziridines
with Isocyanates, Carbodiimides, and Isothiocyanates Catalyzed by. J.
Org. Chem. 2000, 65, 5887−5890.
(16) Kitamura, M.; Yuasa, R.; Van Vranken, D. L. Synthesis of the
Cyclic Prenylguanidine Nitensidine E Using a Palladium-catalyzed
Carbenylative Amination. Tetrahedron Lett. 2015, 56, 3027−3031.
(17) (a) Mulcahy, J. V.; Du Bois, J. A Stereoselective Synthesis of
(+)-gonyautoxin 3. J. Am. Chem. Soc. 2008, 130, 12630−12631.
(b) Su, S.; Rodriguez, R. A.; Baran, P. S. Scalable, Stereocontrolled
Total Syntheses of ( )-axinellamines A and B. J. Am. Chem. Soc.
2011, 133, 13922−13925. (c) Perl, N. R.; Ide, N. D.; Prajapati, S.;
Perfect, H. H.; Duron, S. G.; Gin, D. Y. Annulation of Thioimidates
and Vinyl Carbodiimides to Prepare 2-aminopyrimidines, Competent
Nucleophiles for Intramolecular Alkyne Hydroamination. Synthesis of
(−)-crambidine. J. Am. Chem. Soc. 2010, 132, 1802−1803.
(d) Bhonde, V. R.; Looper, R. E. A Stereocontrolled Synthesis of
(+)-Saxitoxin. J. Am. Chem. Soc. 2011, 133, 20172−20174.
(e) Gibbons, J. B.; Gligorich, K. M.; Welm, B. E.; Looper, R. E.
Synthesis of the Reported Structures for Kealiinines B and C. Org.
Lett. 2012, 14, 4734−4737. (f) Rodriguez, R. A.; Barrios Steed, D.;
Kawamata, Y.; Su, S.; Smith, P. A.; Steed, T. C.; Romesberg, F. E.;
Baran, P. S. Axinellamines as Broad-spectrum Antibacterial Agents:
Scalable Synthesis and Biology. J. Am. Chem. Soc. 2014, 136, 15403−
15413. (g) Gibbons, J. B.; Salvant, J. M.; Vaden, R. M.; Kwon, K. H.;
Welm, B. E.; Looper, R. E. Synthesis of Naamidine A and Selective
Access to N2-Acyl-2-aminoimidazole Analogues. J. Org. Chem. 2015,
80, 10076−10085. (h) Tian, M.; Yan, M.; Baran, P. S. 11-Step Total
Synthesis of Araiosamines. J. Am. Chem. Soc. 2016, 138, 14234−
14237.
(18) (a) Ikegashira, K.; Oka, T.; Hirashima, S.; Noji, S.; Yamanaka,
H.; Hara, Y.; Adachi, T.; Tsuruha, J.-I.; Doi, S.; Hase, Y.; Noguchi, T.;
Ando, I.; Ogura, N.; Ikeda, S.; Hashimoto, H. Discovery of
Conformationally Constrained Tetracyclic Compounds as Potent
Hepatitis C Virus NS5B RNA Polymerase Inhibitors. J. Med. Chem.
2006, 49, 6950−6953. (b) Ganguly, A. K.; Alluri, S. S.; Wang, C.-H.;
Antropow, A.; White, A.; Caroccia, D.; Biswas, D.; Kang, E.; Zhang,
L.-K.; Carroll, S. S.; Burlein, C.; Fay, J.; Orth, P.; Strickland, C.
Structural Optimization of Cyclic Sulfonamide Based Novel HIV-1
Protease Inhibitors to Picomolar Affinities Guided by X-ray
Crystallographic Analysis. Tetrahedron 2014, 70, 2894−2904.
(c) Gerasyuto, A. I.; Arnold, M. A.; Wang, J.; Chen, G.; Zhang, X.;
Smith, S.; Woll, M. G.; Baird, J.; Zhang, N.; Almstead, N. G.;
Narasimhan, J.; Peddi, S.; Dumble, M.; Sheedy, J.; Weetall, M.;
Branstrom, A. A.; Prasad, J. V. N.; Karp, G. M. Discovery and
Optimization of Indolyl-Containing 4-Hydroxy-2-Pyridone Type II
DNA Topoisomerase Inhibitors Active against Multidrug Resistant
Gram-negative Bacteria. J. Med. Chem. 2018, 61, 4456−4475.
(d) Lopez-Tapia, F.; Lou, Y.; Brotherton-Pleiss, C.; Kuglstatter, A.;
So, S.-S.; Kondru, R. A Potent Seven-membered Cyclic BTK
(Bruton’s tyrosine Kinase) Chiral Inhibitor Conceived by Structure-
based Drug Design to Lock Its Bioactive Conformation. Bioorg. Med.
Chem. Lett. 2019, 29, 1074−1078. (e) Heightman, T. D.; Callahan, J.
F.; Chiarparin, E.; Coyle, J. E.; Griffiths-Jones, C.; Lakdawala, A. S.;
McMenamin, R.; Mortenson, P. N.; Norton, D.; Peakman, T. M.;
Rich, S. J.; Richardson, C.; Rumsey, W. L.; Sanchez, Y.; Saxty, G.;
Willems, H. M. G.; Wolfe, L.; Woolford, A. J. A.; Wu, Z.; Yan, H.;
Kerns, J. K.; Davies, T. G. Structure−Activity and Structure−
Conformation Relationships of Aryl Propionic Acid Inhibitors of
the Kelch-like ECH-Associated Protein 1/Nuclear Factor Erythroid 2-
Related Factor 2 (KEAP1/NRF2) Protein−Protein Interaction. J.
Med. Chem. 2019, 62, 4683−4702.
̈
Franken, H.; Hancock, P.; Hollinshead, J.; Jones, I.; Kahm, K.;
Murphy, P. J.; Nash, R.; Potter, D.; Rowles, R. Iodocyclisations
Reactions of Boc- and Cbz-protected N-allylguanidines. Tetrahedron
2014, 70, 4412−4419. (e) Daniel, M.; Blanchard, F.; Nocquet-
Thibault, S.; Cariou, K.; Dodd, R. H. Halocyclization of Unsaturated
Guanidines Mediated by Koser’s Reagent and Lithium Halides. J. Org.
Chem. 2015, 80, 10624−10633. (f) Nishikawa, T.; Sawayama, Y.
Bromocyclization of Alkynyl Guanidine: A New Approach to the
Synthesis of Cyclic Guanidines of Saxitoxin. Synlett 2011, 2011, 651−
654. (g) Fedoseev, P.; Sharma, N.; Khunt, R.; Ermolat’ev, D. S.; Van
der Eycken, E. V. Iodine-mediated Regioselective Guanylation-
amination of Propargylamines towards the Synthesis of Diversely
Substituted 2-aminoimidazoles. RSC Adv. 2016, 6, 75202−75206.
(8) (a) Huber, D.; Leclerc, G.; Ehrhardt, J. D.; Andermann, G. The
3,4-dimethoxybenzyl Group: A Protective Group for New 2-Imino-
imidazolidine Derivates. Tetrahedron Lett. 1987, 28, 6453−6456.
(b) Shipman, M.; Nalli, S.; Clarkson, G.; Franklin, A.; Bellone, G.
Iminophosphorane-Mediated Synthesis of Cyclic Guanidines: Appli-
cation to the Synthesis of a Simplified NA22598A1 Analogue. Synlett
2008, 2008, 2339−2341. (c) Mailyan, A. K.; Young, K.; Chen, J. L.;
Reid, B. T.; Zakarian, A. Stereoselective Synthesis of Cyclic
Guanidines by Directed Diamination of Unactivated Alkenes. Org.
Lett. 2016, 18, 5532−5535. (d) Rao Kovvuri, V. R.; Xue, H.; Romo,
D. Generation and Reactivity of 2-Amido-1,3-diaminoallyl Cations:
Cyclic Guanidine Annulations via Net (3 + 2) and (4 + 3)
Cycloadditions. Org. Lett. 2020, 22, 1407−1413.
(9) Garlets, Z. J.; Silvi, M.; Wolfe, J. P. Synthesis of Cyclic
Guanidines via Silver-Catalyzed Intramolecular Alkene Hydroamina-
tion Reactions of N-Allylguanidines. Org. Lett. 2016, 18, 2331−2334.
(10) (a) Zavesky, B. P.; Babij, N. R.; Fritz, J. A.; Wolfe, J. P.
Synthesis of Cyclic Guanidines via Pd-catalyzed Alkene Carboamina-
tion. Org. Lett. 2013, 15, 5420−5423. (b) Peterson, L. J.; Luo, J.;
Wolfe, J. P. Synthesis of Cyclic Guanidines Bearing N-Arylsulfonyl
and N-Cyano Protecting Groups via Pd-Catalyzed Alkene Carboami-
nation Reactions. Org. Lett. 2017, 19, 2817−2820.
̈
̃
(11) (a) Hovelmann, C. H.; Streuff, J.; Brelot, L.; Muniz, K. Direct
Synthesis of Bicyclic Guanidines through Unprecedented Palladium-
(II) Catalysed Diamination with Copper Chloride as Oxidant. Chem.
Commun. 2008, 2334−2336. (b) Zhao, B.; Du, H.; Shi, Y. Cu(I)-
Catalyzed Cycloguanidination of Olefins. Org. Lett. 2008, 10, 1087−
1090. (c) Peterson, L. J.; Kirsch, J. K.; Wolfe, J. P. Pd-Catalyzed
Alkene Diamination Reactions of Nitrogen Electrophiles: Synthesis of
Cyclic Guanidines and Ureas Bearing Dialkylaminomethyl Groups.
Org. Lett. 2018, 20, 3513−3517.
(12) (a) Gainer, M. J.; Bennett, N. R.; Takahashi, Y.; Looper, R. E.
Regioselective Rhodium(II)-catalyzed Hydroaminations of Propargyl-
guanidines. Angew. Chem., Int. Ed. 2011, 50, 684−687. (b) Kwon, K.
H.; Serrano, C. M.; Koch, M.; Barrows, L. R.; Looper, R. E. Synthesis
of Bicyclic Guanidines via Cascade Hydroamination/Michael
Additions of Mono-N-acryloylpropargylguanidines. Org. Lett. 2014,
16, 6048−6051.
(13) Zavesky, B. P.; Babij, N. R.; Wolfe, J. P. Synthesis of Substituted
2-aminoimidazoles via Pd-catalyzed Alkyne Carboamination Reac-
tions. Application to the Synthesis of Preclathridine Natural Products.
Org. Lett. 2014, 16, 4952−4955.
(14) Kim, M.; Mulcahy, J. V.; Espino, C. G.; Du Bois, J. Expanding
the Substrate Scope for C-H amination Reactions: Oxidative
Cyclization of Urea and Guanidine Derivatives. Org. Lett. 2006, 8,
1073−1076.
(15) (a) Buchi, G.; Rodriguez, A. D.; Yakushijin, K. , Syntheses of
( )-alchorneine and ( )-isoalchorneine. J. Org. Chem. 1989, 54,
(19) (a) Halpern, J. Free radical Mechanisms in Organometallic and
Bioorganometallic Chemistry. Pure Appl. Chem. 1986, 58, 575−584.
(b) Isayama, S.; Mukaiyama, T. A New Method for Preparation of
Alcohols from Olefins with Molecular Oxygen and Phenylsilane by
the Use of Bis(acetylacetonato)cobalt(II). Chem. Lett. 1989, 18,
1071−1074. (c) Eisenberg, D. C.; Norton, J. R. Hydrogen-Atom
Transfer Reactions of Transition-Metal Hydrides. Isr. J. Chem. 1991,
905
https://dx.doi.org/10.1021/acscatal.0c05359
ACS Catal. 2021, 11, 900−906

ACS Catalysis
pubs.acs.org/acscatalysis
Letter
31, 55−66. (d) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M.
Hydrazines and Azides via the Metal-catalyzed Hydrohydrazination
and Hydroazidation of Olefins. J. Am. Chem. Soc. 2006, 128, 11693−
11712. (e) Choi, J.; Tang, L.; Norton, J. R. Kinetics of Hydrogen
Atom Transfer from (h5-C5H5)Cr(CO)3H to Various Olefins:
Influence of Olefin Structure. J. Am. Chem. Soc. 2007, 129, 234−
240. (f) Ishikawa, H.; Colby, D. A.; Seto, S.; Va, P.; Tam, A.; Kakei,
H.; Rayl, T. J.; Hwang, I.; Boger, D. L. Total Synthesis of Vinblastine,
Vincristine, Related Natural Products, and Key Structural Analogues.
J. Am. Chem. Soc. 2009, 131, 4904−4916. (g) King, S. M.; Ma, X.;
Herzon, S. B. A Method for the Selective Hydrogenation of Alkenyl
Halides to Alkyl Halides. J. Am. Chem. Soc. 2014, 136, 6884−6887.
(h) Kuo, J. L.; Hartung, J.; Han, A.; Norton, J. R. Direct Generation
of Oxygen-Stabilized Radicals by H• Transfer from Transition Metal
Hydrides. J. Am. Chem. Soc. 2015, 137, 1036−1039. (i) Crossley, S.
W.; Obradors, C.; Martinez, R. M.; Shenvi, R. A. Mn-, Fe-, and Co-
Catalyzed Radical Hydrofunctionalizations of Olefins. Chem. Rev.
2016, 116, 8912−9000. (j) Obradors, C.; Martinez, R. M.; Shenvi, R.
A. Ph(i-PrO)SiH2: An Exceptional Reductant for Metal-Catalyzed
Hydrogen Atom Transfers. J. Am. Chem. Soc. 2016, 138, 4962−4971.
(k) Lo, J. C.; Kim, D.; Pan, C. M.; Edwards, J. T.; Yabe, Y.; Gui, J.;
Qin, T.; Gutierrez, S.; Giacoboni, J.; Smith, M. W.; Holland, P. L.;
Baran, P. S. Fe-Catalyzed C-C Bond Construction from Olefins via
Radicals. J. Am. Chem. Soc. 2017, 139, 2484−2503. (l) Green, S. A.;
Crossley, S. W. M.; Matos, J. L. M.; Vasquez-Cespedes, S.; Shevick, S.
L.; Shenvi, R. A. The High Chemofidelity of Metal-Catalyzed
Hydrogen Atom Transfer. Acc. Chem. Res. 2018, 51, 2628−2640.
(m) Shevick, S. L.; Obradors, C.; Shenvi, R. A. Mechanistic
Interrogation of Co/Ni-Dual Catalyzed Hydroarylation. J. Am.
Chem. Soc. 2018, 140, 12056−12068. (n) Wang, Y. Y.; Bode, J. W.
Olefin Amine (OLA) Reagents for the Synthesis of Bridged Bicyclic
and Spirocyclic Saturated N-Heterocycles by Catalytic Hydrogen
Atom Transfer (HAT) Reactions. J. Am. Chem. Soc. 2019, 141, 9739−
9745. (o) Zhou, X. L.; Yang, F.; Sun, H. L.; Yin, Y. N.; Ye, W. T.; Zhu,
R. Cobalt-Catalyzed Intermolecular Hydrofunctionalization of
Alkenes: Evidence for a Bimetallic Pathway. J. Am. Chem. Soc. 2019,
141, 7250−7255. (p) Shevick, S. L.; Wilson, C. V.; Kotesova, S.; Kim,
D.; Holland, P. L.; Shenvi, R. A. Catalytic hydrogen atom transfer to
alkenes: a roadmap for metal hydrides and radicals. Chem. Sci. 2020,
11, 12401. (q) Yao, C.; Wang, S.; Norton, J.; Hammond, M.
Catalyzing the Hydrodefluorination of CF3-Substituted Alkenes by
PhSiH3. H• Transfer from a Nickel Hydride. J. Am. Chem. Soc. 2020,
142, 4793−4799. (r) Wu, B.; Zhu, R. Radical Philicity Inversion in
Co- and Fe-Catalyzed Hydrogen-Atom-Transfer-Initiated Cycliza-
tions of Unsaturated Acylsilanes. ACS Catal. 2020, 10, 510−515.
(s) Kattamuri, P. V.; West, J. G. Hydrogenation of Alkenes via
Cooperative Hydrogen Atom Transfer. J. Am. Chem. Soc. 2020, 142,
19316−19326.
Silane-Controlled Enantioselective Hydrofunctionalization of Alkenes
by Cobalt-Catalyzed Hydrogen Atom Transfer and Radical-Polar
Crossover. J. Am. Chem. Soc. 2020, 142, 13481−13490. (h) Nagai, T.;
Mimata, N.; Terada, Y.; Sebe, C.; Shigehisa, H. Catalytic Dealkylative
Synthesis of Cyclic Carbamates and Ureas via Hydrogen Atom
Transfer and Radical-Polar Crossover. Org. Lett. 2020, 22, 5522−
5527.
(21) (a) Touney, E. E.; Foy, N. J.; Pronin, S. V. Catalytic Radical-
Polar Crossover Reactions of Allylic Alcohols. J. Am. Chem. Soc. 2018,
140, 16982−16987. (b) Discolo, C. A.; Touney, E. E.; Pronin, S. V.
Catalytic Asymmetric Radical−Polar Crossover Hydroalkoxylation. J.
Am. Chem. Soc. 2019, 141, 17527−17532. (c) Huang, G.; Ke, M.;
Tao, Y.; Chen, F. Specific Z-Selectivity in the Oxidative Isomerization
of Allyl Ethers to Generate Geometrically Defined Z-Enol Ethers
Using a Cobalt(II)(salen) Complex Catalyst. J. Org. Chem. 2020, 85,
5321−5329. (d) Vrubliauskas, D.; Vanderwal, C. D. Cobalt-Catalyzed
Hydrogen-Atom Transfer Induces Bicyclizations that Tolerate
Electron-Rich and Electron-Deficient Intermediate Alkenes. Angew.
Chem., Int. Ed. 2020, 59, 6115−6121. (e) Yahata, K.; Kaneko, Y.;
Akai, S. Cobalt-Catalyzed Intermolecular Markovnikov Hydroamina-
tion of Nonactivated Olefins: N2-Selective Alkylation of Benzotria-
zole. Org. Lett. 2020, 22, 598−603.
(22) Hypothetical mechanism producing 7b is (1) MHAT to
generate a carbon radical intermediate; (2) intramolecular HAT in
the carbon radical intermediate; (3) radical-polar crossover to
generate iminium intermediate; (4) hydrolysis to produce 7b via
hemiaminal.
́
́
(20) (a) Shigehisa, H.; Aoki, T.; Yamaguchi, S.; Shimizu, N.; Hiroya,
K. Hydroalkoxylation of Unactivated Olefins with Carbon Radicals
and Carbocation Species as Key Intermediates. J. Am. Chem. Soc.
2013, 135, 10306−10309. (b) Shigehisa, H.; Koseki, N.; Shimizu, N.;
Fujisawa, M.; Niitsu, M.; Hiroya, K. Catalytic Hydroamination of
Unactivated Olefins Using a Co Catalyst for Complex Molecule
Synthesis. J. Am. Chem. Soc. 2014, 136, 13534−13537. (c) Shigehisa,
H. Functional Group Tolerant Markovnikov-Selective Hydrofunction-
alization of Unactivated Olefins Using a Cobalt Complex as Catalyst.
Synlett 2015, 26, 2479−2484. (d) Shigehisa, H.; Ano, T.; Honma, H.;
Ebisawa, K.; Hiroya, K. Co-Catalyzed Hydroarylation of Unactivated
Olefins. Org. Lett. 2016, 18, 3622−3625. (e) Shigehisa, H.; Hayashi,
M.; Ohkawa, H.; Suzuki, T.; Okayasu, H.; Mukai, M.; Yamazaki, A.;
Kawai, R.; Kikuchi, H.; Satoh, Y.; Fukuyama, A.; Hiroya, K. Catalytic
Synthesis of Saturated Oxygen Heterocycles by Hydrofunctionaliza-
tion of Unactivated Olefins: Unprotected and Protected Strategies. J.
Am. Chem. Soc. 2016, 138, 10597−10604. (f) Date, S.; Hamasaki, K.;
Sunagawa, K.; Koyama, H.; Sebe, C.; Hiroya, K.; Shigehisa, H.
Catalytic Direct Cyclization of Alkenyl Thioester. ACS Catal. 2020,
10, 2039−2045. (g) Ebisawa, K.; Izumi, K.; Ooka, Y.; Kato, H.;
Kanazawa, S.; Komatsu, S.; Nishi, E.; Shigehisa, H. Catalyst- and
906
https://dx.doi.org/10.1021/acscatal.0c05359
ACS Catal. 2021, 11, 900−906