Zinc base assisted amination of 2-chloropyrimidines by aniline derivatives at room temperature

Article abstract of DOI:10.1055/s-0030-1261220

The amination of 2-chloropyrimidines was performed with several aniline derivatives in the presence of tolylzinc bromide as a base. The organozinc compound has a profound effect on the reactivity of the amines, so that the reaction takes place at room tem

Full text of DOI:10.1055/s-0030-1261220

LETTER
2325
Zinc Base Assisted Amination of 2-Chloropyrimidines by Aniline Derivatives
at Room Temperature
M
ild Amination
u
of 2-Chloro
k
pyrimidines
a
by Various
s
A
nilines in the
B
a
Z
in
.
c
Base Delvos, Jeanne-Marie Begouin, Corinne Gosmini*
Laboratoire ‘Hétéroéléments et Coordination’, École Polytechnique, CNRS, 91128 Palaiseau Cedex, France
Fax +33(1)69334440; E-mail: Corinne.gosmini@polytechnique.edu
Received 7 July 2011
by aniline derivatives and approaches featuring C–N
Abstract: The amination of 2-chloropyrimidines was performed
with several aniline derivatives in the presence of tolylzinc bromide
as a base. The organozinc compound has a profound effect on the
reactivity of the amines, so that the reaction takes place at room
cross-coupling either via Ullmann-type reaction5 or by
Buchwald–Hartwig amination.6 All of these methods
have harsh reaction conditions in common with reaction
temperature. Further studies gave insight into the reaction mecha- temperatures usually over 100 °C. Furthermore noncata-
nism and favor a nucleophilic substitution over a catalytic process.
lytic reactions give just moderate isolated yields and
Buchwald–Hartwig aminations normally rely on an ex-
pensive palladium source and sensitive ligands. Despite
the impressive progress of amination reactions in recent
years, a mild and simple protocol to furnish 2-anilinopyri-
midines is still of interest.
Key words: zinc base, amination, nucleophilic aromatic substitu-
tion, 2-anilinopyrimidine, heterocycles
The 2-anilinopyrimidine moiety is an important motif for
pharmaceuticals and agrochemicals. It can be found in a
variety of biologically active compounds such as antican-
cer agents pazopanib (VotrientTM; 1) and imitanib
(GleevecTM; 2),1a,b fungicide1c cyprodinil (3), anti-HIV
agent1d etravirine (IntelenceTM; 4) and many more
(Figure 1).
The most straightforward strategies2 to synthesize these
structures involve nucleophilic aromatic substitution of 2-
chloro-,3 or more reactive, 2-methylsulfonylpyrimidines4
In the course of our investigation of cobalt-catalyzed C–C
cross-coupling between 2-chloropyrimidines and func-
tionalized arylzinc compounds,7 we tested if the devel-
oped Barbier procedure tolerates amino groups. As
anticipated amines, such as 4-bromoaniline (5a), are not
tolerated under the given conditions, but to our surprise,
we found that the reaction yielded 18% of 2-anilinopyri-
midine (8a) at 50 °C (Scheme 1a).
We were rationalizing that the in situ generated orga-
nozinc compound deprotonates the amino group to facili-
tate either the nucleophilic attack or a C–N coupling with
2-chloropyrimidine (6a) by cobalt catalysis. Thus, we de-
cided to design a zinc base, 2-tolylzinc bromide (9), that
is unable to couple with 2-chloropyrimidine under the giv-
NH2
N
O
S O
HN
N
N
NH
HN
N
N
a)
N
Me
Me
O
N
N
N
N
1) AllylCl, TFA,
N
Me
r.t.
5 min
MeCN
N
H2N
1
2
7 (0%)
CoBr2 + Zn
Cl
Br
2) 50 °C
4 h
NH2
N
H
N
N
N
N
N
Br
O
N
H
N
N
N
N
6a
NH2
H
8a (18%)
N
5a
b)
ZnBr
N
H
N
N
NH2
Cl
N
3
4
9
+
N
8a (49%)
25 °C
5 h
MeCN
N
Figure 1 Selection of important, biologically active compounds
containing the 2-anilinopyrimidine motif
5b
6a
SYNLETT 2011, No. 16, pp 2325–2328
Advanced online publication: 08.09.2011
DOI: 10.1055/s-0030-1261220; Art ID: B12811ST
© Georg Thieme Verlag Stuttgart · New York
x
x
.x
x
.2
0
1
1
Scheme 1 (a) Barbier procedure for the cobalt-catalyzed C–C cou-
pling in the presence of an amino group; (b) amination in the presence
of tolylzinc bromide 9

2326
L. B. Delvos et al.
LETTER
en conditions and does not interfere in a possible amina- Stronger bases like NaH and LiHMDS yielded only traces
tion of halide 6a. We were pleased to see that the reaction of the desired compound (Table 1, entries 4 and 5). We
gave 49% yield at room temperature within five hours in also tested a carbon metal base, tolylmagnesium bromide
the presence of organozinc 9, which is stable and readily 10 that should show comparable basicity as 9. The reac-
accessible in almost quantitative yield by the protocol for tion yielded 8% product, which underlines the necessity
the cobalt-catalyzed zinc insertion developed by our of organozinc 9 as the organometallic reagent of choice
group (Scheme 1b).8 The base is prepared separately and (Table 1, entry 6). One equivalent of zinc base gave a
either filtered or the supernatant is canulated carefully to yield of 48% (Table 1, entry 7). Increasing the equivalents
the reaction flask to guarantee that no remaining zinc is of 9 led to further optimization with two equivalents
transferred with it.9 Toluene is generated as the sole by- yielding the desired compound in 68% yield (Table 1, en-
product after consumption, which can be removed easily try 8). Altering the order of addition to one equivalent of
once the reaction is finished.
9 followed by another one after two hours of reaction time
gave the product in a very good yield of 85% (Table 1, en-
try 9). With these results in hand we started to study the
reaction mechanism. Envisioning that the striking in-
crease in reactivity is due to cobalt catalysis, we synthe-
sized the zinc compound 9 in a cobalt-free matter to verify
the role of the remaining cobalt complex in solution.
Transmetalation of the corresponding Grignard reagent
10 with ZnCl2 by a modified literature procedure10 fur-
nished the cobalt-free zinc compound 11, which was used
as such in THF or after a solvent change to acetonitrile as
described by Oshima and co-workers.11 The fact that no
significant drop of yield was observed favors a cobalt-
independent SNAr mechanism over a cobalt-catalyzed C–
N coupling (Table 1, entries 10 and 11). The solvent
change from MeCN to THF did not alter the yield of 8b.
These results give evidence that the reaction is likely to be
solvent independent.
For practical reasons, we decided to optimize the reaction
with 3,5-dimethylaniline (5c). To study and compare the
reactivity of the zinc base, we tested several routinely
used bases (Table 1).
The zinc base showed to be much superior to other bases.
Common weak organic and inorganic bases gave no reac-
tion under the same conditions (Table 1, entries 2 and 3).
Table 1 Evaluation of Bases for the Amination of 2-Chloropyrimi-
dine with 3,5-Dimethylaniline
H
NH2
Cl
N
N
N
base
+
N
N
25 °C
5 h
MeCN
5c
6a
8b
Entry
Base
none
Equivalentsa Yield (%)b
Encouraged by these results we turned to analyze the
scope of the reaction. With the optimized protocol in hand
we were able to obtain 2-anilinopyrimidine (8a) in a very
good yield of 87% (Table 2, entry 1). The reaction pro-
ceeded with anilines bearing different halides in para- or
meta-position, that allowed for further functionalization,
in good yields (Table 2, entries 3–5). Anilines functional-
ized with an ether, an ester or a nitrile group were also
well tolerated and gave the desired products in good
yields under the given conditions (Table 2, entries 6–8).
In the presence of a sensitive keto group the product was
furnished in acceptable yields (Table 2, entry 9).
1
2
3
4
5
1
1
1
1
1
0
K2CO3
TEA
0
0
NaH
2c
5c
LiHMDSd
MgCl*LiCl
6
1
8c,d
A certain extent of steric hindrance was tolerated in the
case of ortho-toluidine (5k) and the product 8k was ob-
tained in 54% yield (Table 2, entry 11). However, the sec-
ondary aniline 5j showed only moderate conversion with
a yield of 42% despite its higher nucleophilicity (Table 2,
entry 10). This could be due to the increase of steric hin-
drance on the nitrogen. Next we tested several 2-chloro-
pyrimidine derivatives. Reaction of aniline with 2-chloro-
5-ethylpyrimidine (6b) and 2-chloro-4-(trifluorometh-
yl)pyrimidine (6c) gave the desired product in very good
yields (Table 2, entries 12 and 13). Furthermore we could
extend the reaction to the trisubstituted triazine 6d. In this
case only one equivalent of the organozinc compound 9
was necessary to achieve an excellent yield of 90% after
2.5 hours reaction time of the triazine 8n. This result made
us speculate that parts of the second equivalent of base are
consumed by deprotonation of 2-chloropyrimidine.
10d
9e
7
8
9
1
48
9e
9e
2
68
85
2 × 1
ZnCl*LiCl
10
11
2 × 1
2 × 1
72
70
11d
11f
a Regarding the amount of 5c.
b Isolated yield of the pure product.
c GC yield with dodecane as internal standard.
d Base preparation and reaction in THF.
e Base was prepared by Co catalysis in MeCN.
f Reaction was carried out in MeCN after solvent change.
Synlett 2011, No. 16, 2325–2328 © Thieme Stuttgart · New York

LETTER
Mild Amination of 2-Chloropyrimidines by Various Anilines in the Presence of a Zinc Base
2327
In summary we have developed a mild protocol for on transition-metal-catalysis. Extension of the scope with
the amination of 2-chloropyrimidine and its substituted further amines and halides is currently ongoing and will
analogues with functionalized or nonfunctionalized be reported in due course.
anilines.12 Tolylzinc bromide dramatically increases the
reactivity of the amine towards the halide. Furthermore
mechanism studies showed that the reaction does not rely
Table 2 Scope of the Amination of Different 2-Chloropyrimidines with Various Aniline Derivatives under Optimized Conditions
Entry
Amine
Halide
Product
Yield (%)a
H
N
H2N
H2N
Cl
N
N
N
1
5b
6a
8a
87
N
N
N
H
N
2
3
5c
6a
6a
8b
8c
85
74
H
N
H2N
H2N
N
N
5d
N
N
F
F
H
N
Cl
N
4
5e
6a
8d
75
N
Cl
Cl
H
N
H2N
H2N
H2N
N
N
N
5
6
7
8
5a
5f
6a
6a
6a
6a
8e
8f
63
72
69
69
N
N
N
Br
Br
H
N
OMe
CO2Et
OMe
CO2Et
H
N
5g
5h
8g
8h
H
N
H2N
H2N
N
N
N
N
CN
CN
H
N
9
5i
6a
8i
55
O
O
42b
54b
81
HN
N
N
N
10
11
12
5j
6a
6a
6b
8j
8k
8l
N
N
H
N
H2N
H2N
5k
5b
H
Cl
N
N
N
N
N
Et
Et
Synlett 2011, No. 16, 2325–2328 © Thieme Stuttgart · New York

2328
L. B. Delvos et al.
LETTER
Table 2 Scope of the Amination of Different 2-Chloropyrimidines with Various Aniline Derivatives under Optimized Conditions (continued)
Entry
13
Amine
Halide
Product
Yield (%)a
88
Cl
Cl
N
H
F3C
N
N
5b
6c
8m
N
N
N
CF3
N
H
OMe
MeO
N
N
14
5b
6d
8n
90c
N
N
N
OMe
OMe
a Isolated yield of the pure product.
b Reaction time: 16 h.
c Just one equivalent of 9 was used; reaction time was reduced to 2.5 h.
M. P.; Townes, J. A.; VanRens, J. C.; Djung, J. F.; Natchus,
M. G.; De, B.; Hsieh, L. C.; Xu, S. C.; Walter, R. L.; Mekel,
M. J.; Heitmeyer, S. A.; Brown, K. K.; Juergens, K.; Taiwo,
Y. O.; Janusz, M. J. J. Med. Chem. 2004, 47, 2724.
(c) Manley, P. J.; Balitza, A. E.; Bilodeau, M. T.; Coll, K. E.;
Hartmann, G. D.; McFall, R. C.; Rickert, K. W.; Rodmann,
L. D.; Thomas, K. A. Bioorg. Med. Chem. Lett. 2003, 13,
1673.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
L.B.D is grateful for a scholarship from the German Academic Ex-
change Service (DAAD). The authors thank M. Corpet for useful
discussions.
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Song, H.; Park, K. H. Molecules 2009, 14, 5169. (b) Liu,
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References and Notes
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with a stirring bar, a septum and was flushed with nitrogen.
The flask was charged with a solution of 9 (0.8 M, 3 mL) in
MeCN. The amine (2.5 mmol) and 2-chloropyrimidine (3
mmol) were added and the resulting mixture was stirred for
2 h. Another aliquot of the solution of 9 (0.8 M, 3 mL) was
added and the reaction mixture was stirred for further 3 h.
The reaction was quenched with a sat. NH4Cl solution (100
mL) and the aqueous phase was extracted with CH2Cl2 (3 ×
30 mL). The combined organic layers were washed with
brine solution (20 mL) and dried over MgSO4. The drying
reagent was filtered off and the filtrate was concentrated
under reduced pressure. The crude product was purified by
flash chromatography on silica or aluminum oxide.
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