Intermolecular Rhodium(II)-Catalyzed Allylic C(sp3)–H Amination of Cyclic Enamides

Article abstract of DOI:10.1002/adsc.201701188

The intermolecular rhodium(II)-catalyzed C(sp³)–H amination of enamides gives access to new 4-aminopiperidine derivatives that are useful building blocks in medicinal chemistry. This efficient transformation proceeds at room temperature with complete regio- and chemoselectivity in favor of the allylic C(sp³)–H bond, and has a broad functional group tolerance. In addition, the matched combination of the chiral complex Rh₂(S-nta)₄ [nta=(S)-N-1,8-naphthoylalanine] with an optically pure (S)-sulfonimidamide allows the isolation of allylic amines with excellent stereocontrol. (Figure presented.).

Full text of DOI:10.1002/adsc.201701188

Title: Intermolecular Rhodium(II)-Catalyzed Allylic C(sp3)-H Amination
of Cyclic Enamides
Authors: Isabelle Gillaizeau , Philippe Dauban, Gregory jestin, Romain
Rey-Rodriguez, pascal retailleau, and Benjamin Darses
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201701188
Link to VoR: http://dx.doi.org/10.1002/adsc.201701188

10.1002/adsc.201701188
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Intermolecular Rhodium(II)-Catalyzed Allylic C(sp3)-H
Amination of Cyclic Enamides
Romain Rey-Rodriguez,a,b Grégory Jestin,a Vincent Gandon,c Gwendal Grelier,b Pascal
Retailleau,b Benjamin Darses,b Philippe Dauban,b* and Isabelle Gillaizeaua*
a
Institute of Organic and Analytical Chemistry, ICOA UMR 7311 CNRS, Université d’Orléans, rue de Chartres, 45100
Orléans, France
[e-mail: isabelle.gillaizeau@univ-orleans.fr]
Institut de Chimie des Substances Naturelles, CNRS UPR 2301, Université Paris-Sud, Université Paris-Saclay, avenue
b
de la terrasse, 91198 Gif-sur-Yvette, France
[e-mail : philippe.dauban@cnrs.fr]
Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Univ. Paris-Sud, Université Paris-Saclay,
c
91405 Orsay, France
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. The intermolecular Rh(II)-catalyzed C(sp3)–H
amination of enamides gives access to new 4-aminopiperidine
derivatives that are useful building blocks in medicinal
chemistry. This efficient transformation proceeds at room
temperature with complete regio- and chemoselectivity in
favor of the allylic C(sp3)–H bond, and has a broad functional
group tolerance. In addition, the matched combination of the
chiral Rh2(S-nta)4 (nta = (S)-N-1,8-naphthoylalanine) with an
optically pure (S)-sulfonimidamide allows isolation of allylic
amines with excellent stereocontrol.
Keywords: Allylic amination; Enamide; Heterocycle;
Nitrene; Rhodium catalysis
favor the functionalization of the allylic position.
However, the corresponding intermolecular reaction is,
by comparison, much more difficult to achieve. The
Introduction
The ubiquity of nitrogen in life and material sciences
is a source of inspiration for the design of selective C–
N bond forming reactions. Significant achievements
have been made to this end through the discovery of
new processes for the direct amination of C(sp3)–H
bonds.[1] Particularly, the recent development of
transition metal-catalyzed nitrene C(sp3)–H insertion
reactions[2] has culminated in the design of efficient
methods that make catalytic C–H amination now a
standard tool in the total synthesis of complex
molecules.[3]
first
examples
of
efficient
intermolecular
chemoselective allylic C(sp3)–H amination reactions
have been recently reported following the careful
design
of
nitrene
precursors
and
metal
complexes,[11],[12] and these results demonstrate the
need for further investigation to extend their scope.
Catalytic allylic C(sp3)–H amination raises the issue
of chemoselectivity because metallanitrenes are well
known to add to alkenes to afford the corresponding
aziridines.[2-4] Several solutions have first arisen from
the use of tethered reagents that allow for delivering
the metal-bound nitrene species in an intramolecular
manner with high level of chemoselectivity. The
development of fine-tuned Rh,[5] Ru,[6] Fe,[7] Co,[8]
Ag,[9] and Mn[10] complexes has proved fruitful to
Figure 1. Background for the study.
1
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10.1002/adsc.201701188
Advanced Synthesis & Catalysis
Another issue to address with catalytic C(sp3)–H
occurred (entry 13). Control experiments showed no
reactivity in the absence of catalyst or oxidant.
amination reactions is their application to nitrogen
heterocycles. Hyperconjugative effects, particularly,
are responsible for the higher reactivity of C(sp3)–H
bonds to the nitrogen,[13] thereby making the
remote functionalization of other sites difficult to
perform, though efficient solutions have been
reported.[14] We have recently demonstrated that
catalytic nitrene transfers enable the regioselective
intermolecular oxyamidation of various -bonds.[15]
Specifically, the application of rhodium-catalyzed
nitrene additions[16] to enamides and enecarbamates
affords oxyaminated products in high yields, that can
be further transformed via the nucleophilic
displacement of the resulting N,O-acetals (Figure
1a).[15b] However, while exploring the scope of the
reaction, a different reactivity has been uncovered for
C2- or C3-substituted enamides.[17] Herein, we report
a novel access to 4-aminopiperidines,[18] a privileged
Table 1. Catalytic allylic C(sp3)–H amination of 1a.[a]
Entry Catalyst
Oxidant
Solvent
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Yield[b]
90%
88 %
70 %
73 %
0 %
1
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
PhI(OPiv)2
PhI(OAc)2
PhI(OPiv)2
PhI(OPiv)2
2
3c
4d
5e
6d
7f
Rh2(OAc)4 PhI(OPiv)2
Cu(OTf)2
PhI(OPiv)2
PhI(OPiv)2
0%
Cu2O,
0 %
motif
in
medicinal
chemistry
(i.e.
phenantroline
aminobenzoquinolizine) resulting from a catalytic
allylic C(sp3) H amination (Figure 1b).
8
9
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
Rh2(esp)2
PhI(OPiv)2
PhI(OPiv)2
PhI(OPiv)2
(CH2Cl)2
CH3CN
CH2Cl2
45 %
0 %
10
85 %
Results and Discussion
11
PhI(OPiv)2 CCl4/MeOH (1:1) 81 %
PhI(OPiv)2 CCl4/MeOH(1:1) 85 %
12g Rh2(esp)2
13h Rh2(esp)2
Previous studies have shown that the use of the
PhI(OPiv)2
Toluene
0%
TcesNH2
(2,2,2-Trichloroethoxysulfonamide)/
[a] Unless otherwise specified, all reactions were carried out
using: 1a (0.17 mmol), TcesNH2 (0.25 mmol), Rh2(esp)2 (2
mol%), PhI(OPiv)2 (0.33 mmol) in toluene (2 ml) at rt for
2h. [b] Isolated yield. [c] 1 equiv. of oxidant was used. [d] 1
mol% of catalyst was used. [e] The compound of C(sp3)-H
amination of toluene was isolated as the sole side product.
Rh2(esp)2 (esp: α,α,α',α'-tetramethyl-1,3-benzene-
dipropionate) system in the presence of olefins always
affords products resulting from addition to the -
bond.[15,16] However, application to 2-phenyl-enamide
1a[19] of the reaction conditions previously established
for enamide oxyamidation led us to observe a
complete switch in the chemoselectivity of the reaction
(Table 1). Thus, instead of isolating the product
resulting from functionalization of the -bond, we
isolated the allylic C(sp3) H aminated derivative 2a as
the sole compound. No trace of the corresponding
[g]
[f] 1 mol% of catalyst and 2 mol% of ligand were used.
Reaction conducted at 0 °C. [h] TsNH2 (1.5 equiv) was used
as the nitrene source.
1
The optimized reaction conditions for C(sp3)–H
amination were then applied to various C2-substituted
enamides 1a-p (Table 2).[19,21] The high
chemoselectivity for allylic C(sp3)–H amination over
oxyamidation was confirmed in each case. The
expected allylic amines were isolated with yields of up
to 90%. The reaction tolerates the presence of electron-
donating or electron-withdrawing groups on the
aromatic ring, the corresponding products having been
isolated with yields in the 35-82% range (2b-h). It is
worth mentioning that yields are intertwined with the
electronic properties of the aryl substituents; the
lowest yields being observed for electron-withdrawing
substituents (2e-h). Given the prevalence of
heterocycles in medicinal chemistry, we also evaluated
the tolerance of this method to enamides bearing fused
aromatic or heteroaromatic ring system at C2, such as
a naphtalene (1i), a benzothiophene (1j), an indole
(1k), or a benzofuran (1l). The bias of enamides 1j-l
toward allylic C(sp3)–H amination vs. oxyamidation
persisted, and no product arising from the competitive
functionalization of the heterocyclic double bond was
detected.[15a] This result showcases the potential
oxyamidated derivative 3a was observed on the H
NMR spectrum of the crude reaction mixture. The high
and unusual chemoselectivity of the transformation
prompted us to undertake a systematic study as the
intermolecular Rh-catalyzed allylic C(sp3) H
amination of enamide would afford a readily efficient
access to relevant 1,3 diamino motifs. A rapid
screening of the oxidants and their equivalents (Table
1, entries 1-3), the catalysts and their loading (entries
4-7), the solvents (entries 8-12) and the nitrene source
(entry 13) in the presence of compound 1a revealed
that the best yield was obtained by using TcesNH2 (1.5
equiv) as the nitrene source, in the presence of
Rh2(esp)2 (2 mol%) and PhI(OPiv)2 (2 equiv) in
toluene at room temperature (entry 1). Under these
conditions, the corresponding allylic aminated
enamide 2a was isolated in 90% yield after 2 hours of
reaction. Amination of toluene was observed as a side
reaction when Rh2(OAc)4 was used as the catalyst
(entry 5).[20] No side reaction via the formation of the
oxyamidated compound 3a was observed in the
presence of MeOH as a solvent (entries 11-12).[15b] By
using TsNH2 as the nitrene source, no reaction
2
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10.1002/adsc.201701188
Advanced Synthesis & Catalysis
application of this method to late stage diversification
of biologically active compounds. An interesting
result was also obtained starting from the enol
phosphate 1m. The product resulting from the C(sp3)–
H amination reaction was hydrolyzed in situ to the
corresponding 4-aminopiperidin-2-one 2m, which
could be advantageously used for further
functionalization. Finally, enynes 2n and 2o, or
enamide bearing an ester function (2p), which could
serve as valuable synthetic intermediates, were
tolerated.
product 2 under the oxidative reaction conditions. It is
worth mentioning that degradation was observed
starting from C2-alkyl enamides.
Table 3. Rh catalyzed allylic C(sp3)–H amination of C3-
substituted enamides.[a]
Table 2. Rh catalyzed allylic C(sp3)–H amination of C2-
substituted enamides 1.[a]
[a] Isolated yield. [b] Chemoselectivity determined by crude
[c]
1H NMR.
PhI(OAc)2 or PhI(OPiv)2 was used, see
Supporting Information.
These results then prompted us to extend the scope of
the C(sp3)–H amination reaction toward C3-
susbtituted enamides 1q-w (Table 3).[22] Successful
amination at the allylic position of 1q-v was performed
under optimized conditions to afford the
corresponding new 4-amino-substituted enamides 2q-
v with complete chemoselectivity and good yields. We
did not detect the formation of the corresponding
oxyamidated compound 3. Both electron-donating
(2r) and electron-withdrawing (2s-u) functional
groups were tolerated. As observed above, the
electronic nature of aryl substituents directly impacts
the reactivity of the adjacent allylic C(sp3)–H bond;
electron-rich arenes provide the highest yields.[23] This
trend was confirmed with dienamide 1v. The presence
of an electron-withdrawing substituent (i.e ester
group) onto the dienamide reduces the reactivity of the
proximal C(sp3)–H. Low yields observed in some
cases were considered to be due to the instability of
product 2 under the oxidative reaction conditions.
Moreover, these C3-substituted compounds also
permitted us to assess the influence of the N-protecting
group on the chemoselectivity of this process. Thus,
allylic amination was observed starting from the N-
(sulfonyl) dienamide 1v whereas use of the (p-
nitrobenzyl) endo-dienamide 1w led to a complete
switch of reactivity. Allylic amination was thus
disfavored in presence of the enamide 1w, although
C3-substituted, but electronically deactivated. The
oxyamidated product 3w was isolated in 87% yield as
the sole product with a complete diastereoselectivity in
[a] Isolated yield. [b] 3 equiv. of substrate was employed.
These results then prompted us to extend the scope of
the C(sp3)–H amination reaction toward C3-
susbtituted enamides 1q-w (Table 3).[22] Successful
amination at the allylic position of 1q-v was performed
under optimized conditions to afford the
corresponding new 4-amino-substituted enamides 2q-
v with complete chemoselectivity and good yields. We
did not detect the formation of the corresponding
oxyamidated compound 3. Both electron-donating
(2r) and electron-withdrawing (2s-u) functional
groups were tolerated. As observed above, the
electronic nature of aryl substituents directly impacts
the reactivity of the adjacent allylic C(sp3)–H bond;
electron-rich arenes provide the highest yields.[23] This
trend was confirmed with dienamide 1v. The presence
of an electron-withdrawing substituent (i.e ester
group) onto the dienamide reduces the reactivity of the
proximal C(sp3)–H. Low yields observed in some
cases were considered to be due to the instability of
3
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10.1002/adsc.201701188
Advanced Synthesis & Catalysis
favor of the cis isomer.[24] It is also noteworthy that no
reaction occurred with 2,3-disubstituted enamide,
probably due to steric hindrance.[25]
the 2-phenylenamide 1a led exclusively to the chiral
allylic amide 5a isolated in 90% yield as the single (R)-
isomer by analogy with our previous studies.[11b,26]
Notably, the X-ray crystal structure of 5a confirmed
the stereochemistry of the 4-amino enamides 5 (Figure
2).[27] The 4-amino enamides 5c, 5i, 5k, and 5m were
subsequently obtained with yields in the 64-93% range
as single diastereoisomers. It is worth mentioning that
5m thereby offers the possibility of performing further
functionalization.[28] However, contrary to what was
observed in Table 3 using the TcesNH2/Rh2(esp)2
system, no reaction occurred starting from C3-
substituted enamides, because the stereoselective
C(sp3) H amination with sulfonimidamides is
sensitive to steric hindrance as observed in our
previous studies. [11b,c]
Table 4. Diastereoselective Rh-catalyzed C(sp3) H
amination of enamides 1.[a]
Conclusion
In summary, we have demonstrated that the
chemoselectivity of catalytic nitrene additions can be
tuned by the substitution of the alkene in the case of
cyclic enamides. Thus, the presence of a C2- or a C3-
substituent prevents the nitrene transfer from
proceeding at the double bond, and the enamides
undergo an intermolecular rhodium-catalyzed allylic
C(sp3) H amination to afford the corresponding
amines with yields of up to 90%. This result
underscores the ability of the sulfamate/Rh2(esp)2
system to react preferentially with allylic C(sp3) H
bonds in an intermolecular process affording new C4-
aminated enamides under mild conditions. Excellent
reactivity and diastereoselectivity were also observed
using a combination of the (S)-sulfonimidamide 4 and
the chiral rhodium catalyst (Rh2(S-nta)4. This reaction
paves the way to the synthesis of complex biologically
active molecules and/or for late stage diversification.
Further investigations on expanding the scope and
applications of this method are underway in our
laboratory.
[a] Isolated yield.
Figure 2. X-ray structure of 5a.
Experimental Section
General procedure for C4-aminated enamides 2.
The chemoselectivity observed for the allylic C(sp3)
H amination of enamides convinced us to consider
whether we could also reach the same selectivity with
the conditions previously reported for the
stereoselective amination of hydrocarbons.[11b-d] This
C(sp3) H functionalization reaction involves the
combination of the chiral rhodium complex Rh2(S-
nta)4 (nta = (S)-N-1,8-naphthoylalanine) with an
optically pure chiral nitrene precursor, i.e. the (S)-
sulfonimidamide 4 (Table 4).[26] This matched pair of
reagents has been shown to promote the amination of
benzylic and allylic substrates as well as that of
alkanes, enol ethers and terpenes with high yields and
excellent stereocontrol. If successful with enamides, it
should give access to optically pure heterocyclic
structures. Pleasingly, in presence of the (S)-
sulfonimidamide 4 and the chiral complex Rh2(S-nta)4,
In an oven-dried sealable tube, enamide 1 (0.17 mmol, 1
equiv) was dissolved in dry toluene (2 mL). TcesNH2 (57
mg, 0.25 mmol, 1.5 equiv), Rh2(esp)2 (3 mg, 0.0034 mmol,
0.02 equiv), and PhI(OPiv)2 (138 mg, 0.34 mmol, 2 equiv)
were successively added and the reaction was stirred at
room temperature for 2 hours. After completion of the
reaction, the filtrate was concentrated in vacuo and the
residue was purified by column chromatography on silica
gel (petroleum ether/ethyl acetate) to afford the C4-
aminated enamide 2.
General procedure for C4-aminated enamides 5.
In an oven-dried sealable tube, enamide 1 (0.2 mmol, 1
equiv), Rh2(S-nta)4 (5 mg, 0.004 mmol, 0.02 equiv), (-)-N-
(p-toluenesulfonyl)-p-toluenesulfonimidamide 4 (78 mg,
0.24 mmol, 1.2 equiv) and 4Å molecular sieves (100 mg)
were successively added, the tube was capped with rubber
septum then purged three times with argon. 1,1,2,2-
4
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10.1002/adsc.201701188
Advanced Synthesis & Catalysis
tetrachloroethane (0.75 mL) and methanol (0.25 mL) were
added under argon. The tube was cooled to -78°C and
bis(tert-butylcarbonyloxy)iodobenzene (114 mg, 0.28
mmol, 1.4 equiv) was added. The reaction was stirred at -
35°C for 3 days. The filtrate was concentrated in vacuo and
the residue was purified by column chromatography on
silica gel using petroleum ether/ethyl acetate as eluent to
[9] a) J. W. Rigoli, C. D. Weatherly, J. M. Alderson, B. T.
Vo, J. M. Schomaker, J. Am. Chem. Soc. 2013, 135,
17238-17241; b) R. J. Scamp, J. G. Jirak, N. S. Dolan, I.
A. Guzei, J. M. Schomaker, Org. Lett. 2016, 18, 3014-
3017.
give the desired product
diastereoisomer (>99:1).
5
isolated as unique
[10] S. M. Paradine, J. R. Griffin, J. Zhao, A. L. Petronico,
S. M. Miller, M. C. White, Nat. Chem. 2015, 7, 987-994.
[11] a) N. S. Dolan, R. J. Scamp, T. Yang, J. F. Berry, J. M.
Schomaker, J. Am. Chem. Soc. 2016, 138, 14658-14667;
b) C. Liang, F. Collet, F. Robert-Peillard, P. Müller, R.
H. Dodd, P. Dauban, J. Am. Chem. Soc. 2008, 130, 343-
350; c) C. Lescot, B. Darses, F. Collet, P. Retailleau, P.
Dauban, J. Org. Chem. 2012, 77, 7232-7240; d) J.
Buendia, B. Darses, P. Dauban, Angew. Chem. Int. Ed.
2015, 54, 5697-5701. For a recent comprehensive
review on allylic amination, see: e) R. L. Grangea, E. A.
Clizbeb, P. A. Evans, Synthesis 2016, 48, 2911-2968.
Acknowledgements
The authors thank the French National Research Agency (program
n° ANR-11-IDEX-0003-02, CHARMMMAT ANR-11-LABX-0039,
SynOrg ANR-11-LABX-0029, and ANR-15-CE29-0014-01) for
financial support and fellowships (G. J., R. R.-R.).
References
[1] a) H. M. L. Davies, J. R. Manning, Nature 2008, 451,
417-424; b) F. Collet, R.H. Dodd, P. Dauban, Chem.
Commun. 2009, 5061-5074 ; c) D. N. Zalatan, J. Du Bois,
Top. Curr. Chem. 2010, 292, 347-378; d) J. L. Jeffrey,
R. Sarpong, Chem. Sci. 2013, 4, 4092-4106; e) S. Chiba,
H. Chen, Org. Biomol. Chem. 2014, 12, 4051-4060 ; f)
M.-L. Louillat, F. W. Patureau, Chem. Soc. Rev. 2014,
43, 901-910; g) R. R. Karimov, A. Sharma, J. F. Hartwig,
ACS Cent. Sci. 2016, 2, 715-724; h) Y. Park, Y. Kim, S.
Chang, Chem. Rev. 2017, 117, 9247-9301.
[12] For other relevant studies in the area of chemoselective
intermolecular C(sp3)-H amination, see: a) J. L. Roizen,
D. N. Zalatan, J. Du Bois, Angew. Chem. Int. Ed. 2013,
52, 11343-11346; b) E. N. Bess, R. J. DeLuca D. J.
Tindall, M. S. Oderinde, J. L. Roizen, J. Du Bois, M. S.
Sigman, J. Am. Chem. Soc. 2014, 134, 5783-5789; c) J.
Wang, C. Zhao, Y. Weng, H. Xu, Catal. Sci. Technol.,
2016, 6, 5292-5303.
[13] a) S. Toumieux, P. Compain, O. R. Martin, M. Selkti,
Org. Lett. 2006, 8, 4493-4496; b) S. Wang, D. Romo,
Angew. Chem. Int. Ed. 2008, 47, 1284-1286; c) M. Kono,
S. Harada, T. Nemoto, Chem. Eur. J. 2017, 23, 7428-
7432.
[2] a) P. Müller, C. Fruit, Chem. Rev. 2003, 103, 2905-
2960 ; b) M. M. Díaz-Requejo, P. J. Pérez, Chem. Rev.
2008, 108, 3379-3394; c) K. Huard, H. Lebel, Chem. Eur.
J. 2008, 14, 6222-6230; d) S. Fantauzzi, A. Caselli, E.
Gallo, Dalton Trans. 2009, 5434-5443; e) T. G. Driver,
Org. Biomol. Chem. 2010, 8, 3831-3846; f) J. W. W.
Chang, T. M. U. Ton, P. W. H. Chan, Chem. Rec. 2011,
11, 331-357; g) J. L. Roizen, M. E. Harvey, J. Du Bois,
Acc. Chem. Res. 2012, 45, 911-922; h) T. Uchida, T.
Katsuki, Chem. Rec. 2014, 14, 117-129; i) R. J. Scamp,
J. W. Rigoli, J. M. Schomaker, Pure Appl. Chem. 2014,
86, 381-393; j) J. Buendia, G. Grelier, P. Dauban, Adv.
Organomet. Chem. 2015, 64, 77-118.
[14] a) J. M. Howell, K. Feng, J. R. Clark, L. J. Trzepkowski,
M. C. White, J. Am. Chem. Soc. 2015, 137, 1459014593;
b) Y.-J.Liu, H. Xu, W.-J. Kong, M. Shang, H.-X. Dai,
J.-Q. Yu Nature 2014, 515, 389-393.
[15] a) S. Beaumont, V. Pons, P. Retailleau, R. H. Dodd, P.
Dauban, Angew. Chem. Int. Ed. 2010, 49, 1634-1637; b)
N. Gigant, G. Dequirez, P. Retailleau, I. Gillaizeau, P.
Dauban Chem. Eur. J. 2012, 18, 90-94; c) G. Dequirez,
J. Ciesielski, P. Retailleau, P. Dauban, Chem. Eur. J.
2014, 20, 8929-8933; d) J. Ciesielski, G. Dequirez, P.
Retailleau, V. Gandon, P. Dauban, Chem. Eur. J. 2016,
22, 9338-9347.
[3] a) D. Karila, R. H. Dodd, Curr. Org. Chem. 2011, 15,
1507-1538; b) J. Egger, E. M. Carreira, Nat. Prod. Rep.
2014, 31, 449-455; c) B. Darses, R. Rodrigues, L.
Neuville, M. Mazurais, P. Dauban, Chem. Commun.
2017, 53, 493-508.
[16] a) K. Guthikonda, J. Du Bois, J. Am. Chem. Soc. 2002,
124, 13672-13673 ; b) K. W. Fiori, J. Du Bois, J. Am.
Chem. Soc. 2007, 129, 562-568.
[4] L. Degennaro, P. Trinchera, R. Luisi, Chem. Rev. 2014,
114, 7881-7929.
[17] N. Gigant, L. Chausset-Boissarie, I. Gillaizeau, Chem.
Eur. J. 2014, 20, 7548-7564.
[5] a) D. N. Zalatan, J. Du Bois, J. Am. Chem. Soc. 2008,
130, 9220-9221 ; b) K. W. Fiori, C. G. Espino, B. H.
Brodsky, J. Du Bois, Tetrahedron 2009, 65, 3042-3051.
[18] P. Mattei, M. Boehringer, P. Di Giorgio, H. Fischer, M.
Hennig, J. Huwyler, B. Koçer, B. Kuhn, B. M. Loeffler,
A. MacDonald, R. Narquizian, Bioorg. Med. Chem.,
2010, 20, 1109-1113.
[6] M. E. Harvey, D. G. Musaev, J. Du Bois, J. Am. Chem.
Soc. 2011, 133, 17207-17216.
[19] a) 2-substituted enamides 1 were synthesized by Pd
cross-coupling reaction starting from enol phosphate
derivatives: D. Mousset, I. Gillaizeau, J. Hassan, F.
Lepifre, P. Bouyssou, G. Coudert, G. Tetrahedron Lett.
2005, 21, 3703-3705 and see Supporting Informations.
[7] S. M. Paradine, M. C. White, J. Am. Chem. Soc. 2012,
134, 2036-2039.
[8] H. Lu, H. Jiang, Y. Hu, L. Wojtas, X. P. Zhang, Chem.
Sci. 2011, 2, 2361-2366.
5
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10.1002/adsc.201701188
Advanced Synthesis & Catalysis
[20] D. A. Powell, H. Fan, J. Org. Chem. 2010, 75, 2726-
[26] Our previous studies have shown that both chiral
reagents are needed to secure good yields and
stereocontrol. Moreover, the synthesis of known
enantiopure amines and several X-ray crystallographic
studies of various allylic products have demonstrated
that (R)-enantiomers of the C-H aminated compounds
are obtained by combining the (S)-sulfonimidamide with
the (S)-rhodium complex. See: ref. 11b. (a) C. Liang, F.
Robert-Peillard, C. Fruit, P. Müller, R. H. Dodd, P.
Dauban, Angew. Chem. Int. Ed. 2006, 45, 4641-4644. (b)
M. Mazurais, C. Lescot, P. Retailleau, P. Dauban, Eur.
J. Org. Chem. 2014, 66-79.
2729.
[21] Various 5-, 6- and 7-membered ring cyclic enamides
were prepared but the C(sp3)—H amination reaction
proved successful only from the 6-membered ring
compounds.
[22] N. Gigant, L. Chausset-Boissarie, I. Gillaizeau, Org.
Lett. 2013, 15, 816-819 ; d) N. Gigant, L. Chausset-
Boissarie, M.-C. Belhomme, T. Poisson, X.
Pannecoucke, I. Gillaizeau, Org. Lett. 2013, 15, 278-
281; e) N. Gigant, I. Gillaizeau, Org. Lett. 2012, 14,
3304-3307.
[27] CCDC 1584973 (5a) contains the supplementary
crystallographic data for this paper. This data is provided
free of charge by the Cambridge Crystallographic Data
Centre.
[23] See also: a) T. Newhouse, P. S. Baran, Angew. Chem.
Int. Ed., 2011, 50, 3362-3374; b) A. G. H. Wee, B. Liu,
D. D. McLeod, J. Org. Chem. 1998, 63, 4218-4227.
[28] a) X.-H. Hu, X.-F. Yang, T.-P. Loh, Angew. Chem. Int.
Ed., 2015, 54, 15535-15539 and references cited herein;
b) E. Claveau, I. Gillaizeau, A. Bruel, G. Coudert, J. Org.
Chem. 2007, 72, 4832-4836.
[24] The stereochemistry was unambiguously established
by NMR 1D and 2D (see Supporting Information).
[25] Molecular orbital coefficients of C2-Ph substituted
enamide 1a, C3-Ph substituted enamide 1q and non-
substituted enamide were obtained by DFT
computations (see the Supporting Information), but they
did not allow to rationalize the selectivity.
6
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10.1002/adsc.201701188
Advanced Synthesis & Catalysis
FULL PAPER
Intermolecular Rhodium(II)-Catalyzed Allylic
C(sp3)-H Amination of Cyclic Enamides
Adv. Synth. Catal. Year, Volume, Page – Page
Romain Rey-Rodriguez, Grégory Jestin, Vincent
Gandon, Gwendal Grelier, Pascal Retailleau,
Benjamin Darses, Philippe Dauban,* and Isabelle
Gillaizeau*
7
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