Palladium-catalyzed diamination of unactivated alkenes using n-fluorobenzenesulfonimide as source of electrophilic nitrogen

Article abstract of DOI:10.1021/ol9000087

A remarkable Pd-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide (NFBS) as an aminating reagent is described. The reaction occurs in an intra/intermolecular fashion, incorporating one nitrogen donor from the substrate and the

Full text of DOI:10.1021/ol9000087

ORGANIC
LETTERS
2009
Vol. 11, No. 5
1147-1149
Palladium-Catalyzed Diamination of
Unactivated Alkenes Using
N-Fluorobenzenesulfonimide as Source
of Electrophilic Nitrogen
Paul A. Sibbald and Forrest E. Michael*
Department of Chemistry, UniVersity of Washington, Box 351700,
Seattle, Washington 98195-1700
michael@chem.washington.edu
Received January 2, 2009
ABSTRACT
A remarkable Pd-catalyzed diamination of unactivated alkenes using N-fluorobenzenesulfonimide (NFBS) as an aminating reagent is described.
The reaction occurs in an intra/intermolecular fashion, incorporating one nitrogen donor from the substrate and the other from the NFBS,
thereby generating cyclic diamine derivatives in a single step. The products are differentially protected at both nitrogens, allowing for maximal
synthetic flexibility. The intermediacy of the Pd(IV) species is proposed to be responsible for the unusual reactivity of NFBS.
Vicinal diamines are an important class of compounds as
a result of their useful biological activities and their utility
as chiral auxiliaries and ligands in asymmetric synthesis.1
The direct diamination of alkenes is an especially efficient
method for the synthesis of such compounds. However,
in contrast to the ubiquity of the corresponding dihy-
droxylation of alkenes, methods for the direct diamination
of alkenes are rare.2 Recently, several new metal-catalyzed
diamination reactions have been reported, including in-
tramolecular diaminations of urea and sulfamide-tethered
alkenes,3 as well as intermolecular additions of ureas,
sulfamides, and diaziridinones to alkenes.4,5 Despite these
recent successes, current diamination methods generally
suffer from limited substrate scope and/or protecting group
versatility or are limited to the reactions of activated alkenes.
Herein, we report a novel palladium-catalyzed inter/intra-
molecular diamination of unactivated alkenes using N-
fluorobenzenesulfonimide as an electrophilic aminating re-
agent.
We recently disclosed a palladium-catalyzed intramolecu-
lar haloamination of alkenes using N-halosuccinimides6 as
halide sources (eq 1). In an attempt to extend this chemistry
(1) Vicinal diamine review: Lucet, D.; Gall, T. L.; Mioskowski, C.
Angew. Chem., Int. Ed. 1998, 37, 2580.
(3) (a) Mun˜iz, K.; Ho¨velmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008,
130, 763–773. (b) Mun˜iz, K.; Ho¨velmann, C.; Streuff, J.; Campos-Gomez,
(2) For stoichiometric metal-promoted diaminations, see the following.
(a) Pd: Backvall, J. E. Tetrahedron Lett. 1978, 163–166. (b) Hg: Barluenga,
J.; Alonsocires, L.; Asensio, G. Synthesis 1979, 962–964. (c) Se: Sharpless,
K. B.; Singer, S. P. J. Org. Chem. 1976, 41, 2504–2506. (d) Os: Chong,
A. A. O.; Oshima, K.; Sharpless, K. B. J. Am. Chem. Soc. 1977, 99, 3420–
3426. (e) Os: Mun˜iz, K.; Nieger, M.; Mansikkamaki, H. Angew. Chem.,
Int. Ed. 2003, 42, 5958–5961. (f) Co: Becker, P. N.; White, M. A.; Bergman,
R. G. J. Am. Chem. Soc. 1980, 102, 5676–5677. (g) Cu: Zabawa, T. P.;
Chemler, S. R. Org. Lett. 2007, 9, 2035–2038. (h) Cu Zabawa, T. P.; Kasi,
D.; Chemler, S. R. J. Am. Chem. Soc. 2005, 127, 11250–11251.
E. Pure Appl. Chem. 2008, 80, 1089–1096.
(4) (a) Bar, G. L. J.; Lloyd-Jones, G. C.; Booker-Milburn, K. I. J. Am.
Chem. Soc. 2005, 127, 7308–7309. (b) Zhao, B. G.; Yuan, W. C.; Du, H. F.;
Shi, Y. A. Org. Lett. 2007, 9, 4943–4945. (c) Yuan, W. C.; Du, H. F.;
Zhao, B. G.; Shi, Y. A. Org. Lett. 2007, 9, 2589–2591. (d) Du, H. F.; Zhao,
B. G.; Shi, Y. A. J. Am. Chem. Soc. 2007, 129, 762–763
.
(5) Rh- and Fe-catalyzed Ritter-type diamination: (a) Wei, H. X.; Kim,
S. H; Li, G. G. J. Org. Chem. 2002, 67, 4777–4781. (b) Li, G. G.; Wei,
H. X.; Kim, S. H.; Carducci, M. D. Angew. Chem., Int. Ed. 2001, 40, 4277–
4280
.
10.1021/ol9000087 CCC: $40.75
Published on Web 02/09/2009
2009 American Chemical Society

Table 1. Diamination of Protected Aminoalkenes 1aa
to the fluoroamination of these substrates, N-fluorobenze-
nesulfonimide (NFBS) was used as a source of electrophilic
fluorine. Surprisingly, no trace of the expected fluorination
product was observed and diamination product 3a was
isolated as the major species in 48% yield (eq 2). Instead of
acting as a source of “F+”, NFBS serves as an electrophilic
aminating reagent, which is a nearly unprecedented mode
of reactivity for this reagent.7
entry solvent
additive
% yield
1
2
3
4
5
6
THF
EtOAc none
EtOAc BHT (1.0 equiv)
EtOAc TEMPO (0.2 equiv)
EtOAc [Et3NH][N(SO2Ph)2] (0.2 equiv)
EtOAc [Et3NH][N(SO2Ph)2]
(0.2 equiv) and TEMPO (0.2 equiv)
none
55
62
64
68
67
77
a NFBS (2.0 equiv), Pd(TFA)2 (10 mol %), rt, 18 h.
Scheme 1
.
Attempted Fluoroamination of Amidoalkene
Substrate
excellent solvent for this reaction and was used as received
without additional drying of purification, indicating that small
amounts of water are well tolerated.
Under these optimized conditions a number of different
protecting groups on nitrogen were tolerated (Table 2). Both
electron-rich and electron-poor amides successfully under-
went diamination. Carbamates and ureas were also suitable
substrates, albeit in somewhat lower yields.
In addition to the formation of diamination product 3a,
two main byproducts were identified: internal alkene 4a and
chloride 5a (eq 2, X ) Cl). The alkene product arose from
isomerization of the alkene to the more stable internal
position, possibly catalyzed by small amounts of a palladium
hydride complex. Switching to catalytic Pd(TFA)2 signifi-
cantly reduced the amount of isomerization byproduct. More
effectively, addition of radical traps such as 2,6-di-tert-butyl-
4-methylphenol (BHT) and 2,2,6,6-tetramethyl-1-piperidi-
nyloxyl (TEMPO) inhibited the isomerization reaction,
resulting in improved yields of product 3a (Table 1).8
Chloride byproduct 5a presumably arose from incorpora-
tion of the chloride counterion of the palladium salt. Similar
counterion incorporation products were observed with both
Pd(OAc)2 and Pd(TFA)2. We reasoned that displacement of
the counterions of the palladium source with the desired
benzenesulfonimide anion would minimize formation of
these byproducts. Indeed, treatment of the palladium pre-
catalyst with triethylammonium benzenesulfonimide reduced
the formation of byproduct 5a and further improved the yield.
The highest yields were obtained when both TEMPO and
triethylammonium benzenesulfonimide additives were used.
Commercial (“wet”) ethyl acetate was found to be an
Table 2. Effect of Nitrogen Protecting Group on Diaminationa
entry
R
alkene
product
% yield
1
2
3
4
5
6
7
8
p-Tol
Ph
p-MeOC6H4
p-BrC6H4
OBn
Ot-Bu
NHBn
NHPh
1a
1b
1c
1d
1e
1f
3a
3b
3c
3d
3e
3f
77
74
82
73
59
30
57
49
1g
1h
3g
3h
a NFBS (2.0 equiv), Pd(TFA)2 (10 mol %), [Et3NH][N(SO2Ph)2] (0.2
equiv), TEMPO (0.2 equiv), EtOAc, rt, 18 h.
A number of additional substrates successfully underwent
diamination under these conditions (Scheme 2). As expected,
better yields were achieved with the gem-diphenyl substrates
6a,d,e than with their gem-dimethyl counterparts due to their
enhanced Thorpe-Ingold effect. Monosubstituted tethers
could also be used, giving protected diamine products 11
and 13 with moderate levels of diastereoselectivity (eqs 8
and 9).
(6) Michael, F. E.; Sibbald, P. A.; Cochran, B. M. Org. Lett. 2008, 10,
793–796.
(7) We are aware of one exception involving amination of a pyrrole:
De Rosa, M.; Marwaha, V. R. Heterocycles 1994, 37, 979–983.
(8) TEMPO and other radical traps retard alkene isomerization by
reacting with Pd-H complexes. Albe´niz, A. C.; Espinet, P.; Lo´pez-Ferna´ndez,
R.; Sen, A. J. Am. Chem. Soc. 2002, 124, 11278–11279.
One advantage to the use of benzenesulfonimide as the
nitrogen source in this reaction is that the resultant diamine
products are obtained in differentially protected form. For
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Org. Lett., Vol. 11, No. 5, 2009

palladium-alkyl intermediate 19. Rather than acting as a
direct fluorination agent, the strong oxidant NFBS can
oxidatively add to this Pd(II) species to give a Pd(IV)
complex.9 Reductive elimination of the benzenesulfonimide
group would generate the observed diamination product and
regenerate the Pd(II) catalyst. The observed formation of the
byproducts 5a can be explained by competing reductive
elimination of the Pd-derived counterion from the key Pd(IV)
complex 20. It is interesting to note that although reductive
elimination of chloride, acetate, and trifluoroacetate groups
appears to be competitive with that of the benzenesulfon-
imide group, reductive elimination of fluoride to form the
fluoroamination product was never observed.
Scheme 2. Additional Diaminations of Aminoalkenes
Scheme 4. Proposed Mechanistic Cycle
instance, when products 7a and 7d were subjected to basic
ethanol, selective removal of one sulfonyl group could be
effected in high yields. To free the endocyclic amine
selectively, hydrogenolysis of the Cbz protecting group
afforded 15 in 79% yield. Exhaustive deprotection of both
amines was accomplished by heating compound 7a at 135
°C in H2SO4/H2O to yield the free diamine 16 in 77% yield
(Scheme 3).
In conclusion, a mild and facile Pd-catalyzed diamination
of unactivated alkenes using NFBS as a nitrogen source has
been described. This reaction takes place at room temperature
and is tolerant of synthetically useful protecting groups. The
inter/intramolecular nature of this reaction allows for the
production of differentially protected diamine derivatives by
appropriate selection of the aminoalkene substrate, and both
newly introduced amines can be fully deprotected, giving
efficient access to the free diamine.
Scheme 3. Selective Deprotection of 7a and 7d
Acknowledgment. The University of Washington, ACS
PRF, and the NSF CAREER Award are acknowledged for
financial support.
Supporting Information Available: Reaction conditions
and experimental data for synthesis of all starting materials,
catalysts, and diamination products. This material is available
free of charge via the Internet at http://pubs.acs.org.
Although the exact reason for the unique reactivity of
NFBS has yet to be fully elucidated, a possible catalytic cycle
is illustrated in Scheme 4. In a fashion analogous to other
palladium-catalyzed transformations of alkenes, the initial
step is an aminopalladation of the CdC bond, generating
OL9000087
(9) Recent reports have illustrated the key role that Pd(IV) species can
play in other oxidative transformations of Pd-C bonds. See: Dick, A. R.;
Kampf, J. W.; Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790–12791.
Furuya, T.; Ritter, T. J. Am. Chem. Soc. 2008, 130, 10060–10061.
Org. Lett., Vol. 11, No. 5, 2009
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