Stereoselective rhodium-catalyzed amination of alkenes

Article abstract of DOI:10.1021/ol2021516

The first stereoselective rhodium-catalyzed intermolecular aziridination and C-H amination of alkenes to produce chiral carbamate-protected aziridines and allylic amines is described. Good yields and diastereoselectivities were achieved using a readily av

Full text of DOI:10.1021/ol2021516

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5460–5463
Stereoselective Rhodium-Catalyzed
Amination of Alkenes
ꢀ ꢁ
Helene Lebel,* Cedric Spitz, Olivier Leogane, Carl Trudel, and Michael Parmentier
ꢀ
€
ꢀ
Departement de Chimie, Universite de Montreal, C.P. 6128, Succursale Centre-ville,
Montreal, Quebec, Canada H3C 3J7
ꢀ
ꢀ
ꢀ
ꢀ
helene.lebel@umontreal.ca
Received August 8, 2011
ABSTRACT
The first stereoselective rhodium-catalyzed intermolecular aziridination and CÀH amination of alkenes to produce chiral carbamate-protected
aziridines and allylic amines is described. Good yields and diastereoselectivities were achieved using a readily available chiral N-
tosyloxycarbamate and stoichiometric amount of the alkene substrate. Furthermore the protecting group is easy to cleave under mild
reaction conditions.
Nitrogen-containing molecules such as chiral amines are
ubiquitous components of biologically active products.1
Asa result, numeroussyntheticmethodsweredevelopedto
access these building blocks.2 Aziridines are one of the
smallest nitrogen-containing heterocycles which also dis-
play interesting biological activities.3 Furthermore, they
can undergo ring-opening reactions leading to a variety of
amine products.4 Typical methods to create CÀN bonds
involved functional group manipulations.2 Novel meth-
odologies to perform direct CÀH amination or aziridina-
tion reactions of carbon frameworks have recently been
described using metal-catalyzed nitrene transfer.5 Metal
nitrenes can be generated from azides,6 haloamines,5e,7 or,
most frequently, iminoiodinanes.8 Over the past decade,
(1) Hili, R.; Yudin, A. K. Nat. Chem. Biol. 2006, 2, 284.
(2) (a) Stradiotto, M.; Hesp, K. D. ChemCatChem 2010, 2, 1192. (b)
Nugent, T. C.; El-Shazly, M. Adv. Synth. Catal. 2010, 352, 753. (c)
Kobayashi, S.; Mori, Y.; Fossey, J. S.; Salter, M. M. Chem. Rev. 2011,
111, 2626.
(3) Ismail, F. M. D.; Levitsky, D. O.; Dembitsky, V. M. Eur. J. Med.
Chem. 2009, 44, 3373.
(4) (a) McCoull, W.; Davis, F. A. Synthesis 2000, 1347. (b) Hu, X. E.
Tetrahedron 2004, 60, 2701. (c) Taylor, A. M.; Schreiber, S. L. Tetra-
hedron Lett. 2009, 50, 3230. (d) Lu, P. F. Tetrahedron 2010, 66, 2549.
(5) (a) Watson, I. D. G.; Yu, L. L.; Yudin, A. K. Acc. Chem. Res.
2006, 39, 194. (b) Davies, H. M. L.; Manning, J. R. Nature 2008, 451,
417. (c) Collet, F.; Dodd, R. H.; Dauban, P. Chem. Commun. 2009, 5061.
(d) Giri, R.; Shi, B. F.; Engle, K. M.; Maugel, N.; Yu, J. Q. Chem. Soc.
Rev. 2009, 38, 3242. (e) Minakata, S. Acc. Chem. Res. 2009, 42, 1172. (f)
Zalatan, D. N.; Du Bois, J. In Topics in Current Chemistry, CÀH
Activation; Yu, J.-Q., Shi, Z., Eds.; Springer-Verlag: Berlin, 2010; Vol.
292, p 347. (g) Collet, F.; Lescot, C.; Liang, C.; Dauban, P. Dalton Trans.
2010, 39, 10401. (h) Collet, F.; Lescot, C.; Dauban, P. Chem. Soc. Rev.
2011, 40, 1926. (i) Lebel, H. In Catalyzed CarbonÀHeteroatom Bond
Formation; Yudin, A., Ed.; Wiley-VCH: Weinheim, 2011; p 137
(6) (a) Cenini, S.; Gallo, E.; Caselli, A.; Ragaini, F.; Fantauzzi, S.;
Piangiolino, C. Coord. Chem. Rev. 2006, 250, 1234. (b) Kawabata, H.;
Omura, K.; Uchida, T.; Katsuki, T. Chem.;Asian J. 2007, 2, 248. (c)
Ruppel, J. V.; Kamble, R. M.; Zhang, X. P. Org. Lett. 2007, 9, 4889. (d)
Jones, J. E.; Ruppel, J. V.; Gao, G. Y.; Moore, T. M.; Zhang, X. P.
J. Org. Chem. 2008, 73, 7260. (e) Subbarayan, V.; Ruppel, J. V.; Zhu, S.;
Perman, J. A.; Zhang, X. P. Chem. Commun. 2009, 4266. (f) Lu, H.;
Jiang, H.; Wojtas, L.; Zhang, X. P. Angew. Chem., Int. Ed. 2010, 49,
10192.
(7) (a) Albone, D. P.; Challenger, S.; Derrick, A. M.; Fillery, S. M.;
Irwin, J. L.; Parsons, C. M.; Takada, H.; Taylor, P. C.; Wilson, D. J.
Org. Biomol. Chem. 2005, 3, 107. (b) Bhuyan, R.; Nicholas, K. M. Org.
Lett. 2007, 9, 3957. (c) Liu, X. W.; Zhang, Y. M.; Wang, L.; Fu, H.;
Jiang, Y. Y.; Zhao, Y. F. J. Org. Chem. 2008, 73, 6207. (d) Wang, Z.;
Zhang, Y. M.; Fu, H.; Jiang, Y. Y.; Zhao, Y. F. Org. Lett. 2008, 10, 1863.
(8) (a) Dauban, P.; Dodd, R. H. Synlett 2003, 1571. (b) Wirth, T.
Angew. Chem., Int. Ed. 2005, 44, 3656. (c) Karila, D.; Dodd, R. H. Curr.
Org. Chem. 2011, 15, 1507.
r
10.1021/ol2021516
Published on Web 09/15/2011
2011 American Chemical Society

the use of iminoiodinanes has considerably progressed
with the possibility of generating the active species in situ
by oxidation of an amine reagent with a hypervalent iodine
reagent.9 Racemic aziridines were prepared using such a
methodology with a broad scope of substrates in good to
excellent yields.10 Several asymmetric intermolecular azir-
idination reactions of alkenes with iminoiodinanes using
chiral metal complexes have been reported, although the
scope of substrates was rather limited.11 Conversely, high
stereoselectivities were achieved for a wide range of sub-
strates, when azide reagents were used as metal nitrene
precursors in the presence of chiral ruthenium6b and cobalt
catalysts.6e A major drawback associated with these meth-
odologies is the synthesis of the complex chiral ligand
which required many steps. Furthermore, the existing
methods produced N-sulfonyl aziridines that required
harsh conditions to be cleaved, which are not compatible
with sensitive products such as aryl aziridines.12 The
N-(trimethylsilylethylsulfonyl) group has been introduced
to address this issue; however its cleavage required an
excess of expensive TASF and proceeds only in 62À65%
yield with arylaziridines.13 As a result there is still a need for
a general highly stereoselective method to produce pro-
tected aziridines that can be cleaved under mild reaction
conditions. Herein, we report the use of a stable, readily
available chiral N-tosyloxycarbamate as a metal nitrene
precursor to perform stereoselective intermolecular amina-
tion of alkenes in the presence of a chiral rhodium catalyst.
Our group has reported the use of transition-metal-cata-
lyzed decompositions of N-tosyloxycarbamates to perform
CÀH insertion and aziridination reactions.14 A number of
practical advantages are associated with these reagents: they
are easy to prepare via tosylation of N-hydroxycarbamates;
they can be stored at rt for up to 6 months, and thermo-
gravimetric analysis showed decomposition only above
180 °C. The CÀH insertion reaction is not sensitive to water
or solvent purity, proceeds at room temperature, and is
easily scaled up.14e An intermolecular version using trichloro-
ethyl-N-tosyloxycarbamate was developed which allowed
the amination of alkanes and the aziridination of styrenes in
good yields, producing respectively Troc-protected amines
and aziridines.14b,c We have recently reported an asymmetric
copper-catalyzed aziridination of styrenes with a more
hindered N-tosyloxycarbamate (1,1-dimethyl-2,2,2-trichloro-
ethyl-N-tosyloxycarbamate) that proceeded with only mod-
erate levels of enantioselectivities.14f A solution to this ongoing
problem might reside in the use of a chiral N-tosyloxycarba-
mate, in which inherent chirality would allow for double
stereodifferentiation.15 We thus prepared both enantio-
mers of 1-phenyl-2,2,2-trichloroethyl-N-tosyloxycarbamate
((()-1) from the corresponding readily available chiral
alcohol.16
The aziridination of 2-chlorostyrene was then tested in
the presence of various amino acid derived chiral rhodium
dimers.17,18 The best results were obtained with Rh2[(S)-
Br-nttl]4,19,20 which provided the corresponding aziridine
(À)-2 in 74% yield and 28:1 dr for the matched case (eq 1).
(15) Such a strategy has been previously reported by Dodd and
Dauban using a chiral sulfonimidamide (prepared in 23% yield via
fractional recrystallization of diastereomers) for rhodium-catalyzed
benzylic and allylic CÀH insertion reactions; see: Liang, C.; Collet, F.;
(9) (a) Yu, X. Q.; Huang, J. S.; Zhou, X. G.; Che, C. M. Org. Lett.
2000, 2, 2233. (b) Au, S. M.; Huang, J. S.; Che, C. M.; Yu, W. Y. J. Org.
Chem. 2000, 65, 7858. (c) Espino, C. G.; Du Bois, J. Angew. Chem., Int.
Ed. 2001, 40, 598.
€
Robert-Peillard, F.; Muller, P.; Dodd, R. H.; Dauban, P. J. Am. Chem.
Soc. 2008, 130, 343. The scope was however limited when similar chiral
sulfonimidamides were used in aziridination reactions. If acrylate sub-
strates produced the desired aziridine with 94% de, for styrene, only
65% de was obtained. See ref 11d and 11e for details.
(16) (R)-1-Phenyl-2,2,2-trichloroethanol was readily produced in
94% yield and 95% ee on 50 mmol scale via catalytic CBS-reduction,
according to literature procedure: Corey, E. J.; Bakshi, R. K. Tetra-
hedron Lett. 1990, 31, 611. See Supporting Information for details.
(17) See Supporting Information for details.
(10) (a) Guthikonda, K.; Du Bois, J. J. Am. Chem. Soc. 2002, 124,
13672. (b) Guthikonda, K.; Wehn, P. M.; Caliando, B. J.; Du Bois, J.
Tetrahedron 2006, 62, 11331.
(11) Reviews: (a) Pellissier, H. Tetrahedron 2010, 66, 1509. (b) Karila,
D.; Dodd, R. H. Curr. Org. Chem. 2011, 15, 1507. (c) Muchalski, H.;
Johnston, J. N. Sci. Synth., Stereosel. Synth. 2011, 1, 155. Selected
€
publications: (d) Fruit, C.; Robert-Peillard, F.; Bernardinelli, G.; Muller,
P.; Dodd, R. H.; Dauban, P. Tetrahedron: Asymmetry 2005, 16, 3484. (e)
Robert-Peillard, F.; Di Chenna, P. H.; Liang, C. G.; Lescot, C.; Collet, F.;
Dodd, R. H.; Dauban, P. Tetrahedron: Asymmetry 2010, 21, 1447.
(12) Desulfonylation by metal reduction was reported to produce
2-phenylaziridine, although this reaction was either contaminated with
ring-opened product or proceeded in low yield (40%). For further details,
see: Alonso, D. A.; Andersson, P. G. J. Org. Chem. 1998, 63, 9455–9461.
(13) (a) Dauban, P.; Dodd, R. H. J. Org. Chem. 1999, 64, 5304. (b)
Nishimura, M.; Minakata, S.; Takahashi, T.; Oderaotoshi, Y.; Komatsu,
M. J. Org. Chem. 2002, 67, 2101.
(14) (a) Lebel, H.; Huard, K.; Lectard, S. J. Am. Chem. Soc. 2005, 127,
14198. (b) Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639. (c) Lebel, H.;
Lectard, S.; Parmentier, M. Org. Lett. 2007, 9, 4797. (d) Huard, K.; Lebel,
H. Chem.;Eur. J. 2008, 14, 6222. (e) Huard, K.; Lebel, H. Org. Synth.
2009, 86, 59. (f) Lebel, H.; Parmentier, M. Pure Appl. Chem. 2010, 82, 1827.
(18) When the reaction was performed with an achiral catalyst (for
instance [Rh2(Oct)4]), less than 20% conversion of a 1:1 mixture of
diastereomers was obtained.
(19) Muller, P.; Ghanem, A. Org. Lett. 2004, 6, 4347.
(20) The effect of the nitrogen protecting group was less important
than the size of the R group, which is in sharp contrast with results
recently obtained in cyclopropanation reactions with the same catalysts
and diazo compounds. Our results suggested that the C2 or D2 sym-
metry would be the catalyst’s reactive conformation. See: (a) Lindsay,
V. N. G.; Lin, W.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 16383.
(b) DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am.
Chem. Soc. 2009, 131, 7230. (c) Hansen, J.; Davies, H. M. L. Coord.
Chem. Rev. 2008, 252, 545.
Org. Lett., Vol. 13, No. 20, 2011
5461

Lower yields and diastereoselectivities were obtained with
the other enantiomer of the Ph-TrocNHOTs (1) (eq 2).21
After optimizing the reaction conditions, aziridine 2 was
produced in 84% yield and 30:1 dr using 1 equiv of alkene
and 1.2 equiv of Ph-TrocNHOTs (Table 1, entry 1). In
contrast to existing procedures, the reaction is not sensitive
to either water or air and is run at room temperature for
only 90 min.22 The potassium tosylate byproduct is re-
moved by a simple filtration using Celite. Other 2-halos-
tyrenes produced the corresponding aziridine in good yields
and a high level of diastereoselectivity (entries 2À3). The
functional group compatibility with the halide substituent is
excellent, as no side reaction (such as a substitution reaction)
was observed. As a result, further functionalization of the
aziridine products would be possible using cross-coupling
reactions. The aziridine products are highly crystalline
materials, and an X-ray crystal structure was obtained for
aziridine 4 to confirm the absolute stereochemistry.17
Only moderate dr was observed with an electron-donat-
ing group in the ortho position. For instance 5.5:1 diaster-
eoselectivity was obtained for the aziridine derived from
2-methylstyrene (entry 4). Conversely, a good level of
stereoinduction was observed with para-substituted styrenes
(entries 5À9). It was possible to get a single diastereomer by
simple trituration in hexanes (entry 6). Good to excellent
diastereoselectivites were obtained with 2,4-disubstituted
styrenes (entries 10À12) as well as with 2,5- and 2,3-disub-
stituted styrenes (entries 13À15). Whereas 3,4-disubstituted
styrenes led to 7:1À9:1 dr (entries 16À17), quite surpris-
ingly, a low level of stereoinduction was obtained with meta-
substituted styrenes. For instance the 3-bromostyrene pro-
vided the desired aziridine in only a 2.8:1 dr (entry 18).
Additional mechanistic studies are necessary to explain this
latter substituent’s effect with regards to dr.
Table 1. Rhodium-Catalyzed Intermolecular Aziridination of
Styrenes with R-1
Besides the mild reaction conditions and the simplicity
of the purification procedure, another advantage asso-
ciated with this method is to produce Ph-Troc-protected
aziridines. Such a protecting group is easy to cleave under
basic conditions.14c When aziridine 6 was submitted to
lithium hydroxide in a biphasicmedia, free aziridine 19was
obtained in 93% yield without a ring-opening side reac-
tion; the corresponding chiral alcohol can also be recov-
ered in 73% yield without racemization (eq 3).
a Isolated yield by flash chromatography; aziridine products. b De-
termined by HPLC. c After trituration in hexanes using 1.5 equiv of
alkene and 1.0 equiv of R-1. d 1.5 equiv of alkene and 1.0 equiv of R-1.
e Determined by 1H NMR.
cis-β-methylstyrene also exclusively provided aziridine
21, albeit in moderate dr (eq 5). It should be however
noted that no isomerization from cis to trans product
was observed suggesting that the aziridination reaction
is concerted, presumably involving a singlet rhodium
nitrene species.
The aziridination of more substituted double bonds is
quite challenging, as the allylic amination becomes a
competitive pathway. We were pleased to find that the
rhodium-catalyzed aziridination of trans-β-methylstyrene
with R-1 proceeded with an exquisite level of chemo-
selectivity and stereospecificity, producing exclusively the
trans-aziridine 20 with a 17:1 dr (eq 4). The reaction of
(21) If 2 equiv of (()-1 and 1 equiv of alkene are used, the aziridine is
isolated with 88% ee, indicating a kinetic resolution.
(22) Typical asymmetric aziridination reactions are run for more
than 12 h, often at low temperature; see refs 6b, 6e, 11d, and 11e.
5462
Org. Lett., Vol. 13, No. 20, 2011

Other substituted Z-alkenes, such as indene, 1,2-dihy-
dronaphthalene, and Z-β-ethylstyrene also provided ex-
clusively the desired aziridines in 30À52% yields but as a
1:1 mixture of diastereomers. In sharp contrast, more
substituted E-alkenes lead to the corresponding CÀH
amination reaction (Table 2). Allylic amination products
were obtained from E-β-ethylstyrenes in moderate yields
and good diastereoselectivities (entries 1À3).
acetic acid.14d The corresponding allylic amine•HCl 26
was isolated in 92% yield without racemization (eq 6). If
the recovery of the chiral alcohol is necessary, this is
possible via carbamate exchange. Treating the Ph-Troc
allylic amine 24 with lithium methoxide in methanol
produced the methylcarbamate 2724 and the chiral alcohol
in 82% and 61% yield respectively and 97% ee (eq 7).
Table 2. Rhodium-Catalyzed Intermolecular Allylic Amination
of Aromatic E-Alkenes with R-1
In conclusion, a high level of stereoselection was obtained
for rhodium-catalyzed amination and aziridination of al-
kenes using R-1-phenyl-2,2,2-trichloroethyl-N-tosyloxycar-
bamate (R-1) as a chiral reagent. Such a reagent is readily
available on gram scale via a catalytic asymmetric reduction
and is bench stable for up to 6 months. Carbamate-pro-
tected aziridines and amines were produced in good yields.
No excess of starting material is required, and no extra
oxidant needs to be added. Furthermore, it is possible to
easily cleave the Ph-Troc protecting group to recover the
free aziridine or amine in high yields without degradation.
Acknowledgment. This research was supported by
NSERC (Canada), Johnson & Johnson, the Canada Founda-
tion for Innovation, the Canada Research Chair Program, the
ꢀ
Universite de Montreal, and the Centre in Green Chemistry
and Catalysis (CGCC). We thank Francine Belanger-Gariepy
ꢀ
ꢀ
ꢀ
a Isolated yield by flash chromatography; amination products. b Deter-
mined by HPLC. c Separation of diastereomers by flash chromatography.
ꢀ
ꢀ
from the Universite de Montreal for resolution of X-ray
crystal structures as well as Phan viet Minh Tan and Cedric
ꢀ
ꢀ
Malveau from the Universite de Montreal NMR Center.
ꢀ
The absolute stereochemistry was also established for pro-
duct 22 via an X-ray crystal structure. The diastereomeric ratio
could be enhanced by simple purification on silica gel leading
to 24 in 43% yield with >50:1 dr (entry 4). 2-Phenylcyclo-
hexene, a trisubstituted alkene was also reacted chemoselec-
tively to produce the less hindered amine in good yields with a
moderate diastereoselectivity (entry 5). To our knowledge this
is the first time that such a switch of reactivity was observed
for Z-alkenes vs E-alkenes in aziridination reactions.23
Supporting Information Available. Experimental pro-
cedures and spectroscopic data for new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(23) In electrophilic reactions, E-alkenes are known to be more
hindered, thus less reactive than Z-alkenes. It might explain why the
allylic CÀH bond become more reactive with E-alkenes. Further studies
will need to be pursued to fully explain these results.
(24) A few methods have previously reported to cleave allylic methylcar-
bamates without racemization; see: (a) Kresze, G.; Muensterer, H. J. Org.
Chem. 1983,48, 3561. (b) Wei, Z. Y.; Knaus, E. E. J. Org. Chem. 1993,58, 1586.
It is possible to easily cleave the Ph-Troc protecting
group under standard reaction conditions using zinc in
Org. Lett., Vol. 13, No. 20, 2011
5463