α,α′-C-H Bond Difunctionalization of Unprotected Alicyclic Amines

Article abstract of DOI:10.1021/acs.orglett.1c02187

A simple one-pot procedure enables the sequential, regioselective, and diastereoselective introduction of the same or two different substituents to the α- and α′-positions of unprotected azacycles. Aryl, alkyl, and alkenyl substituents are introduced via their corresponding organolithium compounds. The scope of this transformation includes pyrrolidines, piperidines, azepanes, and piperazines.

Full text of DOI:10.1021/acs.orglett.1c02187

pubs.acs.org/OrgLett
Letter
α,α′-C−H Bond Difunctionalization of Unprotected Alicyclic Amines
Daniel A. Valles,∥ Subhradeep Dutta,∥ Anirudra Paul, Khalil A. Abboud, Ion Ghiviriga,
and Daniel Seidel*
Cite This: https://doi.org/10.1021/acs.orglett.1c02187
Read Online
sı
*
Metrics & More
Article Recommendations
Supporting Information
ACCESS
ABSTRACT: A simple one-pot procedure enables the sequential,
regioselective, and diastereoselective introduction of the same or two
different substituents to the α- and α′-positions of unprotected
azacycles. Aryl, alkyl, and alkenyl substituents are introduced via their
corresponding organolithium compounds. The scope of this trans-
formation includes pyrrolidines, piperidines, azepanes, and piper-
azines.
Scheme 1. Overview of Methods for Amine α,α′-C−H Bond
ully or partially saturated azacycles are ubiquitous core
1
Difunctionalization
Fstructures of bioactive materials. The introduction of ring
substituents via the C−H bond functionalization of the parent
heterocycles is a particularly attractive strategy for accessing
complex amines, and is continuing to inspire the development
of diverse synthetic strategies.2,3 While numerous methods for
the α-C−H bond functionalization of amines have emerged,
procedures that achieve an α,α′-C−H bond difunctionalization
in a single operation remain rare (Scheme 1).4−6 Selected
examples include the rhodium-catalyzed metal carbenoid
insertion involving carbamates (Scheme 1b)4a,c and the
ruthenium-catalyzed hydroalkylation of N-2-pyridylamines
(Scheme 1c).4b A rare method enabling the introduction of
two different substituents is the palladium-catalyzed diarylation
of thioamides with boronic acids (Scheme 1d).4d Here we
report a practical one-pot approach for the α,α′-C−H bond
difunctionalization of unprotected alicyclic amines (Scheme
1e). This method utilizes simple ketone oxidants and
organolithium nucleophiles, without requiring the use of
transition-metal catalysts.
We recently reported a method for the α-C−H bond
functionalization of unprotected cyclic amines.7,8 These
substrates are first converted to their corresponding lithium
amides 2 (deprotonation with n-BuLi) before being exposed to
a ketone oxidant (e.g., benzophenone) to form imines 3 in
their monomeric forms (see Scheme 2).9 The addition of an
organolithium nucleophile to 3 results in lithium amide 4,
which, upon workup, provides an α-substituted amine product.
Instead of quenching the reaction upon the formation of 4, we
rationalized that the addition of an appropriate ketone oxidant
should lead to the formation of imine 5. The subsequent
addition of a second organolithium nucleophile, followed by
workup, should provide the α,α′-difunctionalized amine 1 in a
single operation. Indeed, we previously showed that α-
substituted lithium amides 4 can be converted to α,α′-
disubstituted products 5.7 Conducting the α,α′-difunctionali-
zation in a single operation would save 1 equiv of base and
Received: June 29, 2021
https://doi.org/10.1021/acs.orglett.1c02187
© XXXX American Chemical Society
Org. Lett. XXXX, XXX, XXX−XXX
A

Organic Letters
pubs.acs.org/OrgLett
Letter
a
Scheme 2. Scope of the Reaction
a
Reactions were performed in ether solution at −78 °C with 1 mmol of amine, n-BuLi (1 equiv), first ketone oxidant (1.05 equiv), R′−Li (1.07−
b
1.5 equiv), second ketone oxidant (1.2−1.7 equiv), and R″−Li (1.5−2.0 equiv). See the Supporting Information for further details. Benzophenone
c
d
(first oxidation) and t-butyl phenyl ketone (second oxidation) were used. Trifluoroacetophenone (first and second oxidation) was used. While
e
four diastereomers could potentially be formed for product 1e, we only observed trace amounts of a second diastereomer. Trifluoroacetophenone
(first oxidation) and t-butyl phenyl ketone (second oxidation) were used. Reaction was performed on a 0.5 mmol scale starting with the
f
corresponding hydrochloride salt of the amine.
streamline the entire sequence while also having the potential
to provide higher overall yields. Following significant
optimization (see the Supporting Information for details),
the scope of the transformation was established as summarized
in Scheme 2. The α,α′-diphenylation was accomplished with a
range of amines. Likewise, the introduction of two different
substituents (aryl, heteroaryl, alkyl, and alkenyl) could be
demonstrated on a range of amines. While the yields are
mostly moderate and, in some cases, low, the simplicity of the
approach largely compensates for this shortcoming. In all cases
studied previously with a two-step approach, the present one-
pot strategy provides significantly higher yields.10 For the
introduction of two different substituents, we investigated
possible effects based on the order of addition. Selected
B
https://doi.org/10.1021/acs.orglett.1c02187
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
examples are included in Scheme 2. For the product 1ah
derived from pyrrolidine, the introduction of phenyl followed
by n-Bu resulted in a low yield but good diastereoselectivity,
while the introduction of n-Bu followed by phenyl provided an
improved yield but at the expense of diastereoselectivity. In
contrast, for 1ai derived from piperidine, the introduction of
the phenyl group first was found to be beneficial. For the
azepane-derived product 1aj, the introduction of the n-Bu
group first provided favorable results. For both 1ai and 1aj, the
order of addition did not impact the excellent level of
diastereoselectivity.
ACKNOWLEDGMENTS
■
Financial support from the NIH−NIGMS (Grant No.
R01GM101389) is gratefully acknowledged. We thank the
NSF for the funding of the X-ray diffractometer through Grant
No. CHE-1828064. The mass spectrometry instrumentation
was supported by a grant from the NIH (S10 OD021758-
01A1).
REFERENCES
■
(1) (a) Taylor, R. D.; MacCoss, M.; Lawson, A. D. G. Rings in
Drugs. J. Med. Chem. 2014, 57, 5845−5859. (b) Vitaku, E.; Smith, D.
T.; Njardarson, J. T. Analysis of the Structural Diversity, Substitution
Patterns, and Frequency of Nitrogen Heterocycles among U.S. FDA
Approved Pharmaceuticals. J. Med. Chem. 2014, 57, 10257−10274.
(2) Selected reviews on amine C−H bond functionalization:
(a) Campos, K. R. Direct sp3 C-H bond activation adjacent to
nitrogen in heterocycles. Chem. Soc. Rev. 2007, 36, 1069−1084.
(b) Mitchell, E. A.; Peschiulli, A.; Lefevre, N.; Meerpoel, L.; Maes, B.
U. W. Direct alpha-Functionalization of Saturated Cyclic Amines.
Chem. - Eur. J. 2012, 18, 10092−10142. (c) Peng, B.; Maulide, N. The
Redox-Neutral Approach to C-H Functionalization. Chem. - Eur. J.
2013, 19, 13274−13287. (d) Girard, S. A.; Knauber, T.; Li, C.-J. The
Cross-Dehydrogenative Coupling of Csp3-H Bonds: A Versatile
Strategy for C-C Bond Formations. Angew. Chem., Int. Ed. 2014, 53,
74−100. (e) Haibach, M. C.; Seidel, D. C-H Bond Functionalization
through Intramolecular Hydride Transfer. Angew. Chem., Int. Ed.
2014, 53, 5010−5036. (f) Wang, L.; Xiao, J. Advancement in Cascade
[1, n]-Hydrogen Transfer/Cyclization: A Method for Direct
Functionalization of Inactive C(sp3)-H Bonds. Adv. Synth. Catal.
2014, 356, 1137−1171. (g) Vo, C.-V. T.; Bode, J. W. Synthesis of
Saturated N-Heterocycles. J. Org. Chem. 2014, 79, 2809−2815.
(h) Seidel, D. The redox-A3 reaction. Org. Chem. Front. 2014, 1,
426−429. (i) Seidel, D. The Azomethine Ylide Route to Amine C−H
Functionalization: Redox-Versions of Classic Reactions and a
Pathway to New Transformations. Acc. Chem. Res. 2015, 48, 317−
328. (j) Beatty, J. W.; Stephenson, C. R. J. Amine Functionalization
via Oxidative Photoredox Catalysis: Methodology Development and
Complex Molecule Synthesis. Acc. Chem. Res. 2015, 48, 1474−1484.
(k) Mahato, S.; Jana, C. K. Classical-Reaction-Driven Stereo- and
Regioselective C(sp3)−H Functionalization of Aliphatic Amines.
Chem. Rec. 2016, 16, 1477−1488. (l) Qin, Y.; Zhu, L.; Luo, S.
Organocatalysis in Inert C−H Bond Functionalization. Chem. Rev.
2017, 117, 9433−9520. (m) Cheng, M.-X.; Yang, S.-D. Recent
Advances in the Enantioselective Oxidative α-C−H Functionalization
of Amines. Synlett 2017, 28, 159−174. (n) Chu, J. C. K.; Rovis, T.
Complementary Strategies for Directed C(sp3)-H Functionalization:
A Comparison of Transition-Metal-Catalyzed Activation, Hydrogen
Atom Transfer, and Carbene/Nitrene Transfer. Angew. Chem., Int. Ed.
2018, 57, 62−101. (o) Stateman, L. M.; Nakafuku, K. M.; Nagib, D.
A. Remote C−H Functionalization via Selective Hydrogen Atom
Transfer. Synthesis 2018, 50, 1569−1586. (p) Edwards, P. M.;
Schafer, L. L. Early transition metal-catalyzed C−H alkylation:
hydroaminoalkylation for Csp3−Csp3 bond formation in the synthesis
of selectively substituted amines. Chem. Commun. 2018, 54, 12543−
12560. (q) Gonnard, L.; Guérinot, A.; Cossy, J. Transition metal-
catalyzed α-alkylation of amines by C(sp3)-H bond activation.
Tetrahedron 2019, 75, 145−163. (r) Liu, S.; Zhao, Z.; Wang, Y.
Construction of N-Heterocycles through Cyclization of Tertiary
Amines. Chem. - Eur. J. 2019, 25, 2423−2441. (s) Antermite, D.; Bull,
J. A. Transition Metal-Catalyzed Directed C(sp3)−H Functionaliza-
tion of Saturated Heterocycles. Synthesis 2019, 51, 3171−3204.
(t) Zhang, T.; Wu, Y.-H.; Wang, N.-X.; Xing, Y. Advances in C(sp3)−
H Bond Functionalization via Radical Processes. Synthesis 2019, 51,
4531−4548. (u) Trowbridge, A.; Walton, S. M.; Gaunt, M. J. New
Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic
Amines. Chem. Rev. 2020, 120, 2613−2692. (v) Kapoor, M.; Singh,
A.; Sharma, K.; Hua Hsu, M. Site-Selective C(sp3)-H and C(sp2)-H
Functionalization of Amines Using a Directing-Group-Guided
In summary, we have achieved the one-pot α,α′-difunction-
alization of various unprotected cyclic amines. The method is
operationally simple and exhibits a significant synthetic utility.
ASSOCIATED CONTENT
■
sı
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.1c02187.
Experimental details, characterization data, X-ray data,
and copies of NMR spectra (PDF)
Accession Codes
CCDC 2039636−2039637 contain the supplementary crys-
tallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
■
Corresponding Author
Daniel Seidel − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States; orcid.org/0000-0001-
6725-111X; Email: seidel@chem.ufl.edu
Authors
Daniel A. Valles − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States
Subhradeep Dutta − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States
Anirudra Paul − Center for Heterocyclic Compounds,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States
Khalil A. Abboud − Center for X-ray Crystallography,
Department of Chemistry, University of Florida, Gainesville,
Florida 32611, United States
Ion Ghiviriga − Center for NMR Spectroscopy, Department of
Chemistry, University of Florida, Gainesville, Florida 32611,
United States; orcid.org/0000-0001-5812-5170
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c02187
Author Contributions
∥These authors contributed equally.
Notes
The authors declare no competing financial interest.
C
https://doi.org/10.1021/acs.orglett.1c02187
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
Strategy. Adv. Synth. Catal. 2020, 362, 4513−4542. (w) An, X.-D.;
Xiao, J. Recent advances in hydride transfer-involved C(sp3)−H
activation reactions. Org. Chem. Front. 2021, 8, 1364−1383.
(x) Basak, S.; Winfrey, L.; Kustiana, B. A.; Melen, R. L.; Morrill, L.
C.; Pulis, A. P. Electron deficient borane-mediated hydride abstraction
in amines: stoichiometric and catalytic processes. Chem. Soc. Rev.
2021, 50, 3720−3737. (y) Caplin, M. J.; Foley, D. J. Emergent
synthetic methods for the modular advancement of sp3-rich
fragments. Chem. Sci. 2021, 12, 4646−4660. Ohno, S.; Miyoshi, M.;
Murai, K.; Arisawa, M. Non-Directed β- or γ-C(sp3)−H Function-
alization of Saturated Nitrogen-Containing Heterocycles. Synthesis
2021, DOI: 10.1055/a-1483-4575.
A. F.; Faulkner, E. L.; Leach, A. G.; Nelson, A.; Marsden, S. P.
Fragment-oriented synthesis: β-elaboration of cyclic amine fragments
using enecarbamates as platform intermediates. Chem. Commun. 2020,
56, 8802−8805. (s) Holmberg-Douglas, N.; Choi, Y.; Aquila, B.;
Huynh, H.; Nicewicz, D. A. β-Functionalization of Saturated Aza-
Heterocycles Enabled by Organic Photoredox Catalysis. ACS Catal.
2021, 11, 3153−3158. (t) Yi, M.-J.; Zhang, H.-X.; Xiao, T.-F.; Zhang,
J.-H.; Feng, Z.-T.; Wei, L.-P.; Xu, G.-Q.; Xu, P.-F. Photoinduced
Metal-Free α-C(sp3)−H Carbamoylation of Saturated Aza-Hetero-
cycles via Rationally Designed Organic Photocatalyst. ACS Catal.
2021, 11, 3466−3472. (u) Aguilera, E. Y.; Sanford, M. S. Palladium-
Mediated Cγ-H Functionalization of Alicyclic Amines. Angew. Chem.,
Int. Ed. 2021, 60, 11227−11230. (v) Chang, Y.; Cao, M.; Chan, J. Z.;
Zhao, C.; Wang, Y.; Yang, R.; Wasa, M. Enantioselective Synthesis of
N-Alkylamines through β-Amino C−H Functionalization Promoted
by Cooperative Actions of B(C6F5)3 and a Chiral Lewis Acid Co-
Catalyst. J. Am. Chem. Soc. 2021, 143, 2441−2455. (w) Yue, W.-J.;
Day, C. S.; Martin, R. Site-Selective Defluorinative sp3 C−H
Alkylation of Secondary Amides. J. Am. Chem. Soc. 2021, 143,
6395−6400. (x) Koperniku, A.; Schafer, L. L. Zirconium Catalyzed
Hydroaminoalkylation for the Synthesis of α-Arylated Amines and N-
Heterocycles. Chem. - Eur. J. 2021, 27, 6334−6339.
(4) (a) Davies, H. M. L.; Hansen, T.; Hopper, D. W.; Panaro, S. A.
Highly Regio-, Diastereo-, and Enantioselective C-H Insertions of
Methyl Aryldiazoacetates into Cyclic N-Boc-Protected Amines.
Asymmetric Synthesis of Novel C2-Symmetric Amines and threo-
Methylphenidate. J. Am. Chem. Soc. 1999, 121, 6509−6510.
(b) Chatani, N.; Asaumi, T.; Yorimitsu, S.; Ikeda, T.; Kakiuchi, F.;
Murai, S. Ru3(CO)12-Catalyzed Coupling Reaction of sp3 C-H Bonds
Adjacent to a Nitrogen Atom in Alkylamines with Alkenes. J. Am.
Chem. Soc. 2001, 123, 10935−10941. (c) Davies, H. M. L.;
Venkataramani, C.; Hansen, T.; Hopper, D. W. New Strategic
Reactions for Organic Synthesis: Catalytic Asymmetric C-H
Activation α to Nitrogen as a Surrogate for the Mannich Reaction.
J. Am. Chem. Soc. 2003, 125, 6462−6468. (d) Spangler, J. E.;
Kobayashi, Y.; Verma, P.; Wang, D.-H.; Yu, J.-Q. α-Arylation of
Saturated Azacycles and N-Methylamines via Palladium(II)-Catalyzed
C(sp3)−H Coupling. J. Am. Chem. Soc. 2015, 137, 11876−11879.
(e) Tran, A. T.; Yu, J.-Q. Practical Alkoxythiocarbonyl Auxiliaries for
Iridium(I)-Catalyzed C-H Alkylation of Azacycles. Angew. Chem., Int.
Ed. 2017, 56, 10530−10534.
(5) Selected examples in which α,α′-C−H bond difunctionalization
is observed as a side reaction in α-C−H bond functionalization:
(a) Li, Z.; Li, C.-J. Highly efficient copper-catalyzed nitro-Mannich
type reaction: Cross-dehydrogenative-coupling between sp3 C-H
bond and sp3 C-H bond. J. Am. Chem. Soc. 2005, 127, 3672−3673.
(b) Pastine, S. J.; Gribkov, D. V.; Sames, D. sp3 C-H bond arylation
directed by amidine protecting group: α-arylation of pyrrolidines and
piperidines. J. Am. Chem. Soc. 2006, 128, 14220−14221. (c) Pro-
kopcova, H.; Bergman, S. D.; Aelvoet, K.; Smout, V.; Herrebout, W.;
Van der Veken, B.; Meerpoel, L.; Maes, B. U. W. C-2 Arylation of
Piperidines through Directed Transition-Metal-Catalyzed sp3 C-H
Activation. Chem. - Eur. J. 2010, 16, 13063−13067. (d) Kulago, A. A.;
Van Steijvoort, B. F.; Mitchell, E. A.; Meerpoel, L.; Maes, B. U. W.
Directed Ruthenium-Catalyzed C(sp3)H α-Alkylation of Cyclic
Amines Using Dioxolane-Protected Alkenones. Adv. Synth. Catal.
2014, 356, 1610−1618. (e) Shang, M.; Chan, J. Z.; Cao, M.; Chang,
Y.; Wang, Q.; Cook, B.; Torker, S.; Wasa, M. C−H Functionalization
of Amines via Alkene-Derived Nucleophiles through Cooperative
Action of Chiral and Achiral Lewis Acid Catalysts: Applications in
Enantioselective Synthesis. J. Am. Chem. Soc. 2018, 140, 10593−
10601. (f) Rosien, M.; Töben, I.; Schmidtmann, M.; Beckhaus, R.;
Doye, S. Titanium-Catalyzed Hydroaminoalkylation of Ethylene.
Chem. - Eur. J. 2020, 26, 2138−2142.
(3) Selected recent examples of mechanistically diverse methods for
amine C−H bond functionalization: (a) Ohmatsu, K.; Suzuki, R.;
Furukawa, Y.; Sato, M.; Ooi, T. Zwitterionic 1,2,3-Triazolium
Amidate as a Catalyst for Photoinduced Hydrogen-Atom Transfer
Radical Alkylation. ACS Catal. 2020, 10, 2627−2632. (b) Roque, J.
B.; Kuroda, Y.; Jurczyk, J.; Xu, L.-P.; Ham, J. S.; Göttemann, L. T.;
Roberts, C. A.; Adpressa, D.; Saurí, J.; Joyce, L. A.; Musaev, D. G.;
Yeung, C. S.; Sarpong, R. C−C Cleavage Approach to C−H
Functionalization of Saturated Aza-Cycles. ACS Catal. 2020, 10,
2929−2941. (c) Rand, A. W.; Yin, H.; Xu, L.; Giacoboni, J.; Martin-
Montero, R.; Romano, C.; Montgomery, J.; Martin, R. Dual Catalytic
Platform for Enabling sp3 α C−H Arylation and Alkylation of
Benzamides. ACS Catal. 2020, 10, 4671−4676. (d) Liu, W.; Babl, T.;
Röther, A.; Reiser, O.; Davies, H. M. L. Functionalization of
Piperidine Derivatives for the Site-Selective and Stereoselective
Synthesis of Positional Analogues of Methylphenidate. Chem. - Eur.
J. 2020, 26, 4236−4241. (e) Verma, P.; Richter, J. M.; Chekshin, N.;
Qiao, J. X.; Yu, J.-Q. Iridium(I)-Catalyzed α-C(sp3)−H Alkylation of
Saturated Azacycles. J. Am. Chem. Soc. 2020, 142, 5117−5125.
(f) Walker, M. M.; Koronkiewicz, B.; Chen, S.; Houk, K. N.; Mayer, J.
M.; Ellman, J. A. Highly Diastereoselective Functionalization of
Piperidines by Photoredox-Catalyzed α-Amino C−H Arylation and
Epimerization. J. Am. Chem. Soc. 2020, 142, 8194−8202. (g) Chen,
L.; Yang, Y.; Liu, L.; Gao, Q.; Xu, S. Iridium-Catalyzed
Enantioselective α-C(sp3)−H Borylation of Azacycles. J. Am. Chem.
Soc. 2020, 142, 12062−12068. (h) Xu, L.-P.; Roque, J. B.; Sarpong,
R.; Musaev, D. G. Reactivity and Selectivity Controlling Factors in the
Pd/Dialkylbiarylphosphine-Catalyzed C−C Cleavage/Cross-Cou-
pling of an N-Fused Bicyclo α-Hydroxy-β-Lactam. J. Am. Chem. Soc.
2020, 142, 21140−21152. (i) Feng, K.; Quevedo, R. E.; Kohrt, J. T.;
Oderinde, M. S.; Reilly, U.; White, M. C. Late-stage oxidative
C(sp3)−H methylation. Nature 2020, 580, 621−627. (j) Sarver, P. J.;
Bacauanu, V.; Schultz, D. M.; DiRocco, D. A.; Lam, Y.-h.; Sherer, E.
C.; MacMillan, D. W. C. The merger of decatungstate and copper
catalysis to enable aliphatic C(sp3)−H trifluoromethylation. Nat.
Chem. 2020, 12, 459−467. (k) McManus, J. B.; Onuska, N. P. R.;
Jeffreys, M. S.; Goodwin, N. C.; Nicewicz, D. A. Site-Selective C−H
Alkylation of Piperazine Substrates via Organic Photoredox Catalysis.
Org. Lett. 2020, 22, 679−683. (l) Cao, L.; Zhao, H.; Tan, Z.; Guan,
R.; Jiang, H.; Zhang, M. Ruthenium-Catalyzed Hydrogen Evolution o-
Aminoalkylation of Phenols with Cyclic Amines. Org. Lett. 2020, 22,
4781−4785. (m) Chen, Y.; Wan, H.-L.; Huang, Y.; Liu, S.; Wang, F.;
Lu, C.; Nie, J.; Chen, Z.; Yang, G.; Ma, C. B(C6F5)3-Catalyzed β-
Functionalization of Pyrrolidines Using Isatins via Borrowing
Hydrogen: Divergent Access to Substituted Pyrrolidines and Pyrroles.
Org. Lett. 2020, 22, 7797−7803. (n) Oeschger, R.; Su, B.; Yu, I.;
Ehinger, C.; Romero, E.; He, S.; Hartwig, J. Diverse functionalization
of strong alkyl C−H bonds by undirected borylation. Science 2020,
368, 736−741. (o) Short, M. A.; Blackburn, J. M.; Roizen, J. L.
Modifying Positional Selectivity in C−H Functionalization Reactions
with Nitrogen-Centered Radicals: Generalizable Approaches to 1,6-
Hydrogen-Atom Transfer Processes. Synlett 2020, 31, 102−116.
(p) Rickertsen, D. R. L.; Ma, L.; Paul, A.; Abboud, K. A.; Seidel, D.
Traceless Redox-Annulations of Alicyclic Amines. SynOpen 2020, 04,
123−131. (q) Kim, Y.; Heo, J.; Kim, D.; Chang, S.; Seo, S. Ring-
opening functionalizations of unstrained cyclic amines enabled by
difluorocarbene transfer. Nat. Commun. 2020, 11, 4761. (r) Trindade,
(6) Selected examples of multistage, sequential approaches for amine
α,α′-C−H bond difunctionalization: (a) Fraser, R. R.; Passannanti, S.
I. Synthesis of 2,5-Dialkylpyrrolidines via Metallated Nitrosamines, A
Constituent of Fire Ant Venom. Synthesis 1976, 1976, 540−541.
(b) Beak, P.; Lee, W. K. α-Lithioamine synthetic equivalents:
D
https://doi.org/10.1021/acs.orglett.1c02187
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
pubs.acs.org/OrgLett
Letter
syntheses of diastereoisomers from Boc derivatives of cyclic amines. J.
Org. Chem. 1993, 58, 1109−1117. (c) Campos, K. R.; Klapars, A.;
Waldman, J. H.; Dormer, P. G.; Chen, C.-y. Enantioselective,
Palladium-Catalyzed α-Arylation of N-Boc-pyrrolidine. J. Am. Chem.
Soc. 2006, 128, 3538−3539. (d) Stead, D.; O’Brien, P.; Sanderson, A.
A New Sparteine Surrogate for Asymmetric Deprotonation of N-Boc
Pyrrolidine. Org. Lett. 2008, 10, 1409−1412. (e) Jurberg, I. D.; Peng,
B.; Woestefeld, E.; Wasserloos, M.; Maulide, N. Intramolecular
Redox-Triggered C-H Functionalization. Angew. Chem., Int. Ed. 2012,
51, 1950−1953. (f) Cheng, Y.-F.; Rong, H.-J.; Yi, C.-B.; Yao, J.-J.; Qu,
J. Redox-Triggered α-C−H Functionalization of Pyrrolidines: Syn-
thesis of Unsymmetrically 2,5-Disubstituted Pyrrolidines. Org. Lett.
2015, 17, 4758−4761. (g) Nebe, M. M.; Zinn, S.; Opatz, T. A short
and modular approach towards 3,5-disubstituted indolizidine
alkaloids. Org. Biomol. Chem. 2016, 14, 7084−7091. (h) Mahato, S.;
Jana, C. K. Iterative direct C(sp3)−H functionalization of amines:
diastereoselective divergent syntheses of α,α′-disubstituted alicyclic
amines. Org. Biomol. Chem. 2017, 15, 1655−1660. (i) Rong, H.-J.;
Yao, J.-J.; Li, J.-K.; Qu, J. Molecular Iodine-Mediated α-C−H
Oxidation of Pyrrolidines to N,O-Acetals: Synthesis of ( )-Preussin
by Late-Stage 2,5-Difunctionalizations of Pyrrolidine. J. Org. Chem.
2017, 82, 5557−5565.
(7) (a) Chen, W.; Ma, L.; Paul, A.; Seidel, D. Direct α-C−H bond
functionalization of unprotected cyclic amines. Nat. Chem. 2018, 10,
165−169. (b) Paul, A.; Seidel, D. α-Functionalization of Cyclic
Secondary Amines: Lewis Acid Promoted Addition of Organo-
metallics to Transient Imines. J. Am. Chem. Soc. 2019, 141, 8778−
8782. (c) Chen, W.; Paul, A.; Abboud, K. A.; Seidel, D. Rapid
functionalization of multiple C−H bonds in unprotected alicyclic
amines. Nat. Chem. 2020, 12, 545−550. (d) Paul, A.; Kim, J. H.;
Daniel, S. D.; Seidel, D. Diversification of Unprotected Alicyclic
Amines by C-H Bond Functionalization: Decarboxylative Alkylation
of Transient Imines. Angew. Chem., Int. Ed. 2021, 60, 1625−1628.
(e) Kim, J. H.; Paul, A.; Ghiviriga, I.; Seidel, D. α-C−H Bond
Functionalization of Unprotected Alicyclic Amines: Lewis-Acid-
Promoted Addition of Enolates to Transient Imines. Org. Lett.
2021, 23, 797−801. (f) Chen, W.; Seidel, D. α-C−H/N−H
Annulation of Alicyclic Amines via Transient Imines: Preparation of
Polycyclic Lactams. Org. Lett. 2021, 23, 3729−3734.
(8) For an early review on the ability of lithium amides to serve as
reductants, see: (a) Majewski, M.; Gleave, D. M. Reduction with
lithium dialkylamides. J. Organomet. Chem. 1994, 470, 1−16. (b)
Selected key contributions: Wittig, G.; Schmidt, H. J.; Renner, H.
̈
̈
Uber Lithium-diathylamid als Hydrid-Donator. Chem. Ber. 1962, 95,
2377−2383. (c) Wittig, G.; Hesse, A. Zur Reaktionsweise N-
̈
metallierter acyclischer und cyclischer sekundarer Amine. Liebigs
Ann. Chem. 1971, 746, 149−173. (d) Wittig, G.; Hesse, A. Hydrid-
̈
Ubertragung von Lithium-pyrrolidid auf Azomethine. Liebigs Ann.
̈
Chem. 1971, 746, 174−184. (e) Wittig, G.; Häusler, G. Uber die
Reaktivitat von metallierten Aminen als Hydrid-Donatoren. Liebigs
Ann. Chem. 1971, 746, 185−199.
̈
(9) The propensity of alicyclic imines such as 1-pyrroline and 1-
piperideine to undergo the formation of more stable and typically
unreactive trimers is well-documented. For a leading study, see:
Fandrick, D. R.; Hart, C. A.; Okafor, I. S.; Mercadante, M. A.; Sanyal,
S.; Masters, J. T.; Sarvestani, M.; Fandrick, K. R.; Stockdill, J. L.;
Grinberg, N.; Gonnella, N.; Lee, H.; Senanayake, C. H. Copper-
Catalyzed Asymmetric Propargylation of Cyclic Aldimines. Org. Lett.
2016, 18, 6192−6195.
(10) Overall yields for α,α′-diphenylation, when conducted in two
separate synthetic operations: 2,5-diphenylpyrrolidine (1a, 31%), 2,6-
diphenylpiperidine (1b, 41%), 2,7-diphenylazepane (1j, 40%). See ref
7a.
E
https://doi.org/10.1021/acs.orglett.1c02187
Org. Lett. XXXX, XXX, XXX−XXX