Stereoselective radical amination of electron-deficient C(sp3)-H bonds by Co(II)-based metalloradical catalysis: Direct synthesis of α-amino acid derivatives via α-C-H amination

Article abstract of DOI:10.1021/ol302511f

The cobalt(II) complex of 3,5-Di^tBu-IbuPhyrin, [Co(P1)], is an effective catalyst for intramolecular amination of electron-deficient C-H bonds, including those adjacent to electron-withdrawing CO₂R, C(O)NR ₂, C(O)R, and CN groups, in excellent yields with high regio- and stereoselectivity. The [Co(P1)]-catalyzed amination system provides a direct method for the synthesis of α-amino acid derivatives from the corresponding carboxylate precursors.

Full text of DOI:10.1021/ol302511f

ORGANIC
LETTERS
2012
Vol. 14, No. 19
5158–5161
Stereoselective Radical Amination of
Electron-Deficient C(sp3)ÀH Bonds by
Co(II)-Based Metalloradical Catalysis:
Direct Synthesis of r‑Amino Acid
Derivatives via r‑CÀH Amination
Hongjian Lu,†,‡ Yang Hu,† Huiling Jiang,† Lukasz Wojtas,† and X. Peter Zhang*,†
Department of Chemistry, University of South Florida, Tampa, Florida 33620-5250,
United States, and Institute of Chemistry and BioMedical Sciences, Nanjing University,
Nanjing 210046, P. R. China
xpzhang@usf.edu
Received September 12, 2012
ABSTRACT
The cobalt(II) complex of 3,5-DitBu-IbuPhyrin, [Co(P1)], is an effective catalyst for intramolecular amination of electron-deficient CÀH bonds,
including those adjacent to electron-withdrawing CO2R, C(O)NR2, C(O)R, and CN groups, in excellent yields with high regio- and stereoselectivity.
The [Co(P1)]-catalyzed amination system provides a direct method for the synthesis of R-amino acid derivatives from the corresponding
carboxylate precursors.
Nitrogen-containing compounds are of central impor-
tance in biology and medicine.1 The development of
synthetic methodologies that allow for selectiveconversion
of omnipresent CÀH bonds intovaluableamine functional
groups promises to transform the art and practice of
organic synthesis and should lead to many new applica-
tions. Among several approaches, catalytic CÀH amina-
tion via metal-mediated nitrene insertion represents one
of the most general and direct methods for installation
of amino functionalities with potential control of various
selectivities. Research efforts in this direction have been
exceedingly prolific and have led to the development of
a number of CÀH amination systems based on different
combinations of metal catalysts and nitrene sources.2
Represented by dirhodium(II) tetracarboxylate catalysts
in conjunction with in situ generated iminoiodane nitrene
sources, existing catalytic systems have enabled effective
amination of benzylic, allylic, and otherelectron-rich CÀH
bonds with high regio- and stereoselectivity.2 The potential
of catalytic amination, however, has not been fully ex-
tended to other types of more challenging CÀH bonds,
especially the electron-deficient CÀH bonds due to their
incompatibility with electrophilic metallonitrene inter-
mediates intervened in most current catalytic systems.
† University of South Florida.
‡ Nanjing University.
(1) (a) Nugent, T. C. Chiral Amine Synthesis: Methods, Developments
and Applications; Willey-VCH: Weinheim, 2010. (b) Ricci, A. Amino
Group Chemistry: From Synthesis to the Life Sciences; Willey-VCH:
Weinheim, 2008. (c) Ricci, A. Modern Amination Methods; Wiley-VCH:
Weinheim, 2000. (d) Salvatore, R. N.; Yoon, C. H.; Jung, K. W. Tetrahedron
2001, 57, 7785. (e) Johannsen, M.; Jorgensen, K. A. Chem. Rev. 1998, 98,
1689. (f) Muller, T. E.; Beller, M. Chem. Rev. 1998, 98, 675. (g) Wolfe,
J. P.; Wagaw, S.; Marcoux, J. F.; Buchwald, S. L. Acc. Chem. Res. 1998,
31, 805. (h) Hartwig, J. F. Acc. Chem. Res. 1998, 31, 852.
(2) (a) Zalatan, D. N.; Du Bois, J. Top. Curr. Chem. 2010, 292, 347.
(b) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061.
(c) Davies, H. M. L.; Manning, J. R. Nature 2008, 451, 417. (d) Davies,
H. M. L. Angew. Chem., Int. Ed. 2006, 45, 6422. (e) Davies, H. M. L.;
Long, M. S. Angew. Chem., Int. Ed. 2005, 44, 3518. (f) Muller, P.; Fruit,
C. Chem. Rev. 2003, 103, 2905.
r
10.1021/ol302511f
Published on Web 09/21/2012
2012 American Chemical Society

The CÀH bonds in the R-position of electron-withdraw-
ing groups such as esters, amides, ketones, and nitriles are
the common electron-deficient CÀH bonds that have not
been successfully demonstrated for metal-catalyzed amina-
tion. Clearly, this mode of transformation would be highly
desirable because R-CÀH amination of esters and amides
may offer a direct method for stereoselective synthesis of
biologically important R-amino acid derivatives.3 To the
best of our knowledge, the only previous report that briefly
touched the subject is the Rh2-catalyzed intramolecular
R-CÀH amination of N-Boc-protected sulfamide esters.4,5
Evidently, amination of electron-deficient CÀH bonds is
an unaddressed issue that faces formidable challenges in
both reactivity and regioselectivity.
Co(II)/azide-based CÀH amination that involves an unu-
sual Co(III)-nitrene radical intermediate undergoing a step-
wise radical abstractionÀsubstitution pathway.7b,c,12,13 Con-
sidering the nonelectrophilic nature of this radical mechan-
ism, which is fundamentally different from the electrophilic
metallonitrene mechanism shared by the widely studied
Rh2 and other closed-shell systems, we envisaged the pos-
sibility of addressing the aforementioned challenge of intra-
molecular electron-deficient CÀH amination through
Co(II)-based metalloradical catalysis.
Scheme 1. Ligand Effect on Intramolecular Amination of
Electron-Deficient CÀH Bonds by Co(II) Porphyrins
Cobalt(II) porphyrins, a family of stable metalloradicals
with well-defined open-shell doublet d7 electronic struc-
ture, have recently arisen as a new class of catalysts for
selective CÀH amination.6 These Co(II)-based metallor-
adical catalysts have proven to be unusually effective on the
activation of various organic azides, including sulfonyl,7
phosphoryl,8 carbonyl,9 and aryl10 azides, for amination
of broad classes of CÀH bonds under neutral and non-
oxidative conditions.11 Particularly, Co(II) complexes of
D2h-symmetric amidoporphyrins [Co(D2h-Por)] have re-
vealed an uncommon catalytic capacity for efficient intra-
molecular amination of strong primary CÀH bonds7b,8 and
have also displayed excellent chemoselectivity for intra-
molecular allylic CÀH amination over the competitive
CdC aziridination.7c Several lines of experimental and
computational evidence back the radical mechanism of
At the onset of our investigation, we evaluated the
catalytic intramolecular CÀH amination reaction of
N-benzyl sulfamoyl azide 1a,14,15 which contains electron-
deficient secondary CÀH bonds positioned R to the ester
unit, by Co(II) porphyrins (Scheme 1). Under the typical
neutral and nonoxidative conditions of Co(II)-based me-
talloradical catalysis, we were thrilled to find that even the
simple [Co(TPP)] was capable of aminating the electron-
deficient secondary R-CÀH bonds in 1a to form the
corresponding six-membered cyclic sulfamide-based amino
acid ester 2a despite the fact that a relatively higher catalyst
loading (5 mol %) was employed. Although the yield was
moderate (41%), the R-CÀH amination was very clean
without observation of β-CÀH amination, indicative of
its slow reaction rate. When the Co(II) complex of D2h-
symmetric amidoporphyrin 3,5-DitBuIbuPhyin [Co(P1)]
was employed as the catalyst,7b,c,8 the amination rate was
drastically enhanced to afford the desired amino acid
derivative 2a in 98% yield in spite of a lower catalyst
loading (2 mol %). This ligand-enhanced catalysis is pre-
sumably contributed to the cooperative hydrogen bonding
interaction between the groups SdO of the substrate and
N;H of the catalyst.13a,16
(3) (a) Najera, C.; Sansano, J. M. Chem. Rev. 2007, 107, 4584.
(b) Maruoka, K.; Ooi, T. Chem. Rev. 2003, 103, 3013. (c) Easton, C. J.
Chem. Rev. 1997, 97, 53.
(4) Kurokawa, T.; Kim, M.; Du Bois, J. Angew. Chem., Int. Ed. 2009,
48, 2777.
(5) For Cu(I)-catalyzed intermolecular R-amination of arylacetate
esters and aryl ketones with di-tert-butyldiaziridinone for formation of
hydantoins and imidazolinones, respectively, see: (a) Zhao, B. G.; Du,
H. F.; Shi, Y. J. Am. Chem. Soc. 2008, 130, 7220. (b) Zhao, B. G.; Du,
H. F.; Shi, Y. J. Org. Chem. 2009, 74, 4411.
(6) (a) Lu, H. J.; Zhang, X. P. Chem. Soc. Rev. 2011, 40, 1899. (b) Che,
C. M.; Lo, V. K. Y.; Zhou, C. Y.; Huang, J. S. Chem. Soc. Rev. 2011, 40,
1950. (c) Driver, T. G. Org. Biomol. Chem. 2010, 8, 3831.
(7) (a) Ruppel, J. V.; Kamble, R. M.; Zhang, X. P. Org. Lett. 2007, 9,
4889. (b) Lu, H.; Jiang, H.; Wojtas, L.; Zhang, X. P. Angew. Chem., Int.
Ed. 2010, 49, 10192. (c) Lu, H.; Jiang, H.; Yang, H.; Wojtas, L.; Zhang,
X. P. Chem. Sci. 2011, 2, 2361.
(8) Lu, H. J.; Tao, J. R.; Jones, J. E.; Wojtas, L.; Zhang, X. P. Org.
Lett. 2010, 12, 1248.
(9) Lu, H. J.; Subbarayan, V.; Tao, J. R.; Zhang, X. P. Organome-
tallics 2010, 29, 389.
(10) (a) Cenini, S.; Gallo, E.; Penoni, A.; Ragaini, F.; Tollari, S.
Chem. Commun. 2000, 2265. (b) Ragaini, F.; Penoni, A.; Gallo, E.;
Tollari, S.; Gotti, C. L.; Lapadula, M.; Mangioni, E.; Cenini, S. Chem.
Eur. J. 2003, 9, 249.
(11) For reviews on the use of azides as nitrene sources for metal-
catalyzed nitrene transfers, see: (a) Reference 6a. (b) Reference 6b.
(c) Reference 6c. (d) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.;
Fantauzzi, S.; Piangiolino, C. Coord. Chem. Rev. 2006, 250, 1234.
(e) Katsuki, T. Chem. Lett. 2005, 34, 1304.
(14) Sulfamoyl azides were reported to be chemically stable, even in
strong acidic and basic conditions (see ref 15). Our DSC experiments
indicated that these sulfamoyl azides were thermally stable without
decomposition up to at least 100 °C; see Supporting Information for a
representative DSC plot of azide 1a.
(15) (a) Griffith, J. J. Chem. Soc. C 1971, 3191. (b) Goddard-Borger,
E. D.; Stick, R. V. Org. Lett. 2007, 9, 3797.
(16) Ruppel, J. V.; Jones, J. E.; Huff, C. A.; Kamble, R. M.; Chen, Y.;
(12) For detailed studies on the radical mechanism of [Co(Por)]-
catalyzed CÀH amination, including EPR observation of Co(III)-nitrene
radical intermediates, see: Lyaskovskyy, V.; Suarez, A. I. O.; Lu, H.;
Jiang, H.; Zhang, X. P.; de Bruin, B. J. Am. Chem. Soc. 2011, 133, 12264.
(13) For related DFT studies on the radical mechanism of Co(Por)]-
catalyzed olefin aziridination, see: (a) Suarez, A. I. O.; Jiang, H. L.;
Zhang, X. P.; de Bruin, B. Dalton Trans. 2011, 40, 5697. (b) Hopmann,
K. H.; Ghosh, A. ACS Catal. 2011, 1, 597.
Zhang, X. P. Org. Lett. 2008, 10, 1995.
Org. Lett., Vol. 14, No. 19, 2012
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substrates, the [Co(P1)]-catalyzed amination has been
shown to be compatible with sulfamoyl azides having varied
N-substitutions including oxidizable functional groups.7b,c
Relatively slower reaction rates, however, were noticed
for azide substrates that contain N-electron-withdrawing
groups as shown with azides 1m and 1n (entries 13À14).
Scheme 2. Regio- and Stereoselective Intramolecular
Amination of Electron-Deficient CÀH Bonds by [Co(P1)]a,b
To shed some light on the origin of the remarkable
catalytic capacity of the Co(II)-based system toward
selective amination of electron-deficient CÀH bonds, we
performed a direct competition experiment between electron-
deficient and -rich secondary CÀH bonds with similar
steric environments by choosing N-n-butyl sulfamoyl azide
ketone 1o as the amination substrate (eq 1). Under the
standard catalysis of [Co(P1)], the reaction of 1o afforded
two products 2oA and 2oB in 80% and 12% yields, res-
pectively, indicating that 1,6-amination of electron-defi-
cient CÀHA was considerably faster than that of electron-
rich CÀHB. This seemingly very surprising result can be
rationalized on the basis of the stepwise radical abstractionÀ
substitution mechanism of the Co(II)-catalyzed CÀH ami-
nation.7b,c,12,13 Since the CÀHA bond (92 kcal molÀ1) is
significantly weaker than the CÀHB bond (98 kcal molÀ1),17
the H-atom abstraction by the key Co(III)-nitrene radical
intermediate is expected to be more facile for HA than HB.
a [1] = 0.10 M. b Isolated yields. c 4 mol % [Co(P1)]. d 80 °C for 3 h.
e Diastereomeric ratios determined by 1H NMR. f Confirmed by X-ray
crystallographic structure analysis. g Purity of azides: 93À95%. h 5 mol %
of [Co(P1)] at 80 °C for 1 h .
The [Co(P1)]-catalyzed intramolecular amination was
found to be generally effective for various types of elec-
tron-deficient CÀH bonds (Scheme 2). In addition to the
R-CÀH bonds of the ester 1a (entry 1), the Co(II)-based
system could efficiently catalyze R-CÀH amination of
amides, ketones, and nitriles as demonstrated with reac-
tions of azides 1bÀ1d, respectively, affording the desired
amination products2bÀ2dinexcellent yields(entries 2À4).
Its complete regioselectivity toward 1,6-amination of elec-
tron-deficient CÀH bonds was further highlighted by the
high-yielding diastereoselective reactions of the β-substi-
tuted azides 1eÀ1f without any interference from 1,5- or
1,6-amination of the electron-rich CÀH bonds (entries
5À6). Higher to excellent diastereoselectivities were
achieved for regioselective R-CÀH amination of enantio-
pure γ-substituted azide esters 1gÀ1h, affording optically
active bis-R-amino acid derivatives 2gÀ2h in high yields
(entries 7À8), which is in stark contrast to the Rh2-
catalyzed amination.4 Furthermore, β,γ-disubstituted sub-
strates such as cyclohexane-based cis- and trans-azide
ketones 1iÀ1j could be diastereoselectively aminated to
produce the 6,6-bicyclic structures 2iÀ2j in high yields
(entries 9À10). As expected, the [Co(P1)]-catalyzed amina-
tion could be well applied to electron-deficient tertiary
CÀH bonds as exemplified with azide ester 1k and azide
ketone 1l, resulting in high-yielding formation of R,R-
disubstituted R-amino acid and ketone 2k and 2l, respec-
tively (entries 11À12). In addition to N-benzyl-substituted
Additional support for the participation of an H-atom
transfer (HAT) key step in the radical mechanism of the
Co(II)-based metalloradical amination was obtained
through the measurement of kinetic isotope effect (KIE)
(eq 2). When sulfamoyl azide ester 1p, in which one of two
R-H-atoms is replaced with a deuterium atom, was sub-
jected to the standard catalytic conditions by [Co(P1)], the
high-yielding reaction generated a mixture of two R-amino
acid esters 2p-H and 2p-D, which resulted from R-CÀH and
R-CÀD amination, respectively, of the monodeuterated
1
substrate. Analysis of the product mixture by H NMR
provided an intramolecular KIE of 6.6. This degree of
primary KIE, which is substantially greater than the deter-
mined value of 1.9 for Rh2-catalyzed intramolecular amina-
tion of benzylic CÀH bonds,18 is comparable to that
measured for Co(II)-based metalloradical allylic CÀH
amination,7c indicating the involvement of direct CÀH
(17) Luo, Y. R. Comprehensive Handbook of Chemical Bond Energies;
CRC: Boca Raton, FL, 2007.
(18) Fiori, K. W.; Espino, C. G.; Brodsky, B. H.; Du Bois, J.
Tetrahedron 2009, 65, 3042.
5160
Org. Lett., Vol. 14, No. 19, 2012

bond rupture via the HAT process by the key Co(III)-
nitrene radical intermediate.7b,c,12,13
radical abstractionÀsubstitution mechanism of the Co(II)-
based metalloradical CÀH amination.7b,c,12,13
Due to their stereogenic centers that are substituted with
important functionalities such as ester, amide, ketone, and
nitrile groups, the family of six-membered cyclic sulfa-
mides constructed through Co(II)-catalyzed intramolecu-
lar R-amination of electron-deficient CÀH bonds may find
useful applications as intermediates for stereoselective
synthesis, in addition to their known biomedical ap-
plications as potential inhibitors of several important
enzymes.19 In particular, the resulting cyclic sulfamide
esters and amides are the direct precursors for the synthesis
of R,γ-diamino acid derivatives upon removal of the SO2
unit. As a demonstration of this aspect of application,
cyclic sulfamide ester 2m could be effectively converted to
R,γ-diamino acid ester 4m in 88% yield when it was treated
with CCl3CH2OH in the presence of DMAP (eq 3).4 Since
the R- and γ-amine groups in 4m are differentially pro-
tected, its further transformations should provide access to
various R,γ-diamino acid derivatives.
Scheme 3. TEMPO Trapping of Carbon-Based Radical
Intermediate Involved in Radical Mechanism of Co(II)-Based
Metalloradical CÀH Amination
In an effort to trap the resulting carbon-based radical after
H-atom abstraction by the Co(III)-nitrene radical inter-
mediate, we carried out catalytic intramolecular CÀH ami-
nation of azide ester 1a by [Co(P1)] in the presence of stable
oxygen-based radical TEMPO (Scheme 3). Addition of
substoichiometric amounts of TEMPO was found to have
no significant effect on the catalytic reaction as previously
observed for Co(II)-catalyzed intramolecular allylic CÀH
amination.7c This observation, which seems to be abnormal
for a catalytic reaction involved with radical intermediates, is
actually consistent with the very low barrier (or barrierless)
of the subsequent intramolecular homolytic substitution
(SHi) step suggested by the DFT calculations of related
catalytic systems.12,13 When the amount of added TEMPO
was increased to 5 equiv, however, the conversion of 1a was
decreased to 90% with 10% of the starting azide 1a remain-
ing under the same catalytic conditions (Scheme 3). While
the R-amino acid ester 2a was still formed as the major
product in 67% yield, the reaction generated a new product
3a in 18% yield. Detailed characterizations revealed 3a as a
TEMPO-containing sulfamide in which the TEMPO unit is
attached to the R-position of the ester group via CÀO bond
formation. As illustrated in Scheme 3, the production of 3a
was likely originated from the intermediate 1aC that was
formed from TEMPO trapping of the C-based radical
intermediate 1aB. Presumably due to steric reasons, the
initially generated Co(III)-nitrene radical intermediate 1aA
could undergo the HAT process to generate 1aB without
being affected by the presence of TEMPO. Together with the
competition experiment and kinetic isotope effect, we take
these results as new experimental evidence for the stepwise
In summary, we have demonstrated, for the first time, the
stereoselective amination of electron-deficient C(sp3)ÀH
bonds by applying Co(II)-based metalloradical catalysis to
intramolecular R-CÀH amination of esters, amides, ketones,
and nitriles. In addition to high-yielding performance and its
neutral and nonoxidative conditions, the Co(II)-catalyzed
amination can proceed with high regio- and diastereoselec-
tivity. Among other potential applications, the catalytic
process offers an enabling approach for the stereoselective
synthesis of R-amino acid derivatives through direct R-CÀH
amination of the corresponding esters and amides. We have
shown, through the combination of a competition reaction,
measurement of the kinetic isotope effect, and radical trap-
ping experiment, that the unparalleled profile of activity and
selectivity exhibited by Co(II)-catalyzed amination is attrib-
uted to its unique radical mechanism that involves the
Co(III)-nitrene radical intermediate undergoing a stepwise
radical abstractionÀsubstitution pathway. As a further out-
come of metalloradical catalysis, CÀH bond-dissociation
energy (BDE) is recognized as a fundamentally important
factor in controlling and differentiating the reactivity and
selectivity of various CÀH bonds.
Acknowledgment. We are grateful for financial support
by the NSF (CHE-1152767) and NIH (R01-GM098777).
Supporting Information Available. Experimental pro-
cedures and analytical data for all compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(19) (a) Reitz, A. B.; Smith, G. R.; Parker, M. H. Expert Opin. Ther.
Patents 2009, 19, 1449. (b) Winum, J. Y.; Scozzafava, A.; Montero, J. L.;
Supuran, C. T. Expert Opin. Ther. Patents 2006, 16, 27.
The authors declare no competing financial interest.
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