Recent development of regio- and stereoselective aminohalogenation reaction of alkenes

Article abstract of DOI:10.1002/ejoc.200600990

This microreview presents the development of the catalytic aminohalogenation of olefins. The olefin substrates include electron-deficient and functionalized ones, such as α,β-unsaturated esters, α,β-unsaturated ketones and α,β-unsaturated nitriles. In add

Full text of DOI:10.1002/ejoc.200600990

MICROREVIEW
DOI: 10.1002/ejoc.200600990
Recent Development of Regio- and Stereoselective Aminohalogenation Reaction
of Alkenes
Guigen Li,*[a] S. R. S. Saibabu Kotti,[a] and Cody Timmons[a]
Keywords: Aminohalogenation / Haloamidation / Cinnamate / Aziridinium ion / Ionic liquid
This microreview presents the development of the catalytic
aminohalogenation of olefins. The olefin substrates include
electron-deficient and functionalized ones, such as α,β-unsat-
urated esters, α,β-unsaturated ketones and α,β-unsaturated
nitriles. In addition, the first asymmetric aminohalogenation
by the use of Evans chiral auxiliaries is also discussed. The
convincing evidence is provided to support the aziridinium
mechanism of aminohalogenation reaction. The applications
of this reaction are described by converting vicinal haloam-
ines into other important synthetic building blocks.
(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
Germany, 2007)
onto carbon–carbon double bonds.[1] The haloamines can
serve as versatile building blocks for chemical synthesis and
medicinal sciences, it makes this reaction an increasingly
important and active topic in modern organic chemistry.[2]
Although the aminohalogenation reaction has been known
for nearly 40 years,[3–5] it has not been well studied until
recently when our laboratories were involved in its investi-
gation.[6] This situation is probably due to the factor that
1. Introduction
The aminohalogenation (or haloamidation) reaction
converts common petroleum olefins into vicinal haloamine
products by the addition of amine and halogen moieties
[a] Department of Chemistry & Biochemistry, Texas Tech Univer-
sity,
Lubbock, TX 79409-1061, USA
Guigen Li was born in Jiangsu Province, P. R. China in 1962. He came to the US in 1990 and got his Ph.D. in 1995 at
the University of Arizona with Professor Victor J. Hruby. He did his postdoctoral research with Professor K. Barry
Sharpless at the Scripps Research Institute during 1995–1997. In September 1997, he moved to Texas Tech University
as an Assistant Professor. He was early promoted to Associate Professor in 2002 and to Full-Professor in 2006. His
research interest is in the development of new organic reactions of chemical and biomedical importance. During his tenure
at Texas Tech, he has trained more than 10 graduate students and 50 undergraduates. More than 25 undergraduate
students achieved research publications with Professor Li.
Kotti was born at Machilipatnam, India, in 1977. After completing his schooling at St. Mary’s A.A.M.M high school,
he obtained his B.Sc (Hons) in chemistry from Sri Sathya Sai Institute of Higher Learning, Bangalore, India. There
after, he got his master degree in chemistry from Sri Sathya Sai Institute of Higher Learning, Prasanthi Nilayam, India,
in 1999. Then he worked as a Research Chemist at Dr. Reddy’s Research Foundation, Hyderabad, India. He joined Texas
Tech University in the fall of 2002 and obtained his Ph.D degree in chemistry in May 2006 under the guidance of Profs.
Guigen Li and Allan Headley. Currently, he works as a research chemist for Eburon Organics USA Inc.
Cody Timmons was born in Texas, USA, in 1978. He graduated from Motley County High School in Matador, Texas,
in 1997. From there, he entered West Texas A&M University in Canyon, Texas, graduating with B.S. and MS degrees
in Chemistry in the years 2000 and 2002, respectively. His MS thesis dealt with experimental and computational studies
on the degradation of explosives. He then moved to Texas Tech University in the fall of 2002 and joined the group of
Professor Guigen Li, where he studied novel olefin addition and carbon-carbon bond formation methodologies. He com-
pleted his Ph.D. in May 2006 and is currently a postdoctoral research associate in the laboratory of Professor Peter Wipf
at the University of Pittsburgh.
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G. Li, S. R. S. S. Kotti, C. Timmons
MICROREVIEW
the substrate scope of the original aminohalogenation was kenes via different mechanisms under different conditions.
strictly limited to the use of a very few alkenes. Meanwhile, In addition to this reaction, the reactions of p-toluene-
the difficulty in the control of regio- and stereoselectivity sulfonyl chloride with different reactants also showed a sim-
and the confusing mechanism hypothesis of the original ilar behavior, i.e., p-toluenesulfonyl chloride acts as the
aminohalogenation may also have attributed to this situa- chlorine anion source when it reacts with nucleophiles, such
tion.
as amine and hydroxy compounds,[7] but acts as the chlo-
Aminohalogenation reaction employs various nitrogen/ rine cation source when it reacts with lithium enolates.[8]
halogen sources that are derived from amines, amides, Another example is shown by the behaviors of 1,2,3-benzo-
sulfonamides, carbamates, and imides (R1R2NX or triazole derivatives which can be either ionized into benzo-
RNX2).[1,3–4] These nitrogen/halogen sources are subjected triazole anion or N-substituted benzotriazole cations.[9]
to addition reactions with alkenes through either homolytic
This article will summarize the recent progress of the
or heterolytic cleavage of their N–X bonds. The homolytic aminohalogenation reaction that was made mainly by our
cleavage of N–X bond typically requires the use of perox- laboratories and a few others in the past several years. The
ides, light or heat. The heterolytic cleavage of this bond is work on intramolecular aminohalogenation reaction is not
often accelerated by Lewis acid promoters or catalysts. The covered in this mini-review due to the space limitation.[10]
aziridinium or halonium intermediates resulting from the
electrophilic species of N+ or X+ are proposed to exist in
the aminohalogenation process as shown in Scheme 1.
2. Aminohalogenation of α,β-Unsaturated Esters
(1) N,N-Dichloro-p-toluenesulfonamide as the Nitrogen/
Halogen Source
Cinnamic esters are believed to be the most synthetically
useful substrate classes[11] for olefinic oxidations that in-
clude catalytic asymmetric dihydroxylation,[12] epoxid-
ation,[13] aziridination,[14] aminohydroxylation,[15] etc. How-
ever, when these substrates were subjected to the amino-
chlorination reaction with N,N-dichloro-p-toluenesulfon-
amides (TsNCl2) or dichlorocarbamates[4] and the CrCl2-
promoted addition with N-chlorocarbamates[5] there were
no haloamine products generated under the original known
conditions. The screening of catalysts and catalytic condi-
tions revealed that the combination of ZnCl2–MeCN and
Cu(OTf)2–MeCN (metal as the catalyst and acetonitrile as
the solvent) resulted in the successful aminohalogenation of
α,β-unsaturated esters with N,N-dichloro-p-toluenesulfon-
amide (Scheme 2).[6a] Interestingly, a difficult substrate for
olefinic oxidations, methyl trans-p-nitrocinnamate gave an
excellent chemical yield of 91%, albeit an excess amount
Scheme 1.
As indicated in Scheme 1, during the aminohalogenation of TsNCl2 (2 equiv.) and the prolonged period (48 h) were
process a nitrogen/halogen source can be reacted with al- required for complete conversion.
Scheme 2.
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Regio- and Stereoselective Aminohalogenation Reaction of Alkenes
MICROREVIEW
Scheme 3.
It was also found that the transition-metal-ligand com- forts on the asymmetric aminohalogenation assuming the
plex, dichloro(1,10-phenanthroline)palladium(II), can serve complex is associated with the transition state during the
as an effective catalyst for the aminohalogenation of cin- formation of aziridinium intermediate at the rate-limiting
namic esters with the same nitrogen/chlorine source step. Some encouraging results have been obtained and
(Scheme 3).[16] This catalyst showed an advantage over shown in section 5.
ZnCl2 and Cu(OTf)2 in which dichloro(1,10-phenan-
throline)palladium(II) can be handled very conveniently be-
(2) Evidence for an Aziridinium-Based Mechanism
cause it is less hygroscopic than that of the previous two
catalysts. Similar to the previous catalytic systems,[6] this
So far, attempts to isolate or directly detect the aziridin-
reaction can be performed simply by mixing three compo- ium intermediates during aminohalogenation process have
nents, olefin substrates, N,N-dichloro-p-toluenesulfonamide been unsuccessful. However, the electrophilic diamination
and dichloro(1,10-phenanthroline)palladium(II) in acetoni- (or imidazolination) reaction under similar conditions of
trile in a vial of appropriate size. There is no need to use aminohalogenation can unambiguously support the hy-
inert atmosphere protection.
pothesis of aziridinium-based mechanism.[17–19] For exam-
These aminohalogenation processes are suggested to pro- ple, when α,β-unsaturated ketones were subjected to the re-
ceed though a mechanism involving the formation of N- action with N,N-dichloro-p-toluenesulfonamide in acetoni-
chloro-N-tosylaziridinium intermediate at the initial rate- trile at room temperature in the absence of any metal cata-
limiting-step (Scheme 4).[6,16] The catalysts help to remove lysts the vicinal diamine products were obtained predomi-
the chlorine anion from N,N-dichloro-p-toluenesulfon- nantly (Scheme 5, for ester substrates, catalysts are neces-
amide, and also facilitate the formation of “Ts–N+–Cl” spe- sary for this reaction[17]). The resulting regioselectivity and
cies for the electrophilic addition. The nearby metal-associ- syn addition indicated that at the key step the aziridinium
ated “Cl–” around the aziridinium intermediate acts as the ring opening proceeded through [2+3] cyclic addition reac-
nucleophile to open the three-membered ring. The SN2 tion between acetonitrile and the N-(p-tosyl)aziridinium in-
mechanism of this ring opening accounts for the excellent termediate (A) to form 1-N-(p-tosyl)imidazolinium (B). The
anti stereoselectivty. The regioselectivity can be explained following steps involved repeated deprotonation, chlorina-
by the fact that the β position of the aziridinium intermedi- tion, and an SN2Ј-type displacement to afford 2,2-dichlo-
ate is loaded by more positive charge related to its α posi- romethyl-4-phenyl-5-phenylcarbonyl-1-p-tosyl-imidazoline
tion because of the stabilization effect from the phenyl ring. as the final product.
Scheme 4.
Scheme 5.
The latter aminohalogenation catalyzed by the transi-
The above diamination reaction was proven to be ac-
tion-metal–ligand complex should be beneficial to the ef- celerated by several catalysts, such as rhodium(II) hep-
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G. Li, S. R. S. S. Kotti, C. Timmons
MICROREVIEW
tafluorobutyrate, FeCl3·PPh3 complex and manganese(IV) (3) N,N-Dichloro-o-nitrobenzenesulfonamide as the
oxide that help to generate the aziridinium intermediate Nitrogen/Halogen Source
through the coordination with one of the chlorine atoms of
The haloamino compounds with a N-nosyl protecting
N,N-dichloro-p-toluenesulfonamide (Scheme 6).[17] The re-
group showed an advantage over their N-tosyl-protected
action is usually aided by dried 4-Å molecular sieves.
counterparts because the former can be readily cleaved un-
der different mild condition (PhSH/K2CO3 in DMF at
room temperature).[22] When the analogous nitrogen source,
N,N-dichloro-o-nitrobenzenesulfonamide (o-NsNCl2), was
allowed to react with α,β-unsaturated esters under the pre-
vious aminohalogenation conditions, it failed to give the
desired haloamine product. Instead, the anti methyl
3-chloro-2-(o-nitrophenylsulfonamido)-3-phenylpropionate
was determined to be the predominant product.[6b] How-
ever, when the combinational nitrogen and chlorine source,
NsNCl2/NsNHNa (1:2, mol ratio), was used to react with
α,β-unsaturated esters in the presence of copper(I) triflate
as the catalyst, the haloamino products were obtained in
good yields and up to excellent stereoselectivity (Scheme 8).
Furthermore, there was no minor regio isomers detected
under this condition.
Scheme 6.
As shown in Scheme 6, this reaction provides an easy
synthesis of α,β-diamino derivatives that can mimic both α-
and β-amino acids, and therefore, is important for peptido-
mimetic and protein research.
In addition to the N-chloro,N-(p-tosyl)aziridinium inter-
mediate, several similar aziridinium species, such as N-(p-
nosyl)aziridinium,[20] N-(p-tosyl)aziridinium,[19b] and N-
Scheme 8.
chloro-N-(p-nosyl)aziridinium[6b] intermediates, could also
In addition to copper(I) triflate and copper(II) triflate,
copper(I) chloride can also be used for this reaction to give
exist during the diamination processes. For example, when
the combination of 2-NsNH2/NCS was treated with α,β-
similar results. 2-NsNCl2 can be readily prepared by treat-
unsaturated ketones, the regio- and stereoselective imid-
ing 2-nitrobenzenesulfonamide with commercial bleach and
azolines were obtained (Scheme 7).[20] The reaction is also
followed by CH3COOH acidification. As compared to
very convenient to carry out simply by mixing olefin, 2-
pTsNCl2, 2-NsNCl2 was shown to be more stable and can
NsNH2, NCS and 4-Å molecular sieves in freshly distilled
be stored at room temperature for a few months without
acetonitrile at room temperature.
inert gas protection. The 2-NsNHNa salt was obtained by
performing the deprotonation of 2-NsNH2 with sodium hy-
droxide in methanol/water solution, and subsequently, by
drying overnight under vacuum prior to use.
The second 2-NsNCl2-based aminohalogenation was de-
veloped by using N-chloro-N-sodiumsulfonamide as the ni-
trogen/chlorine source and copper(I) triflate as the catalyst
(Scheme 9).[23] This reaction provides a more convenient
protocol by the use of solely pure NsNClNa for the amino-
halogenation reaction as compared to the above mixed ni-
trogen and chlorine sources. In addition to α,β-unsaturated
esters, two simple olefin substrates, trans-stilbene and sty-
rene, were also found to be effective for the reaction
(Scheme 10).
Scheme 7.
The aziridinium-based mechanism has been further sup-
ported by the results of the aminohalogenation of unfunc-
tionalized alkenes which is described in section 4.[21]
Scheme 9.
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Regio- and Stereoselective Aminohalogenation Reaction of Alkenes
MICROREVIEW
3. Aminohalogenation of α,β-Unsaturated
Ketones and Nitriles
The α,β-unsaturated ketones behaved differently from
α,β-unsaturated esters in aminohalogenation reaction.[24]
When zinc dichloride was employed as the catalyst only a
small amount of haloamine product was produced even af-
ter 48 h with most of the olefin starting materials remain-
ing. When rhodium(II) heptafluorobutyrate or the complex
derived from iron(III) chloride and triphenylphosphane was
used as the catalyst, diamine products were predominantly
produced. The reaction of trans-4-phenyl-3-buten-2-one
with 4-TsNCl2 occurred smoothly only when copper(I) trifl-
ate was used as the catalyst, under the previous condition
and gave a promising chemical yield at first (Ͻ40%). Fur-
ther operational modifications resulted in up to 91% yields,
where the modifications are to perform the reaction at 0 °C
Scheme 10.
The possible catalytic pathway is shown in Scheme 11. for 2 h, and then at room temperature for an additional
At the initial stage, 2-NsNClNa reacts with CuI triflate to 10 h. At the same time, 4-TsNCl2 is added slowly into reac-
give N-chloro-2-nitrobenzenesulfonamide copper com- tion mixture via a syringe pump (Scheme 12). Similar to the
pound B. The subsequent electrophilic addition of B onto situation of the previous α,β-unsaturated ester-based sys-
the olefin substrate affords the aziridinium intermediate C tem, the use of 4-Å molecular sieves together with the cata-
in which the copper ion is associated with the nitrogen of lysts further improved the yield. The reaction was found
three-membered ring or concurrently with the oxygen of the to proceed faster than the aminohalogenation of cinnamate
sulfonyl group. The chlorine anion reacts with intermediate esters, which generally required up to 24 h for the comple-
C in a three-membered ring opening by the SN2 mecha- tion.
nism. The SN2 opening is responsible for the high anti
Interestingly, when aliphatic enones were subjected to the
stereoselectivity. Intermediate D could coexist with E in reaction under the same condition, the opposite regioselec-
equilibrium before the reaction is quenched. An excess tivity was obtained for the major isomeric products
amount of 2-NsNClNa was proven to be necessary to drive (Scheme 13). In addition, the aliphatic enones showed
the reaction toward the formation of intermediate E. At the faster reaction rates and can be completely consumed
final stage, the N-chloro-2-nitrobenzenesulfonamide copper within 2 h. Since the aliphatic enones are volatile liquids,
compound, the actual catalytic species, is regenerated from an excess amount of these starting materials can be re-
intermediate E for the continuing catalytic cycles. It seems moved simply by distillation after the reaction. When
that the strong electron-withdrawing ability of 2-nitrophen- 1.0 equiv. of 4-TsNCl2 was slowly added into the reaction
ylsulfonyl (nosyl) group is important for the formation of system containing 2 equiv. of methyl vinyl ketone, nearly
the active species C.
quantitative yields were obtained. In fact, the crude prod-
The successful aminohalogenation of above two simple ucts were almost pure as revealed by crude 1H NMR analy-
olefin substrates, trans-stilbene and styrene, can exclude the sis.
possibility for the reaction to go through the α,β-unsatu-
The 2-nitrobenzenesulfonamide-based aminohalogena-
rated addition mechanism.
tion of α,β-unsaturated ketones has also been achieved by
Scheme 11.
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G. Li, S. R. S. S. Kotti, C. Timmons
MICROREVIEW
phenylacrylonitrile with 4-TsNCl2 under the previous con-
dition in the presence of zinc(II) dichloride catalyst did not
result in any vicinal haloamine product. However, the reac-
tion catalyzed by CuI triflate did occur smoothly to give a
chemical yield of 67%. Furthermore, when the catalyst was
changed to CuICl together with 4-Å molecular sieves, the
yield was enhanced to 79%. The use of 4-Å molecular sieves
was proven to be crucial for this catalytic system. If there
were no 4-Å molecular sieves present in the system, the
yield was decreased to 41%. In contrast to the previous
α,β-unsaturated ketone and ester-based systems where 4 Å
molecular sieves can only improve the chemical yields by
about 5–10%.
Scheme 12.
Scheme 15.
4. Aminohalogenation of Unfunctionalized
Alkenes
(1) Aminochlorination
The aminohalogenation of unfunctionalized alkenes was
re-examined very recently. It was found that palladium ace-
tate was able to catalyze the reaction.[27] The reaction was
conducted in DMF at room temperature, and the product
was readily transferred into aziridines in the presence of
K2CO3. When styrene was used as substrate, a nearly quan-
titative yield of 97% was achieved before it was subjected to
cyclization to aziridine in a one-pot operation (Scheme 16).
Scheme 13.
using the combinational nitrogen and chlorine source, 2-
NsNCl2/2-NsNHNa, in the presence of copper(I) triflate as
the catalyst (Scheme 14).[25] For this reaction, there were no
regioisomers observed and the stereoselectivity was ranged
between 7:1 and 20:1, albeit the chemical yields (41–75%)
are lower than those of α,β-unsaturated esters. Interestingly,
the pure 2-NsNClNa which worked well with α,β-unsatu-
rated esters did not work well for α,β-unsaturated ketones
with only a very small amount of the haloamine product
observed.[23]
Scheme 16.
Carbon dioxide was found to promote aminohalogena-
tion of normal alkenes when chloramine-T was used as the
nitrogen/halogen source by Komatsu and co-workers
(Scheme 17).[28] The reaction was performed at room tem-
perature under CO2 pressure at 10 atm, in benzene as sol-
vent. The reaction proceeded to completion within 6–9 h
without the use of any catalysts to give up to 80% yields
and excellent regioselectivity. Besides the normal alkenes as
Scheme 14.
Similar to the aminohalogenation of α,β-unsaturated the substrates, dienes can also be employed as the substrates
ketones, α,β-unsaturated nitriles also showed a different to give 1,4-haloamine products, albeit higher pressure of
performance from α,β-unsaturated ester-based aminohalo- CO2 and a prolonged period (24 h) were needed for a com-
genation process (Scheme 15).[26] The reaction of 3,3-di- plete conversion.
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Regio- and Stereoselective Aminohalogenation Reaction of Alkenes
MICROREVIEW
Table 1. Results of aminohalogenation of methylidenecyclopro-
panes.
Entry MCP
R1
R2
Yield of 3 (%)
1
2
3
4
5
6
7
8
9
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
H
H
H
H
H
C6H5
3a (48)
3b (53)
3c (77)
3d (72)
4-Me-C6H4
4-MeO-C6H4
2,4-(MeO)2C6H3
3,4,5-(MeO)3C6H2 3e (70)
C10H7
C6H5
4-Me-C6H4
4-MeO-C6H4
3f (44)
3g (54)
3h (75)
3i (99)
C6H5
4-Me-C6H4
4-MeO-C6H4
Again, the aziridinium-based mechanism is suggested for
this reaction as shown in Scheme 18. In the initial step, the
electrophilic addition of TsNCl2 to MCPs forms the corre-
sponding N-chloro-N-(p-tosyl)aziridinium intermediate A,
which is believed to be the rate-limiting step. The second
step is the ring opening of aziridinium by chlorine anion
(Cl–) The C–C hyperconjugation effect enhanced by the
strain in the spiro ring bonds could be important in stabiliz-
ing the positively charged aziridinium intermediate and in
controlling the regioselectivity. The excellent regioselectivity
of the product shows the much stronger ability of cyclopro-
pane to stabilize the positive ion as opposed to the aromatic
ring. This effect was observed regardless of the position of
attachment for the electron-donating group.
Scheme 17.
Interestingly, when methylenecyclopropanes (MCPs) 1
and vinylidenecyclopropanes (VCPs) were employed as the
substrates, the catalyst had to be changed to ion(III) chlo-
ride in a loading of 20 mol-% in order to obtain good chem-
ical yields (Table 1).[29] The reaction can be finished at room
temperature within 8 hours.
A series of methylidenecyclopropanes were next sub-
jected to this reaction by using FeCl3 as the catalyst. For
these substrates, two regioisomers were obtained, and can
be easily separated via silica gel flash chromatography to
give moderate to good combined yields (Table 2). As can
Scheme 18.
To rule out the possibility of bridged chloronium ion
be seen from Table 2, adduct a was proven to be the major mechanism, the control experiments were also performed as
product.
shown in Scheme 19. The aminoiodination product 3j was
Table 2. Results of aminohalogenation of vinylidenecyclopropanes.
Entry
R1
R2
R3
Yield (%), product a
Yield (%), product b
1
2
3
4
5
C6H5
C6H5
C6H5
C6H5
C6H5
H
H
C6H5
p-CH3O-C6H4
CH3
H
CH3
4a (59)
4b (51)
4c (69)
4d (55)
4e (86)
5a (26)
5b (21)
trace
5d (35)
trace
p-CH3O-C6H4
C6H5
C6H5
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G. Li, S. R. S. S. Kotti, C. Timmons
MICROREVIEW
exclusively produced in the presence of NaI, presumably by this Hammet equation is in sharp contrast with that re-
the attack of iodide anion on the aziridinium ring. This ported by Pérez and Che on the aziridination reaction of
observation can further confirm that the aziridinium inter- olefin with PhI=NTs, which is believed to proceed through
mediates exist during the reaction process.
a metal–carbenoid species (M=NTs).[30]
(2) Aminobromination or Bromoamidation
Very recently, Corey and co-workers established the
haloamidation reaction of alkenes by using N-bromoacet-
amide, NCS, and I2 as halogen sources, and various nitriles
and N,N-dimethylcyanamide as nitrogen sources. The reac-
tion is efficiently catalyzed by Lewis acids, such as SnCl4,
SnBr4 and BF3·Et2O (Scheme 20).[2a] Interestingly, the reac-
tion occurred more efficiently when ca. 1 equiv. of H2O was
added into the reaction system. The reaction is believed to
go through the formation of bromonium intermediate,
which was accelerated by Lewis acids. The resulting bro-
monium intermediate is then opened by nitriles and cyan-
amide nucleophiles, which is analogous to the Ritter reac-
tion process.[31]
This reaction has shown a broad substrate scope, and
can serve as a general approach to a variety of important
synthetic building blocks, such as N-acylaziridines, oxazol-
ines, 1,2-amino alcohols, etc. In fact, Corey has already ap-
plied this reaction to the challenging total synthesis of anti-
influenza neuramidase inhibitor, oseltamivir,[32] with an im-
pressive overall yield of 30%.
Scheme 19.
The log(k/k0), where k0 is the reaction rate of MCP 1a,
vs. σ was plotted to figure out the linear free-energy rela-
tionship of this reaction. [σ and σ+ values are obtained
from the literature[49a,49b]]. A straight line was obtained
with a ρ value of –1.35, which implies the existence of a
positive ion intermediate in this reaction (Figure 1). The σ
constants fitted the line much better than those of σ· or σ+,
which deviated from a straight line. This determination may
also indicate the existence of a bridged aziridinium ion.
Further proof against the involvement of a carbocation in-
termediate lies in the difference between the ρ+ values re-
ported before, which can be as negative as –4.1, and the ρ
value acquired: When Another noteworthy factor is that
Recently, Lee and co-workers reported the aminobromi-
nation of α, β- unsaturated phosphonates under the
Sharpless AA conditions by using an excess amount of N-
Figure 1. Linear free energy relationship of the aminohalogenation
of MCPs.
Scheme 21.
Scheme 20.
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Regio- and Stereoselective Aminohalogenation Reaction of Alkenes
MICROREVIEW
Scheme 22.
bromoacetamide as the nitrogen/halogen source.[33] Four
α,β-unsaturated phosphonates were examined and con-
verted into syn β-acetylamino-α-bromophosphonates in
chemical yields ranging from 21% to 35%. The reaction
yielded only syn products, unfortunately, no enantiomeric
excess was observed (Scheme 21). The mechanism was pro-
posed to be similar to the catalytic pathway of the Sharpless
AA reaction, but the catalytic cycle II dominates the pro-
cess in which the osmium(VI) bis(azaglycolate) is attacked
by N-bromoacetamide anion. At the same time, the bro-
mine anion attacks at the α position of glycolates from the
osmium side to give the final product.
Sudalai and co-workers reported the aminobromination
reaction by using the combination of pTsNH2 and NBS as
the halogen/nitrogen source.[34] They found that regioselec-
tivity heavily depends on the types of metal catalysts. When
CuI, V2O5 or MnSO4, were used as the catalysts, an α-
amino, β-bromo product was generated. However, when the
catalyst was changed to MnIII–salen, an α-bromo, β-amino
product was obtained instead (Scheme 22).
Scheme 24.
Scheme 25.
Interestingly, when acetonitrile was used as solvent and
KBr as an additive, the reaction of selectfluor with olefins
led to a vicinal haloamine product (Scheme 25).[37]
5. Ionic Liquid Media for Aminohalogenation
and Asymmetric Aminohalogenation
This ionic addition was further extended to the use of
carbamate-based nitrogen/halogen source, tert-butyl-N,N-
dibromocarbamate (BBC) for aminobromination together
with BF3·OEt2 as reported by Zwierzak and Sliwinska[35–36]
Similar regioselectivity was observed with the final products
being tert-Boc-protected amines (Scheme 23).
Since the aminohalogenation reaction is believed to go
through the formation of aziridinium ion intermediate,
ionic liquids[38–39] should be able to play an important role
on this reaction through ionic solvation effects. They can
help the chlorine atom to leave the nitrogen source (4-
TsNCl2) based on the fact that the partial negative charge
on chlorine is surrounded by positively charged 1,3-dialk-
ylimidazolium ion of the ionic liquid. In addition, ionic li-
quids can also make the resulting aziridinium ion and chlo-
rine anion intermediates more stable.
It has been found that an ionic liquid, [bmim][BF4], is
an effective reaction media for the aminohalogenation of
cinnamates to improve the chemical yields (Scheme 26).[40]
The reaction occurred at a faster rate, and was finished
within 6 h with a reduced amount of catalyst (6 mol-%).
Scheme 23.
The ionic mechanism was proposed based on the fact More importantly, the scope is expected be extended under
that the BBC–BF3·OEt2 complex has a different IR spec- the ionic liquid-based catalytic system. For example, methyl
trum from that of the pure BBC. The shifting of C=O bond o-chlorocinnamate worked more efficiently in [bmim][BF4]
stretch from 1724 cm–1 to 1655 cm–1 and 1630 cm–1 sug- to give an yield of 83% and excellent regio- and stereoselec-
gested the diminishing bond order of the carbonyl moiety. tivities.
The contributing structures that are shown in Scheme 24
Very recently, the 2-Ns-based aminohalogenation of α,β-
(A, B and C) and the IR frequencies were consistent with unsaturated ketones was achieved in another ionic liquid
the assigned structure. The interaction of the boron atom media, 1-n-butyl-3-methylimidazolium bis(trifluoromethyl-
with the carbonyl group of BBC sufficiently ionizes the N– sulfonyl)imide ([bmim][N(SO2CF3)2]).[41] This ionic liquid
Br bond towards dissociation to form the Br+ ion.[36]
resulted in the first aminohalogenation of electron-deficient
Selectfluor, since its inception 1980s has been used exten- alkenes without the use of any catalysts. Interestingly,
sively to introduce fluorine into a variety of compounds [Bmim][N(SO2CF3)2] was found to be superior not only to
under mild conditions. It has also been used in the presence classical organic solvents but also to [bmim][BF4]. Al-
+
of other halogen species such as Cl+, Br+, SCN+ and NO2
.
though [bmim][BF4] was proven to be successful in the
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G. Li, S. R. S. S. Kotti, C. Timmons
MICROREVIEW
The first asymmetric aminohalogenation of alkenes has
also been established by taking advantage of the ionic li-
quid, [bmim][BF4] (Scheme 27).[42] Good chemical yields
(60–72%) and diastereoselectivities (up to 75% de, 7:1 for
Scheme 26.
TsNCl2-based aminohalogenation, it failed to give any
product for this α,β-unsaturated ketone-based aminohalo-
genation in the absence of catalyst.
Scheme 27.
Table 3. Results of asymmetric aminohalogenation in [bmim][BF4].
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Regio- and Stereoselective Aminohalogenation Reaction of Alkenes
MICROREVIEW
Scheme 28.
Entry 2 of Table 3) have been obtained with a good scope of Among aziridine derivatives, alkyl N-pTs- and N-o-Ns-azir-
substrates (Table 3). The resulting individual diastereomers idine-2-carboxylates are particularly useful because they
have been cleanly separated by column chromatography.
can undergo regioselective ring openings to afford α- and
As anticipated the success of this asymmetric aminohalo- β-amino esters when treated with various nucleophiles.[14]
genation is largely attributed to the high polarity of ionic Thus far, the application of 1,2-vicinal haloamines for the
liquids by solvation effects to decrease the energy of re- synthesis of aziridinecarboxylates has not been well docu-
sulting aziridinium intermediate. The diastereochemistry is mented. This is probably due to the fact that olefin-based
controlled by non-chelating template (Scheme 27). The elec- synthesis of anti alkyl 3-halo-2-(p-tolylsulfonamido)-3-aryl-
trophilic species approaches the substrate from the less hin- propionates and anti alkyl 3-halo-2-(o-nitrophenylsulfon-
dered side of the oxazolidinone ring. The ring opening of amido)-3-arylpropionates have not been available until now.
aziridinium intermediate through SN2 substitution has to
proceed through the more bulky side of the phenyl ring of quired the use of 2.0 equiv. of potassium carbonate in ace-
the oxazolidinone to give the anti stereochemistry.
tonitrile solution.[45a] The cyclization can be finished at
The synthesis of N-p-tosyl- and N-o-nosylaziridines re-
The asymmetric catalytic aminohalogenation controlled room temperature within 3 h to give up to 97% yields
by ligand-metal complexes has not been successful. How- (Table 4). Under this condition, there was no epimerization
ever, encouraging preliminary results of this asymmetric re-
action have been obtained in our laboratories as shown in
Scheme 28. This reaction took an advantage of the catalytic
Table 4. Results of cyclization of methyl 3-chloro-2-(p-tolylsulfon-
amido)-3-arylpropionates.
complexes of metal copper and chiral diimine ligand (S,S)
which was initially established by Jacobsen for the asym-
metric aziridination reaction.[14a] The NsNCl2/NsNHNa
combination was used as the nitrogen/halogen source in
acetonitrile. Good yield (70%) and 8.2% ee were deter-
mined with styrene as the substrate. Evans (S)-bis(ox-
azoline)copper complex[14b] was also applied to this reac-
tion and led to enantiomeric excess of 12% ee, although
incomplete conversion (≈ 50%) was observed. These results
indicate that the Lewis acidic metal center of the catalyst
can be associated with the transition-state during the for-
mation of aziridinium intermediate, which is necessary to
generate the enantioselectivity.
6. Applications of Vicinal Haloamine Products
The first application of aminohalogenation was con-
ducted by synthesizing aziridinecarboxylates via intramo-
lecular cyclization of vicinal haloamine products.[43] It is
well known that aziridinecarboxylates are very useful build-
ing blocks for the synthesis of a variety of nitrogen-contain-
ing compounds that are biologically important.[14,44]
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G. Li, S. R. S. S. Kotti, C. Timmons
MICROREVIEW
observed on the α position of 2-methoxycarbonyl-3-phenyl-
1
N-(o-nitrophenyl)sulfonylaziridine as revealed by quick H
NMR analysis.
In a later study, a simple one-pot procedure for the
stereoselective synthesis of anti 3-alkyl and 3-aryl-N-(p-tos-
yl)aziridine-2-carboxylates and ketones was also developed
(Scheme 29).[45b] The one-pot procedure consists of the
Scheme 30.
Scheme 29.
Scheme 31.
Scheme 32.
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Regio- and Stereoselective Aminohalogenation Reaction of Alkenes
MICROREVIEW
aminohalogenation reaction and in situ intramolecular SN2 formation of β-halovinyl palladium and π-allylpalladium
substitution by using triethylamine as the base. For several species.[48]
enone cases, a slightly modified procedure is used in which
1.0 equiv. of pTsNCl2 was slowly added into 2.0 equiv. of
enone for the aminohalogenation reaction followed by 7. Conclusion
quenching with aqueous Na2SO3. This procedure resulted
The aminohalogenation reaction of olefins (aminobromi-
in crude aziridines that were nearly pure as revealed by
nation and aminochlorination) has become a powerful syn-
thetic tool for organic chemistry. More applications of this
1
quick H NMR analysis. Moderate to excellent yields and
high anti stereoselectivity have been achieved for 21 exam-
reaction will be explored in the near future. The new aziridi-
ples.
nium mechanism of this reaction has been strongly sup-
The second application of aminohalogenation reaction
ported by the physical organic chemistry determinations
was represented by the synthesis of N-protected α,β-dehy-
droamino acid derivatives that are important building
and the electrophilic diamination results. Finally, the asym-
metric aminohalogenation will become an increasingly im-
blocks for organic and medicinal research. Much work on
portant and interesting topic in organic chemistry and will
the asymmetric hydrogenation has been strongly dependent
attract more synthetic chemists.
on the use of these compounds to give enantiomerically
pure amino acids.[46–47] In addition, α,β-dehydroamino acid
derivatives have been found to be the structural units in
many biologically active natural products. The known syn-
Acknowledgments
thetic approaches to N-protected dehydroamino acids can
be used for this synthesis, but they suffer from a few short-
We gratefully acknowledge the Robert A. Welch foundation (D-
1361) for their generous support of this project. We also thank the
comings, such as multiple-step synthesis, harsh conditions,
expensive reagents, and unsatisfactory yields. The vicinal
haloamines derived from the aminohalogenation reaction
of α,β-unsaturated esters and ketones were found to un-
dergo the elimination by treatment with 2.0 equiv. of
DABCO to give α,β-dehydroamino acid and ketone deriva-
tives (Scheme 30). Interestingly, other organic bases that
were examined did not result in dehydroamino products.
The tentative reaction mechanism is given in Scheme 31.
The first step involves a typical SN2 substitution reaction [2] a) Y.-Y. Yeung, X. Gao, E. J. Corey, J. Am. Chem. Soc. 2006,
between the vicinal haloamine and DABCO to give quater-
nary amine salt with syn stereoselectivity. The syn diamino
intermediate is subjected to the following elimination reac-
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Received: November 16, 2006
Published Online: April 12, 2007
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