Fast halogenation of some N-heterocycles by means of N,N'-dihalo-5,5- dimethylhydantoin

Article abstract of DOI:10.1002/adsc.201200723

An instantaneous, selective and high-yielding halogenation process is reported. The method operates with imidazoles, pyrazoles, and indoles under benign reaction conditions. The developed process involves the use of N,N'-dihalo-5,5-dimethylhydantoins (halo=chlorine, bromine, iodine) as halogenation reagents that are activated by catalytic quantities of a strong Bronsted acid. Moreover, the halogenation process is switchable to produce either the mono- or di-halogenated products. Issues related to the reaction mechanism are investigated and a proposal for a reaction mechanism is disclosed.

Full text of DOI:10.1002/adsc.201200723

FULL PAPERS
DOI: 10.1002/adsc.201200723
Fast Halogenation of Some N-Heterocycles by Means of
N,N’-Dihalo-5,5-dimethylhydantoin
Alexander H. Sandtorva and Hans-Renꢀ Bjørsvika,*
a
Department of Chemistry, University of Bergen, Allꢀgaten 41, N-5007 Bergen, Norway
Fax : (+47)-55-589-490; phone: (+47)-55-583-452; e-mail: hans.bjorsvik@kj.uib.no
Received: August 14, 2012; Published online: January 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200723.
Abstract: An instantaneous, selective and high-yield- halogenation process is switchable to produce either
ing halogenation process is reported. The method the mono- or di-halogenated products. Issues related
operates with imidazoles, pyrazoles, and indoles to the reaction mechanism are investigated and a pro-
under benign reaction conditions. The developed posal for a reaction mechanism is disclosed.
process involves the use of N,N’-dihalo-5,5-dimethyl-
hydantoins (halo=chlorine, bromine, iodine) as hal- Keywords: N,N’-dihalo-5,5-dimethylhydantoin; halo-
ogenation reagents that are activated by catalytic genation; nitrogen heterocycles; reaction mecha-
quantities of a strong Brønsted acid. Moreover, the nisms; synthetic methods
Introduction
ment.[9] (b) Disubstitution of the imidazole ring fol-
lowed by (c) a selective mono-dehalogenation[10] with
Functionalized imidazoles are of paramount impor- (d) a subsequent coupling reaction. (e) Selective
tance in medicinal chemistry,[1] as precursors for NHC mono-iodination of the imidazole ring followed by (d)
ligands[2] in homogeneous transition metal catalysis, a coupling reaction.
and as organocatalysts.[3] Efficient, selective and envi-
Drawbacks exist for the outlined strategies in that
ronmentally friendly procedures for the functionaliza- pathway (a) demands an independent synthesis for
ꢀ
tion of the imidazole framework are indispensable the linear precursor (HCO R) used in the multi-com-
both for academic research and for industrial applica- ponent reaction, while pathway (b) is composed of
tions. In particular, appropriate synthetic strategies a selective dihalogenation with a subsequent mono-
and custom syntheses that permit unsymmetrical sub- dehalogenation and a versatile coupling method for
stitution on the C-backbone of the imidazole skeleton
are highly desired.
In a previous paper reported from our laboratories,
we revealed that, in order to approach efficient li-
gands for Ru-NHC based catalysts for olefin metathe-
sis, the backbone of the imidazole ring should be sub-
stituted with bulky alkyl groups.[4] Several research
groups have later confirmed experimentally our calcu-
lated results by preparing such NHC ligands.[5]
Three strategies, Figure 1, can be followed to
obtain such molecular entities. (a) The synthesis of
the imidazole skeleton starting from a linear molecu-
lar moiety with embedded functionality. As soon as
Figure 1. Three distinct strategies leading to mono substitut-
the ring closure is carried through, the target-func-
ed imidazoles. (a) Multi-component reaction, (b) di-iodina-
tionalized imidazole is obtained. Several reactions,
tion followed by (c) selective mono-deiodination and (d)
a coupling reaction.[11] (e) Selective mono-iodination fol-
lowed by (d) a coupling reaction. In addition, a correspond-
ing di-substitution of imidazoles exists following pathway
methods, and syntheses can be utilized for this pur-
pose, for example, the Van Leusen imidazole synthe-
sis,[6] Debus reaction,[7] Wallach reaction (chloroimida-
zole synthesis),[8] and the hetero-Cope rearrange- (e’) di-iodination followed by (f’) two coupling reactions.
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Alexander H. Sandtorv and Hans-Renꢀ Bjørsvik
FULL PAPERS
the introduction of the substituent (R). Examples of diiodo-5,5-dimethylhydantoin (DIH) 4. Subsequently,
such methods were previously described by Kirk[10a] the method was successfully extended to operate with
and, Cliff and Pyne.[10b,11] The major drawbacks of this pyrazole and indole, and the two halogenation re-
strategy are that multiple steps and long reaction agents N,N’-dibromo-5,5-dimethylhydantoin (DBH) 5
times are required by the existing methods.
and N,N’-dichloro-5,5-dimethylhydantoin (DCH) 6,
The pathway (c) consists of a selective monohaloge- respectively.
nation and a versatile coupling method. Bhilare and
collaborators[12] revealed an iodination method suita-
ble for this strategy, although this process demanded The Method
an expensive ionic solvent, long reaction time and
only moderate yields were achieved.
The iodination method using N,N’-diiodo-5,5-dime-
For a medicinal chemistry project in progress in our thylhydantoin 4 as reagent can be conducted accord-
laboratory, we needed access to a variety of NHC li- ing to two different paths, namely pathway (a) provid-
gands with different substituents on the backbone and ing the mono-iodinated imidazole, and pathway (b)
the ring-N atoms. Thus we wanted to discover and de- providing di-iodinated imidazole (see Scheme 1).
velop halogenation methods suitable for pathway (c),
Figure 1.
The processes (a) and (b), Scheme 1, were conduct-
ed in water as the reaction medium at 08C. Initially,
Several processes for halogenation of imidazole KI was used as an additional iodine source, but
have been disclosed. However, many of these imply during this investigation we discovered that KI was
the utilization of harsh conditions with long reaction not necessary, and thus excluded it from the halogen-
times and noxious reagents such as KI/I2,[13] KICl2,[14] ation procedure.
m-iodosylbenzoic acid, I2/NaBO3,[12] N-iodosuccini-
It was previously disclosed that the iodination re-
mide (NIS), tetrabutylammonium tribromide with mi- agent (DIH) needed to be activated by a large excess
crowave irradiation, KBr/H2O2,[ 15] cetylpyridinium tri- of sulphuric acid. However, during our investigation,
bromide, Br2/KHCO3, N-bromosuccinimide (NBS), we discovered that only a catalytic quantity of
and NaOCl. A detailed literature overview is provid- a strong mineral acid was necessary.
ed in the Supporting Information.
In order to prepare mono-iodinated imidazoles,
The N,N’-dihalogenated analogues of 5,5-dimethyl- method (a) involved a drop-wise addition (10 min) of
hydantoin have a distinct advantage over NIS and a mixture of DIH (0.25 equiv.) and 10–20% w/w of
NBS as they carry two electrophilic equivalents of the conc. sulphuric acid to the substrate. In order to
halogen. Even though the iodo,[16] bromo,[17] and direct the outcome of the iodination, the quantity of
chloro[18] derivatives are commercially available, sur- iodination reagent DIH is of paramount importance.
prisingly, very few accounts discussing these reagents The mono-iodination proceeds instantaneously to pro-
have previously been reported. We included DIH 4 in vide 4-iodo-1H-imidazole in excellent yield (85% as
our screening for potential iodination reagents and the HCl salt 3).
found promising results.
The di-iodination method shown in path (b) takes
place in a slurry of imidazole and DIH (0.82 equiv.) in
water to which conc. sulphuric acid is added drop-
wise (1 min), producing 4,5-diiodo-1H-imidazole 2 in-
stantaneously in a quantitative yield. The quantity of
Results and Discussion
The objective of the work reported here was to devel-
op a novel selective halogenation process that can be
incorporated in the strategy (c) of Figure 1.
This method is switchable, producing selectively
either mono-iodoimidazole or di-iodoimidazole. The
latter could then be used for the preparation of both
symmetrical[19] and unsymmetrical[20] backbone-substi-
tuted imidazoles.
Initially we developed the method for the prepara-
Scheme 1. Mono- (a) or di-iodination (b) of imidazole con-
tion of mono- and di-iodinated imidazoles using N,N’- trolled by tuning of the experimental conditions.
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Fast Halogenation of Some N-Heterocycles by Means of N,N’-Dihalo-5,5-dimethylhydantoin
DIH is also important for this procedure in order to
obtain the desired di-iodinated product.
Both of the mechanistic investigations discussed
above appeared to us as obscure. We therefore decid-
In both cases, the post-reaction mixtures were ed to explore some mechanistic aspects further using
quenched with aqueous sodium hydroxide. Further the di-iodination of imidazole as a model reaction.
work-ups were performed by neutralization with gla-
An experiment previously not reported involves
cial acetic acid, whereupon the di-iodo product could a reaction performed in dark conditions. Homolytic
be filtered off. In the case of mono-iodination, the cleavage of iodine hydrogen sulphate 8 is dependent
product was extracted with ether as the HCl salt.
on light irradiation and thus absence of light will gen-
erally influence the reaction performance following
pathway (a) of Scheme 2.
Reaction Mechanism
Our experiments performed in the dark and under
light irradiation, respectively, reveal that the reactions
Orazi and collaborators[21] initially discussed a poten- proceed similarly (entries 4 and 5 in Table 1). This in-
tial radical mechanism for iodination with the DIH dicates that a radical mechanism does not occur for
reagent, however, this turned out to be unlikely due the iodination reaction.
to the observation that DIH did not participate in the
Furthermore, we wanted to re-investigate the acid
iodination of toluene with benzoyl peroxide as a radi- activation of the DIH reagent. A series of mineral
cal initiator. Their further investigations lead them to acids was explored. The experimental results, see
suggest a mechanism involving the production of elec- Table 1, show that most of these acids successfully ac-
trophilic I+, which they believed to operate as the io- tivate DIH to provide high yields of the target mole-
dination species.
cule. These results suggest that the pre-iodination spe-
Several years later, Chaikovskii and collaborators[22] cies 8 is not involved in the iodination process under
observed that if DIH was treated with conc. sulphuric catalytic acidic conditions. Spurred by this discovery,
acid, both of the two N bonded iodine atoms were re- we presumed that a large excess of acid was superflu-
moved from DIH, leading them to propose the forma- ous for successful activation of DIH. The quantity of
tion of iodine hydrogen sulphate (HOSO2OI) 8, as the Brønsted acid was thus reduced to only catalytic
the pre-iodination species, see Scheme 2. Accompany- quantities (see entries 3 and 4) and still provided the
ing DFT calculations suggested that the homolytic product in excellent yields.
disassociation of iodine hydrogen sulphate, pathway
Phosphoric acid (entry 10) was the only acid of the
(a), was more likely than a heterolytic bond dissocia- investigated series that did not furnish the product.
tion, pathway (b). However, these results were con-
tradictory to experimental observations. Electronic
absorption spectra (UV) of mixtures of DIH/H2SO4
revealed a lmax that corresponds to the I3 ion, which
led them to the conclusion that this was the active io-
dinating species. The earlier proposal of Orazi and
collaborators[21] suggesting I+ as the active iodination
species appeared thus to be disproven.
Table 1. Activation of DIH.
+
Entry
Acid[a]
Yield [%][b]
1
2
3
4
without acid present
H2SO4[c]
H2SO4[d]
H2SO4[e]
H2SO4
–
95
88
92
81
92
88
97
79
–
5
6
7
8
9
HCl
HNO3 (65%)
HBr
PTSA
H3PO4
10
[a]
Imidazole(1.10 mmol) and DIH (5.8 mmol) were mixed
in water (2 mL) or MeOH (2 mL) on an ice-bath. An
excess quantity of the acid was added drop-wise over
a period of 1 min. The reaction mixture was quenched by
adding NaOH (4M, 20 mL). The pH was then adjusted
to pH 6. The precipitated product (2) was filtered off,
washed with water and air-dried. The crude product was
recrystallized from ethanol.
Isolated yield.
20% w/w of the acid was used.
10% w/w of the acid was used.
10% w/w of the acid was used and the reaction was con-
ducted in dark.
[b]
[c]
[d]
[e]
Scheme 2. Iodine transfer from N,N’-diiodo-5,5-dimethylhy-
dantoin 4 to sulphuric acid. Pathway (a) homolytic cleavage
and (b) heterolytic cleavage.
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Alexander H. Sandtorv and Hans-Renꢀ Bjørsvik
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Table 3. Attempts to iodinate activated and deactivated
arenes.
The organic acid (PTSA) also provided the product,
but in somewhat lower yields (entry 9).
Based on the observations from Table 1, one can
conclude that (i) the previously proposed intermedi-
ate iodine hydrogen sulphate 8 appears not to be cru-
cial in the mechanism, (ii) a strong acid is required for
the activation of DIH (see entries 1 and 4), (iii) inor-
ganic and organic acids can be used, (iv) only a cata-
lytic quantity of the Brønsted acid is required, (v)
light irradiation is not required for the reaction.
Based on these results, we realized that it was nec-
essary to re-investigate the reaction mixtures of DIH
Entry Substrate Product
Method Yield
[%]
[a]
1
2
3
benzoic
acid
benzoic
acid
benzoic
acid
m-iodobenzoic acid
70
[b]
–
–
–
[c]
–
[a]
4
phenol
phenol
2,4,6-triiodophenol
diiodophenol, 2,4,6-triio-
dophenol
80
66
5[d]
[b]
+
and strong acid for the presence of I3 . A series of
such mixtures was thus prepared in methanol and ex-
amined by UV spectroscopy, see Table 2.
[a]
[b]
[c]
Method disclosed by Chaikovskii and collaborators[22]
Our method (adding HCl directly to the reagents).
Our method (mixing HCl and DIH and adding to the
substrate).
Table 2. DIH and strong acid mixtures[a] measured by UV
spectroscopy.
[d]
Selectivity of diiodophenol:2,4,6-triiodophenol=43:57.
Entry
1
Mineral acid
H2SO4
lmax
A
the strong triflic acid was imperative in order to iodi-
nate the deactivated arenes successfully. They pro-
posed that the excess of the acid is required in order
to protonate NIS that results in a transfer of the elec-
trophilic iodine to the triflate moiety. With the excess
presence of the strong acid (triflic acid) the iodotri-
flate reacts further to provide the protonated iodotri-
flate with triflate as the anionic counter ion, which is
proposed to be the active iodinating species.
285
446
285
292
341
286
446
286
292
1.0
1.0
1.4
0.9
1.1
0.9
0.3
1.2
1.0
2
HCl
3
4
HNO3 (65%)
HBr
As a reference, we reproduced the experiment by Proposal of a Reaction Mechanism
Chaikovskii and collaborators[22] with DIH in conc.
sulphuric acid to achieve the expected UV-profile in- Based on the previous literature disclosures and our
+
dicating the I3 ion (entry 1 of Table 2). A similar new findings presented above, we have outlined
UV-profile was also observed when nitric acid was a new proposal for an iodination mechanism with
used (entry 3). Different UV profiles were achieved
when hydrochloric and hydrobromic acids (entries 2
and 4) were used as activating acids. The obtained re-
+
sults (Table 2) indicate that the I3 ion is not present
in all successful iodination experiments and can thus
not be the active iodinating species.
Since our new iodination method is substantially
different from the method disclosed by Chaikovskii
and collaborators,[22] it was necessary to evaluate the
performance of our iodination process with arenes as
substrates. We therefore selected some of the sub-
strates previously investigated for comparison purpos-
es. We used HCl in catalytic quantities as the activat-
ing acid, Table 3. The deactivated arene, benzoic acid
(entries 2 and 3) was not successfully iodinated, while
the activated arene, phenol (entry 5) was iodinated.
These results are in accordance with those of Olah
and collaborators,[23] who used a similar N-halo-
hetero
acid (triflic acid) for iodination of highly deactivated
arenes. They stated that an excess (2–5 equivalents) of tion process using DIH as reagent.
ACHTUNGTRENNUNGcyclic iodination reagent (NIS) and a strong
Scheme 3. Proposal for a reaction mechanism for the iodina-
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Fast Halogenation of Some N-Heterocycles by Means of N,N’-Dihalo-5,5-dimethylhydantoin
Table 4. Halogenation of imidazoles, indoles, and pyrazoles
by DIH, DBH, and DCH.
DIH as reagent, Scheme 3. The first step of the mech-
anism involves protonation of the DIH reagent with
a strong acid HB. The next step is dependent on the
quantity of the acid HB. If a large excess of the acid
HB is present, the protonated DIH reacts further to
provide a species [HBI+] Bꢀ that possess strong elec-
trophilic character, suitable to iodinate even highly
deactivated arenes, path (a). In the other case, path
(b), where catalytic quantities of the acid HB are
Entry Substrate Product
DXH [equiv] Yield[a] [%]
81[b,c]
1
2
3
4
5
6
7
0.24
1.50
1.12
0.30
0.47
1.90
1.10
95
ꢀ
present, the protonated DIH undergoes N I cleavage
to produce the less electrophilic species BI. The iodi-
nating species appears thus to be of two different
forms: (i) under large excess of the strong acid pro-
ducing [HBI+]Bꢀ (a very reactive super-electrophile)
as the active iodination specie and (ii) for catalytic
quantities of the strong acid that produce the iodoni-
um equivalent (BI) as the active iodination species,
which is a less reactive electrophile.
99
21[c]
96
Scope of the Method
93
A series of N-heterocyclic frameworks (Table 4) were
successfully halogenated using N,N’-dihalo-5,5-dime-
thylhydantoin (halo=Cl, Br, I).
78
As described above, the imidazole framework was
easily iodinated giving excellent selectivities and high
yields, see entries 1 and 2. Entry 3 shows a reaction
involving 1H-4-(5)-imidazolecarbaldehyde 12 as sub-
strate. The formyl group underwent an ipso-type sub-
stitution concomitant with the expected iodination of
the non-substituted backbone-C to provide 4,5-
diiodo-1H-imidazole 2 in a yield of 99%. We also per-
formed reactions with reduced quantities of the iodi-
nating reagent DIH (0.59 equiv. and 0.25 equiv.) in
order to investigate if mono-iodination could be car-
ried through. However, we only observed 4,5-diiodo-
1H-imidazole 2 in the post-reaction mixtures with re-
duced yields.
The iodination method was changed to include
other N-heterocycles and the halogenation reagents:
DBH 5 and DCH 6. Entries 4–6 of Table 4 report re-
sults using DBH with imidazoles. The selectivity of
the dibromination reaction (entry 5) was excellent
with high yield (96%). Interestingly, it was also possi-
ble to prepare the 2,4,5-tribromo-1H-imidazole 15
(entry 6) in an excellent yield of 93%. The mono-bro-
mination proceeded modestly to provide a yield of
21% (entry 4). The chlorination of imidazole was also
performed using DCH (entry 7), but in this case, only
the dichloro product 16 was achieved in good yield
(78%).
8
0.93
0.75
1.10
69
53
77
9
10
11
12
13
1.13
2.10
1.10
73
59
70
[a]
Isolated yield.
[b]
Isolated as a HCl salt, that subsequently was neutralized
with NaHCO3 providing the free amine (11) in a yield of
61%.
[c]
Based on the dihalohydantoin as the limiting reactant.
The indole 17 and pyrazole 21 frameworks were the 3-haloindoles in medium to high yields. Entries
both successfully halogenated with the method using 11–13 show results from experiments where pyrazole
all three halogenating reagents. Entries 8–10 show the 21 was treated with the three dihalohydantion re-
results where indole 17 was treated with DIH, DBH, agents, respectively. The various products that were
and DCH, respectively. All three reagents provided obtained were 4-iodopyrazole 22, 3,4-dibromopyra-
Adv. Synth. Catal. 2013, 355, 499 – 507
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Alexander H. Sandtorv and Hans-Renꢀ Bjørsvik
FULL PAPERS
transferred to a round-bottom flask immersed in an ice-
bath. Water (2 mL) was added and the heterogeneous mix-
ture was stirred during the drop-wise addition of sulphuric
acid (1 mL) over 1 min. After the addition, NaOH (3.9M,
15 mL) was added. The resulting, milky solution was then
neutralized (pH~6) with acetic acid which resulted in pre-
cipitation of the product. The crystals were filtered, washed
multiple times with cold water and saturated K2SO3 solution
(3ꢂ3 mL) and allowed to air-dry to constant weight to give
the product as creamy crystals; yield: 0.353 g (95%). Traces
of 4-(5)-iodo-1H-imidazole was observed in the isolated
product.
1H-Imidazole-4(5)-carbaldehyde (0.109 g, 1.13 mmol), KI
(2.2 g, 13 mmol) and N,N’-diiodo-5,5-dimethylhydantoin
(0.487 g, 1.28 mmol) were added to a round-bottom flask
and cooled on an ice-bath. Water (2 mL) was added and the
heterogeneous mixture was stirred as sulphuric acid (1 mL)
was added drop-wise over a period of 1 min. Immediately
following the addition, NaOH (3.7M, 20 mL) was added fol-
lowed by saturated K2SO3 solution in small portions until
the brown colour vanished. The alkaline solution was neu-
tralized with acetic acid (pH~6) precipitating the product as
creamy crystals. The product was filtered, washed with
water, air-dried, and crystallized from EtOH (50%) to give
the title compound as slightly yellow flakes after pooling
three crops; yield: 0.358 g (99%). 1H NMR (400 MHz,
CD3SOCD3): d=7.65; HR-MS (DART): m/z=320.8381,
calcd. for C3N2H3I2 [M+H]+: 320.8386. The recorded spec-
tral data were in accordance with the literature.[13]
zole 23, and 4-chloropyrazole 24, these too in medium
to high yields.
Another series of N-heterocyclic compounds was
also submitted for the halogenation method includ-
ing: 4(5)-nitro-1H-imidazole, 1,2,3-1H-triazole, 1H-
pyrrole, 1,2,4-1H-triazole, thiazole, pyridine, 3,5-dime-
thylpyridine, pyrimidine, isoquinoline, and 2-methoxy-
pyridine. None of these heterocycles were halogenat-
ed by any of the three halohydantoins. In these ex-
periments, only unconverted substrate was observed
in the post-reaction mixture, except for the experi-
ment involving pyrrole, which was oxidized to tars.
Conclusions
In conclusion, we have reported a new versatile and
benign halogenation process that operates with imida-
zoles, pyrazoles, and indoles. The process utilizes
N,N’-dihalo-5,5-dimethylhydantoin (halo=Cl, Br, I)
as halogenation reagents under mild conditions to
produce instantaneously either mono- or di-halo
products in high to excellent yields. Issues related to
the reaction mechanism have been revisited, are dis-
cussed, and a new reaction mechanism is outlined.
The results presented here are currently being utilized
in an ongoing study in order to complete the outlined
strategy (c) of Figure 1. These results will be reported
in the near future.
4(5)-Iodoimidazolium Chloride (3) [new]
A round-bottom flask was filled with water (50 mL) and im-
mersed in an ice-bath. Imidazole (0.388 g, 5.70 mmol) and
KI (12 g, 72 mmol) were transferred to the flask and the
mixture was stirred until the solids were dissolved. NaOH
(3.7M, 50 mL) was then added. Sulphuric acid (5 mL) was
added to N,N’-diiodo-5,5-dimethylhydantoin (0.519 g,
1.4 mmol) and vigorously stirred. The resulting, viscous mix-
ture was added drop-wise to the imidazole solution over
10 min. Immediately following the addition, the reaction
mixture was neutralized with acetic acid (pH~6). A saturat-
ed solution of K2SO3 (1 mL) was added and finally the solu-
tion was saturated with NaCl. The clear solution was ex-
tracted with ether (3ꢂ40 mL) and the combined, organic
phases were again extracted with 10% HCl (3ꢂ10 mL). The
aqueous solution was evaporated to about half the volume
and the white precipitation filtered off. Yellow crystals of
the title compound were crystallized from the aqueous hy-
drochloric acid solution; yield 0.51 g [81% (based on DIH
being a limited reagent)]. 1H NMR (400 MHz, D2O): d=
8.56 (1H), 7.36 (1H); 13C NMR (250 MHz, D2O), d=137.6,
126.7, 68.6; HR-MS (DART): m/z=194.9418, calcd. for
C3N2H4I [MꢀCl]+:194.9419.
Experimental Section
General Methods
GC analyses were performed on a capillary gas chromato-
graph equipped with a fused silica column (l 25 m, 0.20 mm
i.d., 0.33 mm film thickness) at a helium pressure of 200 kPa,
split less/split injector and flame ionization detector. Mass
spectra were obtained on a GC-MS instrument, using a gas
chromatograph equipped with fused silica column (l 30 m,
0.25 mm i.d., 0.25 mm film thickness) and helium as carrier
gas. DART-mass spectra were obtained using PEG as an in-
ternal standard in the positive ionization mode with a TOF
1
mass analyzer. Control H NMR spectra were recorded on
a
NMR spectrometer operating at 400 MHz. Control
13C NMR spectra were recorded on a NMR spectrometer
operating at 100 MHz and 250 MHz. Chemical shifts were
referenced to the deuterated solvent or with TMS as an ex-
ternal reference. The UV-Vis spectra were recorded on
a diode array UV-Vis spectrometer, which can record spec-
tra in the wavelength region l=190–1100 nm.
All chemicals were used as received except imidazole,
which was recrystallized from acetone.
4(5)-Iodo-1H-imidazole (11) [71759-89-2]
4(5)-Iodoimidazolium chloride (0.356 g, 1.55 mmol) was dis-
solved in water (5 mL) and neutralized with a saturated
NaHCO3 solution (pH~6). The solution was saturated with
NaCl and extracted with ether (3ꢂ35 mL). The organic ex-
tracts were combined and dried over Na2SO4, filtered and
evaporated under reduced pressure to give the title com-
4,5-Diiodo-1H-imidazole (2) [15813-09-9]
Imidazole (0.076 g, 1.1 mmol), KI (2.2 g, 13 mmol) and N,N’-
diiodo-5,5-dimethylhydantoin (0.345 g, 0.91 mmol) were
504
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Adv. Synth. Catal. 2013, 355, 499 – 507

Fast Halogenation of Some N-Heterocycles by Means of N,N’-Dihalo-5,5-dimethylhydantoin
pound as white crystals; yield: 0.184 g (61%). 1H NMR
(400 MHz, CD3CN): d=9.60 (1H, br), 7.58 (1H), 7.21 (1H);
MS (EI): m/z (%)=193.9 (M+, 100), 165.8 (69), 126.8 (79),
67.0 (81). The recorded spectral data were in accordance
with the literature.[12]
and air-dried to constant weight to give the title compound
as orange crystals contaminated with 4,5-dibromo-1H-imida-
zole; yield: 0.31 g, (93%) HR-MS (ESI): m/z=302.7767,
calcd. for C3N2HBr3 [M]+: 302.7768.
4,5-Dichloro-1H-imidazole (16) [15965-30-7][27]
4(5)-Bromo-1H-imidazole (13) [2302-25-2][24]
Imidazole (0.078 g, 1.15 mmol) and N,N’-dichloro-5,5-dime-
thylhydantoin (0.25 g, 1.3 mmol) were transferred to
a round-bottom flask that was immersed in an ice-bath.
Water (2 mL) was then added and the mixture was stirred to
produce a slurry. Sulphuric acid (1 mL) was added drop-
wise, which resulted in a white, heterogeneous mixture. The
reaction mixture was quenched with NaOH (3.8M, 25 mL)
and the resulting, yellow solution was neutralized with
acetic acid (pH ~5). The solution was cooled in the fridge
and then agitated, which resulted in a heavy precipitation of
5,5-dimethylhydantoin. The mixture was filtered and the
aqueous phase extracted with ether (3ꢂ20 mL), the organic
extracts dried over anhydrous Na2SO4, filtered and the sol-
vent evaporated. The crude material was recrystallized from
EtOH (50%) to give the title compound as white crystals;
A round-bottom flask was filled with water (10 mL) and im-
mersed in an ice-bath. Imidazole (0.078 g, 1.15 mmol) was
then added and the mixture was stirred until the solid had
dissolved. N,N’-Dibromo-5,5-dimethylhydantoin (0.097 g,
0.34 mmol) was added as a solid to the solution in small por-
tions followed by a few drops of sulphuric acid (2 mL in
total). The brominating agent and the acid were added in
seven portions over five minutes. The reaction mixture was
quenched with NaOH (3.8M, 20 mL) followed by neutrali-
zation with acetic acid (pH~6). About 1/3 of the water was
evaporated, inorganic salts filtered off and the aqueous
phase saturated with NaCl. After extraction with ether (3ꢂ
30 mL), the combined, organic extracts were dried over an-
hydrous Na2SO4, the drying agent filtered off and the sol-
vent evaporated. The crude was purified with column chro-
matography [EtOAc:hexanes (1:1)!EtOAc:NEt3 (10%)] to
give the title compound contaminated with 5,5-dimethylhy-
dantoin (33%) as creamy crystals; yield: 0.020 g (21% [from
1
yield: 0.122 g (78%; pooling two crops). H NMR (400 MHz,
CD3Cl): d=7.51 (1H, s), 5.00 (1H, s, br); MS (EI): m/z
(%)=139.9 (5), 137.9 (30), 135.9 (M+, 47), 128.0 (86), 113.0
(100). The recorded, spectral data were in accordance with
the literature.[28]
1
DBH as limited reagent]). H NMR (400 MHz, CD3Cl): d=
7.60 (1H, s), 7.05 (1H, s), 1.45 (6H, s) [5,5-dimethylhydan-
toin]; MS (EI): m/z (%)=147.9 (M+, 100), 145.9 (99), 113
(41), 67.0 (29).
3-Iodo-1H-indole (18) [26340-47-6]
Indole (0.132 g, 1.13 mmol) and KI (2.30 g, 14 mmol) were
dissolved in MeOH (50 mL) and 3.8M NaOH (20 mL).
N,N’-Diiodo-5,5-dimethylhydantoin (0.398 g, 1.1 mmol) and
sulphuric acid (1 mL) were mixed and added drop-wise to
the indole solution over a period of 5 min. The inorganic
salts were filtered off and the aqueous phase extracted with
ether (3ꢂ30 mL).The combined organic layers were washed
with saturated K2SO3 solution (25 mL) and lastly brine
(20 mL). The ether was dried over anhydrous MgSO4, fil-
tered and evaporated to give the title compound as dark
crystals, which contained some degradation products; yield:
0.19 g (69%). The title compound could be stored under
inert conditions in a fridge for 4 days, but readily decom-
posed to black particles in ambient conditions after 6 days.
1H NMR (400 MHz, CD3Cl): d=7.92 (1H, s), 7.06 (1H, d,
J=7.6 Hz), 6.92 (1H, d, J=8.0 Hz), 6.81 (3H, m, J=
7.0 Hz); 13C NMR (150.9 MHz, CD3Cl): d=135.7, 129.8,
128.6, 123.3, 121.0, 120.8, 111.4, 57.5; MS (EI): m/z (%)=
242.9 (M+, 100), 116.0 (75), 89 (47). The recorded spectral
data were in accordance with the literature.[29]
4,5-Diibromo-1H-imidazole (14) [2302-30-9][25]
A round-bottom flask was filled with water (10 mL) and im-
mersed in an ice-bath. Imidazole (0.074 g, 1.09 mmol) was
then added and the mixture was stirred until the solid had
dissolved. N,N’-Dibromo-5,5-dimethylhydantoin (0.15 g,
0.52 mmol) was added as a solid to the solution in small por-
tions followed by a few drops of sulphuric acid (2 mL in
total). The brominating agent and the acid were added in
five portions over five minutes. The reaction mixture was
quenched with NaOH (3.8M, 20 mL) and then neutralized
with acetic acid (pH~6) which resulted in the precipitation
of the product as white crystals. The product was filtered,
washed with water and air-dried to constant weight provid-
ing the title compound; yield: 0.237 g (96%). 1H NMR
(400 MHz, CD3SOCD3): d=7.80; MS (EI): m/z (%)=227.8
(49), 225.8 (M+, 100), 223.8 (51), 200.8 (23), 198.8 (45), 196.8
(23), 146.9 (24), 144.9 (24).
2,4,5-Tribromo-1H-imidazole (15) [5932-18-3][15,26]
3-Bromo-1H-indole (19) [1484-27-1]
A round-bottom flask was filled with water (10 mL) and im-
mersed in an ice-bath. Imidazole (0.074 g, 1.09 mmol) was
then added and the mixture was stirred until the solid had
dissolved. N,N’-Dibromo-5,5-dimethylhydantoin (0.58 g,
2.0 mmol) was added to the solution in one portion under
stirring followed by drop-wise addition (1 min.) of sulphuric
acid (1 mL). The viscous solution was immediately
quenched with NaOH (3.8M, 20 mL) and the alkali neutral-
ized with acetic acid (pH~6). The solution was cooled in
a fridge until precipitation of the product was complete. The
crystals were filtered, washed with cold water (2ꢂ40 mL)
A roind-bottom flask was filled with MeOH (50 mL) and
immersed in an ice-bath. Indole (0.195 g, 1.66 mmol) was
then added and the mixture was stirred until the solid had
dissolved. N,N’-Dibromo-5,5-dimethylhydantoin (0.36 g,
1.3 mmol) was added as a solid to the solution in small por-
tions followed by a few drops of sulphuric acid (2 mL in
total). The brominating agent and the acid were added in
seven portions over five minutes. The colour changed from
green to dark brown during the addition. The mixture was
stirred for 5 min, after which the reaction mixture was
Adv. Synth. Catal. 2013, 355, 499 – 507
ꢁ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
505

Alexander H. Sandtorv and Hans-Renꢀ Bjørsvik
FULL PAPERS
3,4-Dibromo-1H-pyrazole (23) [5932-18-3][32]
quenched with NaOH (3.8M, 20 mL). Inorganic salts were
filtered off. The resulting MeOH/water phase was extracted
with ether (3ꢂ30 mL) and the combined, organic extracts
were washed with saturated K2SO3 solution (10 mL) and fi-
nally brine (20 mL). The organic layers were combined,
dried over anhydrous MgSO4, filtered and evaporated to
give the crude product as yellow crystals; yield: 0.173 g
(53%). A spectroscopic sample was prepared by recrystalli-
A round-bottom flask containing water (2 mL) was im-
mersed in an ice-bath. Pyrazole (0.077 g, 1.13 mmol) was
then added under gentle stirring whereupon N,N’-dibromo-
5,5-dimethylhydantoin (0.69 g, 2.4 mmol) was added in one
portion under continuous stirring followed by drop-wise ad-
dition of sulphuric acid (1 mL). This resulted in the libera-
tion of Br2 and the formation of a viscous, orange solution.
NaOH (4.0M, 20 mL) was immediately added and the
brown solution was filtered to remove some tan particles.
The solution was then acidified with concentrated HCl and
cooled in a fridge until precipitation of the product was
complete. The crude product was filtered, washed with cold
water (2ꢂ40 mL) and recrystallized from EtOH (50%) to
give the title compound as tan crystals after 3 crops; yield:
1
zation from hexanes. H NMR (400 MHz, CD3Cl): d=7.77
(1H, s, br), 7.16 (1 h, d, J=7.6 Hz), 6.95 (1H, d, J=7.9 Hz),
6.80 (3H, m); MS (EI): m/z (%)=197.0 (62), 195.0 (M+,62),
116.0 (100), 89.0 (49). The recorded spectral data was in ac-
cordance with the literature.[30]
3-Chloro-1H-indole (20) [16863-96-0][31]
1
0.151 g (59%). H NMR (400 MHz, CD3Cl): d=7.67 (s); MS
(EI): m/z (%)=227.9 (50), 224.8 (M+, 100), 223.9 (52), 200.8
A round-bottom flask was filled with methanol (50 mL) and
immersed in an ice-bath, Indole (0.14 g, 1.2 mmol) was the
added and the mixture was stirred until the solid had dis-
(11), 198.8 (27), 196.8 (16).
solved.
N,N’-Dichloro-5,5-dimethylhydantoin
(0.26 g, 4-Chloro-1H-pyrazole (24) [15878-00-9]
1.3 mmol) was added to the solution in small portions (in
a total of 10 portions over 5 min) under vigorous stirring.
After the first portion of the chlorinating agent had been
added, 5 drops of sulphuric acid were added. Then the
colour of the reaction mixture changed to dark amber. The
reaction mixture was then quenched with NaOH (4M,
10 mL). The colour of the reaction mixture then changed to
green. After neutralization with acetic acid (pH~6), the re-
sulting red solution was extracted with hexanes (3ꢂ30 mL).
The extracts were combined and washed with brine
(20 mL), dried over anhydrous Na2SO4 and filtered before
the solvent was removed under reduced pressure to provide
the title product as dark crystals; yield: 0.14 g (77%).
1H NMR (400 MHz, CD3CN): d=8.26 (1H, s), 7.76 (1H, d,
J=7.1 Hz), 7.46 (1H, d, J=7.7 Hz), 7.34 (3H, m); MS (EI):
m/z (%)=153.0 (33), 151.0 (M+, 100), 89.0 (56); 13C NMR
(150.9 MHz, CD3Cl): d=135.2, 125.5, 123.3, 121.1, 120.6,
118.3, 111.7, 106.6.
A round-bottom flask containing water (2 mL) was im-
mersed in an ice-bath. Pyrazole (0.078 g, 1.15 mmol) and
N,N’-dichloro-5,5-dimethylhydantoin
(0.25 g, 1.3 mmol)
were added and the mixture was gently stirred, Sulphuric
acid (1 mL) was then added drop-wise which resulted in
a white, heterogeneous mixture. NaOH (3.8M, 20 mL) was
then added in one portion and the mixture was placed in
a fridge for 10 min after which it was extracted with ether
(3ꢂ20 mL). The organic extracts were dried over anhydrous
Na2SO4, filtered and evaporated to give the title compound
1
as pale yellow crystals; 0.083 g (70%). H NMR (400 MHz,
CD3Cl): d=9.65 (s, 1H, br), 7.18 (s, 1H); MS (EI): m/z
(%)=105.3 (16), 104.0 (M+, 84), 101.9 (100), 76.9 (76), 74.9
(89). The recorded spectral data was in accordance with the
literature.[33]
Acknowledgements
4-Iodo-1H-pyrazole (22) [3469-69-0]
A.H.S. is grateful to the Department of Chemistry at the Uni-
versity of Bergen for funding his research fellowship. Dr.
Bjarte Holmelid is acknowledged for technical assistance in
obtaining the HR-MS data.
A round-bottom flask containing water (2 mL) was im-
mersed in an ice-bath. Pyrazole (0.076 g, 1.12 mmol), KI
(1.94 g, 12 mmol) and N,N’-diiodo-5,5-dimethylhydantoin
(0.481 g, 1.3 mmol) were added and the mixture was stirred
as sulphuric acid (1 mL) was added drop-wise over a short
period of time
ACHTUNGTRENNUNG(1 min). After the addition, the reaction mix-
ture was quenched with NaOH (3.8M, 20 mL) and the
brown solution neutralized with acetic acid (pH~6). Saturat- References
ed K2SO3 solution was added in small portions (1 mL) until
the brown colour disappeared. The water was then evapo-
rated to about 1/3 of the volume and the resulting, white
precipitation filtered and air-dried. The white crystals were
then vigorously stirred in ether (50 mL), filtered again and
the ether solution evaporated to give the crude product;
yield: 0.197 g. The crude was re-crystallized from EtOH
(50%) to give the title compound as fine, translucent nee-
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507