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This review article summarizes published data on the application of N-halo reagents (such as N-halo amines, N-halo amides
and/or imides, N-halo sulfonamides and/or imides, and etc.) in various organic functional group transformations such as:
oxidation reactions, deprotection and protection of different functional groups, halogenation of saturated and unsaturated
compounds, acylation of alcohols, phenols, amines or thiols, epoxidation of alkenes, aziridination and etc. The main purpose of
writing this review is encouraging of active researchers interested to this field for the synthesis of new N-halo reagents specially
with different halogens and applications of these new N-halo reagents in organic reactions or finding more and more applications
of existing N-halo reagents in organic synthesis.
Keywords: N-Halo reagents, N-Halo imides, N-Halo amines, N-Halo sulfonamides, N-Halo amides, N-Halo sulfonimides
This article is dedicated to Professor Seyyed Ahmad Banihashemi one of the founders of polymer chemistry in Iran on the
occasion of his 75th birthday.
Depending on the conditions, a number of highly reactive few hours under mild conditions [13].
intermediates can be formed including halogen radicals, The enantioselective epoxidation of chalcones was carried
halogen cations, halogen anions, N-radicals, N-cations, N- out using TCCA as oxidant in the presence of a chiral
anions, etc. Consequently, N-halo reagents have the potential quaternary ammonium salt as a phase transfer catalyst in good
to promote important reactions such as halogenation, yields with moderate enantiomeric excesses (Scheme 1) [14].
oxidation, and protection as well as formation of C-X, C-O,
and C=O bonds. In addition to the numerous organic and
inorganic halogenating agents, N-halo reagents play an R1 H
1,3,5-triazine-2,4,6-(1H, 3H, 5H)-trione, was first synthesised R = Ar, R' = Alkyl or Aryl
in 1902 from the reaction of the potassium salt of cyauric acid
with chlorine gas [9]. TCCA was commonly named as
Scheme 1
Symclosene, ACL-85 and Chloral [10,11].
TCCA was used in the presence of base as an efficient
O
oxidant for the epoxidation of enones and tandem oxidation-
Cl Cl epoxidation of allylic alcohols in a water suspension system in
N N
the presence of a surfactant (Scheme 2) [15].
O N O
Cl
1
O O O
TCCA
1
R1 R2 R R2
Surfactant, KOH(aq)
Oxidation Reactions R1 R1 OH R1 O
TCCA KOH
Oxidations by TCCA are mainly categorized into two Surfactant, KOH(aq) Cl R2 R3
R2 R3 R2 R3 Et2O, Pentane, r.t.
sections, transfer of oxygen and dehydrogenation. An
R1 = Aryl or Alkyl, R2, R3 = H or Alkyl
interesting application of TCCA is the conversion of ,-
unsaturated carbonyl compounds to their corresponding
epoxides. TCCA has been used for the oxidation of enones in Scheme 3
127
Application of N-Halo Reagents in Organic Synthesis
N-Bromosuccinimide NBS N Br
O
O
Br Br
N N
Tribromoisocyanuric acid TBCA
O N O
Br
O
Br
N N
Sodium monobromo isocyanurate SMBI
O N O- Na+
H
O
N-Bromophthalimide NBPI N Br
O
O Br
N-Bromo-p-toluenesulfonamide sodium salt
- H3C S N
(Bromoamine T) -
+
O Na
O
N-Bromosaccharin NBSa N Br
S
O
O
H3C
N,N'-Dibromo-N,N'-1,2-ethanediyl -bis (p-
BNBTS SO2NCH2 )
toluenesulfonamide) 2
Br
H3C SO2
N-Bromo bis(p-toluenesulfonyl)amine NBBTA N Br
H3C SO2
128
Kolvari et al.
Table 1. Continued
O O O O
O O
1,3-Dibromo-5,5-diethylbarbituric acid - N N
Br Br
O
N -Chlorosuccinimide NCS
N Cl
O
O
Cl Cl
N N
Trichloroisocyanuric acid TCCA
O N O
Cl
O
Cl
N N
Sodium dichloroisocyanurate SDCI
O N O- Na+
Cl
O
N -Chlorophthalimide NCPI N Cl
O
O Cl
N-Chloro-p-toluenesulfonamide
- H3C S N-
sodium salt (Chloramine T) Na+
O
O
N -Chlorosaccharin NCSac N Cl
S
O
O
129
Application of N-Halo Reagents in Organic Synthesis
Table 2. Continued
NHCl
Trichloromelamine TCM N N
ClHN N NHCl
N
2,6-Dichloropyridazin-3(2H)-one - N
Cl
O
Cl Cl
N,N,2,3,4,5,6-Heptachloroaniline N
Cl Cl
-
Cl Cl
Cl
(CH-CH2)
n
Poly[4-vinyl-N,N'-dichlorobenzenesulfonamide]
-
SO2NCl2
N-Fluoroquinuclidinium
- N
tetrafluoroborate
BF4
F
O
O
N-Fluoro-3-cyclohexyl-3-methyl-2,3- S
dihydrobenzo[1,2-d]isothiazole-1,1- CMIT-F NF
dioxide Me
130
Kolvari et al.
Table 3. Continued
O O
S
N-Fluoro-3-ethyl-3-methyl-1,1-dioxo-2,3- NF
- Me
dihydro-16-benzo[e]1,2-thiazin-4-one
Et
O
R
R
N-Fluorocamphorsultam -
N
O S F
O
O O
S
N-Fluoro-o-benzenedisulfonimide NFOBS N F
S
O O
CH2Cl
N
1-(Chloromethyl)-4-fluoro-1,4-diazabicyclo
F-TEDA-BF4
[2,2,2]octane bis(tetrafluoroborate)
N
F
O O
Ph S
N-Fluorobenzensulfonimide NFSi N F
Ph S
O O
NO2
N
N-Flouro-2,4-dinitroimidazole NF-2,4-DNI N F
O2N
O O
F3C S
N-Flouro bis[(trifluoromethyl)sulfonyl]imide - N F
F3C S
O O
O O
S
N
N-t-Butyl-N-flurobenzensulfonamide -
F
N-Iodosuccinimide NIS N I
131
Application of N-Halo Reagents in Organic Synthesis
Table 4. Continued
N-Iodophthalimide NIPI N I
O
O
N-Iodosaccharin NISac N I
S
O
O
H 3C
N,N'-Dibromo-N,N'-1,2-ethanediylbis(p-
BNITS SO2NCH2 )
toluenesulfonamide) 2
I
O R3 OH R3
Cl Cl R2 R2
N N N N
+ AcOH, NaOAc +
O N O R 4
N R 1 CH3CN, CH2Cl2, H2O HO N OH R4 N R1
Cl O
Scheme 4
Oxygen transfer to nitrogen was also achieved by TCCA. TCCA was successfully used for the synthesis of Fipronil
Pyridine and its derivatives were readily oxidized to their N- 2 (a highly efficient insecticide) from the corresponding
oxides with a solution of TCCA, acetic acid, sodium acetate sulfide (Scheme 6) [19].
and water in acetonitrile and dichloromethane with 78-90%
O
yields (Scheme 4) [17]. CH3 CH3
F3C S F3C S
Acetylenic sulfides were oxidized to acetylenic sulfoxides
N N
by a solution of pyridine, water, benzoic acid and TCCA in H2N
N
H2N
N
TCCA
acetonitrile and dichloromethane (Scheme 5) [18].
CH3CN, CH2Cl2, H2O
1h, 70%
O CF3 CF3
TCCA, Py
R1 C C S R2 1
R C C S R2 2
CH3CN, CH2Cl2, H2O
82-94% Scheme 6
R1 =Ph, n-C3H7, n-C4H9, n-C6H13, n-C5H11, -CH2OCH3
R2 = Ph, 4-MeC6H4
The second oxidation mechanism by TCCA involves
Scheme 5 dehydrogenation. This behavior may be applied for the
132
Kolvari et al.
aromatization of cyclic compounds or oxidation of alcohols, TCCA was used for the oxidation of urazoles and bis-
primary amines and hydrazines. TCCA was used for the urazoles to their triazolinediones under both heterogeneous
oxidation of 1,3,5-trisubstituted pyrazolines to their and also solvent-free conditions with excellent yields at room
corresponding pyrazoles under either heterogeneous or temperature (Scheme 10) [24].
solvent-free conditions in good yields at room temperature
(Scheme 7) [20].
R1 H
N N TCCA N N
CH2Cl2, r.t.
R2 N 1 O N O or solvent- free O N O
N R R2 N R1
TCCA N R 2
R 2
CCl4, r.t. 1 2
R 3
or solvent-free R = H or Na, R = Alkyl or Aryl
R3
R1, R2, R3 = Aryl
Scheme 10
Scheme 7
Scheme 8
An interesting application of TCCA was reported by
Chen and his co-workers reported the oxidation of primary Hieagl, et al. in the conversion of -aminoacids into nitriles
amines into nitriles by TCCA in the presence of a catalytic by oxidative decarboxylation in water or methanol in the
amount of TEMPO under mild reaction conditions (Scheme 9) presence of pyridine [26]. For example L-isoleucine was
[23]. Optimization of the reaction condition showed that the converted to (S)-(+)-2-methylbutyronitrile in 88% yield after
best results were obtained in dichloromethane at 10 C and the 3.5 h with no considerable loss of its optical purity (Scheme
use of 1 mol% of the catalyst. 12).
Scheme 9 Scheme 12
133
Application of N-Halo Reagents in Organic Synthesis
TCCA takes part in dehydrogenation of primary and procedure and the total absence of any transition metal make
secondary alcohols for their conversion to aldehydes and the reaction suitable for safe laboratory use (Scheme 15). A
ketones, respectively. Chemoselective oxidation of benzylic mechanism was proposed for these reactions (Scheme 16).
and secondary alcohols was achieved by the use of TCCA and
Boc Boc
wet SiO2 in the presence of a catalytic amount of KBr under
N N
heterogeneous conditions at room temperature (Scheme 13)
TCCA
[27]. TEMPO(cat.), NaBr
N acetone, NaHCO3 N CO2H
Boc OH r.t., 24 h, 100% Boc
O
O H2O Cl Cl
N N
R1 R2
HOCl Scheme 15
O N O
Br O Cl
H H
N N
O N O
Br TCCA
H
N N
OH
O O Cl
Cl + OH R OH
R1 R2
O
Cl
1 2
R , R = Aryl and Alkyl N NH
O N O N
Cl
Scheme 13 O O
O
Cl Cl H R
H2O N N H
In some examples TCCA has been used for the oxidation O N O
of primary alcohols to carboxylic acids. For instance, by the Cl H
R O
combined use of catalytic RuCl3 (1.0 mol%) and stochiometric N
amount of TCCA in the presence of n-Bu4NBr and K2CO3, O O OH
Cl O
smooth oxidation of primary alcohols to carboxylic acids was N NH R H
HOCl HCl
O N O R OH
occurred [28]. Secondary alcohols were oxidized to ketones H
using a similar set of reagents. The method is mild and permits Scheme 16
the chemoselective oxidation of alcohols in the presence of
other sensitive functional groups such as vinyl and ketals Fluorinated alcohols were also oxidized to aldehydes by
(Scheme 14). the use of TCCA in the presence of TEMPO [30]. TCCA was
used for the conversion of primary alcohols and diols to
O
O methyl esters and lactones, respectively, by refluxing in
O
O O dichloromethane (Scheme 17) [31].
OH O
O
TCCA
n-Bu4NBr, K2CO3 O O O
O O
CH3CN/H2O
52% OH TCCA OMe
CH3OH, CH2Cl2
Scheme 14 24 h, 99.6%
O
Efficient oxidation of primary alcohols to the OH TCCA
corresponding carboxylic acids was carried out at room O
OH Py, CH2Cl2
5 h, 97%
temperature and in acetone/water, using TCCA in the presence
of a catalytic amount of TEMPO [29]. The mild conditions of Scheme 17
134
Kolvari et al.
TCCA
RNH2 RNCl2
CH2Cl2, 15 C
Regioselective chlorination of isatin at the 5-position and
R NH2
TCCA RCN
also deactivated aromatic compounds, such as nitrobenzene
Et3N, DMF was carried out by TCCA in H2SO4 [37]. An interesting
15 C
CO2H example of application of TCCA as a chlorinating agent was
TCCA
RCN described in the synthesis of some cyclic dichloroimines
R NH2 NaOH, H2O
5 C (Scheme 22) [38].
R= Aryl or Alkyl
Scheme 18 R R
N
N-Chlorination of various amides, lactams and carbamates TCCA N
Br CHCl3/CH3CN
were proceeded efficiently by TCCA under very mild Cl Br
reflux
condition at room temperature [33]. An interesting example Cl
R= H or Cl
that demonstrates the chemoselectivity of the method is shown
Scheme 22
in Scheme 19.
HO HO
TCCA The preparation of diverse -chloroethers, -chloroacetates
Boc Boc
N CO2Me CH2Cl2, r.t. N CO2Me and chlorohydrins was achieved by the reaction of alkenes
H 3 h, 99% Cl with TCCA in alcohols (MeOH, EtOH, i-PrOH and t-BuOH),
acetic acid or aqueous acetone, respectively (Scheme 23) [39].
Scheme 19
Hiegel et al. reported a procedure for the conversion of R2 R1 R4OH, r.t. R4O R1
alcohols to alkyl chlorides using TCCA in the presence of R1= Ph, Alkyl R3= H, Methyl
triphenylphosphine (Scheme 20) [35]. R2= H, Alkyl R4 = H, Alkyl, Ac
CH3(CH2)8CH2OH
TCCA, Ph3P
CH3(CH2)8CH2Cl
Scheme 23
CH3CN, 60 C
2 h, 74%
TCCA was reacted with alkynes in the presence of water in
Scheme 20 acetone or acetonitrile to form ,-dichloro ketones and in
135
Application of N-Halo Reagents in Organic Synthesis
methanol to form ,-dichlorodimethyl ketals (Scheme 24) They have also reported an easy and general method for
[40]. deprotection of thioacetals to their corresponding carbonyl
compounds using TCCA/silica gel in the presence of water
O
[45]. Similar reactions were also carried out in non-aqueous
TCCA conditions (CHCl3 and DMSO) at room temperature [46]. The
H2O, acetone Cl Cl
59% same group took advantage of TCCA in catalytic preparation
and cleavage of THP-ethers of various hydroxy functional
H3CO OCH3
groups with high yields (Scheme 27) [47]. A mechanism was
TCCA
Cl Cl
CH3OH
62%
TCCA (cat.), DHP
60-80 C
Scheme 24 ROH
TCCA (cat.), MeOH, r.t. RO O
O O
RO TCCA RO RO
P Cl O
P H
RO CH3CN, r.t. RO
10-15 min O
RO O
Cl
R= Phenyl, Benzyl, or Alkyl ROH + N H
ROH
Scheme 25
O
Treatment of styrene-butadiene rubber with TCCA was OR
Cl + N
reported to chlorinated the rubber and improved its adhesion H
H
properties [43,44]. O O
O O S OH OAc
TCCA TCCA
R R R
HS(CH2)nSH n-2 R 1
R 2 Ac2O, CH2Cl2 1
R R2
O O S
CH2Cl2, r.t. r.t.
n = 2, 3
R1, R2 = Alkyl, Aryl
R= Substituted Phenyl, Cinnamyl
Scheme26 Scheme 29
136
Kolvari et al.
A novel and efficient trimethylsilylation of various TCCA and triphenylphosphine in the presence of carboxylic
alcohols and phenols was efficiently carried out with acids resulted in the in situ formation of the corresponding
hexamethyldisilazane (HMDS) in the presence of catalytic acid chlorides [53]. Subsequent addition of amines or alcohols,
amounts of TCCA in good to excellent yields in in the presence of a tertiary amine, afforded the corresponding
dichloromethane at room temperature (Scheme 30) [49]. amides, or esters, in good to excellent yields. The method was
interestingly applied to the synthesis of a protected dipeptide
(Scheme 33).
TCCA (0.06-0.1 mmol),
HMDS (0.8 mmol)
ROH ROSiMe3
CH2Cl2, r.t.
BnO
O O O
R = 1, 2, 3, Benzylic, Naphtyl 1) TCCA, Ph3P, CH2Cl2
0 C to r.t., 45 min
OH N
Scheme 30 NHBoc 2) O NHBoc
N , Et3N, 2 h
85%
H H OBn
Cl
Miscellaneous Reactions
A combination of TCCA and sodium nitrite in the presence Scheme 33
of wet SiO2 has been used for the nitrosation of N,N-dialkyl
amines under mild and heterogeneous conditions [50]. For
example 2-methylpiperidine was converted to its N-nitroso Alcohols were converted into alkyl nitrates, nitrites or
derivative in short time with quantitative yield (Scheme 31). thiocyanates by the action of TCCA and triphenylphosphine
along with silver nitrate, silver nitrite, or sodium thiocyanate,
respectively (Scheme 34) [54].
TCCA, NaNO2
NH N NO
CH2Cl2, wet SiO2
15 min, 99%
TCCA, Ph3P
ROH R-ONO2
CH3CN, AgNO3
Scheme 31
TCCA, Ph3P R-ONO
ROH
CH3CN, AgNO2
TCCA, Ph3P
The same reagent system was used for the mononitration ROH R-SCN
CH3CN, NaSCN
of p-substituted phenols at room temperature in good yields
R= Nonyl, Octyl, Cyclohexyl, Benzyl
(Scheme 32) [51].
Scheme 34
OH OH
NO2
TCCA, NaNO2 Amides were chlorinated on nitrogen using TCCA and the
CH2Cl2, wet SiO2 produced N-chloroamides were then rearranged to the
r.t.
X X corresponding methyl-N-substituted carbamates by sodium
X = F, Cl, CN, CH3, OCH3, COCH3, CHO, CH2Ph, NHOAc, CO2H
methoxide in methanol [55]. Isocyanates were suggested as
the intermediates (Scheme 35).
Scheme 32 TCCA was used efficiently for the synthesis of 3,4-
dihydropyridine-2(1H)-ones through the three-component
Dinitrophenols were also obtained in a similar way but Biginelli reaction of a -ketoester, an aldehyde and urea
under solid-phase reaction conditions [52]. The reaction of (Scheme 36) [56]. TCCA has been used as an initator for the
137
Application of N-Halo Reagents in Organic Synthesis
O O
O
TCCA NaOCH3
R NH2 R N C O R N OCH3
CH3OH R NHCl CH3OH H
Scheme 35
O R1
O O O R 2O NH
R1CHO + + TCCA
OR2 H 2N NH2 O
Solvent-free, 90 C N
H
2h
R1= Alkyl or Aryl, R2= Methyl or Ethyl
Yield: 75-90%
Scheme 36
metal-catalyzed living radical polymerization of methyl An efficient and highly regioselective bromination of
methacrylate [57]. activated aromatic rings promoted by TBCA through in situ
generation of Br+ has been developed by de Almeida et al.
TRIBROMOISOCYANURIC ACID AND [58a]. For example, monobromination of 2-methoxy-
SODIUM MONOBROMOISOCYANURATE naphtalene was carried out in excellent yield after a short
reaction time (Scheme 37). Also, Niknam et al. have reported
There are few reports on the application of
tribromoisocyanuric acid [58a-d] (TBCA, 3) and sodium
Br
monobromoisocyanurate (SMBI, 4) in the bromination of
OCH3 OCH3
aromatic compounds. TBCA
MeOH, r.t.
0.5 h, 90%
O O
Br Br Br Na
N N N N Scheme 37
O N O O N O
nitration of phenols, silylation of alcohols and oxidation
Br H
3 4
Br O
N
O H
CF3CO2H
N
H O
O
SMBI O
O
O Br
N
H
H2SO4
5
O
O
Scheme 38
138
Kolvari et al.
R R
Me N
Me Br
SMBI
CH2Cl2-H2O
6
Br
R = Et, n-Pr, Ac2O Among the methods, which were reported for the
preparation of DBH [69-72], the bromination of 5,5-
Scheme 39 dimethylhydantoin (DMH) in the presence of NaOH or
O
O
Br
N NH Br Br
HN N
O H O
O N O
O N O H H
Na+ H2O
Na+
Br
H Br
Br
O H-OH2
H
Scheme 40
139
Application of N-Halo Reagents in Organic Synthesis
CO2H CO2H
NaHCO3 was studied with precision (Scheme 41) [73]. It was
Step 1: N + NaOH Me N
Me
H Na
Me Me
OMe OMe
2NaOH + Br2 NaOBr + NaBr + H2O OMe
DBH(0.5 eq)
H Br
N
TMSOTf (0.5 eq)
O O O N O r.t., 2 h, 50-86%
Br
Me N + NaOBr N + NaOH Scheme 44
Na Me
Me Na
Me
Me N + HOBr N + NaOH
Na Me Br Br
Me Me Br H
O N O O N OSiMe3 O N O
TMSOTf
NaOH + HBr NaBr + H2O + TfOH
N Me N NH
Me Me
Me Br Me Me
ArBr
Scheme 42 DMH
+ BrOTf
ArH
The application of DBH in organic reactions mainly can be
studied in the following sections. TMSOTf
DMH
Halogenation Reactions
DBH BrOTf ArBr
Bromination reactions. In 1993, Auerbach and co-
workers reported that DBH in aqueous NaOH can be used as
TfOH Ar
an efficient reagent for the bromination of activated benzoic
acids [74]. They also showed that DBH gave better yields than
Scheme 45
NBS (Scheme 43).
140
Kolvari et al.
Similarly, Eguchi and co-workers used DBH in the pyrogallol derivatives by DBH, which gave single
presence of organic and inorganic acids with pKa values less monobromides in 1.5 h at room temperature (Scheme 48) [78].
than -2 to get the monobromide in excellent yields [76]. Very
good yields were obtained even for aromatics having electron-
COOMe COOMe
withdrawing substituents. In some cases, catalytic amounts of
Br
acids were sufficient (Scheme 46). DBH (0.53 eq)
r.t., 1.5 h, 77%
O OH O OH
O O
R R Me Me
Me Me
DBH/acid (0.5/(0.1-1.0 eq)) Scheme 48
r.t. or reflux, 5 min-24 h,
62.4-99.5% Br
Me Bu-t Me Bu-t
COOMe COOMe
Br 7 8
DBH (0.5-0.55 eq)
CHCl3, r.t., 88-99%
R1O OH R1O OH t-Bu t-Bu
OR2 OR2
R1 = Bn, Me; R2 = Me, OH
Br Br
COOMe COOMe
Me Me Me Me
Br
DBH (0.5-0.55 eq) + Br Br
CHCl3, r.t., 80-99%
O OH O OH
1 O O t-Bu
R R1 t-Bu
R2 R1, R2 = H, Me, Ph R2
9 10
Scheme 49
Scheme 47
In 2006, Azarifar et al. reported an efficient method for
They also studied the regioselective bromination of
141
Application of N-Halo Reagents in Organic Synthesis
the conversion of various N-arylglycines to sydnones using Flourination reactions. Hiyana et al. reported the
DBH in the presence of NaNO2/Ac2O under mild and neutral oxidative desulfurization-fluorination of methyl xanthates with
conditions (Scheme 50) [80]. The following mechanism was (HF)9/pyridine and DBH (Scheme 53) [81]. Under the reaction
conditions, trifluoromethyl ethers (R-OCF3) were produced
through R-OCF2SMe intermediates.
Ar
DBH (0.8 eq) N
ArNHCH2CO2H N
NaNO2 (1.25 mmol)/Ac2O (1.5 mmol) O
O
0-5 C, CH2Cl2, 10-16 h, 80-94% S
R (HF)9/Py (2mL, 8.8 mmol of F-)
[R-OCF2SMe]
Scheme 50 O SMe
DBH (3 mmol), CH2Cl2
0 C, 1 h, 48-80%
proposed for these transformations (Scheme 51). R= Substituted Phenyl, Benzyl, n-C10H21 R-OCF3
Scheme 53
Br
O N O O N O
They also showed that -hydroxy orthothioesters 11
N + NaNO2 N Na + BrNO2 derived from both aromatic and aliphatic aldehydes were
Me Me
Me Br Br
Me successfully converted into their corresponding
difluoro(methyl thio)methyl ketones 12 using n-Bu4NH2F3 and
BrNO2 NO + BrO
DBH. Reactions were performed in CH2Cl2 at room
temperature (Scheme 54) [82].
+ NO
ArNH2CH2CO2H HOBr + ArN(NO)CH2CO2H
+ BrO
OH O
Ac2O + HOBr AcOBr SMe n-Bu4NH2F3 (5 mmol) SMe
R DBH (4 mmol)
SMe R F
SMe CH2Cl2, 10 min, r.t.
28-95% F
AcOBr
Ar H 11
O 12
N R= Aryl or Alkyl
Ar OAc
N OH N
-AcOH O OH
+ BrO Scheme 54
N
O
Scheme 51
Br
SMe n-Bu4NH2F3 (3 mmol) SMe
They also showed that DBH is able to promote the R DBH (3 mmol) R
SMe F
bromination of sydnones to their 4-bromo-substituted SMe CH2Cl2, 20 min, 0 C to r.t.
F
52-87%
congeners in excellent yields in DMF at room temperature
Scheme 55
(Scheme 52).
Ar H Ar Br
N
DBH (2 mmol) N mechanism which initiated by the electrophilic attack of Br+ at
N + N +
O
O DMF, r.t., 2.0-2.6 h
O
O the sulfur atom of the substrate has been suggested (Scheme
94-99%
56).
Scheme 52
142
Kolvari et al.
H Br Scheme 58
H Br
SMe
SMe R F
R
F product can be rationalized by the following mechanism
F
F
(Scheme 59). On the basis of the proposed mechanism,
electrophilic attack of Br+ to organic sulfide produces a
Scheme 56 sulfonium ion 14, which is attacked by the fluoride ion to give
the final product. The reaction of RCH(SMe)CF2SMe, under
H SMe F SMe
n-Bu4NH2F3 (3.5 mmol)
CF2SMe DBH (2.5 mmol) CF2SMe
CH2Cl2, r.t., 20 min
68%
Scheme 60
Scheme 61
143
Application of N-Halo Reagents in Organic Synthesis
conversion of gem-disulfides to the corresponding gem- They have also reported a mild method for the preparation
difluorinated compounds by a combination of of trifluoromethyl ethers (R-OCF3). The reaction was carried
hexafluoropropene-dimethylamine and DBH (Scheme 61) out by the reaction of dithiocarbonates (R-OCS2Me) with a
[86]. reagent system consisting of 70% HF/Pyridine and DBH
Using this method, 1,3-dithiolanes derived from ketones (Scheme 65) [88]. When the reaction was applied to
gave better results than those from aldehydes. The probable ROCS2Me wherein R = secondary alkyl, tertiary alkyl or
mechanism of the reaction is shown in Scheme 62. benzylic group, fluorination was leading to corresponding
alkyl fluorides (R-F) (Scheme 66).
BrS
Scheme 65
Br
BrF S F F F F
Scheme 64
OR
OR OR
OR
RO SiF4(gas), DBH (1.1 mmol) Br
RO O H2O (1.0 mmol), HMPA (0-5 mmol) RO RO
RO O RO O RO
+ + RO O
1,4-dioxane (4 mmol) F
0 or 50 C, 1h Br
F F Br
144
Kolvari et al.
absence of HMPA, formation of the -fluorides predominated DBH has also been used for the efficient oxidation of
with ratio of 74:26, and the addition of HMPA improved the mono and bis-urazoles to their corresponding triazolinediones
selectivity in favor of the -isomers. The best stereoselectivity both in solution and under solvent-free conditions (Scheme
was obtained when the reaction was carried out in the presence 71) [94].
of 3.0 eq. of HMPA, in which the - vs. -isomer ratio was
92:8.
H O O H O O
Hiyama et al. has also reported that when alkene was N N
N N
A or B
treated with KHF2/HF/n-Bu4NF/DBH reagent system, the N R2 N N R2 N
related bromofluorinated product was obtained in good to high N N N N
R1 O O R1 O O
yields (Scheme 68) [91]. The stereochemistry of the addition
of F and Br was anti for all of the olefins. A: DBH (2 mmol), 4h, 99-100%, CH2Cl2, r.t.
B: DBH (2 mmol), 4h, 33%, Solvent-free, r.t.
O F O R1 = H, Na, R2 = -(CH2)6- , -C6H4-CH2-C6H4-
n-Bu4NH2F3 (1.5 mmol)
DBH (1.5 mmol) Br
OMe OMe
CH2Cl2, r.t., 13 h, 85 % Scheme 71
R3 R3 Scheme 72
A: DBH (1-4.25 mmol), 0.3-1.75 h, 70-98%, CCl4, r.t.
B: DBH (2-18 mmol), 0.3-4.5 h, 63-92%, Solvent-free, r.t.
A mechanism was proposed for this reaction (Scheme 73).
R1 = Ph, Acetyl, R2 = Aryl, R3 = Substituted Phenyl
Scheme 69 O
Br O
N
The same group has also shown that when the reaction was 2RSH + N Br 2 R S Br N
N
carried out in the presence of silica gel under microwave H
O
irradiation, the products were obtained during very short II O
I
reaction times (Scheme 70) [93].
O
DBH (2.5-4 mmol) H
R1 N R1 N N
N Ph Silica gel (20-32 mg)
N Ph 2 RSBr + N H
II
MW, 1-5 min, 74-90%
R2 R2 O
III
R1 = Aryl, R2 =Substituted Phenyl
2 RSBr RSSR + Br2
Scheme 70
Scheme 73
145
Application of N-Halo Reagents in Organic Synthesis
The same subject has also been investigated by another DBH (1.2 mmol)
R1 N N R3 R1 N N R3
group in 2005 [96]. DBH in accompanying with NaNO2 was 1-15 min, 63-89%
R2 H
used as a co-catalyst for the acceleration of the aerobic R2 Br
1
R = Substituted Benzyl and Phenyl,
oxidation of benzylic alcohols in water catalyzed by TEMPO R2 = H, Substituted Phenyl,Methyl, R3= Substituted Benzyl
(Scheme 74) [97]. All reactions were performed at 80 C and
the products were obtained in good to high yields. Scheme 76
Scheme 75
O O
Br
Br
Br N
N R1 N N R3 N
N Br 1 3 +
R N N R
+ R2 H
R2 H O
O
O
H
R1 N N R3 + N
N H
R2 Br
O
Scheme 77
146
Kolvari et al.
F F
When 1,3-dithiolanes bearing a phenyl or substituted
aromatic group and a methyl (or methylene) group attached to Me
Me
MeO O MeO
C-2 were treated with DBH in the presence of HF/pyridine, a O
Me
Me DBH
rearrangement took place instead of gem-difluorination HF/Pyridine
(Scheme 79) [101]. A mechanism was proposed for this S S Me
MeO O
rearrangement, which is shown in Scheme 80. Me
DBH was also applied for the synthesis of S
diglicodeoxynucleotides containing 2-O-(trifluoromethyl) S
adenosine in the presence of HF/pyridine (Scheme 81) [102]. Scheme 79
Using this method, products were obtained in relatively
acceptable yields under mild reaction conditions. glycosyl S,S-acetals to their corresponding O,O-acetals using
Madhusudan et al. reported the facile conversion of DBH under mild and neutral conditions (Scheme 82) [103].
S S S S Br S S Br
H
Me Br Me Me - H+
MeO O MeO O MeO O
Me Me Me
S S
S S Br H S
S
H
Me - H+ Me
Me
MeO O MeO O
MeO O Me Me
Me
Scheme 80
Scheme 81
OAc OAc
CH(SEt)2 DBH (1 mmol) CH(OMe)2
AcO AcO
30 min, 86%,
OAc OAc r.t. OAc OAc
Scheme 82
147
Application of N-Halo Reagents in Organic Synthesis
The proposed mechanism of this reaction is illustrated in under the same conditions, glycofuranosides were obtained in
(Scheme 83). When glyclic glycosyl S,S-acetals were reacted good to high yields (Scheme 84). In the case of
Br Br
H SEt
OAc H SEt H H SEt
OAc OAc OAc
OAc H SEt
OAc H SEt -EtSBr OAc H SEt Br OAc H OMe
DBH
H OAc
H OAc H OAc H OAc
MeOH
OAc
OAc OAc OAc
AcO
AcO AcO AcO
H H OMe
OAc OAc
-EtSBr OAc H OMe MeOH OAc H OMe
H OAc H OAc
OAc OAc
AcO AcO
Scheme 83
OH
AcO O
CH(SEt)2 DBH (1 mmol) OAc OMe
HO 30 min, 86%,
OH OH r.t.
OAc
Scheme 84
Br
H SEt
OH H SEt H
OH H
OH H SEt OH O
DMF OH H SEt OH H SEt OH H SEt
H OH
H OH H OH H OH
OH
OH OH OH
HO
HO HO HO
H H H
O O O
OH H SEt OH OH H OR
H ROH
Br
H OH H OH H OH
OH OH OH
HO HO HO
Scheme 85
148
Kolvari et al.
glycofuranoside formation, the authors proposed that product Recently, DBH/NaNO2/wet SiO2 has been used as an
was formed by intramolecular nucleophilic attack from the efficient reagent system for the direct nitration of phenols
hydroxyl group at C-4 following by a nuclophilic attack of the (Scheme 87) [106]. All reactions were performed at room
alcohol at C-1 (Scheme 85). temperature and under completely heterogeneous conditions.
Because of the unstability of -aminoaldehydes, which are
reckoned as extremely valuable chiral building blocks in
OH OH
asymmetric synthesis [104], the preparation of N-protected
DBH (1mmol) NO2
derivatives of these compounds is attracted the attention of NaNO2 (1mmol)
many organic chemists. Davis et al. reported that the wet SiO2(50% w/w, 0.4 g)
30 min, 90%
hydrolysis of sulfimine derived N-sulfinyl--amino-1,3- Cl Cl
dithianes with aqueous DBH affords the corresponding N- Scheme 87
tosyl--aminoaldehydes in good yields and high enantiomeric
purities (Scheme 86) [105].
The reaction did not proceed in the absence of wet SiO2. The
following mechanism was proposed for the description of the
O
S
reaction pathway (Scheme 88).
Tosyl
p-Tolyl NH 1) DBH (2 eq.) NH
2) Na2SO3
In the same manner, when N,N-dialkylamines were treated
H H
R S R with DBH/NaNO2/wet SiO2 reagent system, their
S O corresponding N-nitrosated derivatives were obtained in good
to excellent yields (Scheme 89) [107]. The reaction conditions
R = Ph, i-Pr, t-Bu
are very mild and completely heterogeneous.
Scheme 86
O O
Br H
N N
N Br N H
+ 2H2O (wet SiO2) + 2HOBr
O O
HOBr + NO2 HNO2
HNO2 + 2H NO + H3O
N2O3 NO + NO2
2NO2 N2O4
OH OH O OH
NO2
+ NO +H NO2
-NO
-H
Cl Cl Cl Cl
Scheme 88
149
Application of N-Halo Reagents in Organic Synthesis
Scheme 89
A or B
ROH ROY
Recently, an efficient and high yielding method for the
acylation of alcohols with acetic anhydride using DBH has A: DBH (0.015 mmol), HMDS (7.0 mmol), CH3CN, r.t.,
immediately-15 min, 80-95%
been reported (Scheme 90) [108]. The proposed mechanism, B: DBH (0.5 mmol), DHP (1.4 mmol), n-Hexane, r.t.,
Y: TMS, THP
R= Aryl or Alkyl ( 21 substrates)
OH DBH (0.05 mmol)
OAc
Ac2O (2mmol) Scheme 92
R1 R2 1
R R2
CH2Cl2, r.t., 1-38 h,
80-95%
R1, R2 = Alkyl or Aryl selective trimethylsilylation or tetra-hydropyranylation of
various types of alcohols in the presence of tertiary alcohols
Scheme 90 (Scheme 93). The mechanism which has been reported for the
above mentioned method is the same as that reported for the
tetrahydropyranylation of alcohols in the presence of TCCA
which was based on activation of Ac2O by the in situ (Scheme 28).
generated H+, is shown in Scheme 91. DBH has been found to efficiently catalyze the conversion
DBH efficiently enhanced the rate of trimethylsilylation of of various 3-arylsydnones to their corresponding 4-acetyl
different types of alcohols with HMDS [109]. Alcohols were derivatives in the presence of acetic anhydride under neutral
also converted to their corresponding tetrahydropyranyl conditions in satisfactory yields (Scheme 94) [110].
O
O O O
Br
N Br
+ Ac2O N + O
O O O
H
+ ROH ROAc + N
N
O O O
O
H Br +
N + Br N OH
O
Scheme 91
DHP, DBH
n-Hexane
Me3COH + OH OTHP + Me3COTHP
r.t., 30 min
95% 0%
Scheme 93
150
Kolvari et al.
O
Ar
1-BROMO-5,5-DIETHYLBARBITURIC ACID
N Ar
DBH, AcO2 N AND 1,3-DIBROMO-5,5-DIETHYLBARBI-
N N
O
O Reflux
O
O TURIC ACID
Scheme 94 1-Bromo-5,5-diethylbarbituric acid 16 and its 1,3-dibromo
analogue 17 were prepared in 1991 but found little attention of
1,3-DICHLORO-5,5-DIMETHYLHYDANTOIN organic chemsits [115]. They have been used for the oxidative
O
cleavage of different kinds of trimethylsilyl ethers in good
Cl N
N yields at room temperature (Scheme 96) [116]. The conversion
Cl
of benzyl trimethylsilyl ether to benzaldehyde in the presence
O
of both 16 and 17 was conducted in different solvents. The
15
results showed that the efficiency and the yield of the reaction
O O
O O
Cl H
N N
p-TsOH +
R + 1/2 R 1/2 N
N CH3OH/30-35 C Cl O
O H
Cl
R = H, p-CH3, p-OCH3, p-Cl, p-NO2, p-Br, m-NO2, o-NO2
Scheme 95
OSi(Me)3 O
A or B
CH2Cl2
Scheme 96
OH
OH
HO OH
17 (Cat., 20% eq) / HMDS (1.5 eq) TMSO OTMS
r.t./ neat/ 85%
Br
Br
Scheme 97
151
Application of N-Halo Reagents in Organic Synthesis
X
in dichloromethane was better than in other solvents. THP-
Cl
ethers remained intact under the reaction conditions.
Silylation of alcohols and polyols is one of the most N
O N
commonly used methods for their protection. H H
Cl
Cl Cl
Trimethylsilylation is a classic way to produce volatile R1 C R or R1 C H R1 C R or R1 C Cl
Base or Acid
derivatives of alcohols and polyols. The application of 17 as a R2 R2 R2 R2
CH3
CH3 CO2Me
CO2Me CCl4
CH2 C +
CH2 C + 10 h, 87% H3C SO2NCH2
H3C CH2Br
CH3 SO2NCH2
2 H
Br
CH3 CH2Br
CO2Me CO2Me H2
heat
CH2 C + CH2 C C C C C
CH3 CH2Br H2
CH3 CH3
Scheme 99
152
Kolvari et al.
CH3
H3C
SO2NCH2 )
2
Br SO2NBr2 SO2NCl2
I II III
H3C SO2
Br2N NBr2
N Br SO2NCH2 ) S S
2
H3C SO2 Br O O O O
IV V VI
H 3C
Br Br
( H2C N N
S S CH2) n
SO2NCH2 )
O O O O 2
I
VII VIII
Scheme 101
CH3 CH3
CCl4
+ Alkene Bromoalkene +
H3C (PhCO2)2 H3C
SO2NCH2 ) SO2NCH2 )
2 2
Br H
Scheme 102
153
Application of N-Halo Reagents in Organic Synthesis
R R
and characterization of carbonyl compounds. To achieve this
PBBS or TBBDA aim N-halo compounds have been used widely as versatile
CH2Cl2 reagents. Recently a broad range of N-halosulfonamides
25-40 C (NHSs) has been reported for regeneration of carbonyl
30-180 min Br
79-98% compounds from oximes (Scheme 105) [130,131,135-139].
R= -NHCOCH3, -OCH3, -NEt2 N,N-Dibromo-N,N-1,2-ethanediyl bis(p-toluenesulfon-
amide) (BNBTS) has catalytically been applied for
Scheme 103
tetrahydropyranylation of a various range of alcohols and
phenols in dichloromethane and tetrahydropyranylation of
these compounds has been also carried out in methanol at
N,N'-Diiodo-N,N'-ethanediylbis(p-toluenesulfonamide)
room temperature (Scheme 106) [140].
(BNITS) as a novel iodinating agent has been used for
iodination of some aromatic compounds in high yields
(Scheme 104) [132].
BNBTS, CH2Cl2, r.t.
ROH +
O BNBTS, MeOH, r.t.
O O
R R R= 1, 2, 3, Alkyl and Aryl R
NOH NHS O
1 2 1
R R R R2
O Br
O H3C (CH-CH2)
S N Br n
NHS : O O S N
O Br SO2NCH2 )
2
Br
SO2NCl2
Scheme 105
154
Kolvari et al.
OAc O
solid state, H2O, r.t. + BNHTS + 2AcOBr
+ BNBTS H
R OAc R
1.5 to 4 min
90-98%
R = Alky or Aryl
Scheme 107
R1 R1 TBBDA or PBBS
BNBTS HMDS
N NH NO2 O RXH RXSiMe3
CH2Cl2, MW CH2Cl2 or solvent free, r.t.
R2 R2
30-60 min
O2N
89 -95% X = S or O
R1, R2 = Alky or Aryl R= Aryl, Alkyl
n
O Oxidation Reactions
BNBTS, AgNO3
S S Another important application of N-halo reagents in
80% aq. CH3CN, r.t. R1 R2
80-90% organic chemistry is the oxidation of different functional
R1 R2
15-30 min groups through the release of halonium ions. TBBDA and
R1, R2 = Alkyl, Ary, H TCM were used as effective oxidizing agent for the
n = 1, 2 conversion of urazoles and bis-urazoles to the corresponding
Scheme 109 triazolinediones under mild and heterogenous condition at
room temperature with good to excellent yields (Scheme 112)
Deprotection of 1,3-oxathiolanes to carbonyl compounds [146].
has been carried out with BNBTS in good yields under mild
Cl
conditions (Scheme 110) [144]. HN
Br2N NBr2 N Cl
S S N NH
n O O O O O N
BNBTS Cl NH
O S
80% aq. CH3CN, r.t. R1 R2
R1 R2 0.5-10 h N,N'-tetrabromobenzene-1,3- Trichloromelamine (TCM)
82-93% disulfonamide (TBBDA)
n=1, 2 R1 H
R1, R2 = H, Arly or Alkyl N N TCM or TBBDA N N
CH2Cl2, r.t. O O
O N O N
1.5-22 h
Scheme 110 R2 R2
155
Application of N-Halo Reagents in Organic Synthesis
BNBTS OH OCOCH3
R-SH RS-SR
CH2Cl2, r.t. Ac2O, Catalysts
1.5-3.8 h 90-95% R1 R2 R1 R2
CH2Cl2, r.t., 1-48 h
R = Alkyl or Aryl 90-98 %
N,N,N',N'-tetrabromobenzene-1,3-disulfonamide (TBBDA),
Catalysts: X= Br or Cl
BNBTS and PBBS were used as efficient reagents for the
oxidation of 1,3,5-trisubstituted pyrazolines to their SO2NX2
corresponding pyrazoles in solvent-free conditions both under
Scheme 116
microwave irradiation or at room temperature (Scheme 114)
[148-151].
A combination of equal amount of Ph3P and BNBTS has
been used for the conversion of carboxylic acids into esters
and amides in the presence of alcohols and amines,
R1 R2 R1 R2
BNBTS or TBBDA respectively (Scheme 117) [155]. Authors have suggested that
N N N N
MW, Solvent-Free
Ph or CCl4, r.t. Ph
or Solid Phase, r.t.
R1, R2 = Aryl 1) BNBTS, Ph3P 1) BNBTS, Ph3P
CH2Cl2, 0 C CH2Cl2, 0 C
R2R3NCOR RCO2H RCO2R1
Scheme114 2) or R2R3NH, Py, r.t. 2) R1OH, Py, r.t.
R1OH R2R3NH2
Miscellaneous Reactions
N-halo reagents have been also applied as catalyst in
[Ph3P-OCOR]Br
esterification reactions. N,N-dibromo(p-toluenesulfonamide)
and N,N-dichloro(p-toluenesulfonamide) catalyze acetylation
RCO2R1 R2R3NCOR
of structurally drivers alcohols by the reaction of acetic Reaction intermediate
anhydride in chloroform at room temperature (Scheme 116)
[153-154]. Scheme 118
156
Kolvari et al.
Me Me
O I O H
N Na2CO3 N
2R + S CH2 2 S CH2
H O 2 R OMe + O 2
O MeOH, dark O
2.5-42 h
65-90%
R = Alky or Aryl
Scheme 119
SCN R = Me or Et
18 or 19
KSCN Scheme 122
0 or 25 C
R 2-4 h
70-98% R
CHLORAMINE T
CH3 CH3
CH3
Cl
1) o-NsNClNa
COOR CuOTf (10 mol %) COOR
Ar Ar
2) Na2SO3(aq)
NH(o-Ns)
63-76% SO2NClNa
R = Me, Et or i-Pr
20
Scheme 121
Tandem diamination of cynamic esters have been Wang and Li carried out oxidation of hydrocarbons to their
successfully carried out with N,N-di-chloro-2-nitrobenzene- corresponding ketones using the Fe(TPP)Cl/Chloramin T/O2
157
Application of N-Halo Reagents in Organic Synthesis
not found S
Chloramine T Chloramine T
O CHO
Fe(TPP)Cl MeOH, H2O
CH3CN S
24h
83 % Scheme 126
Scheme 123 R1 R3
Ts
Chloramine T, Cat. R1 N R3
Solvent or
Chloramine T was used for the conversion of some amines R2 R4 solvent-free, r.t. R2 R4
and imidazoles to corresponding oxidized compounds under
Solvent: CH3CN or H2O
catalytic conditions (Scheme 124) [162,163]. Catalyst:HPA/CTAB/MS 5 A, Py/HBr3, I2/BTEAC, CuI/Ptc, MPHT or NBS
R1, R2, R3, R4 = Alkyl or Aryl
MPHT = N-methylpyrrolidine-2-one hydrotribromide
N NH2
Chloramine T Scheme 127
Ru Complex
N H3O+ NH2
H
TsNClNa + NBS
Synthesis of chlorolactones by reaction of unsaturated
carboxylic acids with Chloroamine T has been reported TsNClNa
158
Kolvari et al.
2-Pyrazoline and 2-isoxazolines have been prepared by the (Scheme 130) [174]. Minakata et al. reported a new synthetic
reaction of araldehyde hydrazones and aldoximes with procedure for the amino chlorination of a variety of olefins
bifunctional olefins in the presence of Chloramine T. The and conjugated dienes to obtain vicinal chloramine derivatives
generated 2-pyrazolines were also oxidized to the with a combination of Chloramine T and carbon dioxide
corresponding pyrazoles in the course of the reaction (Scheme (Scheme 131) [175].
129) [173].
Reaction of araldoximes with 4 eq. of Chloramine T in
refluxing methanol in the presence of 1,5-diphenyl-1,4- BROMAMINE T
pentadien-3-one, produced N-(p-tolyl)-N-(p-tosyl)-benzamide
via addition of 2 eq. Chloramine T to the intermediate Bromamine T is the brominated analogue of Chloramine
followed by extrusion of sulfur dioxide. The 1,5-diphenyl-1,4- T. It has been used for aziridination of olefins in the presence
pentadien-3-one remained intact in the course of reaction of palladium (Scheme 132) [176]. The proposed mechanism is
Ar'' N Ph
Chloramine T N
ArCOCH=CHSO2Ar' + Ar''CH=NNHPh
MeOH
ArCO SO2Ar'
Scheme 129
OH
H N O O N SO2NH2
SO2
+ Chloramine T
MeOH +
Ph Ph
Cl Cl
Scheme 130
Cl NHTs
1) CO2 (10 atm)
Ts PhH, r.t., 6 h
+ Cl N +
R Na 2) Na2SO3 NHTs Cl
R R
21 22
Yield (%)
Entry R
21 22
1 NO2 (21a) 71 (22a) 0
2 Cl (21b) 74 (22b) 0
3 Me (21c) 54 (22c) 9
4 MeO (21d) 0 (22d) 76
Scheme 131
159
Application of N-Halo Reagents in Organic Synthesis
shown in Scheme 133. are prepared easily starting from saccharin [179].
R1 X R1 X R1 X O
TsNBrNa, Pd (II) R2
+
R2 MeCN, rt R2 N TsHN Br N X
Ts S
2.5-81% 7-19% O
O
Ts : CH3C6H4SO2
R1, R2 = Alkyl or Aryl, X: COOMe, CONMe2, CN, X= Cl, Br, I
COMe, CO(CH3)2, SOPh, Ph, or CH2OH.
23
Scheme 132
NCSac has been shown to undergo electrophilic-Ritter
type reaction with alkenes in acetonitrile. These reactions have
Br
NMe2
Ts N NMe2
been carried out at -42 C up to room temperature and two
TsNBrNa Cl Pd different products have been obtained (imidazoline or
Cl Pd O -NaCl O
Cl aziridine) (Scheme 135) [180].
O
Ts
N SO2Ar
NMe2
1.1 eq. NCSac N
Ts N Pd Cl -PdClBr MeCN, -42 C
NMe2 N N-SO2Ar
Br O R +
then KOEt R
Scheme 133 EtOH,-42 C to r.t.
R
Ar = 2-EtO2CC6H4- R = Aryl
Both Fe() and Mn-porphyrin complexes are effective
catalysts for aziridination of alkenes using Bromamine T, the Scheme 135
reaction proceeded with moderate to low stereospecificity
(Scheme 134) [177,178]. N-halosaccharines have been used for regioselective
cleavage of epoxides into vicinal halohydrins and dihalides in
the presence of Ph3P (Scheme136) [181].
Ts
R1 R3 N
Bromamine T, Cat. R1 R3
R2 MeCN, r.t.
R2 O NXSac (1.2/1.2) X= Br, Cl, I
PhO PhOCH2CH(OH)CH2X
r.t., 1% aq. CH3CN, 3-40 Min
Catalyst = Fe(Por)Cl or Mn Complex
15-95%
R1, R2, R3 = Alkyl or Aryl
NXSac (2.5/2.5)
PhOCH2CHXCH2X
Scheme 134 O reflux, CH3CN
X= Br, Cl,
PhO (75-90%)
X'= Br, Cl, I
NXSac (1.2/1.2)
PhOCH2CHX'CH2X
NX'Sac (2.5/2.5), reflux, CH3CN
N-HALOSACCHARINES
Scheme136
N-halosaccharines proved to be useful and alternative
reagents for diverse organic transformations, such as
halogenation of aromatic compounds, co-halogenation of Chlorinated and brominated aromatic compounds were
alkenes, oxidation of alcohols, halogenation of benzylic and - prepared selectively by reaction of electron-rich aromatic
carbonylic positions, etc. N-Chloro-, N-bromo- and N- compounds with NCSac or NBSac in good yields at room
iodosaccharin, 23 (NCSac, NBSac, and NISac, respectively) temperature (Scheme 137) [182].
160
Kolvari et al.
G G
Sanchez and Fumarola reported an efficient method for
NXSac benzylic and -carbonylic bromination using NBSac under
MeCN, rt
X mild conditions (Scheme 139) [184].
X= Br or Cl
Scheme 137
CH3 CH2Br
O O NBSac
O O R-SH RS-SR
NISac CH2Cl2, MW
R1 R2 R1 R2 3-10 min
15 min to 6 h
I 86-94%
70-90%
R= Aryl or Alkyl
R1, R2 , R3 = Alkyl or Aryl
Scheme 140
Scheme 138
Ionic mechanism:
O O
R-SH + N Br N R S Br
S S
O O H
O O
I II
O
II NH + R S Br
S
O
O
2R S Br RS-SR + Br2
Radically mechanism:
O O
N Br NH
R-SH + + R S Br
S S
O O
O O
Scheme 141
161
Application of N-Halo Reagents in Organic Synthesis
NBSac was applied as an efficient reagent for the oxidative The reactions of NCSac and NBSac with alkenes
cleavage of oximes to the corresponding aldehydes and (cyclohexene, styrene, -methylstyrene, and 1-hexene) gave
ketones under microwave irradiation with reasonable yields the corresponding halohydrins in H2O and acetone as solvent
[186]. The same group has reported the above transformation (Scheme 144) [188].
with NBSac in water and acetone as solvent at room
temperature or by conventional heating or microwave
irradiation (Scheme 142) [187]. R1 R1
NXSac X
2 3 H2O/Me2CO HO
R R R2 R3
10-45 min
71-93%
NOH O X = Cl or Br
NBSac
R 1
R acetone, H2O R1
2
R2 R1 = n-Bu, Ph
r.t, reflux or MW R2 = H
R3 = H, Me
R1, R2= Alkyl or Aryl
Scheme 144
Scheme 142
OH Br
G G OH
product ratio : 66% (6-Bromo)/34% (other isomers)
NBSac Scheme 145
MeCN, r.t.
5-10 min
60-77%
Br Aloui and Fairbanks have reported glycosylation reactions
by NISac in the presence of acetone and methanol for
G G
stereoselective production of acetal-linked -glycosides
NCSac (Scheme 146) [190].
MeCN, r.t.
30-110 min NBSac and NISac reacted with electron-deficient alkenes
53-79% Cl
such as ,-unsaturated ketones, acids, esters and nitriles in
p/o ca. 4.5/1 aqueous organic solvents, yielding the corresponding
halohydrins in good yields (Scheme 147) [191]. The reactions
G =H, -OMe, -NHAc, -NMe2
Scheme 143
BnO BnO
BnO O O
NISac, MeOH (3 eq), acetone BnO
SPh
BnO -78 to 0 C, 2.5 h, 76% BnO
OBn
OBn O OMe
Scheme 146
162
Kolvari et al.
NOH O
took place at room temperature, mostly within short reaction NBP
1
R R2
acetone, H2O 1
R2
times and with high anti stereoselectivity. R
r.t.
R1, R2= Alkyl or Aryl
Scheme 148
OR OR
Y NBSac or NISac Y
Ph Y
Ph solvent, ROH or Ph An interesting example of the chemoselectivity of these
41-97% Br I reactions includes deoximation in the presence of primary
Y = COMe, COPh, CO2H, CO2Me, CN benzylic alcohols (Scheme 149).
R = H, Me, Et,
solvent : CH3CN or acetone/H2O Similar reactions were also carried out under microwave
irradiation in very short times [193]. NBP has been used for
Scheme 147
the oxidation of various organic compounds in the presence of
mercuric acetate as well as in acetic acid medium. Among
them, kinetic studies were carried out for the oxidation of
N-HALOPHTHALIMIDES
glycylglycine [194], aromatic aldehydes [195,196],
acetophenone derivatives [197,198], aliphatic amines [199], -
N-Halophthalimides (NXP) have been used in organic
hydroxy acids [200], and aspirin [201]. NBP was used for the
synthetic methodology especially in the oxidation and
facile oxidation of thiols to symmetrical disulfides in a
bromination reactions. In most cases these reagents are
mixture of acetone-water under microwave irradiation [202].
converted to phthalimide in the end of reactions, as a nontoxic
Both aromatic and aliphatic thiols were selectively oxidized in
chemical.
good to excellent yields (Scheme 150).
N-Bromophthalimide NBP
RSH RS-SR
N-Bromophthalimide (NBP) has been found to be an acetone, H2O
MW
efficient and selective reagent for the mild oxidative cleavage
R = Aroamtic, Aliphatic
of oximes to yield the corresponding carbonyl compounds in
good to excellent yields (Scheme 148) [192]. Scheme 150
NOH O
OH OH
+ NBP
+
acetone, H2O
r.t.
91% 99%
Unchanged alcohol
Scheme 149
R O R O
Et2O
+ N Br + NH
r.t.
72-90%
O O
Br
Scheme 151
163
Application of N-Halo Reagents in Organic Synthesis
Reaction of substituted benzene rings with NBP, under NCP was successfully used in the first step of the ring
neutral conditions, gave the corresponding bromo derivatives expansion of peniciline V sulfoxide p-nitrobenzyl ester 24 to
with a preference for the formation of para over the ortho 3-exomethylene cephalosporin V sulfoxide p-nitrobenzyl ester
isomers (Scheme 151) [203]. NBP has also been used for the 25 (Scheme 153) [206].
bromination of some deoxyhexoses [204].
N-FLUORO REAGENTS
N-Chlorophthalimide
The photoinitiated free radical chlorination of The development of mild and selective methods for
hydrocarbons with N-chloro-phthalimide (NCP) has been introduction of fluorine into organic substrates is an important
reported [205]. Some evidence led authors for the suggestion objective because this element exerts unique influences upon
of the chlorination mechanism (Scheme 152). physical, chemical, and biological properties. Until quite
recently, however, the selective electrophilic fluorination of
O O enolates and carbanions was difficult because most procedures
h employed highly reactive, corrosive and toxic materials such
N Cl N + Cl
as F2, FC1O3, or MeC(O)CF3 . To overcome these limitations,
O O a range of N-fluoro reagents with different reactivities, that
O O were safe and easy to handle without special equipment, was
developed [207]. These reagents are easy to handle but have
RH + N NH + R
low reactivity [208]. Recently, fluorous biphasic and triphasic
O O systems has been developed so that catalysts which has
perfluoroalkyl groups as tags are soluble in perfluoro solvents
O O and insoluble in virtually all common organic solvents
[209,210]. We think that N-fluoro reagents may be effectively
R + N Cl N + RCl
used in the above mentioned systems in future. Several
O O reviews concerning N-fluoro reagents have been published
[211,213]. Therefore in this article some recent applications of
Scheme 152
O
O H H
H H
V SCl
V S
CH3 NCP, toluene
N
N CH3 Polyvinylpyridinedivinylbenzene O CH3
O
CO2PNB CO2PNB
24
O
H
V S
1) SnCl4
N
O
2) MeOH
CO2PNB
25
V= PhOCH2CONH
PNB= p -Nitrobenzyl
Scheme 153
164
Kolvari et al.
F
N-fluoro reagents are reviewed. Sniekus et al. have reported F
flouroniation of aromatic compounds by N- [F+]
+
fluorobenzensulfonimide (NFSi) and N-fluoro-o-
F
benzenesulfonamide (NFOBS) via direct ortho metallation
Scheme 156
(Scheme 154) [214].
R R R
SO2NHMe SO2NHMe F
Br Br F F Br
F
2 eq n-BuLi 1) n-BuLi, -78 C +
THF/ -40 C 2) NFSi
N N N
NFOBS
Me Me 20-78% 4-24%
71% O
R = -OCH2OCH3,
Scheme 154 O
F
Li
H3CO NMe2 NMe2 NMe2
H3CO
H3CO
t-BuLi/pentane NFSi/THF
N -78 C to 0 C 0 C, 2 h N
N
TIPS 40% TIPS
TIPS
TIPS = triisopropylsilylgramine
Scheme 155
NO2 F
N F reflux, 3 day F
+ +
C2H4Cl2, 20 mL
O2N
23%
9:1
Scheme 158
165
Application of N-Halo Reagents in Organic Synthesis
Cl
N N
R R n
Cl N Cl N
F S S O n
BF4 F CF3SO2
F + +
R1 R2 CH2Cl2/ THF/ H2O R1 R2 S S N
H F
R = -NO2, -Cl, -OMe 1 2
R , R = Alkyl or Aryl
Scheme 159
Scheme 162
N-fluoro reagents is shown in Scheme 160.
groups [238-239] to achieve a broad range of -fluorinated
Modified nucleosides have become useful agents for the
organic compounds such as -fluorosulfonamides, -
treatment of cancer and viral diseases due to their good
fluorolactams, -fluoroketones, etc. Various N-alkylimines
antitumor and antiviral activity. In particular, several
derived from acetophenones were successfully
nucleosides with substituents at 4'-position are good
monofluorinated using NFSi in a mixture of acetonitrile and
candidates as antiviral agents. 4'-Fluoro nucleoside is one of
DMF at 0 C. Alternatively, the same procedure in the absence
these moieties that have strong activity including anti-HIV
of DMF gave rise to diflourinated imines when performed at
activity. Jung and Toyota have synthesized 4'-
room temperature. The obtained -fluoro and ,-difluoro-
fluorothymidines using NFSi as fluorinating agent (Scheme
imines were subsequently reduced to give the corresponding
161) [223].
-flouro and ,-diflouroamines (Scheme 163) [237].
O O
NH NH i-Pr
O N
N O N O
3.4-4 eq. i-PrNH2 1.2 eq. NFSI
ButO2C 5.5 eq LDA 0.6 eq. TiCl4 2.0eq. K2CO3
O 4.5 eq t-BuLi F O
Et2O, r.t., 15 h
NFSi ButO2C
OH OH 62% (E/Z 62: 38)
i-Pr
Scheme 161 N O
F F
aq. 2M HCl
CH2Cl2, r.t., 2.h
N-Fluoro-2,4,6-trimethylpyridinium triflate efficiently
cleaved dithioacetals to the parent carbonyl compounds
(Scheme 162) [224]. 91%
O O O O F
F-L
+ +
F
F
Scheme 160
166
Kolvari et al.
chloronium ion because the 1,3,5-triazine ring has strong Et2O room temp.
Cl Cl Cl Cl
Cl Cl
electron-withdrawing character. However, there are few Cl Cl Cl Cl
papers concerning the utilization of TCM in organic synthesis 27 28
[240-241].
Scheme 165
NHCl
N N
N-HALOSUCCINIMIDE
ClHN N NHCl
26
Some specific properties of N-halosuccinimides (NBS,
NCS and NIS) cause their wide application in organic
Kondo et al. have reported a simple and selective method synthesis. The scope of the application of N-halosuccinimides
for the oxidation of alcohols to the corresponding carbonyl is so wide that needs a special review for covering their
compounds and oxidative lactonization of diols with TCM in chemistry. The recent application of NBS as a catalyst,
methylene chloride at room temperature under mild conditions oxidant, selective brominating reagent and the initiator in the
(Scheme 164) [242]. polymerization has been reviewed [245]. Although two
excellent review articles have been published on this subject
[1,245] we think that publishing a new review for covering the
HOCH2(CH2)nCH2OH TCM
(CH2) n O new applications of these compounds in organic synthesis is
CH2Cl2, r.t.
O
necessary. N-Hallosuccinimides are commercially available
R1 R1
and extensively had been used in many fields of fine organic
TCM
CHOH C O synthesis and at natural compounds chemistry as well [1].
R2 CH2Cl2, r.t. R2
Therefore, due to the above mentioned facts we decided to
avoid reviewing the recent application of N-halosuccinimides
R1, R2 = H, alkyl or aryl
in the present manuscript. However, we are preparing a review
n= 2, 3
article on this subject that will be published in near future.
Scheme 164
O
N,N,2,3,4,5,6-Heptachloroaniline 27 and N-chloro-
2,3,4,4,5,6-hexachlorocyclohexa-2,5-dienylideneamine 28 N X
(Scheme165) can be used as chlorinating agents. Compound
28 was used as a new mild and highly regioselective O
chlorinating reagent in the chlorination of phenol and o-cresol NBS: X=Br
NCS: X=Cl
in CCl4, DMF and CH3CN. The effects of C2H5OH, C5H5N, NIS: X=I
167
Application of N-Halo Reagents in Organic Synthesis
O
O
X Y O O
N N X Y
N N S N (CH2)n N S
O N O R'
R O X Y O
Z O
XY R=R' or RR'
XYZ XY X= Br, Cl, I
X=YZ X= Cl, Br or I Y= Br, Cl, I
XY=Z Y= Cl, Br or I
X= Cl, Br or I
Y= Cl, Br or I
Z= Cl, Br or I
Scheme 166
168
Kolvari et al.
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170
Kolvari et al.
171
Application of N-Halo Reagents in Organic Synthesis
172
Kolvari et al.
173
Application of N-Halo Reagents in Organic Synthesis
174