Rhodium(iii)-catalyzed allylic C-H bond amination. Synthesis of cyclic amines from ω-unsaturated N-sulfonylamines

Article abstract of DOI:10.1039/c2cc36067e

For the first time, intramolecular allylic amination was conducted using rhodium(iii) according to an "inner-sphere" type mechanism with amines activated by only one electron-withdrawing group. The activation of C(sp ³)-H bonds was chemoselective and allows the access to a variety of substituted cyclic amines such as pyrrolidines and piperidines.

Full text of DOI:10.1039/c2cc36067e

View Article Online / Journal Homepage / Table of Contents for this issue
Dynamic Article Links
ChemComm
Cite this: Chem. Commun., 2012, 48, 10745–10747
www.rsc.org/chemcomm
COMMUNICATION
Rhodium(III)-catalyzed allylic C–H bond amination. Synthesis of cyclic
amines from x-unsaturated N-sulfonylaminesw
a
a
b
b
b
´
Thomas Cochet, Veronique Bellosta, Didier Roche, Jean-Yves Ortholand, Alfred Greiner
and Janine Cossy*a
Received 21st August 2012, Accepted 10th September 2012
DOI: 10.1039/c2cc36067e
For the first time, intramolecular allylic amination was con-
ducted using rhodium(III) according to an ‘‘inner-sphere’’ type
mechanism with amines activated by only one electron-
withdrawing group. The activation of C(sp3)–H bonds was
chemoselective and allows the access to a variety of substituted
cyclic amines such as pyrrolidines and piperidines.
N-S(O)-R), o-unsaturated N-tosylamides revealed to be the
more promising substrates. Upon extensive screening of the
reaction conditions with o-unsaturated N-tosylamide 1,
rhodium(I), cationic or not, and rhodium(II) were found to
be ineffective in forming compounds 2 and 3. In contrast,
cationic rhodium(III) (Table 1) displayed significant catalytic
activity and good selectivity for the C–H amination, as
pyrrolidine 2 and tetrahydropyridine 3 were formed after
20 h at 120 1C in 55% yield in a 20/1 ratio using [RhCp*Cl2]2/
AgSbF6/Cu(OAc)2ꢀH2O in t-amyl alcohol (Table 1, entry 1).
Switching from t-amyl alcohol to 1,4-dioxane led to better yield
of 2 and 3, as these compounds were obtained in 73% global
yield in a 5.7/1 ratio after 16 h at 120 1C (Table 1, entry 2).
Increasing or decreasing the catalytic amount of [RhCp*Cl2]2
did not give satisfactory results (Table 1, entries 3 and 4).
In addition, all the reactants were necessary for the reaction
to take place. Indeed, by performing control experiments
C–H activation and functionalization has emerged as a power-
ful tool in organic synthesis and is an area of intense focus.1
Due to the prevalence of amino derivatives in biologically
active molecules, the formation of carbon–nitrogen bonds by
reaction of a nitrogen atom with a non-activated C–H bond is
of importance.2 Two strategies are used to realize the amina-
tion of C–H bonds. The first, and most reported one, is the use
of a nitrenoid species for the insertion of a nitrogen atom into
a C–H bond according to an ‘‘outer-sphere’’ mechanism.3,4
The second strategy involves direct activation of a C–H bond
by a metal to form a carbon–metal bond, which is then
functionalized by an amine to create the C–N bond following
an ‘‘inner sphere’’ mechanism.5 We have to point out that in
the ‘‘inner sphere’’ mechanism, the nucleophilic amines have
to be strongly activated by two electron-withdrawing groups.
Herein, we would like to report the first rhodium(III)-
catalyzed intramolecular C(sp3)–H amination using amines
only activated by one electron-withdrawing group such as
N-tosylamines A which led to cyclic amines of type B
(Scheme 1).6
Table 1 Optimisation of reaction conditions
Catalytic system
(mol%)
Yielda (2/3)
t (h) T (1C) (%)
Entry Solvent
1
2
3
4
5
6
t-AmOH [RhCp*Cl2]2 (5),
Cu(OAc)2 (210)
AgSbF6 (20)
Dioxane [RhCp*Cl2]2 (5),
Cu(OAc)2 (210)
AgSbF6 (20)
Dioxane [RhCp*Cl2]2 (10),
Cu(OAc)2 (240)
AgSbF6 (40)
Dioxane [RhCp*Cl2]2 (2.5), 20
Cu(OAc)2 (210)
AgSbF6 (10)
20
16
4
120
120
120
120
120
83
55 (>20/1)
73c (5.7/1b)
63d (only 2)
Traces
Based on previous results, rhodium(I),7 rhodium(II),4 and
rhodium(III),8,9 highly reactive species in oxidative C–H bond
functionalization, have been examined. Among the mono-
activated o-unsaturated amines (N-Boc, N-SO2R, N-C(O)-R,
Dioxane [(MeCN)3RhCp*]- 16
(SbF6)2 (5)
Cu(OAc)2 (210)
70c (2.5/1b)
77c (5/1b)
Scheme 1 General scheme.
DCE
[(MeCN)3RhCp*]- 16
(SbF6)2 (5)
Cu(OAc)2 (210)
a Laboratoire de Chimie Organique, ESPCI ParisTech,
CNRS UMR 7084, 10 rue Vauquelin, 75231-Paris Cedex 05,
France. E-mail: janine.cossy@espci.fr; Fax: +33 (0)140794660)
b Edelris s.a.s. 115, Avenue Lacassagne, 69003-Lyon, France
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc36067e
a
d
b
c
Isolated yield. Separable products. Complete conversion.
Incomplete conversion.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10745–10747 10745

View Article Online
without [RhCp*Cl2]2, AgSbF6 or Cu(OAc)2ꢀH2O, no conver-
sion of the starting material was observed. As AgSbF6 is not
easy to handle (very hygroscopic, rapid degradation), the
stable cationic rhodium(III) [(MeCN)3RhCp*](SbF6)2 was
tested.10 The use of this catalyst (5 mol%) in the presence of
Cu(OAc)2ꢀH2O (2.1 equiv.) under the same conditions as
previously described (1,4-dioxane, 120 1C, 16 h) gave satis-
factory results, as 2 and 3 were obtained in 70% yield, however
in a 2.5/1 ratio (Table 1, entry 5). Finally, using [(MeCN)3-
RhCp*](SbF6)2 (5 mol%) and Cu(OAc)2ꢀH2O (2.1 equiv.) in
1,2-dichloroethane (DCE) revealed to be the best conditions,
as the transformation of 1 proceeded smoothly at 83 1C and,
after 16 h, N-tosylpyrrolidine 2 and N-tosyltetrahydropyridine
3 were isolated in 77% yield in a 5/1 ratio in favour of 2
(Table 1, entry 6).
A variety of o-unsaturated N-tosylamines 4g–4h were
cyclized to test the generality of the method. When N-hex-
5-en-tosylamide 4g was involved in the C–H amination,
2-vinylpyrrolidine 5g was the only isolated product formed
in 50% isolated yield for a conversion of 60% of 4g, after 16 h
(Table 2, entry 7). The use of a-branched N-tosylamides 4h–4j
led to a better conversion of the starting material producing
pyrrolidines 5h–5j and piperidines 6h–6j in favor of the cis-
pyrrolidines 5h–5j (cis-5/trans-5 = 4/1) (Table 2, entries 8–10).
It is worth noting that only traces of the product corre-
sponding to the C–H insertion in aromatic bonds were
observed in the case of 4i (Table 2, entry 9), and no traces of
insertion in the benzylic C–H bond were detected when 4j was
involved in the C–H amination process (Table 2, entry 10). We
have to point out that longer reaction times did not improve
the conversions and yields, and by increasing the catalytic
amount of rhodium(III) species to 10 mol%, a complete
conversion of the starting material was observed without
improvement in the yield of products 5 and 6. The reaction
was extended to the formation of piperidines, as N-hept-6-
en-tosylamide 7 was cyclized into 2-vinylpiperidine 8a and
2-crotylpyrrolidine 8b in a B1/1 ratio, in 31% isolated yield
with a conversion of 45% of 7 (Scheme 2).
As tosylamide 1 gave satisfactory results, diversely substi-
tuted N-arylsulfonamides 4a–4f were examined. Among the
different electron-withdrawing protecting groups tested, the
best in terms of yield and selectivity was the p-methoxy-
benzenesulfonyl group as compound 4a was transformed into
pyrrolidine 5a and tetrahydropyridine 6a in 61% yield in
a ratio of 15/1 in favour of 5a (Table 2, entry 1). The use of
more electron-withdrawing groups, such as benzenesulfonyl
(compound 4b), p-bromobenzenesulfonyl (compound 4c) and
p-nitrobenzenesulfonyl (compound 4d) groups, increased the
acidity of the corresponding sulfonamides, but decreased their
reactivity (Table 2, entries 2–4). In addition, when o-nitrobenzene-
sulfonylamide 4e, a more acidic sulfonamide, was examined,
no evolution was observed (Table 2, entry 5). In contrast,
treatment of alkylsulfonamide 4f with [(MeCN)3RhCp*](SbF6)2/
Cu(OAc)2ꢀH2O led to the desired compounds 2g and 3g in 42%
yield in a 4/1 ratio (Table 2, entry 6).
Scheme 2 Synthesis of piperidines.
Based on the observed data and on the described rhodium(III)
catalytic cycles,8,9,11 the formation of tetrahydropyridines and
pyrrolidines from o-unsaturated N-tosylamides can be explained
by two pathways (Scheme 3). At first, a p-allylic rhodium
intermediate D can be formed and N-metalation can then occur
to produce intermediate E, which leads to pyrrolidine 2 after
reductive elimination. An alternative pathway leading to tetra-
hydropyridine 3 can take place via the formation of the non-
terminal olefin F resulting from the migration of a hydrogen.
From F, a p-allylic rhodium complex can be formed and
N-metalation can occur to produce G, which can lead to
tetrahydropyridine 3a after reductive elimination.
Table 2 Scope of the reactiona
Yieldb
Entry N-tosylamide
Products
% (tC) 5/6
1
2
3
4
5
6
61 (100) 15/1
32 (40) 7/1
25 (28) 3/1
14 (30) 4/1
— (0)
—
42 (100) 4/1c
In order to verify our hypothesis concerning the p-allylic
rhodium complex, compounds 9a and 9b, with respectively an
7
8
50 (60)
50
—
9/1c
9
25 (75) 15/1c
30 (83) 7/1c
10
a
Reaction conditions: 4 (0.1 mmol), catalyst (5 mol%), Cu(OAc)2ꢀH2O
b
c
(2.1 equiv.), DCE (1 mL), 83 1C, 16 h. Isolated yields. Inseparable
products. Ratio determined by 1H NMR.
Scheme 3 Catalytic cycles.
c
10746 Chem. Commun., 2012, 48, 10745–10747
This journal is The Royal Society of Chemistry 2012

View Article Online
Notes and references
1 (a) J. A. Labinger and J. E. Bercaw, Nature, 2002, 417, 507–514;
(b) K. Godula and D. Sames, Science, 2006, 312, 67–72;
´
(c) R. G. Bergman, Nature, 2007, 446, 391–393; (d) M. M. Dıaz-
Requejo and P. J. Perez, Chem. Rev., 2008, 108, 3379–3394;
´
(e) D. A. Colby, R. G. Bergman and J. A. Ellman, Chem. Rev.,
2010, 110, 624–655; (f) T. W. Lyons and M. S. Sanford, Chem.
Rev., 2010, 110, 1147–1169; (g) J. Wencel-Delord, T. Droge, F. Liu
¨
and F. Glorius, Chem. Soc. Rev., 2011, 40, 4740–4761;
(h) O. Baudoin, Chem. Soc. Rev., 2011, 40, 4902–4911.
2 (a) H. M. L. Davies, Angew. Chem., Int. Ed., 2006, 45, 6422–6425;
(b) P. Thansandote and M. Lautens, Chem.–Eur. J., 2009, 15,
5874–5883; (c) B. J. Stokes and T. G. Driver, Eur. J. Org. Chem.,
2011, 4071–4088; (d) F. Collet, C. Lescot and P. Dauban, Chem.
Soc. Rev., 2011, 40, 1926–1936; (e) T. A. Ramirez, B. Zhao and
Y. Shi, Chem. Soc. Rev., 2012, 41, 931–942.
3 (a) P. Muller and C. Fruit, Chem. Rev., 2003, 103, 2905–2920;
¨
(b) H. M. L. Davies and J. R. Manning, Nature, 2008, 451,
417–424; (c) S. Fantauzzi, A. Caselli and E. Gallo, Dalton Trans.,
2009, 5434–5443; (d) H. Lu and X. P. Zhang, Chem. Soc. Rev.,
2011, 40, 1899–1909; (e) G. Dequirez, V. Pons and P. Dauban,
Angew. Chem., Int. Ed., 2012, 51, 7384–7395.
4 (a) R. P. Reddy and H. M. L. Davies, Org. Lett., 2006, 8,
5013–5016; (b) Y. Liu, W. Xiao, M.-K. Wong and C.-M. Che,
Org. Lett., 2007, 9, 4107–4110; (c) C. Liang, F. Collet, F. Robert-
Peillard, P. Muller, R. H. Dodd and P. Dauban, J. Am. Chem. Soc.,
¨
2008, 130, 343–350; (d) T. Kurokawa, M. Kim and J. Du Bois, Angew.
Scheme 4 Control experiments.
E- and a Z-double bond, were prepared. It is worth noting
that those compounds possess two different allylic C–H
bonds at C5 and C8. Thus, substrates 9a and 9b were treated
with [(MeCN)3RhCp*](SbF6)2/Cu(OAc)2ꢀH2O in refluxing
DCE for 16 h to give in both cases piperidines 10 and
pyrrolidines 11 in a 1/1 ratio, possessing an E-double bond,
whatever the starting material (Scheme 4). The formation of
piperidines 10a and 10b can be explained by the insertion
of the rhodium catalyst in the allylic C–H bond at C8 to
form p-allylic complex H, which after N-metalation led to a
7-membered metalacycle producing piperidines 10a and 10b.
In addition, pyrrolidine 11b was obtained with a total isomeri-
zation of the double bond. These two observations are in
accordance with the formation of the p-allylic complexes H
and I. In order to avoid the formation of intermediate H,
sterically hindered N-tosylamide 12 was synthesized and treated
with [(MeCN)3RhCp*](SbF6)2/Cu(OAc)2ꢀH2O in refluxing DCE,
for 16 h (Scheme 5). Under these conditions, only piperidines 13
and 130 were isolated in a 9/1 ratio.
Chem., Int. Ed., 2009, 48, 2777–2779; (e) A. Norder, P. Herrmann,
¨
E. Herdtweck and T. Bach, Org. Lett., 2010, 12, 3690–3692;
(f) R. D. Grigg, J. W. Rigoli, S. D. Pearce and J. M. Schomaker,
Org. Lett., 2012, 14, 280–283; (g) K. Takahashi, D. Yamaguchi,
J. Ishihara and S. Hatakeyama, Org. Lett., 2012, 14, 1644–1647.
5 (a) E. M. Beccalli, G. Broggini, A. Fasana and M. Rigamonti,
J. Organomet. Chem., 2011, 696, 277–295; (b) G. T. Rice and
M. C. White, J. Am. Chem. Soc., 2009, 131, 11707–11711;
(c) S. A. Reed, A. R. Mazzotti and M. C. White, J. Am. Chem.
Soc., 2009, 131, 11701–11706; (d) L. Wu, S. Qiu and G. Liu, Org.
Lett., 2009, 11, 2707–2710; (e) S. A. Reed and C. M. White, J. Am.
Chem. Soc., 2008, 130, 3316–3318.
6 Another rare case of Rh(III)-catalyzed allylic C–H activation:
S. Rakshit, F. W. Patureau and F. Glorius, J. Am. Chem. Soc.,
2010, 132, 9585–9587.
7 H.-A. Ho, T. S. Gray, B. Baird, A. Ellern and A. D. Sadow, Dalton
Trans., 2011, 40, 6500–6514.
8 Reviews on rhodium(III): (a) T. Satoh and M. Miura, Chem.–Eur. J.,
2010, 16, 11212–11222; (b) D. A. Colby, A. S. Tsai, R. G. Bergman
and J. A. Ellman, Acc. Chem. Res., 2011, 45, 814–325; (c) G. Song,
F. Wang and X. Li, Chem. Soc. Rev., 2012, 41, 3651–3678;
(d) F. W. Patureau, J. Wencel-Delord and F. Glorius,
Aldrichimica Acta, 2012, 45, 31–41.
9 (a) T. K. Hyster and T. Rovis, Chem. Commun., 2011, 47,
11846–11848; (b) B.-J. Li, H.-Y. Wang, Q.-L. Zhu and Z.-J. Shi,
Angew. Chem., Int. Ed., 2012, 51, 3948–3952; (c) K. D. Hesp, R. G.
Bergman and J. A. Ellman, J. Am. Chem. Soc., 2011, 133,
11430–11433; (d) K. Morimoto, M. Itoh, K. Hirano, T. Satoh,
Y. Shibata, K. Tanaka and M. Miura, Angew. Chem., Int. Ed., 2012,
51, 5359–5362; (e) R. Zeng, C. Fu and S. Ma, J. Am. Chem. Soc., 2012,
134, 9597–9600; (f) J. Y. Kim, S. H. Park, J. Ryu, S. H. Cho, S. H. Kim
and S. Chang, J. Am. Chem. Soc., 2012, 134, 9110–9113; (g) K.-H. Ng,
Z. Zhou and W.-Y. Yu, Org. Lett., 2012, 14, 272–275; (h) L. Zheng,
J. Ju, Y. Bin and R. Hua, J. Org. Chem., 2012, 77, 5794–5800;
(i) C. Wang, H. Chen, Z. Wang, J. Chen and Y. Huang, Angew.
Chem., Int. Ed., 2012, 51, 7242–7245; (j) X. Wang, X. Li, J. Xiao,
Y. Jiang and X. Li, Synlett, 2012, 1649–1652; (k) L. Yang, B. Qian and
Scheme 5 Synthesis of piperidines.
In summary, we have shown for the first time that a
rhodium(III) catalyst is able to catalyze C(sp3)–H amination,
transforming o-unsaturated N-sulfonylamides into pyrrol-
idines and piperidines in moderate to good yields via,
probably, a p-allylic complex intermediate. In addition, this
transformation is selective towards allylic C–H bonds as
aromatic, benzylic and ethereal C–H bonds are not reactive
under these conditions. Further studies to increase the regio-
selectivity and to confirm the mechanism of this reaction are
under investigation.
¨
H. Huang, Chem.–Eur. J., 2012, 18, 9511–9515; (l) Z. Shi, N. Schroder
and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 8092–8096;
(m) N. Schroder, J. Wencel-Delord and F. Glorius, J. Am. Chem.
¨
Soc., 2012, 134, 8298–8301; (n) J. Wencel-Delord, C. Nimphius, F. W.
Patureau and F. Glorius, Angew. Chem., Int. Ed., 2012, 51, 2247–2251.
10 N. Guimond and K. Fagnou, J. Am. Chem. Soc., 2009, 131,
12050–12051.
11 (a) S. Rakshit, C. Grohman, T. Besset and F. Glorius, J. Am.
Chem. Soc., 2011, 133, 2350–2353; (b) H. Wang and F. Glorius,
Angew. Chem., Int. Ed., 2012, 51, 7318–7322.
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 10745–10747 10747