Palladium-catalyzed intramolecular chloroamination of alkenes

Article abstract of DOI:10.1021/ol702922c

A mild and facile Pd-catalyzed intramolecular chloroamination of unactivated alkenes has been described. This reaction takes place at room temperature and is tolerant of synthetically useful acid-sensitive functional groups. Generally high exo-selectiviti

Full text of DOI:10.1021/ol702922c

ORGANIC
LETTERS
2008
Vol. 10, No. 5
793-796
Palladium-Catalyzed Intramolecular
Chloroamination of Alkenes
Forrest E. Michael,* Paul A. Sibbald, and Brian M. Cochran
Department of Chemistry, UniVersity of Washington, Box 351700,
Seattle, Washington 98195-1700
michael@chem.washington.edu
Received December 3, 2007
ABSTRACT
A mild and facile Pd-catalyzed intramolecular chloroamination of unactivated alkenes has been described. This reaction takes place at room
temperature and is tolerant of synthetically useful acid-sensitive functional groups. Generally high exo-selectivities are observed in the formation
of a variety of 5- and 6-membered rings. This system is unique in its ability to tolerate multidentate ligands on palladium, which opens up the
possibility of controlling the absolute sense of induction using a chiral ligand.
The direct addition of a halogen- and a nitrogen-containing
functional group to alkenes and alkynes is a powerful means
of introducing two distinct functional groups across a
carbon-carbon multiple bond.1 The vicinal haloamines
generated in this fashion have applications as potential
medicinal agents2 but are primarily used as versatile synthetic
intermediates.3
Intramolecular haloaminations (halolactamizations) can
occur directly upon treatment of alkenylamides with rela-
tively active halogen sources such as I2 or Br2.1b,4 However,
precautions must often be taken to avoid cyclization via
oxygen instead of nitrogen.5 This approach is simple and
effective but precludes the possibility of controlling the
absolute stereochemistry of addition.
Transition metal-catalyzed intramolecular haloaminations
remain relatively rare.6,7 Chemler6a and Lu6b have both
reported Pd-catalyzed intramolecular haloamination reactions.
Lu reported that alkenes bearing pendant acylsulfonamides
could be cyclized with Pd(OAc)2 catalyst, using CuCl2 or
CuBr2 as the halogen source. Chemler described the cycliza-
tion of sulfonamidoalkenes with Pd(TFA)2, also using copper
halides as the halogen sources. These reactions proceeded
in high yield but were often plagued by poor regioselectivity
(endo/exo ) 1:1.7 to 100:0, depending on substrate).
Although the use of transition metal catalysis opens up the
possibility of asymmetric catalysis, no enantioselective
haloamination reaction has yet been reported. Herein, we
report a selective palladium-catalyzed chloroamination of
(1) Reviews: (a) Li, G. G.; Kotti, S. R. S. S.; Timmons, C. Eur. J. Org.
Chem. 2007, 2745-2758. (b) Cardillo, G.; Orena, M. Tetrahedron 1990,
46, 3321-3408.
(2) Qiu, J.; Silverman, R. B. J. Med. Chem. 2000, 43, 706-720.
(3) Kemp, J. E. G. In ComprehensiVe Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon: Oxford, 1991; Vol. 7, pp 469-513.
(4) (a) Tamaru, Y.; Kawamura, S.; Bando, T.; Tanaka, K.; Hojo, M.;
Yoshida, Z. J. Org. Chem. 1988, 53, 5491-5501. (b) Tamaru, Y.;
Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetrahedron Lett. 1984, 25, 1063-
1066.
(5) (a) Shen, M.; Li, C. J. Org. Chem. 2004, 69, 7906-7909. (b) Knapp,
S.; Levorse, A. T. J. Org. Chem. 1988, 53, 4006-4014. (c) Biloski, A. J.;
Wood, R. D.; Ganem, B. J. Am. Chem. Soc. 1982, 104, 3233-3235.
(6) (a) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R.
Organometallics 2004, 23, 5618-5621. (b) Lei, A. W.; Lu, X. Y.; Liu, G.
S. Tetrahedron Lett. 2004, 45, 1785-1788.
(7) From azides: Danielec, H.; Klugge, J.; Schlummer, B.; Bach, T.
Synthesis 2006, 551-556. From N-Cl amines: Sjoholm, A.; Hemmerling,
M.; Pradeille, M.; Somfai, P. J. Chem. Soc., Perkin Trans. 1 2001, 891-
899.
10.1021/ol702922c CCC: $40.75
© 2008 American Chemical Society
Published on Web 02/02/2008

protected aminoalkenes that generally gives high regiose-
lectivity for exo cyclization and has the potential for future
enantioselective development.
We have recently reported that Pd complex 1 is highly
effective for the intramolecular hydroamination of unacti-
vated alkenes (eq 1).8 The tridentate ligand on Pd prevents
the normally rapid â-hydride elimination of the intermediate
Pd-alkyl complex, allowing protonolysis to occur instead
(Scheme 1). The success of this strategy prompted an
temperature also resulted in clean conversion to chloroami-
nation product 3a in 86% yield (eq 3). In contrast, ami-
noalkene 4a failed to react with NCS in the absence of Pd
catalyst (both with and without AgBF4), returning only
unreacted starting material and confirming that the reaction
is specifically catalyzed by Pd.
Other Pd complexes were also effective in the chloroami-
nation reaction (Table 1). The presence of the tridentate
Table 1. Chloroamination of Protected Aminoalkene 2a
Scheme 1. Hydroamination via Inhibition of â-hydride
Elimination
entry
catalyst
solvent
yield %
1
2
3
4
5
6
7
8
9
PdCl2(MeCN)2
Pd(OAc)2
Pd(TFA)2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
MeCN
Et2O
94 (93)a
92
93
Pd2(dba)3
88
(pybox)PdCl2
(BINAP)PdCl2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
0b
0b
92
95
90
toluene
a 5 mol % catalyst. b With and without 20 mol % AgBF4
investigation of whether this Pd-alkyl complex could also
be intercepted by other electrophiles, resulting in a catalytic
difunctionalization of alkenes.
ligand is not required, as indicated by the activity of several
simple Pd salts. A Pd(0) complex (entry 4) can also be
employed, as it is presumably oxidized to Pd(II) species
under the reaction conditions. On the other hand, other
multidentate ligand complexes of Pd, such as (pybox)PdCl2
and (BINAP)PdCl2 failed to catalyze any chlorination of 4a,
both in the presence and absence of silver salts. This unique
ability of the PNP pincer ligand to promote cyclization was
also observed in the hydroamination reaction. Toluene, ether,
acetonitrile, and CH2Cl2 were identified as equally suitable
solvents for this transformation (entries 7-9).
Palladium-alkyl complex 2 can be isolated by treatment
of the protected aminoalkene with the palladium complex
in the presence of mild base. Exposure of 2 to acid afforded
the expected hydroamination product.9 Similarly, treatment
of 2 with 1.2 equiv of N-chlorosuccinimide (NCS) at room
temperature resulted in clean conversion to chloroamination
product 3a in 81% yield (eq 2).
Table 2. Effect of Nitrogen Protecting Group on
Haloamination
PG
alkene
product
yield %
Ac
p-toluoyl
Boc
4a
4b
4c
4d
4e
4f
3a
3b
3c
3d
3e
3f
89
94
74
67a
91
72
0
Cbz
CONHBn
CONHPMP
Ts
Having demonstrated the feasibility of the key halogena-
tion step, catalytic conditions were developed. Reaction of
protected aminoalkene 4a with NCS using a catalytic amount
of Pd complex 1 (5 mol %) and AgBF4 (10 mol %) at room
4g
3g
a In toluene
794
Org. Lett., Vol. 10, No. 5, 2008

Substrates bearing a variety of substituents on nitrogen
were effective substrates for chloroamination (Table 2).
Amides and carbamates 4a-d cyclize most readily, including
the synthetically useful Boc and Cbz protected substrates.
Ureas 4d,e also afforded good yields of the chloroamination
products. Substrates bearing a toluenesulfonyl substituent on
nitrogen failed to cyclize, as was observed in the hydroami-
nation reaction,8 and in contrast to the Pd-catalyzed haloami-
nations reported by Chemler and Lu.6
Formation of 6-membered rings using this method was
also successful (entries 7, 8), although the reactions were
complicated by partial displacement of the chloride by the
carbamate protecting group under the reaction conditions
to give the oxazolidinones 16 and 18. By heating the
crude reaction mixture in acetonitrile, full conversion of
the exo cyclyization products to the oxazolidinones was
achieved in good yield. In the case of 17d, a small amount
of the 7-membered endo cyclization product 19d was also
formed.
Other successful chloroamination reactions are depicted
in Table 3. Formation of 5-membered rings is facile with
Table 3. Chloroaminations of Other Aminoalkenes
Extension of this method to the corresponding bromoami-
nation reaction required more finesse. Treatment of original
substrate 4a, which is especially prone to cyclization, with
NBS and NIS did result in formation of the corresponding
bromo- and iodomethylpyrrolidines. However, these reactions
also proceeded in the absence of Pd. On the other hand,
substrates that are less likely to cyclize, like 15d and 17d,
did not react with NBS in the absence of Pd but did provide
moderate yields of the corresponding oxazolidinone or
bromoamination products, respectively, under catalytic con-
ditions (eqs 6, 7).
The presence of an exocyclic chloride functionality in the
chloroamination products provided a convenient handle for
subsequent functionalization (Scheme 2). Product 3b easily
Scheme 2. Nucleophilic Substitutions
underwent nucleophilic substitutions by treatment with the
appropriate nucleophile in refluxing CH3CN. In this fashion,
compounds 21b-24b could be generated in high yield.
a Then dissolved in MeCN and heated to reflux for 18 h.
The proposed reaction mechanism is illustrated in Scheme
3. Coordination of the alkene to the dicationic Pd 25 to form
complex 26 activates the alkene toward nucleophilic attack
by the amide or carbamate to form alkylpalladium intermedi-
ate 27. In the presence of NCS, this alkylpalladium species
is chlorinated to give the observed chloroamination product
and succinamide, regenerating the starting palladium species.
Interestingly, chlorination of the alkylpalladium complex
various substitution patterns on the tether, including allyla-
niline derivatives 9b,c (entries 1-5). 1,1-Disubstituted
alkenes were also efficiently cyclized (entry 6).
(8) Michael, F. E.; Cochran, B. M. J. Am. Chem. Soc. 2006, 128, 4246-
4247.
(9) Cochran, B. M.; Michael, F. E. J. Am. Chem. Soc. 2008, in press.
Org. Lett., Vol. 10, No. 5, 2008
795

palladium sources in this reaction implies that this chlorina-
tion is also more rapid than â-hydride elimination.
Scheme 3. Proposed Mechanistic Cycle
In conclusion, a mild and facile Pd-catalyzed intramo-
lecular haloamination of unactivated alkenes has been
described. This reaction takes place at room temperature and
is tolerant of synthetically useful acid-sensitive functional
groups. The ability of palladium complexes bearing multi-
dentate ligands to catalyze this reaction opens up the
possibility of controlling the absolute sense of induction using
a chiral ligand. Studies toward the development of an
enantioselective version are underway.
Acknowledgment. The University of Washington is
acknowledged for financial support.
Supporting Information Available: Detailed reaction
conditions and experimental data for syntheses of all starting
materials, catalysts, and cyclization products. This material
is available is available free of charge at http://pubs.acs.org.
appears to be faster than protonolysis, since competitive
hydroamination was not observed. The success of unligated
OL702922C
796
Org. Lett., Vol. 10, No. 5, 2008