Highly Regioselective Organocatalytic SNAr Amination of 2,4-Dichloropyrimidine and Related Heteroaryl Chlorides

Article abstract of DOI:10.1002/ejoc.201700459

A highly efficient and regioselective method for the S_NAr amination of 2,4-dichloropyrimidine with oxazolidin-2-one and related weakly nucleophilic amines, using sodium sulfinate and tetrabutylammonium bromide as catalysts, is disclosed. This strategy facilitates the synthesis of various aminopyrimidines in a regio- and chemoselective manner. This approach was successfully used for the amination of various activated N-heteroaromatic substrates.

Full text of DOI:10.1002/ejoc.201700459

DOI: 10.1002/ejoc.201700459
Full Paper
Regioselective Amination
Highly Regioselective Organocatalytic S Ar Amination of
N
2
,4-Dichloropyrimidine and Related Heteroaryl Chlorides
[a,b]
[a]
Fabian Bruening
and Lucie E. Lovelle*
Abstract: A highly efficient and regioselective method for the This strategy facilitates the synthesis of various aminopyr-
SNAr amination of 2,4-dichloropyrimidine with oxazolidin-2-one imidines in a regio- and chemoselective manner. This approach
and related weakly nucleophilic amines, using sodium sulfinate was successfully used for the amination of various activated
and tetrabutylammonium bromide as catalysts, is disclosed. N-heteroaromatic substrates.
Introduction
such as amides, carbamates, pyrroles, or imidazoles in such
[
8,9]
transformations.
To address this problem, we report a highly
Substituted pyrimidines, and 2,4-aminopyrimidines in particu-
lar, are important structural motifs that are present in a wide
variety of pharmaceuticals and biologically active substances.
A recent report shows that the pyrimidine scaffold is the second
most common heteroaromatic ring present in pharmaceutically
active compounds after the pyridine scaffold. Consequently,
efficient routes to this and related heteroaromatic moieties are
urgently required for both drug discovery and process develop-
ment. Conventional syntheses of aminopyrimidines rely on tran-
sition-metal-catalysed amination or nucleophilic aromatic sub-
stitution reactions of activated heteroaryl substrates. Due to
the importance of pyrimidines in pharmaceutical chemistry, a
number of building blocks are now commercially available, with
efficient, regioselective, and economical protocol for the select-
ive C-4 amination of DCP with weakly nucleophilic oxazolidin-
[
1]
2
-ones and related nucleophiles. The procedure was also suc-
cessfully translated into a number of other activated heteroaryl
chlorides.
[
2]
[
3]
Scheme 1. 2,4-Dichloropyrimidine.
2,4-dichloropyrimidine (1a, DCP; Scheme 1) a particularly
notable example. The availability of this building block greatly
simplifies synthetic considerations, but the development of effi-
cient, regioselective methods for the direct amination of this
common precursor remains a major challenge. Generally,
amination reactions of DCP are highly sensitive to changes of
reaction conditions, in particular to the combination of nucleo-
Results and Discussion
For our initial investigations into an efficient and selective
method for the amination of DCP (1a) with weakly nucleophilic
amines, unsubstituted oxazolidin-2-one (2a) was selected as a
model substrate. Aware of the possible formation of regioiso-
meric products, we began our study with the systematic altera-
tion of reaction conditions. Specifically, time, solvent, base, and
catalyst/additive combinations were investigated. We were par-
ticularly interested in the use of mild and environmentally
friendly conditions that would be suitable for large-scale syn-
thesis, and also for the synthesis of more complex structural
motifs. Most of the preliminary control experiments carried out
in the absence of catalyst or additive resulted in moderate
yields and a significant amount of the unwanted regioisomer
[
4]
phile and base. The C-4 position of DCP tends to be more
reactive towards nucleophilic substitution, but the exclusive
formation of a single regioisomer remains challenging, and this
is further complicated by separation issues and loss of prod-
[
5–7]
uct.
These challenges are further increased when weakly
nucleophilic amines are used; most existing methods are
limited to reactive primary and secondary amines. Only a hand-
ful of reports describe the use of weakly nucleophilic amines
(
Scheme 2a). Selected results using K CO and NaH in THF are
2 3
[
[
a] Chemical and Analytical Development, Novartis Campus,
shown in Table 1 (entries 1 and 2). It is important to note that
ethanol and other alcohol solvents that are often used in S Ar
amination reactions were found to be unsuitable in this case;
they often led to the exclusive formation of the alcohol-
addition products (Table 1, entry 3). From previous work,
was known that replacement of the C-4 chloride with a sulfone
differentiates the reactivity of the two electrophilic sites and
Novartis Pharma AG,
4
002 Basel, Switzerland
N
E-mail: lucie.lovelle@novartis.com
b] Department of Chemistry and Applied Biosciences,
Laboratory of Inorganic Chemistry, ETH Zurich,
[
10]
it
Vladimir-Prelog-Weg 1-5/10, 8093 Zürich, Switzerland
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201700459.
Eur. J. Org. Chem. 2017, 3222–3228
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Table 1. Optimisation table.
Entry[a]
Solvent
Base
equiv.)
Ammonium salt
(0.1 equiv.)
Sulfinate
(0.03 equiv.)
Yield
Ratio
3a/4a
[%][
c]
[d]
(
1[b]
2
3
4
5
6
7
8
9
THF
THF
EtOH
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NaH (1.1)
–
–
–
–
–
–
17
20
0
1:2
1:0.8
–
1:0.8
42:1
8:1
K
K
K
K
K
2
2
2
2
2
CO
CO
CO
CO
CO
3
3
3
3
3
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
[e]
–
NaSO
NaSO
–
2
Me
Me
22
91
72
TBABr[
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
g]
2
<2[
<10[
70
f]
1:2
1:1
Li
Na
Cs
2
CO
CO
CO
PO
NEt
3
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
2
2
2
2
2
2
2
2
2
2
2
2
2
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
f]
2
3
2
3
55:1
21:1
1:1.5
10:1
5:1
12:1
24:1
70:1
30:1
3.5:1
8:1
1
1
1
0
1
2
K
3
4
67
(2)
<20[
<10[
67
f]
f]
3
2,6-lutidine (2)
NaH (1.1)
[
b]
13
1
1
1
4
5
6
K
K
K
2
2
2
CO
CO
CO
3
3
3
(1)
(3)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
(2)
74
90
79
71
53
65
75
59
83
81
69
83
TBASO
TBASO
3
Me
[
b]
17
Cs
2
CO
3
3
Me
TMABr]
nBuPyBr[
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
TBABr
h]
18
19
20
21
22
23
24
25
26
K
K
K
K
K
K
K
K
K
2
CO
CO
CO
CO
CO
CO
CO
CO
CO
3
i]
THF
THF
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
NaSO
2
Ph
Me
Me
Me
Me
Me
Me
22:1
8:1
Me-THF
toluene
EtOAc
acetone
MeCN
NaSO
NaSO
NaSO
NaSO
NaSO
NaSO
2
2
2
2
2
2
21:1
50:1
42:1
65:1
>100:1
[
j]
CPME
84
1
[
a] Reactions were carried out at 50 °C. [b] Carried out at room temperature. [c] Isolated yield of 3a. [d] Determined by H NMR spectroscopic analysis of the
1
crude product after workup. [e] Only ethanol substitution. [f] Conversion determined by H NMR spectroscopic analysis of the crude product after workup.
g] TBA: tetrabutylammonium. [h] TMA: trimethylammonium. [i] nBuPyBr: n-butylpyridinium bromide. [j] CPME: cyclopropyl methyl ether.
[
thereby enhances the selectivity, and that this can lead to the sulfinate. The substoichiometric use of sulfinates to promote
exclusive formation of the C-4 substituted pyrimidine 3a the nucleophilic substitution of 2-chloro-4,6-dimethoxypyr-
[
4,7]
(
Scheme 2b).
imidine has already been described, which provided an encour-
[
13]
aging precedent.
However, simply doping the reaction mix-
ture with 0.03 equiv. of NaSO Me did not lead to a noticeable
2
improvement in terms of reactivity or selectivity compared to
the uncatalysed control reaction (Table 1, Entries 2 and 4),
which suggests that the desired sulfone 1b was not formed.
We suspected that this could be due to a problem of solubility,
so a catalytic amount of tetrabutylammonium bromide (TBABr)
was used to assist in solubilising the NaSO Me, and so promote
2
[
14]
the formation of the aryl sulfone. Under these optimised ca-
talysis conditions, the desired regioisomer was formed preferen-
tially with a ratio of 42:1 in favour of product 3a, as confirmed
1
by H NMR spectroscopy; product 3a was isolated as a single
compound in a synthetically useful 91 % yield (Table 1, Entry 5).
The formation of a small quantity of 1b was detected by HPLC
1
and by H NMR spectroscopy when the reaction was run in
Scheme 2. Reactivity difference between DCP and 2-chloro-4-(methyl-
sulfonyl)pyrimidine (1b).
[
D ]THF. Interestingly, a control reaction in which only TBABr
8
was used gave the desired product in 72 % yield (crude ratio
a/4a 8:1; Table 1, Entry 6). This result shows that the solubilisa-
3
[
15]
Based on these results, we envisioned a process in which the tion of NaSO
in-situ formation of the 2-chloro-4-(methylsulfonyl)pyrimidine Returning to the mixed-catalyst procedure, increasing the
Me is not the only effect of the ammonium salt.
2
(
1b) might be realised through the addition of a sulfinate salt TBABr loading or introducing other tetrabutylammonium halide
[
11,12]
[16]
to 1a.
This approach is extremely appealing, since the sub- salts
did not lead to a measurable increase in the yield or
Me
salt needed to form 1b, rendering the reaction catalytic in was found to result in partial substitution of the C-2 chloride
stitution of the SO Me group would regenerate the sulfinate selectivity. However, the use of higher loadings of NaSO
2
2
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with sulfinate, resulting in the formation of an undesired prod-
uct mixture of 3a and 3-[2-(methylsulfonyl)pyrimidin-4-yl]-
oxazolidin-2-one. Further attempts to optimise our catalytic sys-
tem using quaternary ammonium salts, including tetrabutyl-
ammonium methanesulfonate (TBASO Me), tetramethyl-
3
ammonium bromide (TMABr), and n-butylpyridinium bromide
(
nBuPyBr) were unsuccessful (Table 1, Entries 16–19). The results
were generally superior to those obtained in the absence of
catalysts, but TBABr gave the best results. Furthermore, when
NaSO Me was replaced by NaSO Ph, a substantial drop in yield
2
2
and selectivity was noted (Table 1, Entry 20). The choice of base
proved to be critical, and no reaction was observed with either
sodium or lithium carbonate, or with organic bases such as Et N
3
or 2,6-lutidine. Although the use of Cs CO and K PO led to
2
3
3
4
reasonable levels of conversion, the results were inferior to
those obtained with K CO . To complete our investigation, a
2
3
[
17]
screen of commonly used green alternative solvents such as
methyl-THF, toluene, ethyl acetate, and acetone were evaluated.
This screening revealed that the reaction performs satisfactorily
in most solvents under the specified conditions (Table 1, En-
tries 21–26). Reactions were run at 50 °C, and complete conver-
sion was obtained after only a few hours. The reactions also
proceeded to completion at room temperature with no signifi-
cant impact on the regioisomeric ratio, but required extended
reaction times. Having optimised the catalyst system for the
selective C-4 amination of 2,4-dichloropyrimidine with ox-
azolidin-2-one, a variety of other amines were evaluated
(
Scheme 3).
The method was found to work very well for various carb-
amates and similar weakly nucleophilic amines, giving yields
from 53 to 91 %. In some cases, longer reaction times and
higher temperatures were necessary to drive the reaction to
completion (see the Experimental Section for full details). Our
investigation of the substrate scope started with structurally
similar cyclic amines. Thiazolidin-2-one, pyrrolidin-2-one, and 1-
methylimidazolidin-2-one gave the corresponding products
3
b–3d in synthetically useful yields. The less nucleophilic 2-
Scheme 3. Scope of the reaction in terms of nucleophiles. [a] Method A: THF,
pyrrolidinone 2c required slightly harsher conditions (cyclo-
pentyl methyl ether at 100 °C) to obtain 3c with full conversion.
Aryl- and alkyl-substituted oxazolidin-2-ones proved to be
viable substrates as well, and gave aminopyrimidines 3e–3h in
acceptable yields (69–81 %). Other substituted amines includ-
ing (1-chloroethyl)- (3j), {1-[(tert-butyldimethylsilyl)oxy]ethyl}-
5
0 °C. [b] Method B: THF, reflux. [c] Method C: CPME, 100 °C. [d] Regioisomeric
ratio could not be determined due to side-product formation.
3
o) as heteroaromatic amines; the successful results obtained
with these compounds demonstrate the versatility of the proto-
col with unreactive substrates. It should be noted that for the
(
2i), and dimethyl- (2k) -oxazolidin-2-ones could also be used,
and the corresponding products were formed in good yields.
The unprotected 4-(1-hydroxyethyl)oxazolidin-2-one led to a
complex mixture of products. We next examined different
indoline-derived amines. When benzo[d]oxazol-2(3H)-one was
used as substrate for the formation of 3l, the reaction pro-
ceeded with the concomitant formation of increased levels of
by-products, and the overall yield decreased to 43 %. These by-
products were predominantly derived from opening of the
oxazolidin-2-one ring (Scheme 4). Surprisingly, the formation of
structural analogue 3m was found to proceed more selectively.
This may be due to the more electron-rich thiocarbamate being
less susceptible to ring-opening. The final two substrates inves-
tigated were pyrrole (leading to 3n) and imidazole (leading to
Scheme 4. Potential degradation pathways.
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reactions with substrates 2l–2o, the regioisomeric side-product we found that the reaction was efficient with other activated
could not be identified, and therefore no regioisomeric ratio heteroaryl scaffolds, such as the two symmetrical dichlorodi-
could be determined. Also, no significant improvement in re- azines, which gave the corresponding products 6i and 6j in 72
gioselectivity was observed when reactive primary and second- and 60 % yields, respectively.
ary amines were used under the described reaction conditions,
and much lower conversions were observed for acyclic carb-
amates.
Conclusions
Following the study of different amines, the scope of acti-
vated heteroaryl chlorides that could undergo amination using
our developed protocol was investigated (Scheme 5). Additional
substitution on the C-5 position of 2,4-dichloropyrimidine with
We have developed an efficient protocol for the catalytic regio-
selective S Ar amination of 2,4-dichloropyrimidine with weakly
N
nucleophilic oxazolidin-2-ones in yields ranging from 43 to
9
1 % and with high selectivities. This mild and environmentally
a methyl group (formation of 6a) or a bromide (formation of
b) resulted in a drop of yield and selectivity. We presume that
the decreased selectivity is due to an increased steric demand.
,4,6-Trichloropyrimidine (TCP) showed a high reactivity, even
at room temperature, but the selectivity dropped to a moderate
:1 ratio. With symmetrical dichloropyrimidines such as 4,6-di-
friendly method works in a number of different solvents. The
observed C-4 selectivity could be achieved by in-situ sulfone
formation using sodium methanesulfinate, and promoted by
the use of tetrabutylammonium bromide as a catalyst. The
method also gives access to a number of different oxazolidin-
6
2
7
2
-one-substituted heteroaryl scaffolds in 52–95 % yield.
chloro-2-methylpyrimidine (formation of 6d) and 4,6-dichloro-
pyrimidine (formation of 6e), only the desired monoaddition
adduct was formed. The reaction of 4,5-dichloropyrimidine
gave the corresponding product 6f in good yield with a select-
ivity of 11:1. Similarly, methyl substitution at C-5 delivered the
product 6g in 86 % yield.
Experimental Section
General Reaction Procedure for the Amination of 2,4-Dichloro-
pyrimidines and Heteroaryl Chlorides with Oxazolidin-2-ones:
The heteroaryl chloride (2.00 mmol), amine (2.10 mmol), K CO
2
3
(
551 mg, 3.99 mmol), TBABr (64.0 mg, 0.199 mmol), and NaSO Me
2
(6.1 mg, 0.060 mmol) were successively added to an oven-dried vial
equipped with a magnetic stirrer bar. Then THF or CPME (1.5 mL)
was added, and the reaction mixture was heated to the appropriate
temperature while stirring. The reaction progress was monitored,
and when the heteroaryl chloride was fully consumed, the mixture
was cooled to 0 °C. The mixture was then added dropwise to ice-
cold HCl (1
M aq.; 6 mL), and, if necessary, the pH was adjusted to
pH 3–7 to prevent hydrolysis of the oxazolidinone. EtOAc (15 mL)
and brine (5 mL) were added, the phases were separated, and the
aqueous phase was further extracted with EtOAc (3 × 15 mL). The
combined organic layers were washed with brine (10 mL), dried
with Na SO , and filtered, and the solvent was removed under re-
2
4
duced pressure. The crude product was purified by flash column
chromatography on silica gel using n-heptane and EtOAc.
3
-(2-Chloropyrimidin-4-yl)oxazolidin-2-one (3a):[8] Prepared us-
ing 2,4-dichloropyrimidine (1.32 mmol) and oxazolidin-2-one ac-
cording to the general procedure. The reaction mixture was stirred
in THF at 50 °C for 3 h. Purification by column chromatography
(
SiO ; heptane/EtOAc, 3:1) gave 3a (239 mg, 91 %) as a colourless
2
1
solid. H NMR (400 MHz, CDCl ): δ = 8.45 (d, J = 5.8 Hz, 1 H), 8.14
3
(
d, J = 5.8 Hz, 1 H), 7.26 (s, 1 H), 4.57–4.52 (m, 2 H), 4.30–4.23 (m, 2
13
H), –0.02 (s, 1 H) ppm. C NMR (101 MHz, CDCl ): δ = 160.4, 159.5,
3
1
58.6, 154.1, 107.4, 62.7, 43.5 ppm.
-(2-Chloropyrimidin-4-yl)thiazolidin-2-one (3b): Prepared using
,4-dichloropyrimidine and thiazolidin-2-one according to the gen-
eral procedure. The reaction mixture was stirred in THF at 50 °C for
3
2
5
1
h. Purification by column chromatography (SiO ; heptane/EtOAc,
2
0:1 to 2:1 over 30 min) gave 3b (402 mg, 93 %) as fine, colourless
1
needles. M.p. 149–151 °C. H NMR (400 MHz, CDCl ): δ = 8.43 (d,
3
J = 5.8 Hz, 1 H), 8.10 (d, J = 6.0 Hz, 1 H), 4.41 (t, J = 7.3 Hz, 2 H),
Scheme 5. Scope of the reaction in terms of electrophiles. [a] Method A: THF,
3.40 (t, J = 7.3 Hz, 2 H) ppm. 13C NMR (101 MHz, CDCl
): δ = 172.7,
5
0 °C. [b] Method B: THF, reflux. [c] Method C: CPME, 100 °C. [d] Method D:
3
THF, room temperature.
160.0, 159.7, 158.7, 108.7, 48.0, 25.4 ppm. IR (neat): ν˜ = 1705, 1683,
1
1
562, 1535, 1459, 1429, 1378, 1332, 1280, 1280, 1237, 1206, 1172,
142, 1098, 1088, 1018, 991, 924, 861, 839, 767, 748, 691, 664, 643,
When the chloride substituent at the C-2 position was re-
–
1
+
placed with a phenyl group, a higher reaction temperature was 628, 491, 439 cm . HRMS (ES): calcd. for C H ClN OS [M + H]
7
7
3
required (CPME, 100 °C) to obtain a good yield of 6h. Finally, 215.99929; found 215.99930.
3225 © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1
-(2-Chloropyrimidin-4-yl)pyrrolidin-2-one (3c): Prepared using
1650, 1571, 1543, 1437, 1388, 1372, 1343, 1307, 1177, 1142, 1125,
–
1
2
,4-dichloropyrimidine and pyrrolidin-2-one according to the gen- 1085, 1049, 971, 841, 82, 764, 701, 665, 594, 459 cm . HRMS (ES):
+
eral procedure. The reaction mixture was stirred in CPME at 90 °C
calcd. for C H ClN O [M + H] 214.03778; found 214.03778.
8 9 3 2
for 2 h. Purification by column chromatography (SiO ; heptane/
2
3
-(2-Chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one
(3h):
EtOAc, 5:1) gave 3c (243 mg, 64 %) as a colourless solid. M.p. 163–
Prepared using 2,4-dichloropyrimidine and 4-isopropyloxazolidin-2-
one according to the general procedure, using THF at 50 °C for
1
1
64 °C. H NMR (400 MHz, CDCl ): δ = 8.43 (d, J = 5.8 Hz, 1 H), 8.33
3
(
(
d, J = 5.8 Hz, 1 H), 4.10–4.05 (m, 2 H), 2.71–2.65 (m, 2 H), 2.20–2.12
2
1
4 h. Purification by column chromatography (SiO ; heptane/EtOAc,
9:1 to 4:1 over 25 min) gave 3h (349 mg, 73 %) as colourless crys-
m, 2 H) ppm. 13C NMR (101 MHz, CDCl ): δ = 176.1, 160.2, 159.5,
2
3
1
1
8
1
59.1, 108.6, 46.82, 33.6, 17.6 ppm. IR (neat): ν = 3117, 2900, 1723,
˜
1
tals. M.p. 89–91 °C. H NMR (400 MHz, CDCl ): δ = 8.43 (d, J = 6.0 Hz,
3
565, 1537, 1427, 1381, 1341, 1246, 1205, 1183, 1090, 1001, 977,
1
4
H), 8.14 (d, J = 6.0 Hz, 1 H), 4.76 (td, J = 3.5, 8.3 Hz, 1 H), 4.41–
.31 (m, 2 H), 2.63–2.51 (m, 1 H), 0.96 (d, J = 7.0 Hz, 3 H), 0.84 (d,
–
1
+
73, 834, 787, 770 cm . HRMS (ES): calcd. for C H ClN O [M + H]
8
9
3
98.04287; found 198.04288.
13
J = 6.8 Hz, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 160.0, 159.6,
3
1
-(2-Chloropyrimidin-4-yl)-3-methylimidazolidin-2-one
(3d): 158.3, 154.2, 107.6, 63.5, 58.7, 27.5, 17.9, 14.3 ppm. IR (neat): ν =
˜
Prepared using 2,4-dichloropyrimidine and 1-methylimidazolidin-2-
3153, 2959, 2877, 1766, 1570, 1543, 1443, 1391, 1345, 1301,
1203, 1175, 1146, 1119, 1060, 982, 841, 791, 771, 676, 606, 455,
516 cm . HRMS (ES): calcd. for C H ClN O [M + H] 242.06908;
one according to the general procedure, using THF at 68 °C for
–
1
+
1
8 h. Purification by column chromatography (SiO ; heptane/EtOAc,
2
10 13 3 2
1
0:1 to 1:1 over 40 min) gave 3d (284 mg, 67 %) as colourless crys- found 242.06917.
1
tals. M.p. 178–179 °C. H NMR (400 MHz, CDCl ): δ = 8.26 (d, J =
3
(
R)-4-{(R)-1-[(tert-Butyldimethylsilyl)oxy]ethyl}-3-(2-chloropyr-
6
.0 Hz, 1 H), 8.17 (d, J = 6.0 Hz, 1 H), 4.04–3.98 (m, 2 H), 3.55–3.48
1
3
imidin-4-yl)oxazolidin-2-one (3i): Prepared using 2,4-dichloro-
pyrimidine and 4-(1-hydroxyethyl)oxazolidin-2-one according to the
general procedure (0.80 mmol scale), using THF at 50 °C for 24 h.
Purification by column chromatography (SiO ; heptane/EtOAc, 19:1
to 4:1 over 25 min) gave 3i (227.3 mg, 78 %) as colourless crystals.
M.p. 129–130 °C. H NMR (400 MHz, CDCl
1
H), 4.47–4.55 (m, 2 H), 4.26 (t, J = 8.91 Hz, 1 H), 0.93 (d, J = 6.27 Hz,
3
(m, 2 H), 2.91 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 160.1,
3
1
1
1
7
+
59.6, 158.1, 155.8, 106.8, 43.7, 40.5, 30.9 ppm. IR (neat): ν˜ = 2901,
715, 1577, 1535, 154, 1488, 1466, 1433, 1406, 1382, 1333, 1294,
265, 1226, 1203, 1154, 1122, 1079, 1040, 979, 848, 787, 769, 745,
2
–
1
21, 654, 544, 453, 410 cm . HRMS (ES): calcd. for C H ClN O [M
8
10
4
1
+
3
): δ = 8.32 (d, J = 5.77 Hz,
H] 213.05377; found 213.05368.
H), 8.00 (d, J = 5.77 Hz, 1 H), 4.64 (ddd, J = 8.53, 4.14, 2.89 Hz, 1
4
-Benzyl-3-(2-chloropyrimidin-4-yl)oxazolidin-2-one (3e): Pre-
pared using 2,4-dichloropyrimidine and 4-benzyloxazolidin-2-one
according to the general procedure, using THF at 50 °C for 6 h.
13
H), 0.77 (s, 8 H), 0.03 (s, 3 H), 0.00 (s, 3 H) ppm. C NMR (101 MHz,
CDCl ): δ = 160.3, 159.8, 158.1, 154.2, 107.2, 64.7, 63.6, 57.8, 25.7 (3
C), 17.9, 16.1, –4.8, –4.9 ppm. IR (neat): ν = 2953, 2931, 2887, 2858,
3
Purification by column chromatography (SiO ; heptane/EtOAc, 19:1
2
˜
to 3:1 over 25 min) gave 3e (465 mg, 81 %) as a colourless solid.
1779, 1572, 1543, 1445, 1387, 1348, 1299, 1253, 1207, 1181, 1137,
1
M.p. 79–80 °C. H NMR (400 MHz, CDCl ): δ = 8.50 (d, J = 5.8 Hz, 1
–1
3
1105, 1051, 1034, 982, 942, 830, 803, 777, 754, 717, 673 cm . HRMS
H), 8.17 (d, J = 5.8 Hz, 1 H), 7.38–7.23 (m, 5 H), 5.06–4.95 (m, 1 H),
+
(ES): calcd. for C H ClN O Si [M + H] 358.1348; found 358.1355.
15 25 3 3
4
1
1
.37–4.30 (m, 2 H), 3.45 (dd, J = 3.3, 13.3 Hz, 1 H), 2.85 (dd, J = 9.5,
3.3 Hz, 1 H) ppm. 13C NMR (101 MHz, CDCl ): δ = 160.4, 159.9,
(±)-(R)-4-[(S)-1-Chloroethyl]-3-(2-chloropyrimidin-4-yl)oxazol-
idin-2-one (3j): Prepared using 2,4-dichloropyrimidine and 4-(1-
chloroethyl)oxazolidin-2-one according to the general procedure
3
58.2, 153.8, 135.3, 129.5, 129.1, 127.5, 107.7, 66.9, 55.9, 37.6 ppm.
IR (neat): ν˜ = 3030, 2984, 2917, 1764, 1567, 1541, 1442, 1393, 1347,
(1.25 mmol scale), using THF at 50 °C for 4 h. Purification by column
1
6
+
288, 1170, 1119, 1087, 1034, 1002, 981, 841, 808, 763, 743, 702,
–
1
chromatography (SiO ; heptane/EtOAc, 19:1 to 4:1 over 25 min)
gave 3i (198 mg, 61 %) as white crystals. M.p. 128–129 °C. H NMR
71, 658, 615, 571, 509 cm . HRMS (ES): calcd. for C H ClN O [M
2
1
4
13
3 2
1
+
H] 290.06906; found 290.06908.
(400 MHz, CDCl ): δ = 8.43 (d, J = 6.0 Hz, 1 H), 8.13 (d, J = 5.8 Hz,
3
3
-(2-Chloropyrimidin-4-yl)-4-phenyloxazolidin-2-one (3f): Pre-
1
9
H), 4.81–4.89 (m, 2 H), 4.53 (dd, J = 9.0, 3.5 Hz, 1 H), 4.44 (t, J =
pared using 2,4-dichloropyrimidine and 4-phenyloxazolidin-2-one
according to the general procedure, using THF at 50 °C for 19 h.
13
.3 Hz, 1 H), 1.49 (d, J = 6.8 Hz, 3 H) ppm. C NMR (101 MHz,
CDCl ): δ = 160.1, 160.0, 158.0, 153.6, 107.9, 77.2, 62.9, 58.7, 55.3,
3
Purification by column chromatography (SiO ; heptane/EtOAc, 20:1
2
2
1
0.4 ppm. IR (neat): ν˜ = 2988, 1748, 1568, 1546, 1477, 1442, 1403,
to 4:1 over 25 min) gave 3f (459 mg, 84 %) as colourless crystals.
–1
348, 1186, 1144, 1121, 1047, 839, 753, 677 cm . HRMS (ES): calcd.
1
M.p. 99–101 °C. H NMR (400 MHz, CDCl ): δ = 8.42 (d, J = 5.8 Hz,
+
3
for C H Cl N O [M + H] 262.0145; found 262.0143.
9
9
2 3 2
1
8
H), 8.15 (d, J = 5.8 Hz, 1 H), 7.40–7.32 (m, 5 H), 5.78 (dd, J = 3.5,
.8 Hz, 1 H), 4.83 (t, J = 8.8 Hz, 1 H), 4.45 (dd, J = 3.6, 8.9 Hz, 1 H)
3-(2-Chloropyrimidin-4-yl)-4,4-dimethyloxazolidin-2-one (3k):
Prepared using 2,4-dichloropyrimidine and 4,4-dimethyloxazolidin-
13
ppm. C NMR (101 MHz, CDCl ): δ = 160.1, 159.8, 158.0, 154.2,
3
1
2
1
38.6, 129.3, 129.0, 126.8, 108.1, 70.7, 58.1 ppm. IR (neat): ν˜ = 3034, 2-one according to the general procedure, using THF at 68 °C for
995, 1757, 1565, 1540, 1440, 1389, 1343, 1291, 1200, 1172, 1124,
48 h. After 24 h, a second portion of 2,4-dichloropyrimidine
–
1
081, 1043, 981, 838, 787, 753, 711, 694, 672, 585, 525 cm . HRMS (0.5 equiv.) was added. Purification by column chromatography
+
(
ES): calcd. for C H ClN O [M + H] 276.05341; found 276.05343.
(SiO
8 %) as colourless crystals. M.p. 90–92 °C. H NMR (400 MHz,
CDCl ): δ = 8.43 (d, J = 5.8 Hz, 1 H), 8.01 (d, J = 5.8 Hz, 1 H), 4.13
2
; heptane/EtOAc, 19:1 to 3:1 over 30 min) gave 3k (203 mg,
13
11
3 2
1
5
3
-(2-Chloropyrimidin-4-yl)-4-methyloxazolidin-2-one (3g): Pre-
3
pared using 2,4-dichloropyrimidine and 4-methyloxazolidin-2-one
according to the general procedure, using THF at 50 °C for 18 h.
13
(s, 2 H), 1.73 (s, 6 H) ppm. C NMR (101 MHz, CDCl ): δ = 159.6,
3
1
3
1
6
2
59.5, 159.2, 154.5, 109.7, 75.8, 61.7, 25.0 ppm. IR (neat): ν˜ = 3156,
005, 2977, 2928, 1754, 1572, 1538, 1463, 1438, 1396, 1382, 1340,
282, 1216, 1167, 1091, 1037, 981, 948, 875, 841, 795, 762, 704, 677,
14, 585, 458 cm . HRMS (ES): calcd. for C H ClN O [M + H]
28.05341; found 228.05343.
Purification by column chromatography (SiO ; heptane/EtOAc, 19:1
2
to 3:1 over 30 min) gave 3g (292 mg, 69 %) as colourless crystals.
1
M.p. 115–117 °C. H NMR (400 MHz, CDCl ): δ = 8.42 (d, J = 5.8 Hz,
3
–1
+
9
11
3 2
1
1
H), 8.09 (d, J = 5.8 Hz, 1 H), 4.93–4.81 (m, 1 H), 4.54 (t, J = 8.4 Hz,
H), 4.12 (dd, J = 3.3, 8.8 Hz, 1 H), 1.51 (d, J = 6.3 Hz, 3 H) ppm.
1
3
C NMR (101 MHz, CDCl ): δ = 160.2, 159.6, 158.3, 153.9, 107.9,
3-(2-Chloropyrimidin-4-yl)benzo[d]oxazol-2(3H)-one (3l): Pre-
pared using 2,4-dichloropyrimidine and benzo[d]-oxazol-2-(3H)-one
3
6
9.6, 51.2, 19.0 ppm. IR (neat): ν = 2990, 2973, 2934, 2912, 1756,
˜
Eur. J. Org. Chem. 2017, 3222–3228
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
according to the general procedure, using THF at 50 °C for 16 h.
according to the general procedure, using THF at 50 °C for 8 h.
Purification by column chromatography (SiO ; heptane/EtOAc, 10:1
Purification by column chromatography (SiO ; heptane/EtOAc, 10:1
2
2
to 2:1 over 25 min) gave 3l (212 mg, 43 %) as a colourless solid.
to 1:2 over 40 min) gave 6b (390 mg, 71 %) as colourless crystals.
1
1
M.p. 179–181 °C. H NMR (400 MHz, CDCl ): δ = 8.69 (d, J = 5.8 Hz, M.p. 162–164 °C. H NMR (400 MHz, CDCl ): δ = 8.69 (s, 1 H), 4.57
3
3
13
1
8
H), 8.40 (d, J = 7.1 Hz, 1 H), 8.42–8.38 (m, 1 H), 8.37–8.34 (m, 1 H),
.35 (d, J = 5.7 Hz, 1 H), 7.35–7.25 (m, 3 H) ppm. C NMR (101 MHz,
(t, J = 7.7 Hz, 1 H), 4.25 (t, J = 7.5 Hz, 1 H) ppm. C NMR (101 MHz,
1
3
CDCl ): δ = 163.4, 158.6, 157.8, 152.7, 112.2, 63.4, 45.6 ppm. IR
3
CDCl ): δ = 161.0, 160.4, 157.8, 151.4, 142.6, 127.7, 125.3, 125.0, (neat): ν˜ = 3065, 2950, 2901, 1764, 1659, 1537, 1520, 1469, 1426,
3
1
1
1
6
16.7, 110.3, 108.9 ppm. IR (neat): ν˜ = 3062, 1785, 1627, 1563, 1550, 1392, 1337, 1283, 1220, 1175, 1133, 1113, 1060, 119, 974, 954, 833,
–1
476, 1439, 1378, 1357, 1329, 1249, 1223, 1197, 1158, 1137, 1099,
769, 753, 728, 679, 647, 601, 520, 446 cm . HRMS (ES): calcd. for
+
086, 1042, 986, 967, 936, 882, 849, 799, 765, 752, 706, 676, 659, C H BrClN O [M + H] 277.9326; found 277.9332.
7
6
3 2
–
1
15, 501, 459, 444, 426, 406 cm . HRMS (ES): calcd. for C H ClN O
3 2
3-(2,6-Dichloropyrimidin-4-yl)oxazolidin-2-one (6c):[12] Prepared
1
1
7
+
[
M + H] 248.02214; found 248.02213.
using 2,4,6-trichloropyrimidine and oxazolidin-2-one according to
the general procedure, using THF at room temp. for 20 h. Purifica-
3
-(2-Chloropyrimidin-4-yl)benzo[d]thiazol-2(3H)-one (3m): Pre-
tion by column chromatography (SiO ; heptane/EtOAc, 19:1 to 1:1
pared using benzo[d]thiazol-2(3H)-one according to the general
procedure, using THF at 50 °C for 24 h. Purification by column chro-
matography (SiO ; heptane/EtOAc, 10:1 to 2:1 over 25 min) gave
2
over 25 min) gave 6c (462 mg, 73 %) as colourless crystals. M.p.
1
1
50–152 °C. H NMR (400 MHz, CDCl ): δ = 8.18 (s, 1 H), 4.58–4.52
3
2
13
1
(m, 2 H), 4.28–4.22 (m, 2 H) ppm. C NMR (101 MHz, CDCl ): δ =
3m (381 mg, 72 %) as a colourless solid. M.p. 171–172 °C. H NMR
3
162.5, 159.6, 159.1, 153.8, 106.9, 62.8, 43.7 ppm.
(400 MHz, CDCl ): δ = 8.78 (d, J = 5.5 Hz, 1 H), 7.97 (d, J = 8.1 Hz,
3
1
7
H), 7.90 (d, J = 5.5 Hz, 1 H), 7.46 (dd, J = 1.3, 7.8 Hz, 1 H), 7.41–
.34 (m, 1 H), 7.31–7.26 (m, 1 H) ppm. C NMR (101 MHz, CDCl3):
3-(6-Chloro-2-methylpyrimidin-4-yl)oxazolidin-2-one (6d): Pre-
pared using 4,6-dichloro-2-methylpyrimidine and oxazolidin-2-one
according to the general procedure, using THF at 68 °C for 19 h.
1
3
δ = 170.0, 161.4, 160.6, 157.8, 134.5, 127.1, 125.4, 122.6, 122.0, 115.4,
1
1
6
15.0 ppm. IR (neat): ν˜ = 1684, 1586, 1548, 1467, 1423, 1343, 1311, Purification by column chromatography (SiO ; heptane/EtOAc, 19:1
2
213, 1151, 1088, 1070, 1030, 969, 910, 835, 771, 751, 735, 709, 687,
to 1:1 over 30 min) gave 6d (375 mg, 89 %) as colourless crystals.
–
1
1
63, 635, 543 494, 440 422 cm . HRMS (ES): calcd. for C H ClN OS
M.p. 115–116 °C. H NMR (400 MHz, CDCl ): δ = 8.03 (s, 1 H), 4.51
1
1
7
3
3
+
13
[
M + H] 263.99927; found 263.99929.
(t, J = 8.0 Hz, 2 H), 4.23 (t, J = 8.0 Hz, 2 H), 2.59 (s, 3 H) ppm.
C
NMR (101 MHz, CDCl ): δ = 168.5, 161.3, 157.7, 154.3, 105.5, 62.6,
3
2
-Chloro-4-(1H-pyrrol-1-yl)pyrimidine (3n): Prepared using 1H-
4
1
8
+
3.7, 25.9 ppm. IR (neat): ν = 3168, 2988, 1926, 1765, 1559, 1540,
˜
pyrrole according to the general procedure, using THF at 68 °C for
440, 1384, 1534, 1221, 1205, 1152, 1114, 1092, 1038, 979, 896, 849,
2
4 h. Purification by column chromatography (SiO ; heptane/EtOAc,
2
–1
13, 753, 703, 605, 583 cm . HRMS (ES): calcd. for C H ClN O [M
8
9
3 2
2
0:1 to 3:1 over 30 min) gave 3n (187 mg, 53 %) as a slightly yellow-
+
H] 214.0378; found 214.0379.
-(6-Chloropyrimidin-4-yl)oxazolidin-2-one (6e):[8] Prepared us-
1
ish/white solid. M.p. 108–110 °C. H NMR (400 MHz, CDCl ): δ = 8.49
3
3
(d, J = 5.8 Hz, 1 H), 7.52–7.48 (m, 2 H), 7.13 (d, J = 5.8 Hz, 1 H),
1
3
ing 4,6-dichloropyrimidine and oxazolidin-2-one according to the
general procedure, using THF at 68 °C for 24 h. Purification by col-
6
1
1
7
.41–6.37 (m, 2 H) ppm. C NMR (101 MHz, CDCl ): δ = 161.4, 160.3,
3
58.3, 118.4, 114.0, 105.8 ppm. IR (neat): ν˜ = 3146, 3073, 1562, 1477,
umn chromatography (SiO ; heptane/EtOAc, 5:1) gave 6e (375 mg,
450, 1398, 1347, 1301, 1211, 1181, 1113, 1061, 1031, 984, 938, 831,
2
1
–
1
95 %) as colourless crystals. M.p. 143–145 °C. H NMR (400 MHz,
84, 739, 687, 676, 583, 515, 422 cm . HRMS (ES): calcd. for
+
CDCl ): δ = 8.67 (s, 1 H), 8.23 (s, 1 H), 4.54 (t, J = 8.2 Hz, 1 H), 4.25
C H ClN [M + H] 180.03230; found 180.03230.
3
8
7
3
13
(
t, J = 8.0 Hz, 1 H) ppm. C NMR (101 MHz, CDCl ): δ = 161.6, 158.1,
3
2
2
-Chloro-4-(1H-imidazol-1-yl)pyrimidine (3o):[18] Prepared using
,4-dichloropyrimidine and 1H-imidazole according to the general
1
57.7, 154.2, 108.8, 62.7, 43.6 ppm.
-(5-Chloropyrimidin-4-yl)oxazolidin-2-one (6f): Prepared using
,5-dichloropyrimidine and oxazolidin-2-one according to the gen-
3
4
procedure, using THF at 50 °C for 16 h. Purification by column chro-
matography (SiO ; heptane/EtOAc, 10:1 to 0:1 over 40 min) gave 3o
2
eral procedure, using THF at 50 °C for 5 h. Purification by column
1
(199 mg, 56 %) as a colourless solid. H NMR (400 MHz, CDCl ): δ =
3
chromatography (SiO ; heptane/EtOAc, 19:1 to 1:1 over 40 min)
2
8
.64 (d, J = 5.8 Hz, 1 H), 8.42 (s, 1 H), 7.64 (t, J = 1.4 Hz, 1 H), 7.26
1
gave 6f (315 mg, 80 %) as a yellowish oil. H NMR (400 MHz, CDCl ):
d, J = 5.5 Hz, 1 H), 7.20 (dd, J = 0.8, 1.5 Hz, 1 H) ppm. 1 C NMR
3
3
(
(
δ = 8.88 (s, 1 H), 8.72 (s, 1 H), 4.57 (t, J = 7.5 Hz, 2 H), 4.25 (t, J =
101 MHz, CDCl ): δ = 161.7, 161.5, 156.4, 135.4, 132.1, 115.8,
3
13
7
.7 Hz, 2 H) ppm. C NMR (101 MHz, CDCl ): δ = 158.8, 155.7, 154.7,
3
1
06.8 ppm.
1
53.4, 124.9, 63.4, 45.4 ppm. IR (neat): ν˜ = 2983, 2916, 1760, 1551,
3
-(2-Chloro-5-methylpyrimidin-4-yl)oxazolidin-2-one (6a): Pre- 1446, 1386, 1178, 1159, 1123, 1053, 1032, 969, 926, 771, 752, 723,
–
1
H ClN O
[M + H]+
7 7 3 2
pared using 2,4-dichloro-5-methylpyrimidine and oxazolidin-2-one
684, 651, 601 cm . HRMS (ES): calcd. for C
according to the general procedure, using THF at 68 °C for 28 h.
200.0221; found 200.0226.
Purification by column chromatography (SiO ; heptane/EtOAc, 20:1
to 1:1 over 35 min) gave 6a (219 mg, 52 %) as colourless crystals.
The remaining starting material could be removed by recrystallisa-
2
3-(5-Methylpyrimidin-4-yl)oxazolidin-2-one (6g): Prepared using
-chloro-5-methylpyrimidine according to the general procedure,
using THF at 50 °C for 20 h. Purification by column chromatography
SiO ; heptane/EtOAc, 1:1 to 0:1 over 25 min) gave 6g (341 mg,
4
tion from CPME or TBME (tert-butyl methyl ether). M.p. 119–121 °C.
(
2
1
H NMR (400 MHz, CDCl ): δ = 8.40 (s, 1 H), 4.54 (t, J = 7.7 Hz, 2 H),
.24 (t, J = 7.5 Hz, 2 H), 2.29 (s, 3 H) ppm. C NMR (101 MHz, CDCl3):
1
3
86 %) as a colourless solid. M.p. 84–86 °C. H NMR (400 MHz, CDCl ):
3
1
3
4
δ = 8.81 (s, 1 H), 8.52 (s, 1 H), 4.52 (t, J = 7.7 Hz, 2 H), 4.23 (t, J =
δ = 162.3, 158.4, 157.5, 154.0, 123.4, 63.3, 45.5, 15.6 ppm. IR (neat):
13
7
.5 Hz, 2 H), 2.30 (s, 3 H) ppm. C NMR (101 MHz, CDCl ): δ = 160.1,
3
ν = 3008, 2954, 2902, 1768, 1543, 1417, 1395, 1371, 1341, 1315,
˜
156.5, 155.7, 154.6, 125.0, 63.2, 45.4, 16.0 ppm. IR (neat): ν = 2978,
˜
1
6
2
207, 1189, 1155, 1102, 1024, 1000, 946, 856, 773, 756, 744, 690,
2
915, 1749, 1557, 1463, 1394, 1383, 1317, 1215, 1184, 1139, 1032,
–
1
+
53, 568, 452 cm . HRMS (ES): calcd. for C H ClN O [M + H]
–1
8
9
3
2
1000, 966, 832, 780, 756, 693, 663, 585, 427 cm . HRMS (ES): calcd.
14.0378; found 214.0381.
+
for C H N O [M + H] 180.0768; found 180.0769.
8
10 3 2
3
-(5-Bromo-2-chloropyrimidin-4-yl)oxazolidin-2-one (6b): Pre-
3-(2-Phenylpyrimidin-4-yl)oxazolidin-2-one (6h): Prepared using
pared using 5-bromo-2,4-dichloropyrimidine and oxazolidin-2-one
4-chloro-2-phenylpyrimidine and oxazolidin-2-one according to the
Eur. J. Org. Chem. 2017, 3222–3228
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© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
general procedure, using CPME at 100 °C for 18 h. Purification by
[2] S. D. Roughley, A. M. Jordan, J. Med. Chem. 2011, 54, 3451–3479.
[
[
3] K. Walsh, H. F. Sneddon, C. J. Moody, ChemSusChem 2013, 6, 1455–1460.
4] R. Baiazitov, W. Du, C.-S. Lee, S. Hwang, N. G. Almstead, Y.-C. Moon, Syn-
thesis 2013, 45, 1764–1784.
column chromatography (SiO ; heptane/EtOAc, 10:1 to 1:1 over
2
3
1
8
5 min) gave 6h (321 mg, 67 %) as a colourless solid. M.p. 197–
1
99 °C. H NMR (400 MHz, CDCl ): δ = 8.67 (d, J = 5.8 Hz, 1 H), 8.42–
3
[
5] R. P. Frutos, T. G. Tampone, J. A. Mulder, S. Rodriguez, N. K. Yee, B.-S.
Yang, C. H. Sananayake, Org. Process Res. Dev. 2016, 20, 982–988.
6] J. T. Kuethe, M. Journet, Z. Peng, D. Zhao, A. McKeown, G. R. Humphrey,
Org. Process Res. Dev. 2016, 20, 227–232.
.37 (m, 2 H), 8.06 (d, J = 5.8 Hz, 1 H), 7.52–7.44 (m, 3 H), 4.58–4.50
1
3
(m, 2 H), 4.4–4.34 (m, 2 H) ppm. C NMR (101 MHz, CDCl ): δ =
3
[
1
4
1
7
2
63.9, 157.8, 156.9, 154.6, 137.2, 131.1, 128.6, 128.2, 106.9, 62.6,
3.4 ppm. IR (neat): ν˜ = 3050, 2992, 2910, 1767, 1588, 1555, 1484,
459, 1431, 1388, 1359, 1211, 1136, 1114, 1048, 1029, 989, 840,
[7] For recent reports on selective C-2 amination, see: a) S. M. Smith, S. L.
Buchwald, Org. Lett. 2016, 18, 2180–2183; b) M. O'Donnell, J.-D. Charrier,
Tetrahedron 2015, 71, 1515–1522; c) M. Lee, T. Rucil, D. Hesek, A. G. Ol-
iver, J. F. Fisher, S. Mobashery, J. Org. Chem. 2015, 80, 7757–7763; d) D. T.
Richter, J. C. Kath, M. J. Luzzio, N. Keene, M. A. Berliner, M. D. Wessel,
Tetrahedron Lett. 2013, 54, 4610–4612.
[8] a) D. Montebugnoli, P. Bravo, E. Corradi, G. Dettori, C. Mioskowski, A.
Volonterio, A. Wagner, M. Zanda, Tetrahedron 2002, 58, 2147–2153; b) S.
Sengmany, J. Lebre, E. Le Gall, E. Léonel, Tetrahedron 2015, 71, 4859–
4867.
–1
+
50, 695, 671, 645 cm . HRMS (ES): calcd. for C H N O [M + H]
1
3 12 3 2
42.0924; found 242.0925.
-(6-Chloropyrazin-2-yl)oxazolidin-2-one (6i): Prepared using
,6-dichloropyrazine according to the general procedure, using THF
3
2
at 50 °C for 24 h. Purification by column chromatography (SiO2;
heptane/EtOAc, 19:1 to 4:1 over 35 min) gave 6i (284 mg, 72 %) as
1
colourless crystals. M.p. 150–152 °C. H NMR (400 MHz, CDCl ): δ =
3
[
9] M. Zanda, P. Talaga, A. Wagner, C. Mioskowski, Tetrahedron Lett. 2000,
41, 1757–1761.
9
(
.42 (s, 1 H), 8.30 (s, 1 H), 7.26 (s, 1 H), 4.59–4.53 (m, 2 H), 4.26–4.19
m, 2 H) ppm. 1 C NMR (101 MHz, CDCl ): δ = 154.2, 146.9, 146.2,
3
3
[
[
10] The use of the chlorosulfone 1b instead of DCP was envisioned; how-
ever, its inherent reactivity renders its use inconvenient for large-scale
processes.
11] For recent examples of the formation of aryl sulfones using sodium
methylsulfinate, see: a) S. Liang, M. Bolte, G. Manolikakes, Chem. Eur. J.
1
1
9
38.1, 133.4, 62.8, 43.5 ppm. IR (neat): ν˜ = 3051, 2993, 2928, 1743,
556, 1522, 1481, 1440, 1416, 1393, 1316, 1238, 1165, 1145, 1047,
–
1
97, 973, 882, 825, 752, 714, 469, 456 cm . HRMS (ES): calcd. for
+
C H ClN O [M + H] 200.0221; found 214.0221.
7
7
3 2
2
017, 23, 96–100; b) X. Tang, L. Huang, Y. Xu, J. Yang, W. Wu, H. Jiang,
Angew. Chem. Int. Ed. 2014, 53, 4205–4208; Angew. Chem. 2014, 126,
289–4292; c) F. Xiao, H. Chen, H. Xie, S. Chen, L. Yang, G.-J. Deng, Org.
3
-(6-Chloropyridazin-3-yl)oxazolidin-2-one (6j): Prepared using
3
,6-dichloropyridazine according to the general procedure, using
4
THF at 50 °C for 24 h. Purification by column chromatography (SiO2;
heptane/EtOAc, 20:1 to 0:1 over 35 min) gave 6j (238 mg, 60 %) as
colourless crystals. M.p. 173–174 °C. H NMR (400 MHz, CDCl ): δ =
Lett. 2014, 16, 50–53.
[
12] For a discussion of the formation of sulfones vs. sulfinate esters, see:J. S.
Meek, J. S. Fowler, J. Org. Chem. 1968, 33, 3422–3424.
1
3
8
4
1
2
1
.49 (d, J = 9.3 Hz, 1 H), 7.48 (d, J = 9.5 Hz, 1 H), 4.62–4.53 (m, 2 H),
[13] a) Y. Bessard, R. Crettaz, Tetrahedron 2000, 56, 4739–4745; b) Y. Bessard,
G. Stucky (Lonza Ltd.), EP 802193, 1997 [Chem. Abstr. 1997, 127, 358872].
1
3
.42–4.34 (m, 2 H) ppm. C NMR (101 MHz, CDCl ): δ = 154.8, 153.2,
3
[
14] For the synthesis of sulfones using tetraalkylammonium sulfinates, see:
a) G. E. Veenstra, B. Zwanenburg, Synthesis 1975, 519–520. For the use
of phase-transfer catalysts to increase the solubility of metal sulfinates,
see: b) T. Murakami, K. Furusawa, Synthesis 2002, 4, 479–482; c) J. Wilde-
man, A. M. van Leusen, Synthesis 1979, 733–734; A. J. Crandall, C. Pradat,
J. Org. Chem. 1985, 50, 1327–1329.
52.4, 129.6, 119.8, 62.7, 44.0 ppm. IR (neat): ν˜ = 3091, 3055, 2981,
919, 1756, 1571, 1540, 1477, 1423, 1399, 1290, 1226, 1131, 1102,
–
1
305, 951, 865, 746, 717, 596, 495 cm . HRMS (ES): calcd. for
+
C H ClN O [M + H] 200.0221; found 214.0223.
7
7
3 2
[
2 2 3
15] In addition to solubilising NaSO Me and the inorganic base (K CO ), we
Acknowledgments
F. B. and L. E. L. are indebted to Dustin Bornemann for his syn-
thetic support.
suspect that TBABr also further selectively modifies the electrophilicity
of the dichloropyrimidine as no soluble base gave a comparable level of
reactivity.
[
16] As water has a detrimental effect on the reaction, the use of TBAF and
TBAX salt hydrates is not advised to avoid hydrolysis of the oxazol-
idinone moiety.
Keywords: Amination · Nitrogen heterocycles · Aromatic
substitution · Phase-transfer catalysis · Regioselectivity
[
17] a) D. Prat, O. Pardigon, H.-W. Flemming, S. Letestu, V. Ducandas, P. Isnard,
E. Guntrum, T. Senac, S. Ruisseau, P. Cruciani, P. Hosek, Org. Process Res.
Dev. 2013, 17, 1517–1525; b) K. Watanabe, N. Yamagiwa, Y. Torisawa, Org.
Process Res. Dev. 2007, 11, 251–258.
[
1] a) M. Baumann, I. R. Baxendale, Beilstein J. Org. Chem. 2013, 9, 2265–
319; b) R. Mah, in Bioactive Heterocyclic Compound Classes, Wiley–VCH,
012, pp. 255–273; c) Y. Shao, A. G. Cole, M. R. Brescia, L. Y. Qin, J. Duo,
[18] T. Borowski, M. Krol, E. Broclawik, T. C. Baranowski, L. Strekowski, M. J.
2
2
Mokrosz, J. Med. Chem. 2000, 43, 1901–1909.
T. M. Stauffer, L. L. Rokosz, B. F. McGuinness, I. Henderson, Bioorg. Med.
Chem. Lett. 2009, 19, 1399–1402.
Received: April 3, 2017
Eur. J. Org. Chem. 2017, 3222–3228
www.eurjoc.org
3228
© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim