Bromination of pyrimidines: A simple inexpensive method

Article abstract of DOI:10.1071/CH14416

Although the introduction of halogens into the pyrimidine ring has been accomplished numerous times, the methods usually involve either specialised reagents or very aggressive conditions. This communication paper describes the introduction of bromine into position 5 of the pyrimidine ring using common inorganic salts at room temperature. An evaluation of the substituents required for successful reaction is provided.

Full text of DOI:10.1071/CH14416

RESEARCH FRONT
CSIRO PUBLISHING
Aust. J. Chem. 2015, 68, 254–255
Communication
http://dx.doi.org/10.1071/CH14416
Bromination of Pyrimidines: A Simple Inexpensive Method
A B
,
A
Thomas J. Delia
and Robin J. Hood
A
Department of Chemistry, Central Michigan University, Mount Pleasant,
MI 48858, USA.
B
Corresponding author. Email: delia1tj@cmich.edu
Although the introduction of halogens into the pyrimidine ring has been accomplished numerous times, the methods
usually involve either specialised reagents or very aggressive conditions. This communication paper describes the
introduction of bromine into position 5 of the pyrimidine ring using common inorganic salts at room temperature. An
evaluation of the substituents required for successful reaction is provided.
Manuscript received: 25 June 2014.
Manuscript accepted: 11 August 2014.
Published online: 16 October 2014.
The introduction of halogens into the pyrimidine ring, especially
at position 5, has been accomplished by numerous investiga-
tors.[1a] All four of the halogens can be introduced into a variety
of pyrimidines, with F being the most difficult. In reality,
chlorinations and brominations have been the subject of the
majority of such investigations. Interest in having a halogen in
position 5 remains high as this provides a vehicle for the intro-
duction of other functional groups via replacement of the
halogen.
Typically, chlorinations are accomplished using Cl2,
SOCl2, or N-chlorosuccinimide ranging from room temperature
to 1008C.[1b] Brominations likewise proceed via Br2 or
N-bromosuccinimide (NBS), again ranging from room tem-
perature to 1008C.[1c] The majority of iodinations usually
involve I2.[1d]
It is clear that at least one activating group (e.g. MeO,
NMe2) is necessary at one of the positions surrounding C-5 to
accomplish the bromination process (compounds 1, 3, 5, 7).
The presence of a mild deactivating group, Cl (as in pyrimi-
dines 3, 5), did not preclude the reaction from occurring.
Even hydrogen (as in pyrimidine 7) did not affect the
outcome. However, if C-5 was surrounded by two chlorine
atoms (see pyrimidine 9) or even one chlorine and a hydrogen
atom (see pyrimidine 10), depriving C-5 of the presence of an
activating group, no reaction occurred. The higher yield of
compound 4 might suggest a radical process that is not
constrained as it would be in an ionic process. However,
based on the lack of a-halogenation of compound 1, this
possibility is less likely.
Recently, we began a series of experiments designed to
achieve replacement of an amino group by a halogen. Thus, a
series of 2-aminopyrimidines bearing other groups at positions 4
and 6 was treated with sodium nitrite and a potassium salt, KX
(X ¼ F, Cl, Br, I). Although no reaction occurred with KF, each
of the other salts led to mixtures of 2-halo and 2,5-dihalo
products. This introduction of halogen into position 5 was quite
unexpected under these reaction conditions. Consequently, we
focussed our efforts on examining this observation further by
carrying out reactions of pyrimidines without an amino group.
The results were inconsistent except in the case of bromination.
Herein, we report on the results of this investigation.
In order to understand the requirements for a successful
bromination at position 5 of the pyrimidine ring, we chose a
series of compounds that offered a variety of substituents,
especially at positions 4 and 6. Table 1 contains a group of six
pyrimidines that possess both activating and deactivating groups
at these two locations.
Table 1. Bromination of selected pyrimidines
R4
R4
Br
N
NaNO2, KBr
N
glacial CH3CO2H, rt
N
R6
R2
R6
R2
N
Compound no.
R2
R4
R6
Product
Percentage
yield
(isolated)
1
OCH3
OCH3
Cl
OCH3
OCH3
N(CH3)2
OCH3
Cl
CH3
Cl
Cl
H
2[2]
4[3]
6A
8[4]
NRB
NR
69
96
45
68
3
5
7
OCH3
Cl
9
Cl
H
We opted to use glacial acetic acid as the sole solvent, both
for the ability to dissolve the relatively non-polar pyrimidines
and to provide the weakly acidic environment required to initiate
reaction with NaNO2.
10
Cl
Cl
ASee Experimental section for characterisation of this compound.
BNR: no reaction.
Journal compilation Ó CSIRO 2015
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Bromination of Pyrimidines
255
A review of the literature failed to uncover any prior use of
sodium nitrite and a bromide salt as a method for bromination.
As our experience with the C-5 position of pyrimidines sug-
gested an electrophilic process, we initially considered this to
be the pathway for bromination. However, it was hard to
rationalize the oxidation of the bromine anion to a bromine
cation. The formation of the active brominating agent will have
to be examined further.
However, in an effort to further define a possible pathway for
the observed reactions, compound 1 was treated with Br2 in
glacial acetic acid. Analysis of the reaction mixture by gas
chromatography–mass spectrometry (GC-MS) showed that
compound 2 was, indeed, formed and isolated in a yield of
85 %. Consequently, formation of Br2 from NaNO2 and KBr is a
viable possibility for the actual brominating agent. Further
investigation of this observation is warranted and will be
pursued.
reasonable retention times compared with starting material, and
predictable ion fragmentation. In addition, melting points of
isolated products were obtained and were consistent with the
reported values.
Typical Experimental Procedure for Bromination
The pyrimidine (,1 mmol) was dissolved in glacial acetic acid
(,5 mL), and solid NaNO2 (,2 mmol) and solid KBr
(,2 mmol) were added all at once. An immediate evolution of
brown fumes was observed and the mixture was stirred at room
temperature (rt) overnight. Progress of the reaction was fol-
lowed by GC-MS analysis. In those cases where the reaction was
incomplete, as observed by the presence of starting pyrimidine,
additional NaNO2 was added and gentle heating applied
(,508C) for up to 1 h until no starting material was observed by
GC-MS analysis. Workup consisted of evaporation of the acetic
acid (in a fume hood at atmospheric pressure) followed by
suspension of the residue in Et2O (,20 mL). This was passed
through a short bed of silica gel (60–100 mesh), and eluted with
Et2O until the effluent showed no UV absorption. Evaporation
of the Et2O led to pure product.
We conclude from these experiments that any pyrimidine
containing at least one activating group adjacent to C-5 will
provide a 5-bromopyrimidine. Thus, this process represents a
novel approach to C-5 bromination under quite mild conditions
and without the use of either specialized brominating agents,
e.g. NBS, or harsh and toxic reagents, e.g. Br2.
5-Bromo-2,6-dichloro-4-dimethylaminopyrimidine 6: mp
96–988C. dH 3.254 ((CH3)2). dC 41.617 (N–CH3), 99.470
(C5–Br), 156.423 (C6–N), 161.474 (C4–Cl), 163.351 (C2–Cl).
m/z (HRMS) 270.9090. Calc. 270.9098. See Supplementary
Material for complete NMR and MS.
Experimental
All chemicals used in these reactions were obtained commer-
cially. 1H and 13C NMR spectra for compound 6 were obtained
in [D3]chloroform on an Agilent (Varian) Mercury-300 or Inova
500 instrument and a high-resolution mass spectrum (HRMS)
for compound 8 (see Supplementary Material) was obtained on a
Waters GCT mass spectrometer, coupled to an Agilent 7890 GC
instrument (with appropriate software that factors in relevant
isotope ratios and masses). Reactions were followed using the
same instrument employing the following conditions: GC oven
temperature raised from 408C to 3008C in 6.5 min and held at
3008C for 3.5 min; column was an MS-5, 10-m, 0.1-mm inside
diameter (ID), 0.1-mm film thickness; flow rate of 1 mL minꢀ1
and an ionization energy of 70 eV for the mass spectrometer.
Because the known compounds (2, mp 76–778C;[2] 4, mp
97–988C;[3] and 8, mp 63–648C[4]) have been adequately
described in the literature and the chemistry involved here does
not materially change the structures of the starting pyrimidines,
GC-MS spectra were used to confirm the expected product
formation. This confirmation included purity of the product,
Supplementary Material
1H NMR, 13C NMR, and HRMS spectra of compound 6 are
available on the Journal’s website.
References
[1] (a) Seepp. 329–342inD. J. Brown, ThePyrimidines1994 (JohnWiley&
Sons: New York, NY).
(b)Seep. 348inD. J. Brown, The Pyrimidines1994(John Wiley & Sons:
New York, NY).
(c) See p. 349in D. J. Brown, The Pyrimidines 1994(JohnWiley & Sons:
New York, NY).
(d)Seep. 350inD. J. Brown, The Pyrimidines1994(John Wiley & Sons:
New York, NY).
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doi:10.1021/JO01079A028
[3] C. O. Okafor, J. Org. Chem. 1973, 38, 4386. doi:10.1021/JO00965A008
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doi:10.1021/JA01316A041